Stabilised insulin compositions

Abstract

The present invention provides pharmaceutical compositions comprising insulin and novel ligands for the HisB10 Zn2+ sites of the R-state insulin hexamer. The resulting preparations have improved physical and chemical stability.

Description

FIELD OF THE INVENTION

This invention relates to insulin compositions stabilised by adding ligands for the His^B10 Zn²⁺ sites of the R-state insulin hexamer, as well as methods for preparation and use of such preparations.

BACKGROUND OF THE INVENTION

Diabetes is a general term for disorders in man having excessive urine excretion as in diabetes mellitus and diabetes insipidus. Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost.

Since the discovery of insulin in the 1920's, continuous strides have been made to improve the treatment of diabetes mellitus. To help avoid extreme glycaemia levels, diabetic patients often practice multiple injection therapy, whereby insulin is administered with each meal. Many diabetic patients are treated with multiple daily insulin injections in a regimen comprising one or two daily injections of a protracted insulin composition to cover the basal requirement, supplemented by bolus injections of rapid acting insulin to cover the meal-related requirements.

Insulin compositions having a protracted profile of action are well known in the art. Thus, one main type of such insulin compositions comprises injectable aqueous suspensions of insulin crystals or amorphous insulin. Typically, the insulin in these compositions is provided in the form of protamine insulin, zinc insulin or protamine zinc insulin

Soluble, rapid acting insulin compositions usually comprise insulin, insulin analogue or insulin derivative together with zinc ion, phenolic preservative, isotonicity agent, and a buffer substance. In addition, the preparation may optionally contain some salts and/or surfactants. Such preparations contain insulin in the form of an R-state hexamer.

Insulin Allostery.

The insulin hexamer is an allosteric protein that exhibits both positive and negative cooperativity and half-of-the-sites reactivity in ligand binding. This allosteric behaviour consists of two interrelated allosteric transitions designated L^A₀ and L^B₀, three inter-converting allosteric conformation states (eq. 1),

		LA0		LB0
	T6	⇄	T3R3	⇄	R6	equation (1)

designated T₆, T₃R₃, and R₆ and two classes of allosteric ligand binding sites designated as the phenolic pockets and the His^B10 anion sites. These allosteric sites are associated only with insulin subunits in the R conformation. Insulin Hexamer Structures and Ligand Binding.

The T- to R-transition of the insulin hexamer involves transformation of the first nine residues of the B chain from an extended conformation in the T-state to an alpha-helical conformation in the R-state. This coil-to-helix transition causes the N-terminal residue, Phe^B1, to undergo an ˜30 Å change in position. This conformational change creates hydrophobic pockets (the phenolic pockets) at the subunit interfaces (three in T₃R₃, and six in R₆), and the new B-chain helices form 3-helix bundles (one in T₃R₃ and two in R₆) with the bundle axis aligned along the hexamer three-fold symmetry axis. The His^B10 Zn²⁺ in each R₃ unit is forced to change coordination geometry from octahedral to either tetrahedral (monodentate ligands) or pentahedral (bidentate ligands). Formation of the helix bundle creates a narrow hydrophobic tunnel in each R₃ unit that extends from the surface ˜12 Å down to the His^B10 metal ion. This tunnel and the His^B10 Zn²⁺ ion form the anion binding site. Ligands for the His^B10 Zn²⁺ sites of the R-state insulin hexamer have been disclosed in U.S. Pat. No. 5,830,999.

Hexamer Ligand Binding and Stability of Insulin Compositions.

The in vivo role of the T to R transition is unknown. However, the addition of allosteric ligands (e.g. phenol and chloride ion) to insulin compositions is widely used. Hexamerization is driven by coordination of Zn²⁺ at the His^B10 sites to give T₆. Following subcutaneous injection, some dilution of the depot will take place over time and the ligands of soluble hexamers most likely diffuse away from the protein relatively rapidly. This is probably due to one or more phenomena including the binding of Zn²⁺ by surrounding tissue and albumin, the relatively larger space available for diffusion of the hydrophobic phenolic preservatives, and the generally larger diffusion coefficients characteristic of the smaller sized molecules.

Insulin compositions are usually stored for extended periods of time e.g. in vials or cartridges. Furthermore, insulin pumps are becoming more widely used, which places an additional demand on the chemical and physical stability of the insulin composition due to the elevated temperatures and physical stress these preparations are exposed to. There is thus a need for insulin compositions that are more physically and chemically stable. It has been found that stabilising Zn²⁺-site ligands may be added to insulin compositions to improve these properties.

SUMMARY OF THE INVENTION

The present invention provides pharmaceutical compositions comprising insulin and novel ligands for the His^B10 Zn²⁺ sites of the R-state insulin hexamer. The ligands belong to different subclasses of compounds, e.g. benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles. The insulin may be rapid-acting. The insulin may be selected from human insulin, or an analogue or derivative thereof. The formulation may also comprise a phenolic compound, an isotonicity agent, and buffer. Also claimed are methods of treating type 1 or 2 diabetes comprising administration of a pharmaceutical composition of the invention.

DESCRIPTION OF THE DRAWINGS

FIGS. 1-8 show ThT assays of various combinations of insulin formulations and ligands of the invention.

FIG. 9 shows disappearance rate of various combinations of insulin formulations and ligands of the invention from the subcutaneous depot following injection in pigs.

FIGS. 10-14 show reverse phase chromatography of various combinations of insulin formulations and ligands of the invention.

DEFINITIONS

The following is a detailed definition of the terms used to describe the invention:

“Halogen” designates an atom selected from the group consisting of F, Cl, Br and I.

The term “alkyl” as used herein represents a saturated, branched or straight hydrocarbon group having the indicated number of carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

The term “alkylene” as used herein represents a saturated, branched or straight bivalent hydrocarbon group having the indicated number of carbon atoms. Representative examples include, but are not limited to, methylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, and the like.

The term “alkenyl” as used herein represents a branched or straight hydrocarbon group having the indicated number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.

The term “alkynyl” as used herein represents a branched or straight hydrocarbon group having the indicated number of carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.

The term “alkoxy” as used herein refers to the radical —O— alkyl, wherein alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term “cycloalkyl” as used herein represents a saturated, carbocyclic group having the indicated number of carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “cycloalkenyl” as used herein represents a non-aromatic, carbocyclic group having the indicated number of carbon atoms containing one or two double bonds. Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4-cyclooctadienyl and the like.

The term “heterocyclyl” as used herein represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

The term “aryl” as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems. Representative examples are phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.

The term “arylene” as used herein is intended to include divalent, carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, divalent, carbocyclic, aromatic ring systems. Representative examples are phenylene, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

The term “aryloxy” as used herein denotes a group —O-aryl, wherein aryl is as defined above.

The term “aroyl” as used herein denotes a group —C(O)-aryl, wherein aryl is as defined above.

The term “heteroaryl” as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, thiazolidinyl, 2-thiooxothiazolidinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

The term “heteroarylene” as used herein is intended to include divalent, aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur. Representative examples are furylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, isoxazolylene, isothiazolylene, 1,2,3-triazolylene, 1,2,4-triazolylene, pyranylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene, 1,2,3-triazinylene, 1,2,4-triazinylene, 1,3,5- triazinylene, 1,2,3-oxadiazolylene, 1,2,4-oxadiazolylene, 1,2,5-oxadiazolylene, 1,3,4-oxadiazolylene, 1,2,3-thiadiazolylene, 1,2,4-thiadiazolylene, 1,2,5-thiadiazolylene, 1,3,4-thiadiazolylene, tetrazolylene, thiadiazinylene, indolylene, isoindolylene, benzofurylene, benzothienylene, indazolylene, benzimidazolylene, benzthiazolylene, benzisothiazolylene, benzoxazolylene, benzisoxazolylene, purinylene, quinazolinylene, quinolizinylene, quinolinylene, isoquinolinylene, quinoxalinylene, naphthyridinylene, pteridinylene, carbazolylene, azepinylene, diazepinylene, acridinylene and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranylene, pyrrolinylene, pyrazolinylene, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.

The term “ArG1” as used herein is intended to include an aryl or arylene radical as applicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, and azulenyl as well as the corrresponding divalent radicals.

The term “ArG2” as used herein is intended to include an aryl or arylene radical as applicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, fluorenyl, and indenyl, as well as the corrresponding divalent radicals.

The term “Het1” as used herein is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3 triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,54hiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, thiazolidinyl, 2-thiooxothiazolidinyl, as well as the corrresponding divalent radicals.

The term “Het2” as used herein is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, carbazolyl, thiazolidinyl, 2-thiooxothiazolidinyl, as well as the corrresponding divalent radicals.

The term “Het3” as used herein is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, tetrazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, quinoxalinyl, carbazolyl, thiazolidinyl, 2-thiooxothiazolidinyl, as well as the corrresponding divalent radicals.

“Aryl-C₁-C₆-alkyl”, “heteroaryl-C₁-C₆-alkyl”, “aryl-C₂-C₆-alkenyl” etc. is intended to mean C₁-C₆-alkyl or C₂-C₆-alkenyl as defined above, substituted with an aryl or heteroaryl as defined above, for example:

The term “optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

Furthermore, when using the terms “independently are” and “independently selected from” it should be understood that the groups in question may be the same or different.

The term “substituted with one or more substituents” as used herein is intended to include one to four substituents, such as one to three substitents, one to two substituents, or even one substituent.

The term “treatment” as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. The patient to be treated is preferably a mammal, in particular a human being. When in the specification or claims mention is made of groups of compounds such as benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles, these groups of compounds are intended to include also derivatives of the compounds from which the groups take their name.

The term “insulin” as used herein refers to human insulin as well as derivatives ans analogues hereof as defined below.

The term “human insulin” as used herein refers to insulin naturally produced in the human body or recombinantly produced insulin identical thereto. Recombinant human insulin may be produced in any suitable host cell, for example the host cells may be bacterial, fungal (including yeast), insect, animal or plant cells.

The term “insulin derivative” as used herein (and related terms) refers to human insulin or an analogue thereof in which at least one organic substituent is bound to one or more of the amino acids.

By the term “analogue of human insulin” as used herein (and related terms) is meant human insulin in which one or more amino acids have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or human insulin comprising additional amino acids, i.e. more than 51 amino acids, such that the resulting analogue possesses insulin activity.

Rapid acting insulin is intended to mean human insulin, insulin analogues or insulin derivatives having an onset of action after injection or any other form of administration faster or equal to that of soluble and neutral formulations of human insulin.

The term “phenolic compound” or similar expressions as used herein refers to a compound in which a hydroxyl group is bound directly to a benzene or substituted benzene ring. Examples of such compounds include, but are not limited to, phenol, o-cresol, m-cresol, p-cresol, chloro-cresol, thymol, and 7-hydroxyindole.

DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that the two known ligand binding sites of the R-state insulin hexamer can be used to obtain an insulin composition having improved physical and chemical stability.

The basic concept underlying the present invention involves reversible attachment of a ligand to the His^B10 Zn²⁺ site of the R-state hexamer. The anions currently used in insulin compositions as allosteric ligands for the R-state hexamers (notably chloride ion) bind only weakly to the His^B10 anion site.

The His^B10 Zn²⁺ site consists of a tunnel or cavity with a triangular-shaped cross-section that extends ˜12 Å from the surface of the hexamer down to the His^B10 Zn²⁺ ion. The diameter of the tunnel varies along its length and, depending on the nature of the ligand occupying the site, the opening can be capped over by the Asn^B3 and Phe^B1 side chains. The walls of the tunnel are made up of the side chains of the amino acid residues along one face each of the three alpha-helices. The side chains from each helix that make up the lining of the tunnel are Phe^B1, Asn^B3, and Leu^B6. Therefore, except for the zinc ion, which is coordinated to three His^B10 residues and is positioned at the bottom of the tunnel, the site is principally hydrophobic. Depending on the ligand structure, it may be possible for substituents on the ligand to make H-bonding interactions with AsnB³ and with the peptide linkage to Cys^B7.

In one aspect the invention provides a pharmaceutical composition comprising insulin and a zinc-binding ligand which reversibly binds to a HisB10 Zn2+ site of an insulin hexamer, wherein the ligand is selected from the group consisting of benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In one embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is wherein

• • X is ═O, ═S or ═NH
  • Y is —S—, —O— or —NH—
  • R¹ and R⁴ are independently selected from hydrogen or C₁-C₆-alkyl,
  • R² is hydrogen or C₁-C₆-alkyl or aryl, R¹ and R² may optionally be combined to form a double bond,
  • R³ and R⁵ are independently selected from hydrogen, halogen, aryl, C₁-C₆-alkyl, or —C(O)NR¹¹R¹²,
  • A and B are independently selected from C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl or heteroaryl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁶ and the aryl or heteroaryl is optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰,
  • A and R³ may be connected through one or two valence bonds, B and R⁵ may be connected through one or two valence bonds,
  • R⁶ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁷, R⁸, R⁹ and R¹⁰ are independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², —NR¹¹C(O)R¹², —CH₂C(O)NR¹¹R¹², —OC₁-C₆-alkyl-C(O)NR¹¹R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₁₅-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C₂-C₆-alkenyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, C(O)R¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹, ═O, or —C₂-C₆-alkenyl-C(═O)-NR¹¹R¹²,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which may optionally be substituted with one or more substituents independently selected from R¹³,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl, or C₃-C₆ cycloalkyl, of which each cyclic moiety may optionally be substituted with one or more substituents independently selected from R¹⁴,
  • R¹¹ and R¹² are independently selected from hydrogen, OH, C₁-C₂₀-alkyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶; R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R¹³ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR¹¹, —C(O)OR¹¹, —NR¹¹R¹², and —C(O)NR¹¹R¹²,
  • R¹⁴ is independently selected from halogen, —C(O)OR¹¹, —CH₂C(O)OR¹¹, —CH₂OR¹¹, —CN, —CF₃, —OCF₃, —NO₂, —OR¹¹, —NR¹¹R¹², S(O)₂R¹¹, aryl and C₁-C₆-alkyl,
  • R¹⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,
  • R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceutical composition wherein X is ═O or ═S.

In another embodiment the invention provides a pharmaceutical composition wherein X is ═O.

In another embodiment the invention provides a pharmaceutical composition wherein X is ═S.

In another embodiment the invention provides a pharmaceutical composition wherein Y is —O— or —S—.

In another embodiment the invention provides a pharmaceutical composition wherein Y is —O—.

In another embodiment the invention provides a pharmaceutical composition wherein Y is —S—.

In another embodiment the invention provides a pharmaceutical composition wherein A is aryl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is selected from ArG1 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is phenyl or naphtyl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is

In another embodiment the invention provides a pharmaceutical composition wherein A is phenyl.

In another embodiment the invention provides a pharmaceutical composition wherein A is heteroaryl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is selected from Het1 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is selected from Het2 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is selected from Het3 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is selected from the group consisting of indolyl, benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein each heteroaryl may optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is benzofuranyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is

In another embodiment the invention provides a pharmaceutical composition wherein A is carbazolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is

In another embodiment the invention provides a pharmaceutical composition wherein A is quinolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is

In another embodiment the invention provides a pharmaceutical composition wherein A is indolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein A is

In another embodiment the invention provides a pharmaceutical composition wherein R¹ is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R² is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R¹ and R² are combined to form a double bond.

In another embodiment the invention provides a pharmaceutical composition wherein R³ is C₁-C₆-alkyl, halogen, or C(O)NR¹⁶R¹⁷.

In another embodiment the invention provides a pharmaceutical composition wherein R³ is C₁-C₆-alkyl or C(O)NR¹⁶R¹⁷.

In another embodiment the invention provides a pharmaceutical composition wherein R³ is methyl.

In another embodiment the invention provides a pharmaceutical composition wherein B is phenyl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴ is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵ is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶ is aryl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶ is phenyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —NR¹¹C(O)R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC_-C6-alkyl-C(O)NR¹¹R¹², —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C₂-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴

In another embodiment the invention provides a pharmaceutical composition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl or C₁-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴

In another embodiment the invention provides a pharmaceutical composition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂CC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl or C₁-C₆— which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴

In another embodiment the invention provides a pharmaceutical composition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)O^R11,
  • C₁-C₆-alkyl which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aryl-C₁-C₆-alkoxy,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment the invention provides a pharmaceutical composition wherein R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)O^R11,
  • C₁-C₆-alkyl which may optionally be substituted with one or more substituents independently selected from R¹³
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment the invention provides a pharmaceutical composition wherein R¹¹ and R¹² are independently selected from hydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶; R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.

In another embodiment the invention provides a pharmaceutical composition wherein R¹¹ and R¹² are independently selected from hydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶.

In another embodiment the invention provides a pharmaceutical composition wherein R¹¹ and R¹² are independently selected from phenyl or phenyl-C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein one or both of R¹¹ and R¹² are methyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹³ is independently selected from halogen, CF₃, OR¹¹ or NR¹¹R¹².

In another embodiment the invention provides a pharmaceutical composition wherein R¹³ is independently selected from halogen or OR¹¹.

In another embodiment the invention provides a pharmaceutical composition wherein R¹³ is OR¹¹.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁴ is independently selected from halogen, —C(O)OR¹¹, —CN, —CF₃, —OR¹¹, S(O)₂R¹¹, and C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁴ is independently selected from halogen, —C(O)OR¹¹, or —O^R11.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁵ is independently selected from halogen, —CN, —CF₃, —C(O)OC₁-C₆-alkyl, and —COOH.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁵ is independently selected from halogen or —C(O)OC₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —NO₂, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —NO₂, or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is wherein

• • R¹⁹ is hydrogen or C₁-C₆-alkyl,
  • R²⁰ is hydrogen or C₁-C₆-alkyl,
  • D and F are a valence bond or C₁-C₆-alkylene optionally substituted with one or more substituents independently selected from R⁷²,
  • R⁷² is independently selected from hydroxy, C₁-C₆-alkyl, or aryl,
  • E is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents R²¹, R²² and R²³,
  • G is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶,
  • R¹⁷ R¹⁸, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷S(O)₂R²⁸, —S(O)₂NR²⁷R²⁸, —S(O)NR²⁷R²⁸, —S(O)R²⁷, —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR ²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
    • which may optionally be substituted with one or more substituents independently selected from R²⁹,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰,
  • R²⁷ and R²⁸ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R²⁷ and R²⁸ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R²⁹ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR²⁷, and —NR²⁷R²⁸,
  • R³⁰ is independently selected from halogen, —C(O)OR²⁷, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸ and C₁-C₆-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base. In another embodiment the invention provides a pharmaceutical composition wherein D is a valence bond.

In another embodiment the invention provides a pharmaceutical composition wherein D is C₁-C₆-alkylene optionally substituted with one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceutical composition wherein E is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceutical composition wherein E is aryl optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceutical composition wherein E is selected from ArG1 and optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceutical composition wherein E is phenyl optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)R²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)-C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)O²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁹ is hydrogen or methyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁹ is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is Hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein F is a valence bond.

In another embodiment the invention provides a pharmaceutical composition wherein F is C₁-C₆-alkylene optionally substituted with one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceutical composition wherein G is C₁-C₆-alkyl or aryl, wherein the aryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceutical composition wherein G is C₁-C₆-alkyl or ArG1, wherein the aryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceutical composition wherein G is C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein G is phenyl optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)R²⁷, —SC₁-C₆-alkyl-C(O)—R²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR ²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁰ is hydrogen or methyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁰ is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen or C₁-C₆-alkyl or ArG1.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —S(O)R²⁷, —S(O)R²⁷, —C(O)NR²⁷R²⁸, —CH₂OR²⁷, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)R²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R² , or —C(O)OR²⁷
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁷ is hydrogen, methyl or ethyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R²⁸ is hydrogen, methyl or ethyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁷² is —OH or phenyl.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is of the form H—I-J wherein H is wherein the phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R³¹

• • I is selected from
    • a valence bond,
    • —CH₂N(R³²)— or —SO₂N(R³³)—, wherein Z¹ is S(O)₂ or CH₂, Z² is —NH—, —O— or —S—, and n is 1 or 2,
  • J is
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R³⁴,
    • Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-, aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl, heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R³⁷,
    • hydrogen,
  • R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵, —NR³⁵—C(═)—C₁-C₆-alkyl-C(═O)OR³⁵, —NR³⁵—C(═)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or —C(O)OR³⁵,
  • R³² and R³³ are independently selected from hydrogen, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is of the form H—I-J, wherein H is wherein the phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R³¹,

• • I is selected from
    • a valence bond,
    • —CH₂N(R³²)— or —SO₂N(R³³)—, wherein Z¹ is S(O)₂ or CH₂, Z² is N, —O— or —S—, and n is 1 or 2,
  • J is
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R³⁴,
    • Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-, aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl, heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R³⁷,
    • hydrogen,
  • R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆-alkenyl-C(═O)OR³⁵, —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵, —NR³⁵—C(═O)-C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or —C(O)OR³⁵,
  • R³² and R³³ are independently selected from hydrogen, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base,

With the proviso that R³¹ and J cannot both be hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein H is

In another embodiment the invention provides a pharmaceutical composition wherein H is

In another embodiment the invention provides a pharmaceutical composition wherein H is

In another embodiment the invention provides a pharmaceutical composition wherein I is a valence bond, —CH₂N(R³²)—, or —SO₂N(R³³)—.

In another embodiment the invention provides a pharmaceutical composition wherein I is a valence bond.

In another embodiment the invention provides a pharmaceutical composition wherein J is

• • hydrogen,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • aryl, or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment the invention provides a pharmaceutical composition wherein J is

• • hydrogen,
  • aryl or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment the invention provides a pharmaceutical composition wherein J is

• • hydrogen,
  • ArG1 or Het3, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment the invention provides a pharmaceutical composition wherein J is

• • hydrogen,
  • phenyl or naphthyl optionally substituted with one or more substituents independently selected from R³¹.

In another embodiment the invention provides a pharmaceutical composition wherein J is hydrogen.

In another embodiment the invention provides a pharmaceutical composition wherein R³² and R³³ are independently selected from hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁴ is hydrogen, halogen, —CN, —CF₃, —OCF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁶, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵ or -C(O)OR³⁵.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵C(O)R³⁶, or —C(O)OR³⁵.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, or —NR³⁵C(O)R³⁶.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁴ is hydrogen, halogen, or —OR³⁵.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, or aryl.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁵ and R³⁶ are independently selected from hydrogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁷ is halogen, —C(O)OR³⁵, —CN, —CF₃, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁷ is halogen, —C(O)OR³⁵, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment the invention provides a pharmaceutical composition wherein R³⁷ is halogen, —C(O)OR³⁵ or —OR³⁵.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, —C(═O)—, or —C(═O)—NH—, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸,

• • U is a valence bond, C₁-C₆-alkenylene, —C₁-C₆-alkyl-O— or C₁-C₆-alkylene wherein any C₁-C₆-alkyl moiety is optionally substituted with C₁-C₆-alkyl,
  • R³⁸ is C₁-C₆-alkyl, aryl, wherein the alkyl or aryl moieties are optionally substituted with one or more substituents independently selected from R³⁹,
  • R³⁹ is independently selected from halogen, cyano, nitro, amino,
  • M is a valence bond, arylene or heteroarylene, wherein the aryl or heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁴⁰,
  • R⁴⁰ is selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁴ , —NR⁴¹R⁴², —SR⁴¹, —NR⁴¹S(O)₂R⁴², —S(O)₂NR⁴¹R⁴², —S(O)NR⁴¹R⁴², —S(O)R⁴¹, —S(O)₂R⁴¹, —OS(O)₂ R⁴¹, —C(O)NR⁴¹R⁴², —OC(O)NR⁴¹R⁴², —NR⁴¹C(O)R⁴², —CH₂C(O)NR⁴¹R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —CH₂OR⁴¹, —CH₂OC(O)R⁴¹, —CH₂NR⁴¹R⁴², —OC(O)R⁴¹, —OC₁-C₆-alkyl-C(O)OR⁴¹, —OC₁-C₆-alkyl-OR⁴¹, —S—C₁-C₆-alkyl-C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)OR⁴¹, —NR⁴¹-C(═O)—C₁-C₆-alkyl-C(═O)OR⁴¹, —NR⁴¹—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)R⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R⁴³,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴,
  • R⁴¹ and R⁴² are independently selected from hydrogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkenyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl moieties may optionally be substituted with one or more substituents independently selected from R⁴⁵, and the aryl moieties may optionally be substituted with one or more substituents independently selected from R⁴⁶; R⁴¹ and R⁴² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁴³ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁴¹, and —NR⁴¹R⁴²
  • R⁴⁴ is independently selected from halogen, —C(O)OR⁴¹, —CH₂C(O)OR⁴¹, —CH₂OR⁴¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴² and C₁-C₆-alkyl,
  • R⁴⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃, —O—C₁-C₆-alkyl, —C(O)—O—C₁-C₆-alkyl, —COOH and —NH₂,
  • R⁴⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionally substituted with one or more substituents independently selected from R⁴⁸,
  • R⁴⁷ and R48 are independently selected from hydrogen, C₁-C₆-alkyl, aryl optionally substituted with one or more R⁴⁹,
  • R⁴⁹ is independently selected from halogen and —COOH,
  • T is
    • hydrogen,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkyloxy-carbonyl, wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰,
    • aryl, aryloxy, aryloxy-carbonyl, aryl-C₁-C₆-alkyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkyny-, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl,
    • wherein any alkyl, alkenyl , alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁰,
  • R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl, heteroaryl, heteroaryl-C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the aryl or heteroaryl moieties are optionally substituted with one or more R⁵³,
  • R⁵¹ and R⁵² are independently selected from hydrogen and C₁-C₆-alkyl,
  • R⁵³ is independently selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, or —N(R⁵¹R⁵²),
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, or —C(═O)—, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸. l

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, or —C₁-C₆-alkyl-O, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond, C₁-C₆-alkylene, or —NH—C(═O)—U, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond or C₁-C₆-alkylene, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond or —NH—C(═O)—U.

In another embodiment the invention provides a pharmaceutical composition wherein K is a valence bond.

In another embodiment the invention provides a pharmaceutical composition wherein U is a valence bond or —C₁-C₆-alkyl-O—.

In another embodiment the invention provides a pharmaceutical composition wherein U is a valence bond.

In another embodiment the invention provides a pharmaceutical composition wherein M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is ArG1 or Het1, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is ArG1 or Het2, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is ArG1 or Het3, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is phenylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is indolylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is

In another embodiment the invention provides a pharmaceutical composition wherein M is carbazolylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment the invention provides a pharmaceutical composition wherein M is

In another embodiment the invention provides a pharmaceutical composition wherein R⁴⁰ is selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
  • C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R⁴³,
  • aryl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, or heteroaryl-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴⁰ is selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
  • C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R⁴³,
  • ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, ArG1-C₂-C₆-alkenyl, Het3, Het3-C₁-C₆-alkyl, or Het3-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴⁰ is selected from

• • hydrogen, halogen, —CF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, ═O, or —NR⁴¹C(O)R⁴²,
  • C₁-C₆-alkyl,
  • ArG1.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴⁰ is selected from

• • Halogen, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, or —NR⁴¹C(O)R⁴²,
  • Methyl,
  • Phenyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴¹ and R⁴² are independently selected from hydrogen, C₁-C₆-alkyl, or aryl, wherein the aryl moieties may optionally be substituted with halogen or —COOH.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴¹ and R⁴² are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or —COOH.

In another embodiment the invention provides a pharmaceutical composition wherein Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH-C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionally substituted with one or more substituents independently selected from R⁴⁸.

In another embodiment the invention provides a pharmaceutical composition wherein Q is a valence bond, —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —NH—CH₂—, —NH—CH₂—CH₂—, —NH—C(═O)—, —C(═O)—NH—, —O—CH₂—, —O—CH₂—CH₂—, or —C(═O)—.

In another embodiment the invention provides a pharmaceutical composition wherein R⁴⁷ and R⁴⁸ are independently selected from hydrogen, methyl and phenyl.

In another embodiment the invention provides a pharmaceutical composition wherein T is

• • hydrogen,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁰,
  • aryl, aryl-C₁-C₆-alkyl, heteroaryl, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceutical composition wherein T is

• • hydrogen,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁰,
  • ArG1, ArG1-C₁-C₆-alkyl, Het3, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceutical composition wherein T is

• • hydrogen,
  • C₁-C₆-alkyl, optionally substituted with one or more substituents independently selected from R⁵⁰,
  • phenyl, phenyl-C₁-C₆-alkyl, wherein the alkyl and phenyl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl, heteroaryl, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the aryl or heteroaryl moieties are optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy , —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is C₁-C₆-alkyl, aryloxy, aryl-C₁-C₆-alkoxy, —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is C₁-C₆-alkyl, ArG1-O—, ArG1-C₁-C₆-alkoxy, —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is phenyl, methyl or ethyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁰ is methyl or ethyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵¹ is methyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵³ is C₁-C₆-alkyl, C₁-C₆-alkoxy, —OR⁵¹, halogen, or —CF₃.

In another embodiment the invention provides a pharmaceutical composition wherein the zinc-binding ligand is wherein V is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C_1-6-alkyl- or aryl-C_2-6-alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁵⁵,

• • R⁵⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁵⁵ is independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁵⁶, —NR⁵⁵R⁵⁷, —SR⁵⁶, —NR⁵⁶S(O)₂R⁵⁷, —S(O)₂NR⁵⁶R⁵⁷, —S(O)NR⁵⁶R⁵⁷, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —OS(O)₂ R⁵⁶, —C(O)NR⁵⁶R⁵⁷, —OC(O)NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷, —CH₂C(O)NR⁵⁶R⁵⁷, —OC₁-C₆-alkyl-C(O)NR⁵⁵R⁵⁷, —CH₂OR⁵⁵, —CH₂OC(O)R⁵⁶, —CH₂NR⁵⁵R⁵⁷, —OC(O)R⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —OC₁-C₆-alkyl-OR⁵⁶, —SC₁-C₆-alkyl-C(O)OR⁵⁶, —C₂-C₆-alkenyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkyl-C(═O)OR⁵⁶, —NR⁵⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁵⁶, —C(O)OR⁵⁶, or C₂-C₆-alkenyl-C(═O)R⁵⁶,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
    • which may optionally be substituted with one or more substituents selected from R⁵⁸,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R⁵⁹,
  • R⁵⁶ and R⁵⁷ are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R⁶⁰, and the aryl groups may optionally be substituted with one or more substituents independently selected from R⁶¹; R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁵⁸ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁵⁶, and —NR⁵⁶R⁵⁷,
  • R⁵⁹ is independently selected from halogen, —C(O)OR⁵⁶, —CH₂C(O)OR⁵⁶, —CH₂OR⁵⁶, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷ and C₁-C₆-alkyl,
  • R⁶⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —C(═O)—R⁶², —COOH and —NH₂,
  • R⁶¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • R⁶² is C₁-C₆-alkyl, aryl optionally substituted with one or more substituents independently selected from halogen, or heteroaryl optionally substituted with one or more C₁-C₆-alkyl independently,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceutical composition wherein V is aryl, heteroaryl, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected R⁵⁴, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is aryl, Het1, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is aryl, Het2, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is aryl, Het3, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is aryl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is ArG1 optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is phenyl, naphthyl or anthranyl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein V is phenyl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁵ is independently selected from

• • halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁸
  • aryl, aryl-C₁-C₆-alkyl, heteroaryl, or heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R⁵⁹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁵ is independently selected from

• • halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or −C(O)OR⁵⁶
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁸
  • ArG1, ArG1-C₁-C₆-alkyl, Het3, or Het3-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R⁵⁹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁵ is independently selected from halogen, —OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷ or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁵ is independently selected from halogen, —OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷, methyl or ethyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁶ and R⁵⁷ are independently selected from hydrogen, CF₃, C₁-C₁₂-alkyl, or —C(═O)—C₁-C₆-alkyl; R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁶ and R⁵⁷ are independently selected from hydrogen or C₁-C₁₂-alkyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment the invention provides a pharmaceutical composition wherein R⁵⁶ and R⁵⁷ are independently selected from hydrogen or methyl, ethyl, propyl butyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment the invention provides a pharmaceutical composition 1 wherein the zinc-binding ligand is wherein AA is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C_1-6-alkyl- or aryl-C_2-4-alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁶³, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁶⁴,

• • R⁶³ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁶⁴ is independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶, —SR⁶⁵, —NR⁶⁵S(O)₂R⁶⁶, —S(O)₂NR⁶⁵R⁶⁶, —S(O)NR⁶⁵R⁶⁶, —S(O)R⁶⁵, —S(O)₂R⁶⁵, —C(O)NR⁶⁵R⁶⁶, —OC(O)NR⁶⁵R⁶⁶, —NR⁶⁵C(O)R⁶⁶, —CH₂C(O)NR⁶⁵R⁶⁶, —OC₁-C₆-alkyl-C(O)NR⁶⁵R⁶⁶, —CH₂OR⁶⁵, —CH₂OC(O)R⁶⁵, —CH₂NR⁶⁵R⁶⁶, —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, —OC, —C₆-alkyl-OR⁶⁵, —SC₁-C₆-alkyl-C(O)OR⁶⁵, —C₂-C₆-alkenyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁶⁵, —C(O)OR⁶⁵, or —C₂-C₆-alkenyl-C(═O)R⁶⁵,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which may optionally be substituted with one or more substituents selected from R⁶⁷,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R⁶⁸,
  • R⁶⁵ and R⁶⁶ are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—R⁶⁹, aryl or heteroaryl, wherein the alkyl groups may optionally be substituted with one or more substituents selected from R⁷⁰, and the aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from R⁷¹; R⁶⁵ and R⁶⁶ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁶⁷ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁶⁵, and —NR⁶⁵R⁶⁶,
  • R⁶⁸ is independently selected from halogen, —C(O)OR⁶⁵, —CH₂C(O)OR⁶⁵, —CH₂OR⁶⁵, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶ and C₁-C₆-alkyl,
  • R⁶⁹ is independently selected from C₁-C₆-alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more C₁-C₆-alkyl,
  • R⁷⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,
  • R⁷¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment the invention provides a pharmaceutical composition wherein AA is aryl, heteroaryl or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more R⁶³, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is aryl or heteroaryl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is ArG1 or Het1 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is ArGl or Het2 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is ArG1 or Het3 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is phenyl, naphtyl, anthryl, carbazolyl, thienyl, pyridyl, or benzodioxyl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein AA is phenyl or naphtyl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁴ is independently selected from hydrogen, halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, C₁-C₆-alkyl —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, aryl-C₂-C₆-alkenyl, aryloxy or aryl, wherein C₁-C₆-alkyl is optionally substituted with one or more substituents independently selected from R⁶⁷, and the cyclic moieties optionally are substituted with one or more substituents independently selected from R⁶³.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁴ is independently selected from halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, methyl, ethyl, propyl, —OC(O)R⁶⁵, —OCH₂—C(O)OR⁶⁵, —OCH₂—CH₂—C(O)OR⁶⁵, phenoxy optionally substituted with one or more substituents independently selected from R⁶⁸.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently selected from hydrogen, CF₃, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyl optionally substituted with one or more R⁷¹ independently; or isoxazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment the invention provides a pharmaceutical composition wherein R⁷¹ is halogen or C₁-C₆-alkyl.

In another embodiment the invention provides a pharmaceutical composition wherein R⁷¹ is halogen or methyl.

In another aspect the invention provides a pharmaceutical composition comprising insulin and a zinc-binding ligand which reversibly binds to a His^B10 Zn²⁺ site of an insulin hexamer, wherein the ligand is selected from the group consisting of benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or 4-cyano-1,2,3-triazoles, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In one embodiment hereof the zinc-binding ligand is wherein

• • X is ═O, ═S or ═NH
  • Y is —S—, —O— or —NH—
  • R¹, R^1A and R⁴ are independently selected from hydrogen or C₁-C₆-alkyl,
  • R² and R^2A are hydrogen or C₁-C₆-alkyl or aryl, R¹ and R² may optionally be combined to form a double bond, R^1A and R^2A may optionally be combined to form a double bond,
  • R³, R^3A and R⁵ are independently selected from hydrogen, halogen, aryl optionally substituted with one or more substituents independently selected from R¹⁶, C₁-C₆-alkyl, or —C(O)NR¹¹R¹²,
  • A, A¹ and B are independently selected from C₁-C₆-alkyl, aryl, aryl-C₁-C₆-alkyl, —NR¹¹-aryl, aryl-C₂-C₆-alkenyl or heteroaryl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁶ and the aryl or heteroaryl is optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰,
  • A and R³ may be connected through one or two valence bonds, B and R⁵ may be connected through one or two valence bonds,
  • R⁶ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁷, R⁸, R⁹ and R¹⁰ are independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², —NR¹¹C(O)R¹², —CH₂C(O)NR¹¹R¹² , —OC₁-C₆-alkyl-C(O)NR¹¹R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₁₅-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹ —C₂-C₆-alkenyl-C(═O)OR¹¹, —NR¹¹—C(═O)—C₁-C₆-alkyl-C(═O)OR¹¹, —NR¹¹—C(═O)-C₁-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, C(O)R¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹, ═O, or —C₂-C₆-alkenyl-C(═O)—NR¹¹R¹²,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which may optionally be substituted with one or more substituents independently selected from R¹³,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl, or C₃-C₆ cycloalkyl,
    • of which each cyclic moiety may optionally be substituted with one or more substituents independently selected from R¹⁴,
  • R¹¹ and R¹² are independently selected from hydrogen, OH, C₁-C₂₀-alkyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶; R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R¹³ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR¹¹, —C(O)OR¹¹, —NR¹¹R¹², and —C(O)NR¹¹R¹²,
  • R¹⁴ is independently selected from halogen, —C(O)OR¹¹, —CH₂C(O)OR¹¹, —CH₂OR¹¹, —CN, —CF₃, —OCF₃, —NO₂, —OR¹¹, —NR¹¹R¹², —NR¹¹C(O)R¹¹, —S(O)₂R¹¹, aryl and C₁-C₆-alkyl,
  • R¹⁵ is independently selected from halogen, —CN, —CF₃, ═O, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,
  • R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof X is ═O or ═S.

In another embodiment hereof X is ═O.

In another embodiment hereof X is ═S.

In another embodiment hereof Y is —O— or —S—.

In another embodiment hereof Y is —O—.

In another embodiment hereof Y is —NH—.

In another embodiment hereof Y is —S—.

In another embodiment hereof A is aryl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is selected from ArG1 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is phenyl or naphtyl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is

In another embodiment hereof A is phenyl.

In another embodiment hereof A is heteroaryl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is selected from Het1 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is selected from Het2 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is selected from Het3 optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is selected from the group consisting of indolyl, benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein each heteroaryl may optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is benzofuranyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is

In another embodiment hereof A is carbazolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is

In another embodiment hereof A is quinolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is

In another embodiment hereof A is indolyl optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof A is

In another embodiment hereof R¹ is hydrogen.

In another embodiment hereof R² is hydrogen.

In another embodiment hereof R¹ and R² are combined to form a double bond.

In another embodiment hereof R³ is C₁-C₆-alkyl, halogen, or C(O)NR¹⁶R¹⁷.

In another embodiment hereof R³ is C₁-C₆-alkyl or C(O)NR¹⁶R¹⁷.

In another embodiment hereof R³ is methyl.

In another embodiment hereof B is phenyl optionally substituted with up to four substituents, R⁷, R⁸, R⁹, and R¹⁰ which may be the same or different.

In another embodiment hereof R⁴ is hydrogen.

In another embodiment hereof R⁵ is hydrogen.

In another embodiment hereof R⁶ is aryl.

In another embodiment hereof R⁶ is phenyl.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SRR¹¹, —NR¹¹S(O)₂R¹², —S(O)₂NR¹¹R¹², —S(O)NR¹¹R¹², —S(O)R¹¹, —S(O)₂R¹¹, —OS(O)₂R¹¹, —NR¹¹C(O)R¹², —CH₂OR¹¹, —CH₂OC(O)R¹¹, —CH₂NR¹¹R¹², —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-C(O)NR¹¹R¹², —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C₂-C₆-alkenyl-C(═O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl or C₁-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —NO₂, —OR¹¹, —NR¹¹R¹², —SR¹¹, —S(O)₂R¹¹, —OS(O)₂ R¹¹, —CH₂OC(O)R¹¹, —OC(O)R¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, —OC₁-C₆-alkyl-OR¹¹, —SC₁-C₆-alkyl-C(O)OR¹¹, —C(O)OR¹¹, or —C₂-C₆-alkenyl-C(═O)R¹¹,
  • C₁-C₆-alkyl or C₁-C₆—which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,
  • C₁-C₆-alkyl which may each optionally be substituted with one or more substituents independently selected from R¹³
  • aryl, aryloxy, a ryl-C₁ -C₆-alkoxy,
  • of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,
  • C₁-C₆-alkyl which may each optionally be substituted with one or more substituents independently selected from R¹³
  • ArG1, ArG1oxy, ArG1-C₁-C₆-alkoxy, of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment hereof R⁷, R⁸, R⁹ and R¹⁰ are independently selected from

• • hydrogen, halogen, —OR¹¹, —OC₁-C₆-alkyl-C(O)OR¹¹, or —C(O)OR¹¹,
  • C₁-C₆-alkyl which may optionally be substituted with one or more substituents independently selected from R¹³
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R¹⁴.

In another embodiment hereof R¹¹ and R¹² are independently selected from hydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶; R¹¹ and R¹² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.

In another embodiment hereof R¹¹ and R¹² are independently selected from hydrogen, C₁-C₂₀-alkyl, aryl or aryl-C₁-C₆-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R¹⁵, and the aryl groups may optionally be substituted one or more substituents independently selected from R¹⁶.

In another embodiment hereof R¹¹ and R¹² are independently selected from phenyl or phenyl-C₁-C₆-alkyl.

In another embodiment hereof one or both of R¹¹ and R¹² are methyl.

In another embodiment hereof R¹³ is independently selected from halogen, CF₃, OR¹¹ or NR¹¹R².

In another embodiment hereof R¹³ is independently selected from halogen or OR¹¹.

In another embodiment hereof R¹³ is OR¹¹.

In another embodiment hereof R¹⁴ is independently selected from halogen, —C(O)OR¹¹, —CN, —CF₃, —OR¹¹, S(O)₂R¹¹, and C₁-C₆-alkyl.

In another embodiment hereof R¹⁴ is independently selected from halogen, —C(O)OR¹¹, or —OR¹¹.

In another embodiment hereof R¹⁵ is independently selected from halogen, —CN, —CF₃, —C(O)OC₁-C₆-alkyl, and —COOH.

In another embodiment hereof R¹⁵ is independently selected from halogen or —C(O)OC₁-C₆-alkyl.

In another embodiment hereof R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —NO₂, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl.

In another embodiment hereof R¹⁶ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —NO₂, or C₁-C₆-alkyl.

In another embodiment hereof the zinc-binding ligand is wherein

• • R¹⁹ is hydrogen or C₁-C₆-alkyl,
  • R²⁰ is hydrogen or C₁-C₆-alkyl,
  • D, D¹ and F are a valence bond, C₁-C₆-alkylene or C₁-C₆-alkenylene optionally substituted with one or more substituents independently selected from R⁷²,
  • R⁷² is independently selected from hydroxy, C₁-C₆-alkyl, or aryl,
  • E is C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents R²¹, R²² and R²³,
  • G and G¹ are C₁-C₆-alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶,
  • R¹⁷, R¹⁸, R²¹, R²², R²³, R²⁴, R²⁵ and R²⁶ are independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, ═O, —OR²⁷, —NR²⁷R²⁸, —SR²⁷S(O)₂R²⁸, —S(O)₂NR²⁷R²⁸, —S(O)NR²⁷R²⁸, —S(O)R², —S(O)₂R²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂N R²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)-C₁-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
    • which may optionally be substituted with one or more substituents independently selected from R²⁹,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰,
  • R²⁷ and R²⁸ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R²⁷ and R²⁸ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R²⁹ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR²⁷, and —NR²⁷R²⁸,
  • R³⁰ is independently selected from halogen, —C(O)OR²⁷, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸ and C₁-C₆-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof D is a valence bond.

In another embodiment hereof D is C₁-C₆-alkylene optionally substituted with one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment hereof E is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof E is aryl optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof E is selected from ArG1 and optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof E is phenyl optionally substituted with up to three substituents independently selected from R²¹, R²² and R²³.

In another embodiment hereof the zinc-binding ligand is

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C_1-C6-alkyl, Het3, Het3-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁹ is hydrogen or methyl.

In another embodiment hereof R¹⁹ is hydrogen.

In another embodiment hereof R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof F is a valence bond.

In another embodiment hereof F is C₁-C₆-alkylene optionally substituted with one or more hydroxy, C₁-C₆-alkyl, or aryl.

In another embodiment hereof G is C₁-C₆-alkyl or aryl, wherein the aryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment hereof G is C₁-C₆-alkyl or ArG1, wherein the aryl is optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment hereof G is C₁-C₆-alkyl.

In another embodiment hereof G is phenyl optionally substituted with up to three substituents R²⁴, R²⁵ and R²⁶.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —SCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —C(O)NR²⁷R²⁸, —OC(O)NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —CH₂C(O)NR²⁷R²⁸, —OCH₂C(O)NR²⁷R²⁸, —CH₂OR²⁷, —CH₂NR²⁷R²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkyl-C(═O)OR²⁷, —NR²⁷—C(═O)—C₁-C₆-alkenyl-C(═O)OR²⁷—, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²⁴, R²⁵ and R²⁶ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²¹, R²² and R²³ are independently selected from

• • hydrogen, halogen, —OCF₃, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —NR²⁷C(O)R²⁸, —NR²⁷C(O)OR²⁸, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR²⁷, —SC₁-C₆-alkyl-C(O)OR²⁷, —C₂-C₆-alkenyl-C(═O)OR²⁷, —C(═O)NR²⁷—C₁-C₆-alkyl-C(═O)OR²⁷, —C₁-C₆-alkyl-C(═O)OR²⁷, or —C(O)OR²⁷,
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²⁰ is hydrogen or methyl.

In another embodiment hereof R²⁰ is hydrogen.

In another embodiment hereof R²⁷ is hydrogen, C₁-C₆-alkyl or aryl.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl or ArG1.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, —SR²⁷, —S(O)R²⁷, —S(O)R²⁷, —C(O)NR²⁷R²⁸, —CH₂OR²⁷, —OC(O)R²⁷, —OC₁-C₆-alkyl-C(O)OR, —SC₁-C₆-alkyl-C(O)OR²⁷, or —C(O)OR²⁷,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • aryl, aryloxy, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷
  • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R²⁹
  • ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, Het3, Het3-C₁-C₆-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R¹⁷ and R¹⁸ are independently selected from

• • hydrogen, halogen, —CN, —CF₃, —NO₂, —OR²⁷, —NR²⁷R²⁸, or —C(O)OR²⁷
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R²⁹
  • phenyl, phenyloxy, phenyl-C₁-C₆-alkoxy, phenyl-C₁-C₆-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R³⁰.

In another embodiment hereof R²⁷ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁷ is hydrogen, methyl or ethyl.

In another embodiment hereof R²⁸ is hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R²⁸ is hydrogen, methyl or ethyl.

In another embodiment hereof R⁷² is —OH or phenyl.

In another embodiment hereof the zinc-binding ligand is

In another embodiment hereof the zinc-binding ligand is of the form H—I-J wherein H is wherein the phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R³¹

• • I is selected from
    • a valence bond,
    • —CH₂N(R³²)— or —SO₂N(R³³)—,
    • wherein Z¹ is S(O)₂ or CH₂, Z² is —NH—, —O— or —S—, and n is 1 or 2,
  • J is
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R³⁴,
    • Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-, aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl, heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R³⁷,
    • hydrogen,
  • R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R , —S(O)₂NR³⁵R³⁵, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁵, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵−C₂-C₆-alkenyl-C(═O)OR³⁵, —NR³⁵—C(═)—C₁-C₆-alkyl-C(═O)OR³⁵, —NR³⁵—C(═)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or —C(O)OR³⁵,
  • R³² and R³³ are independently selected from hydrogen, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • R³⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R³¹ is independently selected from halogen, —C(O)OR³⁵, —C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof the zinc-binding ligand is of the form H—I-J, wherein H is wherein the phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R³¹,

• • I is selected from
    • a valence bond,
    • —CH₂N(R³²)— or —SO₂N(R³³)—,
    • wherein Z¹ is S(O)₂ or CH₂, Z² is N, —O— or —S—, and n is 1 or 2,
  • J is
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R³⁴,
    • Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C₁-C₆-alkoxy-, aryl-C₁-C₆-alkyl-, aryl-C₂-C₆-alkenyl-, aryl-C₂-C₆-alkynyl-, heteroaryl, heteroaryl-C₁-C₆-alkyl-, heteroaryl-C₂-C₆-alkenyl- or heteroaryl-C₂-C₆-alkynyl-, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R³⁷,
    • hydrogen,
  • R³¹ is independently selected from hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵S(O)₂R³⁶, —S(O)₂NR³⁵R³⁶, —S(O)NR³⁵R³⁶, —S(O)R³⁵, —S(O)₂R³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵C(O)R³⁶, —CH₂C(O)NR³⁵R³⁶, —OCH₂C(O)NR³⁵R³⁶, —CH₂OR³⁵, —CH₂NR³⁵R³⁶, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵—C₂-C₆alkenyl-C(═O)OR³⁵, —NR³⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR³⁵, —NR³⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR³⁵—, C₁-C₆-alkyl, C₁-C₆-alkanoyl or —C(O)OR³⁵,
  • R³² and R³³ are independently selected from hydrogen, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • R³⁴is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, aryl-C₁-C₆-alkyl or aryl, or R³⁵ and R³⁶ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R³⁷ is independently selected from halogen, —C(O)OR³⁵, —C(O)H, —CN, —CF₃, —OCF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base,

With the proviso that R³¹ and J cannot both be hydrogen.

In another embodiment hereof H is

In another embodiment hereof H is

In another embodiment hereof H is

In another embodiment hereof I is a valence bond, —CH₂N(R³²)—, or —SO₂N(R³³)—.

In another embodiment hereof I is a valence bond.

In another embodiment hereof J is

• • hydrogen,
  • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
  • which may optionally be substituted with one or more substituents selected from halogen, —CN, —CF₃, —OCF₃, —OR³⁵, and —NR³⁵R³⁶,
  • aryl, or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment hereof J is

• • hydrogen,
  • aryl or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment hereof J is

• • hydrogen,
  • ArG1 or Het3, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment hereof J is

• • hydrogen,
  • phenyl or naphthyl optionally substituted with one or more substituents independently selected from R³⁷.

In another embodiment hereof J is hydrogen.

In another embodiment hereof R³² and R³³ are independently selected from hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CN, —CF₃, —OCF₃, —SCF₃, —NO₂, —OR³⁵, —C(O)R³⁹, —NR³⁵R³⁶, —SR³⁵, —C(O)NR³⁵R³⁶, —OC(O)NR³⁵R³⁶, —NR³⁵, —OC(O)R³⁵, —OC₁-C₆-alkyl-C(O)OR³⁵, —SC₁-C₆-alkyl-C(O)OR³⁵ or —C(O)OR³⁵.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, —SR³⁵, —NR³⁵C(O)R³⁶, or —C(O)OR³⁵.

In another embodiment hereof R³⁴ is hydrogen, halogen, —CF₃, —NO₂, —OR³⁵, —NR³⁵R³⁶, or —NR³⁵C(O)R³⁶.

In another embodiment hereof R³⁴ is hydrogen, halogen, or —OR³⁵.

In another embodiment hereof R³⁵ and R³⁶ are independently selected from hydrogen, C₁-C₆-alkyl, or aryl.

In another embodiment hereof R³⁵ and R³⁶ are independently selected from hydrogen or C₁-C₆-alkyl.

In another embodiment hereof R³⁷ is halogen, —C(O)OR³⁵, —CN, —CF₃, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment hereof R³⁷ is halogen, —C(O)OR³⁵, —OR³⁵, —NR³⁵R³⁶, C₁-C₆-alkyl or C₁-C₆-alkanoyl.

In another embodiment hereof R³¹ is halogen, —C(O)OR³⁵ or —OR³⁵.

In another embodiment hereof the zinc-binding ligand is wherein K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, —C(═O)—, or —C(═O)—NH—, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸,

• • U is a valence bond, C₁-C₆-alkenylene, —C₁-C₆-alkyl-O- or C₁-C₆-alkylene wherein any C₁-C₆-alkyl moiety is optionally substituted with C₁-C₆-alkyl,
  • R³⁸ is C₁-C₆-alkyl, aryl, wherein the alkyl or aryl moieties are optionally substituted with one or more substituents independently selected from R³⁹,
  • R³⁹ is independently selected from halogen, cyano, nitro, amino,
  • M is a valence bond, arylene or heteroarylene, wherein the aryl or heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁴⁰,
  • R⁴⁰ is selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —NR⁴¹S(O)₂R⁴², —S(O)₂NR⁴¹R⁴², —S(O)NR⁴¹R⁴², —S(O)R⁴¹, —S(O)₂R⁴¹, —OS(O)₂ R⁴¹, —C(O)NR⁴¹R⁴², —OC(O)NR⁴¹R⁴², —NR⁴¹C(O)R⁴², —CH₂C(O)NR⁴¹R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹ R⁴², —CH₂OR⁴¹, —CH₂OC(O)R⁴¹, —CH₂NR⁴¹R⁴², —OC(O)R⁴¹, —OC₁-C₆-alkyl-C(O)OR⁴¹, —OC₁-C₆-alkyl-OR⁴¹, —S—C₁-C₆-alkyl-C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)OR⁴¹, —NR⁴¹-C(═O)-C₁-C₆-alkyl-C(═O)OR⁴¹, —NR⁴¹-C(═O)-C₁-C₆-alkenyl-C(═O)OR⁴¹ , —C(O)OR⁴¹, —C₂-C₆-alkenyl-C(═O)R⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, which may each optionally be substituted with one or more substituents selected from R⁴³,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴,
  • R⁴¹ and R⁴² are independently selected from hydrogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkenyl, aryl-C₁-C₆-alkyl or aryl, wherein the alkyl moieties may optionally be substituted with one or more substituents independently selected from R⁴⁵, and the aryl moieties may optionally be substituted with one or more substituents independently selected from R⁴⁶; R⁴¹ and R⁴² when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁴³ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁴¹, and —NR⁴¹R⁴²
  • R⁴⁴ is independently selected from halogen, —C(O)OR⁴¹, —CH₂C(O)OR⁴¹, —CH₂OR⁴¹, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴² and C₁-C₆-alkyl,
  • R⁴⁵ is independently selected from halogen, —CN, —CF₃, —OCF₃, —O—C₁-C₆-alkyl, —C(O)—O—C₁-C₆-alkyl, —COOH and —NH₂,
  • R⁴⁵ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionally substituted with one or more substituents independently selected from R⁴⁸,
  • R⁴⁷ and R⁴⁸ are independently selected from hydrogen, C₁-C₆-alkyl, aryl optionally substituted with one or more R⁴⁹,
  • R⁴⁹ is independently selected from halogen and —COOH,
  • T is
    • hydrogen,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl , C₂-C₆-alkynyl, C₁-C₆-alkyloxy-carbonyl, wherein the alkyl alkenyl and alkynyl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰,
    • aryl, aryloxy, aryloxy-carbonyl, aryl-C₁-C₆-alkyl, aroyl, aryl-C₁-C₆-alkoxy, aryl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkyny-, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl, heteroaryl-C₂-C₆-alkynyl,
    • wherein any alkyl, alkenyl , alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁰,
  • R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl —C(═O)—NR^50A—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_mC₁-C₆-alkyl-COOH, heteroaryl, heteroaryl-C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein m is 1, 2, 3 or 4, and wherein the aryl or heteroaryl moieties are optionally substituted with one or more R⁵³, and the alkyl moieties are optionally substituted with one or more R^50B.
  • R^50A and R^50B are independently selected from —C(O)OC₁-C₆-alkyl, —COOH, —C₁-C₆-alkyl-C(O)OC₁-C₆-alkyl, —C₁-C₆-alkyl-COOH, or C₁-C₆-alkyl,
  • R⁵¹ and R⁵² are independently selected from hydrogen and C₁-C₆-alkyl,
  • R⁵³ is independently selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, —C₁-C₆-alkyl-COOH, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, or —N(R⁵¹R⁵²),
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, —C₁-C₆-alkyl-O—, or —C(═O)—, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene, —NH—C(═O)—U—, —C₁-C₆-alkyl-S—, or —C₁-C₆-alkyl-O, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond, C₁-C₆-alkylene, or —NH—C(═O)—U, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond or C₁-C₆-alkylene, wherein any C₁-C₆-alkyl moiety is optionally substituted with R³⁸.

In another embodiment hereof K is a valence bond or —NH—C(═O)—U.

In another embodiment hereof K is a valence bond.

In another embodiment hereof U is a valence bond or —C₁-C₆-alkyl-O—.

In another embodiment hereof U is a valence bond.

In another embodiment hereof M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het1, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het2, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is ArG1 or Het3, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is phenylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is indolylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is

In another embodiment hereof M is carbazolylene optionally substituted with one or more substituents independently selected from R⁴⁰.

In another embodiment hereof M is

In another embodiment hereof R⁴⁰ is selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)N R⁴¹R⁴², —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
  • C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R⁴³,
  • aryl, aryloxy, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, or heteroaryl-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴.

In another embodiment hereof R⁴⁰ is selected from

• • hydrogen, halogen, —CN, —CF₃, —OCF₃, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —SR⁴¹, —S(O)₂R⁴¹, —NR⁴¹C(O)R⁴², —OC₁-C₆-alkyl-C(O)NR⁴¹R⁴², —C₂-C₆-alkenyl-C(═O)OR⁴¹, —C(O)OR⁴¹, ═O, —NH—C(═O)—O—C₁-C₆-alkyl, or —NH—C(═O)—C(═O)—O—C₁-C₆-alkyl,
  • C₁-C₆-alkyl or C₂-C₆-alkenyl which may each optionally be substituted with one or more substituents independently selected from R⁴³,
  • ArG1, ArG1-O—, ArG1-C₁-C₆-alkoxy, ArG1-C₁-C₆-alkyl, ArG1-C₂-C₆-alkenyl, Het3, Het3-C₁-C₆-alkyl, or Het3-C₂-C₆-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R⁴⁴.

In another embodiment hereof R⁴⁰ is selected from

• • hydrogen, halogen, —CF₃, —NO₂, —OR⁴¹—NR⁴¹R⁴²—C(O)OR⁴¹, ═O, or —NR⁴¹C(O)R⁴²,
  • C₁-C₆-alkyl,
  • ArG1.

In another embodiment hereof R⁴⁰ is hydrogen.

In another embodiment hereof R⁴⁰ is selected from

• • Halogen, —NO₂, —OR⁴¹, —NR⁴¹R⁴², —C(O)OR⁴¹, or —NR⁴¹C(O)R⁴²,
  • Methyl,
  • Phenyl.

In another embodiment hereof R⁴¹ and R⁴² are independently selected from hydrogen, C₁-C6-alkyl, or aryl, wherein the aryl moieties may optionally be substituted with halogen or —COOH.

In another embodiment hereof R⁴¹ and R⁴² are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or —COOH.

In another embodiment hereof Q is a valence bond, C₁-C₆-alkylene, —C₁-C₆-alkyl-O—, —C₁-C₆-alkyl-NH—, —NH—C₁-C₆-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C₁-C₆-alkyl, —C(═O)—, or —C₁-C₆-alkyl-C(═O)—N(R⁴⁷)— wherein the alkyl moieties are optionally substituted with one or more substituents independently selected from R⁴⁸.

In another embodiment hereof Q is a valence bond, —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—CH₂—O—, —CH₂—NH—, —CH₂—CH₂—NH—, —NH—CH₂—, —NH—CH₂—CH₂—, —NH—C(═O)—, —C(═O)—NH—, —O—CH₂—. —O—CH₂—CH₂—, or —C(═O)—.

In another embodiment hereof R⁴⁷ and R⁴⁸ are independently selected from hydrogen, methyl and phenyl.

In another embodiment hereof T is

• • Hydrogen,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁰,
  • aryl, aryl-C₁-C₆-alkyl, heteroaryl, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment hereof T is

• • hydrogen,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁰,
  • ArG1, ArG1-C₁-C₆-alkyl, Het3, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment hereof T is

• • hydrogen,
  • C₁-C₆-alkyl, optionally substituted with one or more substituents independently selected from R⁵⁰,
  • phenyl, phenyl-C₁-C₆-alkyl, wherein the alkyl and phenyl moieties are optionally substituted with one or more substituents independently selected from R⁵⁰.

In another embodiment hereof T is phenyl substituted with R⁵⁰.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, aryl-C₁-C₆-alkoxy, —C(═O)—NH—C₁-C₆-alkyl-aryl, —C(═O)—NR^50A—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_mC₁-C₆-alkyl-COOH, heteroaryl, —C₁-C₆-alkyl-COOH, —O—C₁-C₆-alkyl-COOH, —S(O)₂R⁵¹, —C₂-C₆-alkenyl-COOH, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, —CN, ═O, —N(R⁵¹R⁵²), wherein the aryl or heteroaryl moieties are optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl, aryloxy, —C(═O)—NR^50A—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_mC₁-C₆-alkyl-COOH, aryl-C₁-C₆-alkoxy, —OR⁵¹, —NO₂, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, aryloxy, —C(═O)—NR^50A—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_mC₁-C₆-alkyl-COOH, aryl-C₁-C₆-alkoxy , —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is C₁-C₆-alkyl, ArG1-O—, —C(═O)—NR^50A—C₁-C₆-alkyl, —C(═O)—NH—(CH₂CH₂O)_mC₁-C₆-alkyl-COOH, ArG1-C₁-C₆-alkoxy , —OR⁵¹, halogen, —COOH, —CF₃, wherein any aryl moiety is optionally substituted with one or more R⁵³.

In another embodiment hereof R⁵⁰ is —C(═O)—NR^50A—CH₂, —C(═O)—NH—(CH₂CH₂O)₂CH₂I—COOH, or —C(═O)—NR^50ACH₂CH₂.

In another embodiment hereof R⁵⁰ is phenyl, methyl or ethyl.

In another embodiment hereof R⁵⁰ is methyl or ethyl.

In another embodiment hereof m is 1 or 2.

In another embodiment hereof R⁵¹ is methyl.

In another embodiment hereof R⁵³ is C₁-C₆-alkyl, C₁-C₆-alkoxy, —OR⁵¹, halogen, or —CF₃.

In another embodiment hereof R^50A is —C(O)OCH₃, —C(O)OCH₂CH₃—COOH, —CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃, —CH₂CH₂C(O)OCH₂CH₃, —CH₂COOH, methyl, or ethyl.

In another embodiment hereof R^50B is —C(O)OCH₃, —C(O)OCH₂CH₃—COOH, —CH₂C(O)OCH₃, —CH₂C(O)OCH₂CH₃, —CH₂CH₂C(O)OCH₃, —CH₂CH₂C(O)OCH₂CH₃, —CH₂COOH, methyl, or ethyl.

In another embodiment hereof the zinc-binding ligand is wherein V is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C_1-6-alkyl- or aryl-C_2-6-alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁵⁵,

• • R⁵⁴ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁵⁵ is independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —SR⁵⁶, —NR⁵⁶S(O)₂R⁵⁷, —S(O)₂NR⁵⁶R⁵⁷, —S(O)NR⁵⁶R⁵⁷, —S(O)R⁵⁶, —S(O)₂R⁵⁶, —OS(O)₂ R⁵⁶, —C(O)NR⁵⁶R⁵⁷, —OC(O)NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷, —CH₂C(O)NR⁵⁶R⁵⁷, —OC₁-C₆-alkyl-C(O)NR⁵⁶R⁵⁷, —CH₂OR⁵⁶, —CH₂OC(O)R⁵⁶, —CH₂NR⁵⁶R⁵⁷, —OC(O)R⁵⁶, —OC₁-C₆-alkyl-C(O)OR⁵⁶, —OC₁-C₆-alkyl-OR⁵⁶, —SC₁-C₆-alkyl-C(O)OR⁵⁶, —C₂-C₆-alkenyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkyl-C(═O)OR⁵⁶, —NR⁵⁶—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁵⁶, —C(O)OR⁵⁶, or —C₂-C₆-alkenyl-C(═O)R⁵⁶,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl,
    • which may optionally be substituted with one or more substituents selected from R⁵⁸,
    • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-alkenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R⁵⁹,
  • R⁵⁶ and R⁵⁷ are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—C₁-C₆-alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R⁶⁰, and the aryl groups may optionally be substituted with one or more substituents independently selected from R⁶¹; R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁵⁸ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁵⁶, and —NR⁵⁶R⁵⁷,
  • R⁵⁹ is independently selected from halogen, —C(O)OR⁵⁶, —CH₂C(O)OR⁵⁶, —CH₂OR⁵⁶, —CN, —CF₃, —OCF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷ and C₁-C₆-alkyl,
  • R⁶⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —C(═O)—R⁶², —COOH and —NH₂,
  • R⁶¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • R⁶² is C₁-C₆-alkyl, aryl optionally substituted with one or more substituents independently selected from halogen, or heteroaryl optionally substituted with one or more C₁-C₆-alkyl independently,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof V is aryl, heteroaryl, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected R⁵⁴, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is aryl, Het1, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is aryl, Het2, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is aryl, Het3, or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R⁵⁴, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is aryl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is ArG1 optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is phenyl, naphthyl or anthranyl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof V is phenyl optionally substituted with one or more substituents independently selected from R⁵⁵.

In another embodiment hereof R⁵⁵ is independently selected from

• • halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶,
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁸
  • aryl, aryl-C₁-C₆-alkyl, heteroaryl, or heteroaryl-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R⁵⁹.

In another embodiment hereof R⁵⁵ is independently selected from

• • halogen, C₁-C₆-alkyl, —CN, —OCF₃, —CF₃, —NO₂, —OR⁵⁶, —NR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷ —SR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, or —C(O)OR⁵⁶
  • C₁-C₆-alkyl optionally substituted with one or more substituents independently selected from R⁵⁸
  • ArG1, ArG1-C₁-C₆-alkyl, Het3, or Het3-C₁-C₆-alkyl
  • of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R⁵⁹.

In another embodiment hereof R⁵⁵ is independently selected from halogen, —OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷ or C₁-C₆-alkyl.

In another embodiment hereof R⁵⁵ is independently selected from halogen, —OR⁵⁶, —NR⁵⁶R⁵⁷, —C(O)OR⁵⁶, —OC₁-C₈-alkyl-C(O)OR⁵⁶, —NR⁵⁶C(O)R⁵⁷, methyl or ethyl.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected from hydrogen, CF₃, C₁-C₁₂-alkyl, or —C(═O)—C₁-C₆-alkyl; R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected from hydrogen or C₁-C₁₂-alkyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment hereof R⁵⁶ and R⁵⁷ are independently selected from hydrogen or methyl, ethyl, propyl butyl, R⁵⁶ and R⁵⁷ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.

In another embodiment hereof the zinc-binding ligand is wherein AA is C₁-C₆-alkyl, aryl, heteroaryl, aryl-C_1-6alkyl- or aryl-C_2-6-alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R⁶³, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁶⁴,

• • R⁶³ is independently selected from halogen, —CN, —CF₃, —OCF₃, aryl, —COOH and —NH₂,
  • R⁶⁴ is independently selected from
    • hydrogen, halogen, —CN, —CH₂CN, —CHF₂, —CF₃, —OCF₃, —OCHF₂, —OCH₂CF₃, —OCF₂CHF₂, —S(O)₂CF₃, —OS(O)₂CF₃, —SCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶, —SR⁶⁵, —NR⁶⁵S(O)₂R⁶⁶, —S(O)₂NR⁶⁵R⁶⁶, —S(O)NR⁶⁵R⁶⁶, —S(O)R⁶⁵, —S(O)₂R⁶⁵, —OS(O)₂ R⁶⁵, —C(O)NR⁶⁵R⁶⁶, —OC(O)NR⁶⁵R⁶⁶, —NR⁶⁵C(O)R⁶⁶, —CH₂C(O)NR⁶⁵R⁶⁶, —OC₁-C₆-alkyl-C(O)NR⁶⁵R⁶⁶, —CH₂OR⁶⁵, —CH₂OC(O)R⁶⁵, —CH₂NR⁶⁵R⁶⁶, —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, —OC₁-C₆-alkyl-OR⁶⁵, —SC₁-C₆-alkyl-C(O)OR⁶⁵, —C₂-C₆-alkenyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkyl-C(═O)OR⁶⁵, —NR⁶⁵—C(═O)—C₁-C₆-alkenyl-C(═O)OR⁶⁵, —C(O)OR⁶⁵, or —C₂-C₆-alkenyl-C(═O)R⁶⁵,
    • C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkynyl, each of which may optionally be substituted with one or more substituents selected from R⁶¹,
  • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkyl, aryl-C₂-C₆-alkenyl, aroyl-C₂-C₆-alkenyl, aryl-C₂-C₆-alkynyl, heteroaryl, heteroaryl-C₁-C₆-alkyl, heteroaryl-C₂-C₆-a Ikenyl or heteroaryl-C₂-C₆-alkynyl,
    • of which the cyclic moieties optionally may be substituted with one or more substituents selected from R⁶⁸,
  • R⁶⁵ and R⁶⁶ are independently selected from hydrogen, OH, CF₃, C₁-C₁₂-alkyl, aryl-C₁-C₆-alkyl, —C(═O)—R⁶⁹, aryl or heteroaryl, wherein the alkyl groups may optionally be substituted with one or more substituents selected from R⁷⁰, and the aryl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from R⁷¹; R⁶⁵ and R⁶⁶ when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R⁶⁷ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OR⁶⁵, and —NR⁶⁵R⁶⁶,
  • R⁶⁸ is independently selected from halogen, —C(O)OR⁶⁵, —CH₂C(O)OR⁶⁵, —CH₂OR⁶⁵, —CN, —CF₃, —OCF₃, —NO₂, —OR⁶⁵, —NR⁶⁵R⁶⁶ and C₁-C₆-alkyl,
  • R⁶⁹ is independently selected from C₁-C₆-alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more C₁-C₆-alkyl,
  • R⁷⁰ is independently selected from halogen, —CN, —CF₃, —OCF₃, —OC₁-C₆-alkyl, —C(O)OC₁-C₆-alkyl, —COOH and —NH₂,
  • R⁷¹ is independently selected from halogen, —C(O)OC₁-C₆-alkyl, —COOH, —CN, —CF₃, —OCF₃, —NO₂, —OH, —OC₁-C₆-alkyl, —NH₂, C(═O) or C₁-C₆-alkyl,
  • or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.

In another embodiment hereof AA is aryl, heteroaryl or aryl-C_1-6-alkyl-, wherein the alkyl is optionally substituted with one or more R⁶³, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is aryl or heteroaryl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is ArG1 or Het1 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is ArG1 or Het2 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is ArG1 or Het3 optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is phenyl, naphtyl, anthryl, carbazolyl, thienyl, pyridyl, or benzodioxyl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof AA is phenyl or naphtyl optionally substituted with one or more substituents independently selected from R⁶⁴.

In another embodiment hereof R⁶⁴ is independently selected from hydrogen, halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, C₁-C₆-alkyl , —OC(O)R⁶⁵, —OC₁-C₆-alkyl-C(O)OR⁶⁵, alkenyl, aryloxy or aryl, wherein C₁-C₆-alkyl is optionally substituted with one or more substituents independently selected from R⁶⁷, and the cyclic moieties optionally are substituted with one or more substituents independently selected from R⁶⁸.

In another embodiment hereof R⁶⁴ is independently selected from halogen, —CF₃, —OCF₃, —OR⁶⁵, —NR⁶⁵R⁶⁶, methyl, ethyl, propyl, —OC(O)R⁶⁵, —OCH₂—C(O)OR⁶⁵, —OCH₂—CH₂—C(O)OR⁶⁵, phenoxy optionally substituted with one or more substituents independently selected from R⁶⁸.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently selected from hydrogen, CF₃, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen, C₁-C₁₂-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁶⁵ and R⁶⁶ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyl optionally substituted with one or more R⁷¹ independently; or isoxazolyl optionally substituted with one or more substituents independently selected from R⁷¹.

In another embodiment hereof R⁷¹ is halogen or C₁-C₆-alkyl.

In another embodiment hereof R⁷¹ is halogen or methyl.

The following aspects are also provided by the present invention, wherein the compounds of the invention may be any of the above described embodiments.

In one aspect the invention provides a pharmaceutical composition wherein the insulin is rapid acting insulin.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is selected from the group consisting of human insulin, an analogue thereof, a derivative thereof, and combinations of any of these.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is an analogue of human insulin selected from the group consisting of

• • i. An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala and position B29 is Lys or Pro; and
  • ii. des(B28-B30), des(B27) or des(B30) human insulin.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is des(B30) human insulin.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is is an analogue of human insulin wherein position B3 is Lys and position B29 is Glu or Asp.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin is a derivative of human insulin having one or more lipophilic substituents.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin derivative is selected from the group consisting of B29-N^ε-myristoyl-des(B30) human insulin, B29-N^ε-palmitoyl-des(B30) human insulin, B29-N^ε-myristoyl human insulin, B29-N^ε-palmitoyl human insulin, B28-N^ε-myristoyl LYS^B28 Pro^B29 human insulin, B28-N^ε-palmitoyl Lys^B28 Pro^B29 human insulin, B30-N^ε-myristoyl-Thr^B29LyS^B30 human insulin, B30-N^ε-palmitoyl-Thr^B29Lys^B30 human insulin, B29-N^ε-(N-palmitoyl-γ-glutamyl)-des(B30) human insulin, B29-N^ε-(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-N^ε-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N^ε-(ω-carboxyheptadecanoyl) human insulin.

In another embodiment the invention provides a pharmaceutical composition wherein the insulin derivative is B29-N^ε-myristoyl-des(B30) human insulin.

In another embodiment the invention provides a pharmaceutical composition comprising 2-6 moles zinc²⁺ ions per mole insulin.

In another embodiment the invention provides a pharmaceutical composition comprising 2-3 moles zinc²⁺ ions per mole insulin.

In another embodiment the invention provides a pharmaceutical composition further comprising at least 3 molecules of a phenolic compound per insulin hexamer.

In another embodiment the invention provides a pharmaceutical composition further comprising an isotonicity agent.

In another embodiment the invention provides a pharmaceutical composition further comprising a buffer substance.

A method of stabilising an insulin composition comprising adding a zinc-binding ligand to the insulin composition.

A method of treating type 1 or type 2 diabetes comprising administering to a patient in need thereof a pharmaceutically effective dose of an insulin composition.

In one embodiment of the invention the concentration of added ligand for the zinc site is between 0.2 and 10 times that of zinc ion in the preparation. In another embodiment the concentration is between 0.5 and 5 times that of zinc ion. In another embodiment the ligand concentration is identical to that of zinc ion in the preparation.

The compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.

Furthermore, when a double bond or a fully or partially saturated ring system or more than one centre of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention.

The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, picric, pyruvic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.

Also intended as pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.

Furthermore, the pharmaceutically acceptable salts comprise basic amino acid salts such as lysine, arginine and ornithine.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.

In one embodiment of the invention the stabilized preparations are used in connection with insulin pumps. The insulin pumps may be prefilled and disposable, or the insulin compositions may be supplied from a reservoir which is removable. Insulin pumps may be skin-mounted or carried, and the path of the insulin composition from the storage compartment of the pump to the patient may be more or less tortuous. The elevated temperature and increased physical stress the insulin composition is thus exposed to challenges the stability of the constituent insulin. Non-limiting examples of insulin pumps are disclosed in U.S. Pat. No. 5,957,895, 5,858,001, 4,468,221, 4,468,221, 5,957,895, 5,858,001, 6,074,369, 5,858,001, 5,527,288, and U.S. Pat. No. 6,074,369.

In another embodiment the stabilized preparations are used in connection with pen-like injection devices, which may be prefilled and disposable, or the insulin compositions may be supplied from a reservoir which is removable. Non-limiting examples of pen-like injection devices are FlexPen®, InnoLet®, InDuo™, Innovo®.

In a further embodiment stabilized preparations are used in connection with devices for pulmonary administration of aqueous insulin compositions, a non-limiting example of which is the AerX® device.

In one aspect of the invention, the ligands are added to rapid acting insulin. The resulting preparations have improved physical and chemical stability while still retaining a high rate of absorbtion from subcutaneous tissue.

The present invention also relates to pharmaceutical compositions for the treatment of diabetes in a patient in need of such a treatment comprising an R-state hexamer of insulin according to the invention together with a pharmaceutically acceptable carrier.

In one embodiment of the invention the insulin composition comprises 60 to 3000 nmol/ml of insulin.

In another embodiment of the invention the insulin composition comprises 240 to 1200 nmol/ml of insulin.

In another embodiment of the invention the insulin composition comprises about 600 nmol/ml of insulin.

Zinc ions may be present in an amount corresponding to 13 to 33 μg Zn/100 U insulin, more preferably 15 to 26 μg Zn/100 U insulin.

Insulin formulations of the invention are usually administered from multi-dose containers where a preservative effect is desired. Since phenolic preservatives also stabilize the R-state hexamer the formulations may contain up to 50 mM of phenolic molecules. Non-limiting examples of phenolic molecules are phenol, m-cresol, chloro-cresol, thymol, 7-hydroxyindole or any mixture thereof.

In one embodiment of the invention 0.5 to 4.0 mg/ml of phenolic compound may be employed.

In another embodiment of the invention 0.6 to 4.0 mg/ml of m-cresol may be employed.

In another embodiment of the invention 0.5 to 4.0 mg/ml of phenol may be employed.

In another embodiment of the invention 1.4 to 4.0 mg/ml of phenol may be employed.

In another embodiment of the invention 0.5 to 4.0 mg/ml of a mixture of m-cresol or phenol may be employed.

In another embodiment of the invention 1.4 to 4.0 mg/ml of a mixture of m-cresol or phenol may be employed.

The pharmaceutical composition may further comprise a buffer substance, such as a TRIS, phosphate, glycine or glycylglycine (or another zwitterionic substance) buffer, an isotonicity agent, such as NaCl, glycerol, mannitol and/or lactose. Chloride would be used at moderate concentrations, in one embodiment of the invention up to 50 mM to avoid competition with the zinc-site ligands of the present invention. In another embodiment the chloride concentration would be from 3 to 20 mM.

The in vivo action of insulin may be modified by the addition of physiologically acceptable agents that increase the viscosity of the pharmaceutical composition. Thus, the pharmaceutical composition according to the invention may furthermore comprise an agent which increases the viscosity, such as polyethylene glycol, polypropylene glycol, copolymers thereof, dextrans and/or polylactides.

In one embodiment the insulin composition of the invention comprises between 0.0005% by weight and 1% by weight of a non-ionic or zwitter-ionic surfactant, for example tween 20 or Polox 188. A nonionic detergent can be added to stabilise insulin against fibrillation during storage and handling.

The insulin composition of the present invention may have a pH value in the range of 3.0 to 8.5, e.g. 7.4 to 7.9.

EXAMPLES

The following examples and general procedures refer to intermediate compounds and final products identified in the specification and in the synthesis schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of compounds of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when referring to solvents and eluents.

HPLC-MS (Method A)

The following instrumentation was used:

• • Hewlett Packard series 1100 G1312A Bin Pump
  • Hewlett Packard series 1100 Column compartment
  • Hewlett Packard series 1100 G13 15A DAD diode array detector
  • Hewlett Packard series 1100 MSD

The instrument was controlled by HP Chemstation software.

The HPLC pump was connected to two eluent reservoirs containing:

• • A: 0.01% TFA in water
  • B: 0.01% TFA in acetonitrile

The analysis was performed at 40° C. by injecting an appropriate volume of the sample (preferably 1 μL) onto the column, which was eluted with a gradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settings used are given in the following table.

Column    Waters Xterra MS C-18 × 3 mm id
Gradient  10%-100% acetonitrile lineary during 7.5 min at 1.0 mL/min
Detection UV: 210 nm (analog output from DAD)
MS        Ionisation mode: API-ES
          Scan 100-1000 amu step 0.1 amu

HPLC-MS (Method B)

The following instrumentation was used:

• • Sciex API 100 Single quadropole mass spectrometer
  • Perkin Elmer Series 200 Quard pump
  • Perkin Elmer Series 200 autosampler
  • Applied Biosystems 785A UV detector
  • Sedex 55 evaporative light scattering detector

A Valco column switch with a Valco actuator controlled by timed events from the pump.

The Sciex Sample control software running on a Macintosh PowerPC 7200 computer was used for the instrument control and data acquisition.

The HPLC pump was connected to four eluent reservoirs containing:

• • A: Acetonitrile
  • B: Water
  • C: 0.5% TFA in water
  • D: 0.02 M ammonium acetate

The requirements for samples are that they contain approximately 500 μg/mL of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)

The analysis was performed at room temperature by injecting 20 μL of the sample solution on the column, which was eluted with a gradient of acetonitrile in either 0.05% TFA or 0.002 M ammonium acetate. Depending on the analysis method varying elution conditions were used.

The eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 μL/min through approx. 1 m. 75μ fused silica capillary to the API interface of API 100 spectrometer.

The remaining 1.48 mL/min was passed through the UV detector and to the ELS detector.

During the LC-analysis the detection data were acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.

The LC conditions, detector settings and mass spectrometer settings used for the different methods are given in the following table.

Column	YMC ODS-A 120Å s − 5μ 3 mm × 50 mm id
Gradient	5%-90% acetonitrile in 0.05% TFA linearly during 7.5 min
	at 1.5 mL/min
Detection	UV: 214 nm	ELS: 40° C.
MS	Experiment: Start: 100 amu Stop: 800 amu Step: 0.2 amu
	Dwell: 0.571 msec
	Method: Scan 284 times = 9.5 min

HPLC-MS (Method C) The following instrumentation is used:

• • Hewlett Packard series 1100 G1312A Bin Pump
  • Hewlett Packard series 1100 Column compartment
  • Hewlett Packard series 1100 G1315A DAD diode array detector
  • Hewlett Packard series 1100 MSD
  • Sedere 75 Evaporative Light Scattering detector

The instrument is controlled by HP Chemstation software.

The HPLC pump is connected to two eluent reservoirs containing:

A 0.01% TFA in water
B 0.01% TFA in acetonitrile

The analysis is performed at 40° C. by injecting an appropriate volume of the sample (preferably 1 μl) onto the column which is eluted with a gradient of acetonitrile.

The HPLC conditions, detector settings and mass spectrometer settings used are given in the following table.

Column    Waters Xterra MS C-18 × 3 mm id 5 μm
Gradient  5%-100% acetonitrile linear during 7.5 min at 1.5
          ml/min
Detection 210 nm (analogue output from DAD)
          ELS (analogue output from ELS)
MS        ionisation mode API-ES
          Scan 100-1000 amu step 0.1 amu

After the DAD the flow is divided yielding approximately 1 ml/min to the ELS and 0.5 ml/min to the MS.

HPLC-MS (Method D)

The following instrumentation was used:

• • Sciex API 150 Single Quadropole mass spectrometer
  • Hewlett Packard Series 1100 G1312A Bin pump
  • Gilson 215 micro injector
  • Hewlett Packard Series 1100 G1315A DAD diode array detector
  • Sedex 55 evaporative light scattering detector

A Valco column switch with a Valco actuator controlled by timed events from the pump.

The Sciex Sample control software running on a Macintosh Power G3 computer was used for the instrument control and data acquisition.

The HPLC pump was connected to two eluent reservoirs containing:

• • A: Acetonitrile containing 0.05% TFA
  • B: Water containing 0.05% TFA

The requirements for the samples are that they contain approximately 500 μg/ml of the compound to be analysed in an acceptable solvent such as methanol, ethanol, acetonitrile, THF, water and mixtures thereof. (High concentrations of strongly eluting solvents will interfere with the chromatography at low acetonitrile concentrations.)

The analysis was performed at room temperature by injecting 20 μL of the sample solution on the column, which was eluted with a gradient of acetonitrile in 0.05% TFA

The eluate from the column was passed through a flow splitting T-connector, which passed approximately 20 μl/min through approx. 1 m 75μ fused silica capillary to the API interface of API 150 spectrometer.

The remaining 1.48 ml/min was passed through the UV detector and to the ELS detector. During the LC-analysis the detection data were acquired concurrently from the mass spectrometer, the UV detector and the ELS detector.

The LC conditions, detector settings and mass spectrometer settings used for the different methods are given in the following table.

Column	Waters X-terra C18 5μ 3 mm × 50 mm id
Gradient	5%-90% acetonitrile in 0.05% TFA linearly during 7.5 min
	at 1.5 ml/min
Detection	UV: 214 nm	ELS: 40° C.
MS	Experiment: Start: 100 amu Stop: 800 amu Step: 0.2 amu
	Dwell: 0.571 msec
	Method: Scan 284 times = 9.5 min

EXAMPLES

4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester (5.2 g, 17.6 mmol) was dissolved in THF (60 mL) and methanol (10 mL) was added followed by 1N sodium hydroxide (35 mL). The mixture was stirred at room temperature for 16 hours and then 1N hydrochloric acid (45 mL) was added. The mixture was added water (200 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were evaporated in vacuo to afford 0.44 g of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid. By filtration of the aqueous phase a further crop of 4-[(1H-benzotriazole-5-carbonyl)amino]benzoic acid was isolated (0.52 g).

¹H-NMR (DMSO-d₆): δ 7.97 (4H, s), 8.03 (2H, m), 8.66 (1H, bs), 10.7 (1H, s), 12.6 (1H, bs); HPLC-MS (Method A): m/z: 283 (M+1); Rt=1.85 min. General Procedure (A) for Preparation of Compounds of General Formula I₁: wherein D, E and R¹⁹ are as defined above, and E is optionally substituted with up to three substituents R²¹, R²² and R²³ independently as defined above.

The carboxylic acid of 1H-benzotriazole-5-carboxylic acid is activated, ie the OH functionality is converted into a leaving group L (selected from eg fluorine, chlorine, bromine, iodine, 1-imidazolyl, 1,2,4-triazolyl, 1-benzotriazolyloxy, 1-(4-aza benzotriazolyl)oxy, pentafluorophenoxy, N-succinyloxy 3,4-dihydro-4-oxo-3-(1,2,3-benzotriazinyl)oxy, benzotriazole 5-COO, or any other leaving group known to act as a leaving group in acylation reactions. The activated benzotriazole-5-carboxylic acid is then reacted with R²—(CH₂)_n—B′ in the presence of a base. The base can be either absent (i.e. R²—(CH₂)_n—B′ acts as a base) or triethylamine, N-ethyl-N,N.-diisopropylamine, N-methylmorpholine, 2,6-lutidine, 2,2,6,6-tetramethylpiperidine, potassium carbonate, sodium carbonate, caesium carbonate or any other base known to be useful in acylation reactions. The reaction is performed in a solvent solvent such as THF, dioxane, toluene, dichloromethane, DMF, NMP or a mixture of two or more of these. The reaction is performed between 0° C. and 80° C., preferably between 20° C. and 40° C. When the acylation is complete, the product is isolated by extraction, filtration, chromatography or other methods known to those skilled in the art.

The general procedure (A) is further illustrated in the following example:

0102-0000-1020Example 9

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid phenylamide

Benzotriazole-5-carboxylic acid (856 mg), HOAt (715 mg) and EDAC (1.00 g) were dissolved in DMF (17.5 mL) and the mixture was stirred at room temperature 1 hour. A 0.5 mL aliqot of this mixture was added to aniline (13.7 μL, 0.15 mmol) and the resulting mixture was vigorously shaken at room temperature for 16 hours. 1N hydrochloric acid (2 mL) and ethyl acetate (1 mL) were added and the mixture was vigorously shaken at room temperature for 2 hours. The organic phase was isolated and concentrated in vacuo to afford the title compound.

HPLC-MS (Method B): m/z: 239 (M+1); Rt=3.93 min.

The compounds in the following examples were similarly made. Optionally, the compounds may be isolated by filtration or by chromatography.

0102-0000-1019Example 10

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (4-methoxyphenyl)amide

HPLC-MS (Method A): m/z: 269 (M+1) & 291 (M+23); Rt=2.41 min

HPLC-MS (Method B): m/z: 239 (M+1); Rt=3.93 min.

0102-0000-1021 Example 11

(General Procedure (A))PEM

{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}carbamic acid tert-butyl ester

HPLC-MS (Method B): m/z: 354 (M+1); Rt=4.58 min.

0102-0000-1022Example 12

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (4-acetylaminophenyl)amide

HPLC-MS (Method B): m/z: 296 (M+1); Rt=3.32 min.

0102-0000-1023Example 13

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (3-fluorophenyl)amide

HPLC-MS (Method B): m/z: 257 (M+1); Rt=4.33 min.

0102-0000-1024Example 14

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (2-chlorophenyl)amide

HPLC-MS (Method B): m/z: 273 (M+1); Rt=4.18 min.

0102-0000-1025Example 15

(General Procedure (A))PEM

4-[(1H-Benzotriazole-5-carbonyl)amino]benzoic acid methyl ester

HPLC-MS (Method A):m/z: 297 (M+1); Rt: 2.60 min. HPLC-MS (Method B): m/z: 297 (M+1); Rt=4.30 min.

0102-0000-1026Example 16

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (4-butylphenyl)amide

HPLC-MS (Method B): m/z: 295 (M+1); Rt=5.80 min.

0102-0000-1027Example 17

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (1-phenylethyl)amide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.08 min.

0102-0000-1028Example 18

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid benzylamide

HPLC-MS (Method B): m/z: 253 (M+1); Rt=3.88 min.

0102-0000-1029Example 19

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid 4-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.40 min.

0102-0000-1030Example 20

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid 2-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.25 min.

0102-0000-1031 Example 21

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid 4-methoxybenzylamide

HPLC-MS (Method B): m/z: 283 (M+1); Rt=3.93 min.

0102-0000-1032Example 22

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid 3-methoxybenzylamide

HPLC-MS (Method B): m/z: 283 (M+1); Rt=3.97 min.

0102-0000-1033Example 23

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (1,2-diphenylethyl)amide

HPLC-MS (Method B): m/z: 343 (M+1); Rt=5.05 min.

0102-0000-1034Example 24

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid 3-bromobenzylamide

HPLC-MS (Method B): m/z: 331 (M+1); Rt=4.45 min.

0102-0000-1035Example 25

(General Procedure (A))PEM

4-{[(1H-Benzotriazole-5-carbonyl)amino]methyl}benzoic acid

HPLC-MS (Method B): m/z: 297 (M+1); Rt=3.35 min.

0102-0000-1036Example 26

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid phenethylamide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.08 min.

0102-0000-1037Example 27

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(4-chlorophenyl)ethyl]amide

HPLC-MS (Method B): m/z: 301 (M+1); Rt=4.50 min.

0102-0000-1038Example 28

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(4-methoxyphenyl)ethyl]amide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=4.15 min.

0102-0000-1039Example 29

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(3-methoxyphenyl)ethyl]amide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=4.13 min.

0102-0000-1040Example 30

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(3-chlorophenyl)ethyl]amide

HPLC-MS (Method B): m/z: 301 (M+1); Rt=4.55 min.

0102-0000-1041 Example 31

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (2,2-diphenylethyl)amide

HPLC-MS (Method B): m/z: 343 (M+1); Rt=5.00 min.

0102-0000-1042Example 32

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (3,4-dichlorophenyl)methylamide

HPLC-MS (Method B): m/z: 321 (M+1); Rt=4.67 min.

0102-0000-1043Example 33

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid methylphenylamide

HPLC-MS (Method B): m/z: 253 (M+1); Rt=3.82 min.

0102-0000-1044Example 34

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid benzylmethylamide

HPLC-MS (Method B): m/z: 267 (M+1); Rt=4.05 min.

0102-0000-1046Example 35

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(3-chloro-4-methoxyphenyl)ethyl]methyl-amide

HPLC-MS (Method B): m/z: 345 (M+1); Rt=4.37 min.

0102-0000-1046Example 36

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid methylphenethylamide

HPLC-MS (Method B): m/z: 281 (M+1); Rt=4.15 min.

0102-0000-1047Example 37

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid [2-(3,4-dimethoxyphenyl)ethyl]methylamide

HPLC-MS (Method B): m/z: 341 (M+1); Rt=3.78 min;

0102-0000-1048Example 38

(General Procedure (A))PEM

1H-Benzotriazole-5-carboxylic acid (2-hydroxy-2-phenylethyl)methylamide

HPLC-MS (Method B): m/z: 297 (M+1); Rt=3.48 min.

Example 39

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (3-bromophenyl)amide

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.19 min.

Example 40

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (4-bromophenyl)amide

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.18 min.

Example 41

(General procedure (A))

{4-[(1H-Benzotriazole-5-carbonyl)amino]benzoylamino}acetic acid

HPLC-MS (Method A): m/z: 340 (M+1); Rt=1.71 min.

Example 42

(General procedure (A))

{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acetic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=2.02 min.

Example 43

(General procedure (A))

3-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acrylic acid

HPLC-MS (Method A): m/z: 309 (M+1); Rt=3.19 min.

Example 44

(General procedure (A))

{3-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}acetic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=2.10 min.

Example 45

(General procedure (A))

2-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenoxy}-2-methylpropionic acid

HPLC-MS (Method A): m/z: 341 (M+1); Rt=2.42 min.

Example 46

(General procedure (A))

3-{4-[(1H-Benzotriazole-5-carbonyl)amino]benzoylamino}propionic acid

HPLC-MS (Method A): m/z: 354 (M+1); Rt=1.78 min.

Example 47

(General procedure (A))

3-{4-[(1H-Benzotriazole-5-carbonyl)amino]phenyl}propionic acid

HPLC-MS (Method A): m/z: 311 (M+1); Rt=2.20 min.

Example 48

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (4-benzyloxyphenyl)amide

HPLC-MS (Method A): m/z: 345 (M+1); Rt=3.60 min.

Example 49

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (3-chloro-4-methoxyphenyl)amide

HPLC-MS (Method A): m/z: 303 (M+1); Rt=2.88 min.

Example 50

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (4-phenoxyphenyl)amide

HPLC-MS (Method A): m/z: 331 (M+1); Rt=3.62 min.

Example 51

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (4-butoxyphenyl)amide

HPLC-MS (Method A): m/z: 311 (M+1); Rt=3.59 min.

Example 52

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (3-bromo-4-trifluoromethoxyphenyl)amide

HPLC-MS (Method A): m/z: 402 (M+1); Rt=3.93 min.

Example 53

(General procedure (A))

1H-Benzotriazole-5-carboxylic acid (3,5-dichloro-4-hydroxyphenyl)amide

HPLC-MS (Method A): m/z: 323 (M+1); Rt=2.57 min.

Example 54

(General procedure (A))

4-{[(1H-Benzotriazole-5-carbonyl)amino]methyl}benzoic acid

HPLC-MS (Method A): m/z: 297 (M+1); Rt=1.86 min.

Example 55

(General procedure (A))

{4-[(1H-Benzotriazole-5-carbonyl)amino]phenylsulfanyl}acetic acid

HPLC-MS (Method A): m/z: 329 (M+1); Rt=2.34 min.

Example 56

N-(1H-Benzotriazol-5-yl)acetamide

HPLC-MS (Method A): m/z: 177 (M+1); Rt=0.84 min.

Example 57

(General Procedure (A))

1H-Benzotriazole-5-carboxylic acid 4-nitrobenzylamide

The following compound is prepared according to general procedure (N) as described below:

Example 58

(General procedure (N))

1H-Benzotriazole-5-carboxylic acid 4-chlorobenzylamide

HPLC-MS (Method B): m/z: 287 (M+1); Rt=4.40 min.

Example 59

2-[(1H-Benzotriazol-5-ylimino)methyl]-4,6-dichlorophenol

Example 60

Diethyl 2-[(1H-benzotriazol-6-ylamino)methylidene]malonate

Example 61

N1-(1H-Benzotriazol-5-yl)-3-chlorobenzamide

Example 62

N1-(1H-Benzotriazol-5-yl)-3,4,5-trimethoxybenzamide

Example 63

N2-(1H-Benzotriazol-5-yl)-3-chlorobenzo[b]thiophene-2-carboxamide

Example 64

6-Bromo-1H-benzotriazole

Example 65

2-[(1H-Benzotriazol-5-ylimino)methyl]-4-bromophenol

General Procedure (B) for Preparation of Compounds of General Formula I₂: wherein X, Y, A and R³ are as defined above and A is optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ as defined above.

The chemistry is well known (eg Lohray et al., J. Med. Chem., 1999, 42, 2569-81) and is generally performed by reacting a carbonyl compound (aldehyde or ketone) with the heterocyclic ring (eg thiazolidine-2,4-dione (X═O; Y═S), rhodanine (X═Y═S) and hydantoin (X═O; Y═NH) in the presence of a base, such as sodium acetate, potassium acetate, ammonium acetate, piperidinium benzoate or an amine (eg piperidine, triethylamine and the like) in a solvent (eg acetic acid, ethanol, methanol, DMSO, DMF, NMP, toluene, benzene) or in a mixture of two or more of these solvents. The reaction is performed at room temperature or at elevated temperature, most often at or near the boiling point of the mixture. Optionally, azeotropic removal of the formed water can be done.

This general procedure (B) is further illustrated in the following example:

Example 66

General Procedure (B)

5-(3-Phenoxybenzylidene)thiazolidine-2,4-dione

A solution of thiazolidine-2,4-dione (90%, 78 mg, 0.6 mmol) and ammonium acetate (92 mg, 1.2 mmol) in acetic acid (1 mL) was added to 3-phenoxybenzaldehyde (52 μL, 0.6 mmol) and the resulting mixture was shaken at 115° C. for 16 hours. After cooling, the mixture was concentrated in vacuo to afford the title compound.

HPLC-MS (Method A): m/z: 298 (M+1); Rt=4.54 min.

The compounds in the following examples were similarly prepared. Optionally, the compounds can be further purified by filtration and washing with water, ethanol and/or heptane instead of concentration in vacuo. Also optionally the compounds can be purified by washing with ethanol, water and/or heptane, or by chromatography, such as preparative HPLC.

Example 67

General Procedure (B)

5-(4-Dimethylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 249 (M+1); Rt=4.90 min

Example 68

General procedure (B)

5-Naphthalen-1-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.16 min.

Example 69

General procedure (B)

5-Benzylidene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 206 (M+1); Rt=4.87 min.

Example 70

General procedure (B)

5-(4-Diethylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 277 (M+1); Rt=4.73 min.

Example 71

General Procedure (B)

5-(4-Methoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 263 (M+1); Rt=4.90 min.

Example 72

General Procedure (B)

5-(4-Chloro-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 240 (M+1); Rt=5.53 min.

Example 73

General Procedure (B)

5-(4-Nitro-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 251 (M+1); Rt=4.87 min.

Example 74

General Procedure (B)

5-(4-Hydroxy-3-methoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 252 (M+1); Rt=4.07 min.

Example 75

General Procedure (B)

5-(4-Methylsulfanylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 252 (M+1); Rt=5.43 min.

Example 76

General Procedure (B)

5-(2-Pentyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 292 (M+1); Rt=4.75 min. ¹H NMR (DMSO-d₆): δ=0.90 (3H, t), 1.39 (4H, m), 1.77 (2H, p), 4.08 (2H, t), 7.08 (1H, t), 7.14 (1H, d), 7.43 (2H, m), 8.03 (1H, s), 12.6 (1H, bs).

Example 77

General Procedure (B)

5-(3-Fluoro-4-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 354 (M+1); Rt=4.97 min.

Example 78

General Procedure (B)

5-(4-tert-Butylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 262 (M+1); Rt=6.70 min.

Example 79

General Procedure (B)

N-[4-2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]acetamide

HPLC-MS (Method A): m/z: 263 (M+1); Rt=3.90 min.

Example 80

General Procedure (B)

5-Biphenyl-4-ylmethylene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 282 (M+1); Rt=4.52 min.

Example 81

General Procedure (B)

5-(4-Phenoxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 298 (M+1); Rt=6.50 min.

Example 82

General Procedure (B)

5-(3-Benzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=6.37 min.

Example 83

General Procedure (B)

5-(3-p-Tolyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=6.87 min.

Example 84

General Procedure (B)

5-Naphthalen-2-ylmethylene-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.15 min.

Example 85

General Procedure (B)

5-Benzo[1,3]dioxol-5-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1), Rt=3.18 min.

Example 86

General Procedure (B)

5-(4-Chlorobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 256 (M+1); Rt=4.51 min.

Example 87

General Procedure (B)

5-(4-Dimethylaminobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 265 (M+1); Rt=5.66 min.

Example 88

General Procedure (B)

5-(4-Nitrobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 267 (M+1); Rt=3.94 min.

Example 89

General Procedure (B)

5-(4-Methylsulfanylbenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 268 (M+1); Rt=6.39 min.

Example 90

General Procedure (B)

5-(3-Fluoro-4-methoxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 270 (M+1); Rt=5.52 min.

Example 91

General Procedure (B)

5-Naphthalen-2-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 272 (M+1); Rt=6.75 min.

Example 92

General Procedure (B)

5-(4-Diethylaminobenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 293 (M+1); Rt=5.99 min.

Example 93

General Procedure (B)

5-Biphenyl-4-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 298 (M+1); Rt=7.03 min.

Example 94

General Procedure (B)

5-(3-Phenoxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 314 (M+1); Rt=6.89 min.

Example 95

General Procedure (B)

5-(3-Benzyloxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 328 (M+1); Rt=6.95 min.

Example 96

General Procedure (B)

5-(4-Benzyloxybenzylidene)-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 328 (M+1); RT=6.89 min.

Example 97

General Procedure (B)

5-Naphthalen-1-ylmethylene-2-thioxothiazolidin-4-one

HPLC-MS (Method A): m/z: 272 (M+1); Rt=6.43 min.

Example 98

General Procedure (B)

5-(3-Methoxybenzyl)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 236 (M+1); Rt=3.05 min.

Example 99

General Procedure (D)

4-[2-Chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid ethyl ester

HPLC-MS (Method A): m/z: 392 (M+23), Rt=4.32 min.

Example 100

General Procedure (D)

4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-butyric acid

HPLC-MS (Method A): m/z: 410 (M+23); Rt=3.35 min.

Example 101

General Procedure (B)

5-(3-Bromobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 285 (M+1); Rt=4.01 min.

Example 102

General Procedure (B)

5-(4-Bromobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 285 (M+1); Rt=4.05 min.

Example 103

General Procedure (B)

5-(3-Chlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 240 (M+1); Rt=3.91 min.

Example 104

General Procedure (B)

5-Thiophen-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 212 (M+1); Rt=3.09 min.

Example 105

General Procedure (B)

5-(4-Bromothiophen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 291 (M+1); Rt=3.85 min.

Example 106

General Procedure (B)

5-(3,5-Dichlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 274 (M+1); Rt=4.52 min.

Example 107

General Procedure (B)

5-(1-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 259 (M+1); Rt=3.55 min.

Example 108

General Procedure (B)

5-(1H-Indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 245 (M+1); Rt=2.73 min.

Example 109

General Procedure (B)

5-Fluoren-9-ylidenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 280 (M+1); Rt=4.34 min.

Example 110

General Procedure (B)

5-(1-Phenylethylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 220 (M+1); Rt=3.38 min.

Example 111

General Procedure (B)

5-[1-(4-Methoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=3.55 min.

Example 112

General Procedure (B)

5-(1-Naphthalen-2-yl-ethylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 270 (M+1); Rt=4.30 min.

Example 113

General Procedure (B)

5-[1-(4-Bromophenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.18 min.

Example 114

General Procedure (B)

5-(2,2-Diphenylethylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 296 (M+1); Rt=4.49 min.

Example 115

General Procedure (B)

5-[1-(3-Methoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=3.60 min.

Example 116

General Procedure (B)

5-[1-(6-Methoxynaphthalen-2-yl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.26 min.

Example 117

General Procedure (B)

5-[1-(4-Phenoxyphenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 312 (M+1); Rt=4.68 min.

Example 118

General Procedure (B)

5-[1-(3-Fluoro-4-methoxyphenyl)ethylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 268 (M+1); Rt=3.58 min.

Example 119

General Procedure (B)

5-[1-(3-Bromophenyl)-ethylidene]-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 300 (M+1); Rt=4.13 min.

Example 120

General Procedure (B)

5-Anthracen-9-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 306 (M+1); Rt=4.64 min.

Example 121

General Procedure (B)

5-(2-Methoxynaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.02 min.

Example 122

General Procedure (B)

5-(4-Methoxynaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.31 min.

Example 123

General Procedure (B)

5-(4-Dimethylaminonaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 299 (M+1); Rt=4.22 min.

Example 124

General Procedure (B)

5-(4-Methylnaphthalen-1-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 270 (M+1); Rt=4.47 min.

Example 125

General Procedure (B)

5-Pyridin-2-ylmethylene-thiazolidine-2,4-dione

Example 126

5-Pyridin-2-ylmethyl-thiazolidine-2,4-dione

5-Pyridin-2-ylmethylene-thiazolidine-2,4-dione (5 g) in tetrahydrofuran (300 ml) was added 10% Pd/C (1 g) and the mixture was hydrogenated at ambient pressure for 16 hours. More 10% Pd/C (5 g) was added and the mixture was hydrogenated at 50 psi for 16 hours. After filtration and evaporation in vacuo, the residue was purified by column chromatography eluting with a mixture of ethyl acetate and heptane (1:1). This afforded the title compound (0.8 g, 16%) as a solid.

TLC: R_f=0.30 (SiO₂; EtOAc: heptane 1:1)

Example 127

General Procedure (B)

5-(1H-Imidazol-4-ylmethylene)-thiazolidine-2,4-dione

Example 128

General Procedure (B)

5-(4-Benzyloxy-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 6.43 min; 99% (2A)

Example 129

General Procedure (B)

5-[4-(4-Fluorobenzyloxy)benzylidene]-2-thioxothiazolidin-4-one

Example 130

General Procedure (B)

5-(4-Butoxybenzylidene)-2-thioxothiazolidin-4-one

Example 131

General Procedure (B)

5-(3-Methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 236 (M+1); Rt=4.97 min

Example 132

General Procedure (B)

5-(3-Methoxybenzylidene)imidazolidine-2,4-dione

HPLC-MS (Method A): m/z: 219 (M+1); Rt=2.43 min.

Example 133

General Procedure (B)

5-(4-Methoxybenzylidene)imidazolidine-2,4-dione

HPLC-MS (Method A): m/z: 219 (M+1); Rt=2.38 min.

Example 134

General Procedure (B)

5-(2,3-Dichlorobenzylidene)thiazolidine-2,4-dione

Example 135

General Procedure (B)

5-Benzofuran-7-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.57 min.

Example 136

General Procedure (B)

5-Benzo[1,3]dioxol-4-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 250 (M+1); Rt=4.00 min.

Example 137

General Procedure (B)

5-(4-Methoxy-2,3-dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 264 (M+1); Rt=5.05 min.

Example 138

General Procedure (B)

5-(2-Benzyloxy-3-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 342 (M+1); Rt=5.14 min.

Example 139

General Procedure (B)

5-(2-Hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 222 (M+1); Rt=3.67 min.

Example 140

General Procedure (B)

5-(2,4-Dichlorobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.60 (2H, “s”), 7.78 (1H, s), 7.82 (1H, s).

Example 141

General Procedure (B)

5-(2-Chlorobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.40 (1H, t), 7.46 (1H, t), 7.57 (1H, d), 7.62 (1H, d), 7.74 (1H, s).

Example 142

General Procedure (B)

5-(2-Bromobenzylidene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): 7.33 (1H, t), 7.52 (1H, t), 7.60 (1H, d), 7.71 (1H, s), 7.77 (1H, d).

Example 143

General Procedure (B)

5-(2,4-Dimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 266 (M+1) Rt=4.40 min.

Example 144

General Procedure (B)

5-(2-Methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 236 (M+1); Rt=4.17 min.

Example 145

General Procedure (B)

5-(2,6-Difluorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 242 (M+1); Rt=4.30 min.

Example 146

General Procedure (B)

5-(2,4-Dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 234 (M+1); Rt=5.00 min.

Example 147

General Procedure (B)

5-(2,4,6-Trimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 296 (M+1); Rt=4.27 min.

Example 148

General Procedure (B)

5-(4-Hydroxy-2-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 252 (M+1); Rt=3.64 min.

Example 149

General Procedure (B)

5-(4-Hydroxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

¹H-NMR (DMSO-d₆): δ=7.04 (1H, d), 7.57 (2H, m), 7.67 (1H, t), 8.11 (1H, d), 8.25 (1H, d), 8.39 (1H, s) 11.1 (1H, s), 12.5 (1H, bs). HPLC-MS (Method C): m/z: 272 (M+1); Rt=3.44 min.

Example 150

General Procedure (B)

5-(2-Trifluoromethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 290 (M+1); Rt=4.94 min.

Example 151

General Procedure (B)

5-Biphenyl-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 282 (M+1); Rt=5.17 min.

Example 152

General Procedure (B)

5-(2-Benzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 312 (M+1); Rt=5.40 min.

Example 153

General Procedure (B)

5-Adamantan-2-ylidenethiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 250 (M+1); Rt=4.30 min.

Example 154

General Procedure (B)

5-[3-(4-Nitrophenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 277 (M+1); Rt=3.63 min.

Example 155

General Procedure (B)

5-[3-(2-Methoxyphenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 262 (M+1); Rt=3.81 min.

Example 156

General Procedure (B)

5-[3-(4-Methoxyphenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 262 (M+1); Rt=3.67 min.

Example 157

General Procedure (B)

5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione

Example 158

General Procedure (B)

5-(4-Dimethylaminobenzylidene)pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=260 (M+1) Rt=2.16 min.

Example 159

General Procedure (B)

5-(9-Ethyl-9H-carbazol-2-ylmethylene)-pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=334 (M+1); Rt=3.55 min.

Example 160

General Procedure (B)

5-(4-Hexyloxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=356 (M+1); Rt=5.75 min.

Example 161

General Procedure (B)

5-(4-Decyloxynaphthalen-1-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=412 (M+1); Rt=6.44 min.

Example 162

General Procedure (B)

5-[4-(2-Aminoethoxy)-naphthalen-1-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=315 (M+1); Rt=3.24 min.

Example 163

General Procedure (B)

5-(2,4-Dimethyl-9H-carbazol-3-ylmethylene)-pyrimidine-2,4,6-trione

HPLC-MS (Method C): m/z=334 (M+1); Rt=3.14 min.

Example 164

General Procedure (B)

4-(4-Hydroxy-3-methoxybenzylidine)hydantoin

Example 165

General Procedure (B)

5-Benzylidenehydantoin

General Procedure (C) for Preparation of Compounds of General Formula I₂: wherein X, Y, A, and R³ are as defined above and A is optionally substituted with up to four substituents R⁷, R⁸, R⁹, and R¹⁰ as defined above.

This general procedure (C) is quite similar to general procedure (B) and is further illustrated in the following example:

Example 166

General Procedure (C)

5-(3,4-Dibromobenzylidene)thiazolidine-2,4-dione

A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), 3,4-dibromobenzaldehyde (132 mg, 0.5 mmol), and piperidine (247 μL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110° C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo.

The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound.

¹H NMR (Acetone-d₆): δ_H 7.99 (d, 1H), 7.90 (d, 1H), 7.70 (s, 1H), 7.54 (d, 1H); HPLC-MS (Method A): m/z: 364 (M+1); Rt=4.31 min.

The compounds in the following examples were similarly prepared. Optionally, the compounds can be further purified by filtration and washing with water instead of concentration in vacuo. Also optionally the compounds can be purified by washing with ethanol, water and/or heptane, or by preparative HPLC.

Example 167

General Procedure (C)

5-(4-Hydroxy-3-iodo-5-methoxybenzylidene)thiazolidine-2,4-dione

Mp=256° C.; ¹H NMR (DMSO-d₆) δ=12.5 (s,broad, 1H), 10.5 (s,broad, 1H), 7.69 (s, 1H), 7.51 (d, 1H), 7.19 (d, 1H)3.88 (s,3H), ¹³C NMR (DMSO-d₆) δ_C=168.0, 167.7, 149.0, 147.4, 133.0, 131.2, 126.7, 121.2, 113.5, 85.5, 56.5; HPLC-MS (Method A): m/z: 378 (M+1); Rt=3.21 min.

Example 168

General Procedure (C)

5-(4-Hydroxy-2,6-dimethylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 250 (M+1); Rt.=2.45 min.

Example 169

General Procedure (C)

4-[5-Bromo-6-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-2-yloxymethyl]-benzoic acid

HPLC-MS (Method C): m/z: 506 (M+23); Rt.=4.27 min.

Example 170

General Procedure (C)

5-(4-Bromo-2,6-dichlorobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 354 (M+1); Rt.=4.36 min.

Example 171

General Procedure (C)

5-(6-Hydroxy-2-naphthylmethylene)thiazolidine-2,4-dione

Mp 310-314° C., ¹H NMR (DMSO-d₆): δ_H=12.5 (s,broad, 1H), 8.06(d, 1H), 7.90-7.78(m,2H),7.86 (s, 1H), 7.58 (dd, 1H),7.20 7.12 (m,2H). ¹³C NMR (DMSO-d₆): δ_C=166.2, 165.8, 155.4, 133.3, 130.1, 129.1, 128.6, 125.4, 125.3, 125.1, 124.3, 120.0, 117.8, 106.8; HPLC-MS (Method A): m/z: 272 (M+1); Rt=3.12 min.

Preparation of the Starting Material, 6-hydroxy-2-naphtalenecarbaldehyde

6-Cyano-2-naphthalenecarbaldehyde (1.0 g, 5.9 mmol) was dissolved in dry hexane (15 mL) under nitrogen. The solution was cooled to −60° C. and a solution of diisobutyl aluminium hydride (DIBAH) (15 mL, 1M in hexane) was added dropwise. After the addition, the solution was left at room temperature overnight. Saturated ammonium chloride solution (20 mL) was added and the mixture was stirred at room temperature for 20 min, subsequently aqueous H₂SO₄ (10% solution, 15 mL) was added followed by water until all salt was dissolved. The resulting solution was extracted with ethyl acetate (3×), the combined organic phases were dried with MgSO₄, evaporated to dryness to afford 0.89 g of 6-hydroxy-2-naphtalenecarbaldehyde.

Mp.: 153.5-156.5° C.; HPLC-MS (Method A): m/z: 173 (M+1); Rt=2.67 min; ¹H NMR (DMSO-d₆): δ_H=10.32(s, 1H), 8.95 (d, 1H), 10.02 (s, 1H), 8.42 (s,broad, 1H), 8.01 (d, 1H), 7.82-7.78 (m,2H), 7.23-7.18 (m,2H).

Alternative Preparation of 6-hydroxy-2-naphtalenecarbaldehyde

To a stirred cooled mixture of 6-bromo-2-hydroxynaphthalene (25.3 g, 0.113 mol) in THF (600 mL) at −78° C. was added n-BuLi (2.5 M, 100 mL, 0.250 mol) dropwise. The mixture turned yellow and the temperature rose to −64° C. After ca 5 min a suspension appeared. After addition, the mixture was maintained at −78° C. After 20 minutes, a solution of DMF (28.9 mL, 0.373 mol) in THF (100 mL) was added over 20 minutes. After addition, the mixture was allowed to warm slowly to room temperature. After 1 hour, the mixture was poured in ice/water (200 mL). To the mixture citric acid was added to a pH of 5. The mixture was stirred for 0.5 hour. Ethyl acetate (200 mL) was added and the organic layer was separated and washed with brine (100 mL), dried over Na₂SO₄ and concentrated. To the residue was added heptane with 20% ethyl acetate (ca 50 mL) and the mixture was stirred for 1 hour. The mixture was filtered and the solid was washed with ethyl acetate and dried in vacuo to afford 16 g of the title compound.

Example 172

General Procedure (C)

5-(3-Iodo-4-methoxybenzylidene)thiazolidiene-2,4-dione

¹H NMR (DMSO-d₆): δ_H 12.55 (s,broad, 1H), 8.02 (d, 1H), 7.72 (s, 1H), 7.61 (d, 1H)7.18(d, 1H), 3.88 (s,3H); ¹³C NMR (DMSO-d₆): δ_C 168.1, 167.7, 159.8, 141.5, 132.0, 130.8, 128.0, 122.1, 112.5, 87.5, 57.3. HPLC-MS (Method A): m/z: 362 (M+1); Rt=4.08 min.

Preparation of the Starting Material, 3-iodo-4-methoxybenzaldehyde

4-Methoxybenzaldehyde (0.5 g, 3.67 mmol) and silver trifluoroacetate (0.92 g, 4.19 mmol) were mixed in dichloromethane (25 mL). Iodine (1.19 g, 4.7 mmol) was added in small portions and the mixture was stirred overnight at room temperature under nitrogen. The mixture was subsequently filtered and the residue washed with DCM. The combined filtrates were treated with an acqueous sodium thiosulfate solution (1 M) until the colour disappeared. Subsequent extraction with dichloromethane (3×20 mL) followed by drying with MgSO₄ and evaporation in vacuo afforded 0.94 g of 3-iodo-4-methoxybenzaldehyde.

Mp 104-107° C.; HPLC-MS (Method A): m/z:263 (M+1); Rt=3.56 min.;¹H NMR (CDCl₃): δ_H=8.80 (s, 1H), 8.31 (d, 1H), 7.85 (dd, 1H) 6.92 (d, 1H), 3.99 (s, 3H).

Example 173

General Procedure (C)

5-(1-Bromonaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z:=336 (M+1); Rt=4.46 min.

Example 174

General Procedure (C)

1-[5-(2,4-Dioxothiazolidin-5-ylidenemethyl)thiazol-2-yl]piperidine-4-carboxylic acid ethyl ester

¹H NMR (DMSO-d₆): δ_H=7.88 (s, 1H), 7.78 (s, 1H), 4.10 (q,2H), 4.0-3.8 (m,2H), 3.40-3.18 (m,2H), 2.75-2.60 (m, 1H), 2.04-1.88 (m,2H), 1.73-1.49 (m,2H), 1.08 (t,3H); HPLC-MS (Method A): m/z: 368 (M+1); Rt=3.41 min.

Example 175

General Procedure (C)

5-(2-Phenyl-[1,2,3]triazol-4-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_H=12.6 (s,broad, 1H), 8.46 (s, 1H), 8.08 (dd,2H), 7.82 (s, 1H), 7.70-7.45 (m, 3H). HPLC-MS (Method A): m/z: 273 (M+1); Rt=3.76 min.

Example 176

General Procedure (C)

5-(Quinolin-4-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 257 (M+1); Rt=2.40 min.

Example 177

General Procedure (C)

5-(6-Methylpyridin-2-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_H=12.35 (s,broad, 1H), 7.82 (t, 1H), 7.78 (s, 1H), 7.65 (d, 1H), 7.18 (d, 1H), 2.52 (s,3 H); HPLC-MS (Method A): m/z: 221 (M+1); Rt=3.03 min.

Example 178

General Procedure (C)

5-(2,4-dioxothiazolidin-5-ylidenemethyl)-furan-2-ylmethylacetate

¹H NMR (DMSO-d₆): δ_H=12.46 (s,broad, 1H), 7.58 (s, 1H), 7.05 (d, 1H), 6.74 (s, 1H), 5.13 (s,2H), 2.10 (s,3H). HPLC-MS (Method A): m/z: 208 (M-CH₃COO); Rt=2.67 min.

Example 179

General Procedure (C)

5-(2,4-Dioxothiazolidin-5-ylidenemethyl)furan-2-sulfonic acid

HPLC-MS (Method A): m/z:276 (M+1); Rt=0.98 min.

Example 180

General Procedure (C)

5-(5-Benzyloxy-1H-pyrrolo[2,3-c]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 352 (M+1); Rt=3.01 min.

Example 181

General Procedure (C)

5-(Quinolin-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 257 (M+1); Rt=3.40 min.

Example 182

General Procedure (C)

5-(2,4-Dioxothiazolidin-5-ylidenemethyl)thiophene-2-carboxylic acid

HPLC-MS (Method A): m/z: 256 (M+1); Rt=1.96 min.

Example 183

General Procedure (C)

5-(2-Phenyl-1H-imidazol-4-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 272 (M+1); Rt=2.89 min.

Example 184

General Procedure (C)

5-(4-Imidazol-1-yl-benzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 272 (M+1); Rt=1.38 min.

Example 185

General Procedure (C)

5-(9-Ethyl-9H-carbazol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 323 (M+1); Rt=4.52 min.

Example 186

General Procedure (C)

5-(1,4-Dimethyl-9H-carbazol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 323 (M+1); Rt=4.35 min.

Example 187

General Procedure (C)

5-(2-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 259 (M+1); Rt=3.24 min.

Example 188

General Procedure (C)

5-(2-Ethylindol-3-ylmethylene)thiazolidine-2,4-dione

2-Methylindole (1.0 g, 7.6 mmol) dissolved in diethyl ether (100 mL) under nitrogen was treated with n-Butyl lithium (2 M in pentane, 22.8 mmol) and potassium tert-butoxide (15.2 mmol) with stirring at RT for 30 min. The temperature was lowered to −70 C and methyl Iodide (15.2 mmol) was added and the resulting mixture was stirred at −70 for 2 h. Then 5 drops of water was added and the mixture allowed to warm up to RT. Subsequently, the mixture was poured into water (300 mL), pH was adjusted to 6 by means of 1N hydrochloric acid and the mixture was extracted with diethyl ether. The organic phase was dried with Na₂SO₄ and evaporated to dryness. The residue was purified by column chromatography on silica gel using heptane/ether( 4/1) as eluent. This afforded 720 mg (69%) of 2-ethylindole.

¹H NMR (DMSO-d₆): δ=10.85 (1H,s); 7.39 (1H,d); 7.25 (1H,d); 6.98(1H,t); 6.90(1H,t); 6.10 (1H,s); 2.71 (2H,q); 1.28 (3H,t).

2-Ethylindole (0.5 g, 3.4 mmol) dissolved in DMF (2 mL) was added to a cold (0° C.) premixed (30 minutes) mixture of DMF (1.15 mL) and phosphorous oxychloride(0.64 g, 4.16 mmol). After addition of 2-ethylindole, the mixture was heated to 40° C. for 1 h, water (5 mL) was added and the pH adjusted to 5 by means of 1 N sodium hydroxide.The mixture was subsequently extracted with diethyl ether, the organic phase isolated, dried with MgSO₄ and evaporated to dryness affording 2-ethylindole-3-carbaldehyde (300 mg).

HPLC-MS (Method C): m/z:174 (M+1); Rt.=2.47 min.

2-Ethylindole-3-carbaldehyde (170 mg) was treated with thiazolidine-2,4-dione using the general procedure (C) to afford the title compound (50 mg).

HPLC-MS (Method C):m/z: 273 (M+1); Rt.=3.26 min.

Example 189

General Procedure (C)

5-[2-(4-Bromophenylsulfanyl)-1-methyl-1H-indol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 447 (M+1); Rt=5.25 min.

Example 190

General Procedure (C)

5-[2-(2,4-Dichlorobenzyloxy)-naphthalen-1-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): (anyone 1) m/z: 430 (M+1); Rt=5.47 min.

Example 191

General Procedure (C)

5-{4-[3-(4-Bromophenyl)-3-oxopropenyl]-benzylidene}thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 416 (M+1); Rt=5.02 min.

Example 192

General Procedure (C)

5-(4-Pyridin-2-ylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 283 (M+1), Rt=2.97 min.

Example 193

General Procedure (C)

5-(3,4-Bisbenzyloxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 418 (M+1); Rt=5.13 min.

Example 194

General Procedure (C)

5-[4-(4-Nitrobenzyloxy)-benzylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 357 (M+1); Rt=4.45 min.

Example 195

General Procedure (C)

5-(2-Phenyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 321 (M+1); Rt=3.93 min.

Example 196

General Procedure (C)

5-(5-Benzyloxy-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 351 (M+1); Rt=4.18 min.

Example 197

General Procedure (C)

5-(4-Hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 222 (M+1); Rt=2.42 min.

Example 198

General Procedure (C)

5-(1-Methyl-1H-indol-2-ylmethylene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_H=12.60 (s,broad, 1H), 7.85 (s, 1H), 7.68 (dd, 1H), 7.55 (dd, 1H), 7.38 (dt, 1H), 7.11 (dt, 1H) 6.84 (s, 1H), 3.88 (s,3H); HPLC-MS (Method A): m/z: 259 (M+1); Rt=4.00 min.

Example 199

General Procedure (C)

5-(5-Nitro-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

Mp 330-333° C., ¹H NMR (DMSO-d₆): δ_H=12.62 (s,broad, 1H), 8.95 (d, 1H), 8.20 (s, 1H), 8.12 (dd, 1H), 7.98 (s,broad, 1H), 7.68 (d, 1H); HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.18 min.

Example 200

General Procedure (C)

5-(6-Methoxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 286 (M+1); Rt=4.27 min.

Example 201

General Procedure (C)

5-(3-Bromo-4-methoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 314 (M+1), Rt=3.96 min.

Example 202

General Procedure (C)

3-{(2-Cyanoethyl)-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]amino}propionitrile

HPLC-MS (Method A): m/z: 327 (M+1); Rt=2.90 min.

Example 203

General Procedure (C)

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylic acid methyl ester

HPLC-MS (Method A): m/z: 303 (M+1); Rt=3.22-3-90 min.

Example 204

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylic acid pentyl ester

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-6-carboxylic acid methyl ester (example 203, 59 mg; 0.195 mmol) was stirred in pentanol (20 mL) at 145° C. for 16 hours. The mixture was evaporated to dryness affording the title compound (69 mg).

HPLC-MS (Method C): m/z: 359 (M+1); Rt.=4.25 min.

Example 205

General Procedure (C)

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-7-carboxylic acid

HPLC-MS (Method A): m/z: 289 (M+1); Rt=2.67 min.

Example 206

General Procedure (C)

5-(1-Benzylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 335 (M+1); Rt=4.55 min.

Example 207

General Procedure (C)

5-(1-Benzenesulfonylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z:=385 (M+1); Rt=4.59 min.

Example 208

General Procedure (C)

5-(4-[1,2,3]Thiadiazol-4-ylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.45 min.

Example 209

General Procedure (C)

5-[4-(4-Nitrobenzyloxy)-benzylidene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 357 (M+1); Rt=4.42 min.

Example 210

General Procedure (C)

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-1-carboxylic acid ethyl ester

HPLC-MS (Method A): m/z: 317 (M+1); Rt=4.35 min.

Example 211

General Procedure (C)

5-[2-(4-Pentylbenzoyl)-benzofuran-5-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 420 (M+1); Rt=5.92 min.

Example 212

General Procedure (C)

5-[1-(2-Fluorobenzyl)-4-nitroindol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): (Anyone 1) m/z: 398 (M+1); Rt=4.42 min.

Example 213

General Procedure (C)

5-(4-Benzyloxyindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 351 (M+1); Rt=3.95 min.

Example 214

General Procedure (C)

5-(4-Isobutylbenzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 262 (M+1); Rt=4.97 min.

Example 215

General Procedure (C)

Trifluoromethanesulfonic acid 4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yl ester

HPLC-MS (Method A): m/z: 404 (M+1); Rt=4.96 min.

Preparation of Starting Material:

4-Hydroxy-1-naphthaldehyde (10 g, 58 mmol) was dissolved in pyridin (50 ml) and the mixture was cooled to 0-5° C. With stirring, trifluoromethanesulfonic acid anhydride (11.7 ml, 70 mmol) was added drop-wise. After addition was complete, the mixture was allowed to warm up to room temperature, and diethyl ether (200 ml) was added. The mixture was washed with water (2×250 ml), hydrochloric acid (3N, 200 ml), and saturated aqueous sodium chloride (100 ml). After drying (MgSO4), filtration and concentration in vacuo, the residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 8.35 g (47%) trifluoromethanesulfonic acid 4-formylnaphthalen-1-yl ester, mp 44-46.6° C.

Example 216

General Procedure (C)

5-(4-Nitroindol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 290 (M+1); Rt=3.14 min.

Example 217

General Procedure (C)

5-(3,5-Dibromo-4-hydroxy-benzylidene)thiazolidine-2,4-dione

¹H NMR (DMSO-d₆): δ_H=12.65 (broad, 1H), 10.85 (broad, 1H), 7.78 (s,2H), 7.70 (s, 1H); HPLC-MS (Method A): m/z: 380 (M+1); Rt=3.56 min.

Example 218

General Procedure (C)

HPLC-MS (Method A): m/z: 385 (M+1); Rt=5.08 min.

General Procedure for Preparation of Starting Materials for Examples 218-221:

Indole-3-carbaldehyde (3.8 g, 26 mmol) was stirred with potassium hydroxide (1.7 g) in acetone (200 mL) at RT until a solution was obtained indicating full conversion to the indole potassium salt. Subsequently the solution was evaporated to dryness in vacuo. The residue was dissolved in acetone to give a solution containing 2.6 mmol/20 mL.

20 mL portions of this solution were mixed with equimolar amounts of arylmethylbromides in acetone (10 mL). The mixtures were stirred at RT for 4 days and subsequently evaporated to dryness and checked by HPLC-MS. The crude products, 1-benzylated indole-3-carbaldehydes, were used for the reaction with thiazolidine-2,4-dione using the general procedure C.

Example 219

General Procedure (C)

4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-ylmethyl]benzoic acid methyl ester

HPLC-MS (Method A): m/z: 393 (M+1); Rt=4.60 min.

Example 220

General Procedure (C)

5-[1-(9,10-Dioxo-9,10-dihydroanthracen-2-ylmethyl)-1H-indol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 465 (M+1); Rt=5.02 min.

Example 221

General Procedure (C)

4′-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-ylmethyl]biphenyl-2-carbonitrile

HPLC-MS (Method A): m/z: 458 (M+23); Rt=4.81 min.

Example 222

General Procedure (C)

3-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methylindol-1-ylmethyl]benzonitrile

2-Methylindole-3-carbaldehyde (200 mg, 1.26 mmol) was added to a slurry of 3-bromomethylbenzenecarbonitrile (1.26 mmol) followed by sodium hydride, 60%, (1.26 mmol) in DMF (2 mL). The mixture was shaken for 16 hours, evaporated to dryness and washed with water and ethanol. The residue was treated with thiazolidine-2,4-dione following the general procedure C to afford the title compound (100 mg).

HPLC-MS (Method C): m/z: 374 (M+1); Rt.=3.95 min.

Example 223

General Procedure (C)

5-(1-Benzyl-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

This compound was prepared in analogy with the compound described in example 222 from benzyl bromide and 2-methylindole-3-carbaldehyde, followed by reaction with thiazolidine-2,4-dione resulting in 50 mg of the title compound.

HPLC-MS (Method C): m/z: 349 (M+1); Rt.=4.19 min.

Example 224

4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-methylindol-1-ylmethyl]benzoic acid methyl ester

This compound was prepared in analogy with the compound described in example 222 from 4-(bromomethyl)benzoic acid methyl ester and 2-methylindole-3-carbaldehyde, followed by reaction with thiazolidine-2,4-dione.

HPLC-MS (Method C): m/z: 407 (M+1); Rt.=4.19 min.

Example 225

General Procedure (C)

5-(2-Chloro-1-methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 293 (M+1); Rt=4.10 min.

Example 226

General Procedure (C)

5-(4-Hydroxy-3,5-diiodo-benzylidene)-thiazolidine-2,4-dione

HPLC-MS (Method A): m/z: 474 (M+1); Rt=6.61 min.

Example 227

General Procedure (C)

5-(4-Hydroxy-3-iodobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 348 (M+1); Rt.=3.13 min ¹H-NMR: (DMSO-d₆): 11.5 (1H,broad); 7.95(1H,d); 7.65(1H,s); 7.45 (1H,dd); 7.01(1H,dd); 3.4 (1H,broad).

Example 228

General Procedure (C)

5-(2,3,6-Trichlorobenzylidene)thiazolidine-2,4-dione

H PLC-MS (Method C): m/z: 309 (M+1); Rt.=4.07 min

Example 229

General Procedure (C)

5-(2,6-Dichlorobenzylidene)thiazolidine-2,4-dione

Mp. 152-154° C. HPLC-MS (Method C): m/z: 274 (M+1), Rt.=3.70 min ¹H-NMR: (DMSO-d₆): 12.8 (1H, broad); 7.72 (1H,s); 7.60 (2H,d); 7.50 (1H,t).

Example 230

General Procedure (C)

5-[1-(2,6-Dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-1H-pyrrol-3-ylmethylene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 436 (M+1); Rt. 4.81 min

Example 231

General Procedure (C)

5-[1-(3,5-Dichlorophenyl)-5-(4-methanesulfonylphenyl)-2-methyl-1H-pyrrol-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 508 (M+1); Rt.=4.31 min

Example 232

General Procedure (C)

5-[1-(2,5-Dimethoxyphenyl)-5-(4-methanesulfonylphenyl)-2-methyl-1H-pyrrol-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 499 (M+1); Rt.=3.70 min

Example 233

General Procedure (C)

4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2,5-dimethylpyrrol-1-yl]benzoic acid

HPLC-MS (Method C): m/z:342 (M+1); Rt.=3.19 min

Example 234

General Procedure (C)

5-(4-Hydroxy-2,6-dimethoxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:282( M+1); Rt.=2.56, mp=331-333° C.

Example 235

General Procedure (C)

5-(2,6-Dimethylbenzylidene)thiazolidine-2,4-dione

M.p: 104-105° C. HPLC-MS (Method C): m/z: 234 (M+1); Rt.=3.58 min,

Example 236

General Procedure (C)

5-(2,6-Dimethoxybenzylidene)thiazolidine-2,4-dione

Mp: 241-242° C. HPLC-MS (Method C): m/z: 266 (M+1); Rt.=3.25 min;

Example 237

General Procedure (C)

5-[4-(2-Fluoro-6-nitrobenzyloxy)-2,6-dimethoxybenzylidene]thiazolidine-2,4-dione

Mp: 255-256° C. HPLC-MS (Method C): m/z: 435 (M+1), Rt 4.13 min,

Example 238

General Procedure (C)

5-Benzofuran-2-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z:246 (M+1); Rt.=3.65 min, mp=265-266° C.

Example 239

General Procedure (C)

5-[3-(4-Dimethylaminophenyl)allylidene]thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:276(M+1); Rt.=3.63, mp=259-263° C. ¹H-NMR: (DMSO-d₆) δ=12.3 (1H,broad); 7.46 (2H,d); 7.39 (1H,d); 7.11 (1H,d); 6.69 (2H,d); 6.59 (1H, dd); 2.98 (3H,s).

Example 240

General Procedure (C)

5-(2-Methyl-3-phenylallylidene)thiazolidine-2,4-dione

Mp: 203-210° C. HPLC-MS (Method C): m/z: 246 (M+1); Rt=3.79 min.

Example 241

General Procedure (C)

5-(2-Chloro-3-phenylallylidene)thiazolidine-2,4-dione

Mp: 251-254° C. HPLC-MS (Method C): m/z: 266 (M+1; Rt=3.90 min

Example 242

General Procedure (C)

5-(2-Oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

Mp: 338-347° C. HPLC-MS (Method C): m/z: 273 (M+1); Rt.=2.59 min.

Example 243

General Procedure (C)

5-(2,4,6-Tribromo-3-hydroxybenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 459 (M+1);Rt.=3.65 min.

Example 244

General Procedure (C)

5-(5-Bromo-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 339 (M+1); Rt=3.37 min.

Example 245

General Procedure (C)

5-(7-Bromo-2-methylindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 319 (M+1); Rt=3.48 min.

Example 246

General Procedure (C)

5-(6-Bromoindol-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 325 (M+1); Rt=3.54 min.

Example 247

General Procedure (C)

5-(8-Methyl-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 287 (M+1); Rt=2.86 min.

Example 248

General Procedure (C)

5-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 303 (M+1); Rt=2.65 min.

Example 249

General Procedure (C)

5-Quinolin-3-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 257 (M+1); Rt=2.77 min.

Example 250

General Procedure (C)

5-(8-Hydroxyquinolin-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 273 (M+1); Rt=3.44 min.

Example 251

General Procedure (C)

5-Quinolin-8-ylmethylenethiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 257 (M+1); Rt=3.15 min.

Example 252

General Procedure (C)

5-(1-Bromo-6-methoxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 366 (M+1); Rt=4.44 min.

Example 253

General Procedure (C)

5-(6-Methyl-2-oxo-1,2-dihydroquinolin-3-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 287 (M+1); Rt.=2.89 min.

Example 254

General Procedure (D)

5-(2,6-Dichloro-4-dibenzylaminobenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 469 (M+1); Rt=5.35 min.

Example 255

General Procedure (C)

7-(2,4-Dioxothiazolidin-5-ylidenemethyl)-4-methoxybenzofuran-2-carboxyic acid

HPLC-MS (Method C): m/z: 320 (M+1); Rt=2.71 min.

Preparation of the Intermediate, 7-formyl-4-methoxybenzofuran-2-carboxylic acid

A mixture of 2-hydroxy-6-methoxybenzaldehyde (6.4 g, 42 mmol), ethyl bromoacetate (14.2 mL, 128 mmol) and potassium carbonate (26 g, 185 mmol) was heated to 130° C. After 3 h the mixture was cooled to room temperature and acetone (100 mL) was added, the mixture was subsequently filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 7.5 g (55%) of ethyl 4-methoxybenzofuran-2-carboxylate.

A solution of ethyl 4-methoxybenzofuran-2-carboxylate (6.9 g, 31.3 mmol) in dichloromethane (70 ml) was cooled to 0° C. and a solution of titanium tetrachloride (13.08 g, 69 mmol) was added drop wise. After 10 minutes dichloromethoxymethane (3.958 g, 34 mmol) was added over 10 minutes. After addition, the mixture was warmed to room temperature for 18 hours and the mixture poured into hydrochloric acid (2N, 100 mL). The mixture was stirred for 0.5 hour and then extracted with a mixture of ethyl acetate and toluene (1:1). The organic phase was dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 5.8 g (80%) of ethyl 7-formyl-4-methoxybenzofuran-2-carboxylate.

7-formyl4-methoxybenzofuran-2-carboxylate (5.0 g, 21.5 mmol) and sodium carbonate (43 mmol) in water (100 mL) was refluxed until a clear solution appeared (about 0.5 hour). The solution was filtered and acidified to pH=1 with hydrochloric acid (2 N), the resulting product was filtered off and washed with ethyl acetate and ethanol and dried to afford 3.5 g (74%) of 7-formyl-4-methoxybenzofuran-2-carboxylic acid as a solid.

¹H NMR (DMSO-d₆): δ=10.20 (s, 1H); 8.07 (d, 1H); 7.70 (s, 1H); 7.17 (d, 1H); 4.08 (s, 3H).

Example 256

General Procedure (C)

5-(4-Methoxybenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 267 (M+1); Rt=3.30 min.

Preparation of the Intermediate, 4-methoxybenzofuran-7-carbaldehyde

A mixture of 7-formyl-4-methoxybenzofuran-2-carboxylic acid (3.0 g, 13.6 mmol) and Cu (0.6 g, 9.44 mmol) in quinoline (6 mL) was refluxed. After 0.5 h the mixture was cooled to room temperature and water (100 mL) and hydrochloric acid (10 N, 20 mL) were added. The mixture was extracted with a mixture of ethyl acetate and toluene (1:1), filtered through celite and the organic layer separated and washed with a sodium carbonate solution, dried over Na₂SO₄ and concentrated in vacuo to afford 1.5 g crude product. Column chromatography SiO₂, EtOAc/heptanes=1/4 gave 1.1 g (46%) of 4-methoxybenzofuran-7-carbaldehyde as a solid.

¹H NMR (CDCl₃): δ: 10.30 (s, 1H); 7.85 (d, 1H); 7.75 (d, 1H); 6.98 (d, 1H); 6.87 (d, 1H); 4.10 (s,3H). HPLC-MS (Method C):m/z: 177 (M+1); Rt.=7.65 min.

Example 257

General Procedure (C)

5-(4-Hydroxybenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z:=262 (M+1); Rt 2.45 min.

Preparation of the Intermediate, 4-hydroxybenzofuran-7-carbaldehyde

A mixture of 4-methoxybenzofuran-7-carbaldehyde (1.6 g, 9.1 mmol) and pyridine hydrochloride (4.8 g, 41.7 mmol) in quinoline (8 mL) was refluxed. After 8 h the mixture was cooled to room temperature and poured into water (100 mL) and hydrochloric acid (2 N) was added to pH=2. The mixture was extracted with a mixture of ethyl acetate and toluene (1:1), washed with a sodium carbonate solution, dried with Na₂SO₄ and concentrated in vacuo to afford 0.8 g crude product. This was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and heptane (1:3). This afforded 250 mg of 4-hydroxybenzofuran-7-carbaldehyde as a solid.

¹H NMR (DMSO-d₆): δ=11.35 (s, broad, 1H); 10.15 (s, 1H); 8.05 (d, 1H); 7.75 (d, 1H); 7.10 (d, 1H); 6.83 (d, 1H). HPLC-MS (Method C): m/z: 163 (M+1); Rt.=6.36 min.

Example 258

General Procedure (C)

5-(5-Bromo-2,3-dihydrobenzofuran-7-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 328 (M+1); Rt=3.66 min.

Preparation of the Intermediate, 5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde

To a cooled (15° C.) stirred mixture dihydrobenzofuran (50.9 g, 0.424 mol) in acetic acid (500 mL), a solution of bromine (65.5 mL, 1.27 mol) in acetic acid (200 mL) was added drop wise over 1 hour. After stirring for 18 hours, a mixture of Na₂S₂O₅ (150 g) in water (250 mL) was added carefully, and the mixture was concentrated in vacuo. Water (200 mL) was added and the mixture was extracted with ethyl acetate containing 10% heptane, dried over Na₂SO₄ and concentrated in vacuo to give crude 5,7-dibromo-2,3-dihydrobenzofuran which was used as such for the following reaction steps. To a cooled solution (−78° C.) of crude 5,7-dibromo-2,3-dihydrobenzofuran (50.7 g, 0.182 mol) in THF (375 mL) a solution of n-BuLi (2.5 M, 80 mL, 0.200 mol) in hexane was added. After addition, the mixture was stirred for 20 min. DMF (16 mL) was then added drop wise at −78° C. After addition, the mixture was stirred at room temperature for 3 h and then the mixture was poured into a mixture of ice water, (500 mL) and hydrochloric acid (10 N, 40 mL) and extracted with toluene, dried over Na₂SO₄ and concentrated in vacuo. Column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:4) afforede 23 g of 5-bromo-2,3-dihydrobenzofuran-7-carbaldehyde as a solid.

¹H NMR (CDCl₃): δ 10.18 (s, 1H); 7.75 (d, 1H);7.55 (d, 1H); 4.80 (t,2H); 3.28 (t,2).

Example 259

General Procedure (C)

5-(4-Cyclohexylbenzylidene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z: 288 (M+1); Rt=5.03 min.

Preparation of the Intermediate, 4-cyclohexylbenzaldehyde

This compound was synthesized according to a modified literature procedure (J. Org. Chem., 37, No.24, (1972), 3972-3973).

Cyclohexylbenzene (112.5 g, 0.702 mol) and hexamethylenetetramine (99.3 g, 0.708 mol) were mixed in TFA (375 mL). The mixture was stirred under nitrogen at 90° C. for 3 days. After cooling to room temperature the red-brown mixture was poured into ice-water (3600 ml) and stirred for 1 hour. The solution was neutralized with Na₂CO₃ (2 M solution in water) and extracted with dichloromethane (2.5 L). The organic phase was dried (Na₂SO₄) and the solvent was removed in vacuo. The remaining red-brown oil was purified by fractional distillation to afford the title compound (51 g, 39%).

¹H NMR (CDCl₃): δ 9.96 (s, 1H), 7.80 (d, 2H), 7.35 (d, 2H), 2.58 (m, 1H), 1.94-1.70 (m, 5 H), 1.51-1.17 (m, 5H)

Other ligands of the invention include

• • 3′,5′-Dichloro-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-4-carboxylic acid:

Example 260

General Procedure (C)

5-(1-Bromo-6-hydroxynaphthalen-2-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=350 (M+1); Rt.=3.45 min.

Example 261

General Procedure (C)

5-[4-(2-Bromoethoxy)-naphthalen-1-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=380 (M+1); Rt=3.52 min.

Example 262

General Procedure (C)

5-(2-Methyl-5-nitro-1H-indol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=304 (M+1); Rt=2.95 min.

Example 263

General Procedure (C)

5-(4-Naphthalen-2-yl-thiazol-2-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=339 (M+1); Rt.=4.498 min.

Example 264

General Procedure (C)

5-[4-(4-Methoxy-naphthalen-1-yl)-thiazol-2-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=369 (M+1); Rt.=4.456 min.

Example 265

General Procedure (C)

5-(2-Pyridin-4-yl-1H-indol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=322 (M+1); Rt.=2.307 min.

Example 266

General Procedure (C)

5-[5-(4-Chlorophenyl)-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=306 (M+1); Rt.=3.60 min.

Example 267

General Procedure (C)

5-[5-(2,5-Dimethylphenyl)-1H-pyrazol-4-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=300 (M+1); Rt.=3.063 min.

Example 268

General Procedure (C)

5-(2-Phenyl-benzo[d]imidazo[2,1-b]thiazol-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=378 (M+1); Rt=3.90 min.

Example 269

General Procedure (C)

N-{4-[2-(2,4-Dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acetamide

HPLC-MS (Method C): m/z=355 (M+1); Rt 3.33 min.

Example 270

General Procedure (C)

5-(2-Phenyl-imidazo[1,2-a]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=322 (M+1); Rt.=2.78 min.

Example 271

General Procedure (C)

5-(2-Naphthalen-2-yl-imidazo[1,2-a]pyridin-3-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=372 (M+1); Rt.=2.78 min.

Example 272

General Procedure (C)

5-[6-Bromo-2-(3-methoxyphenyl)-imidazo[1,2-a]pyridin-3-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=431 (M+1); Rt.=3.30 min.

Example 273

General Procedure (C)

5-(1,2,3,4-Tetrahydrophenanthren-9-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=310 (M+1); Rt.=4.97 min.

Example 274

General Procedure (C)

5-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethylene)thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=330 (M+1); Rt.=5.33 min.

Example 275

General Procedure (C)

5-[6-(2,4-Dichloro-phenyl)-imidazo[2,1-b]thiazol-5-ylmethylene]-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=396 (M+1); Rt.=3.82 min.

Example 276

General Procedure (C)

5-(5-Bromobenzofuran-7-ylmethylene)-thiazolidine-2,4-dione

HPLC-MS (Method C): m/z=324 (M+1); Rt.=3.82 min.

Example 277

General Procedure (C)

4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)-1,4-dimethylcarbazol-9-ylmethyl]-benzoic acid

HPLC-MS (Method C): m/z=457 (M+1); Rt=4.23 min.

Preparation of Intermediary Aldehyde:

1,4 Dimethylcarbazol-3-carbaldehyde (0.68 g, 3.08 mmol) was dissolved in dry DMF (15 mL), NaH (diethyl ether washed) (0.162 g, 6.7 mol) was slowly added under nitrogen and the mixture was stirred for 1 hour at room temperature. 4-Bromomethylbenzoic acid (0.73 g, 3.4 mmol) was slowly added and the resulting slurry was heated to 40° C. for 16 hours. Water (5 mL) and hydrochloric acid (6N, 3 mL) were added. After stirring for 20 min at room temperature, the precipitate was filtered off and washed twice with acetone to afford after drying 0.38 g (34%) of 4-(3-formyl-1,4-dimethylcarbazol-9-ylmethyl)benzoic acid.

HPLC-MS (Method C): m/z=358 (M+1), RT.=4.15 min.

Example 278

General Procedure (C)

4-[7-(2,4-Dioxothiazolidin-5-ylidenemethyl)-benzofuran-5-yl]-benzoic acid

Starting aldehyde commercially available (Syncom BV, NL)

HPLC-MS (Method C): m/z=366 (M+1); Rt.=3.37 min.

Example 279

General procedure (C)

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-2-nitrophenoxy]-benzoic acid methyl ester

HPLC-MS (Method C): m/z=401 (M+1); Rt.=4.08 min.

Example 280

General Procedure (C)

3′,5′-Dichloro-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)-biphenyl-4-carboxylic acid

Starting aldehyde commercially available (Syncom BV, NL)

HPLC-MS (Method C): m/z=394 (M+1); Rt.=3.71 min.

Example 281

General Procedure (C)

HPLC-MS (Method C): m/z=232( M+1); Rt.=3.6 min.

Example 282

5-(2-Methyl-1H-indol-3-ylmethyl)-thiazolidine-2,4-dione

5-(2-Methyl-1H-indol-3-ylmethylene)thiazolidine-2,4-dione (prepared as described in example 187,1.5 g, 5.8 mmol) was dissolved in pyridine (20 mL) and THF (50 mL), LiBH₄ (2 M in THF, 23.2 mmol) was slowly added with a syringe under cooling on ice. The mixture was heated to 85° C. for 2 days. After cooling, the mixture was acidified with concentrated hydrochloric acid to pH 1. The aquous layer was extracted 3 times with ethyl acetate, dried with MgSO₄ treated with activated carbon, filtered and the resulting filtrate was evaporated in vacuo to give 1.3 g (88%) of the title compound.

HPLC-MS (Method C): m/z=261 (M+1); Rt.=3.00 min.

Example 283

4-[4-(2,4-Dioxothiazolidin-5-ylmethyl)naphthalen-1-yloxy]butyric acid

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid (4.98 g, 13.9 mmol, prepared as described in example 469) was dissolved in dry THF (50 mL) and added dry pyridine (50 mL) and, in portions, lithium borohydride (2.0 M, in THF, 14 mL). The resulting slurry was refluxed under nitrogen for 16 hours, added (after cooling) more lithium borohydride (2.0 M, in THF, 7 mL). The resulting mixture was refluxed under nitrogen for 16 hours. The mixture was cooled and added more lithium borohydride (2.0 M, in THF, 5 mL). The resulting mixture was refluxed under nitrogen for 16 hours. After cooling to 5° C., the mixture was added water (300 mL) and hydrochloric acid (150 mL). The solid was isolated by filtration, washed with water (3×500 mL) and dried. Recrystallization from acetonitrile (500 mL) afforded2.5 g of the title compound.

¹H-NMR (DMSO-d₆, selected peaks): δ=3.42 (1H, dd), 3.90 (1H, dd), 4.16 (2H, “t”), 4.95 (1H, dd), 6.92 (1H, d), 7.31 (1H, d), 7.54 (1H, t), 7.62 (1H, t), 8.02 (1H, d), 8.23 (1H, d), 12.1 (1H, bs), 12.2 (1H, bs).

HPLC-MS (Method C): m/z=382 (M+23); Rt=3.23 min.

Example 284

5-Naphthalen-1-ylmethylthiazolidine-2,4-dione

5-Naphthalen-1-ylmethylenethiazolidine-2,4-dione (1.08 g, 4.2 mmol, prepared as described in example 68) was dissolved in dry THF (15 mL) and added dry pyridine (15 mL) and, in portions, lithium borohydride (2.0 M, in THF, 4.6 mL). The resulting mixture was refluxed under nitrogen for 16 hours. After cooling to 5° C., the mixture was added water (100 mL), and, in portions, concentrated hydrochloric acid (40 mL). More water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with water (3×100 mL), dried and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) added activated carbon, filtered and concentrated in vacuo and dried to afford 0.82 g (75%) of the title compound.

¹H-NMR (DMSO-d₆): δ=3.54 (1H, dd), 3.98 (1H, dd), 5.00 (1H, dd), 7.4-7.6 (4H, m), 7.87 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 12.2 (1H, bs). HPLC-MS (Method C): m/z=258 (M+1); Rt=3.638 min.

The following preferred compounds of the invention may be prepared according to procedures similar to those described in the three examples above:

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The following compounds are commercially available and may be prepared using general procedures (B) and/or (C).

Example 380

5-(5-Bromo-1H-indol-3-ylmethylene)thiazolidine-2,4-dione

Example 381

5-Pyridin4-ylmethylenethiazolidine-2,4-dione

Example 382

5-(3-Bromo-4-methoxybenzylidene)thiazolidine-2,4-dione

Example 383

5-(3-Nitrobenzylidene)thiazolidine-2,4-dione

Example 384

5-Cyclohexylidene-1,3-thiazolidine-2,4-dione

Example 385

5-(3,4-Dihydroxybenzylidene)thiazolidine-2,4-dione

Example 386

5-(3-Ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 387

5-(4-Hydroxy-3-methoxy-5-nitrobenzylidene)thiazolidine-2,4-dione

Example 388

5-(3-Ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 389

5-(4-Hydroxy-3,5-dimethoxybenzylidene)thiazolidine-2,4-dione

Example 390

5-(3-Bromo-5-ethoxy-4-hydroxybenzylidene)thiazolidine-2,4-dione

Example 391

5-(3-Ethoxy-4-hydroxy-5-nitrobenzylidene)thiazolidine-2,4-dione

Example 392

Example 393

Example 394

Example 395

Example 396

Example 397

Example 398

Example 399

Example 400

Example 401

Example 402

Example 403

Example 404

Example 405

5-(3-Hydroxy-5-methyl-phenylamino)-thiazolidine-2,4-dione

Example 406

Example 407

Example 408

Example 409

Example 410

Example 411

Example 412

Example 413

Example 414

Example 415

Example 416

Example 417

Example 418

Example 419

Example 420

Example 421

Example 422

Example 423

Example 424

Example 425

Example 426

Example 427

Example 428

Example 429

Example 430

Example 431

5-(4-Diethylamino-2-methoxy-benzylidene)-imidazolidine-2,4-dione

Example 432

Example 433

Example 434

Example 435

Example 436

Example 437

Example 438

Example 439

Example 440

Example 441

Example 442

Example 443

Example 444

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Example 446

Example 447

Example 448

Example 449

Example 450

Example 451

Example 452

Example 453

Example 454

5-(4-Diethylamino-benzylidene)-2-imino-thiazolidin-4-one

Example 455

Example 456

Example 457

Example 458

Example 459

General Procedure (D) for Preparation of Compounds of General Formula wherein X, Y, and R³ are as defined above,

• • n is 1 or 3-20,
  • E is arylene or heterarylene (including up to four optional substituents, R¹³, R¹⁴, R¹⁵, and R^15A as defined above),
  • R′ is a standard carboxylic acid protecting group, such as C₁-C₆-alkyl or benzyl and Lea is a leaving group, such as chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy or the like.

Step 1 is an alkylation of a phenol moiety. The reaction is preformed by reacting R¹⁰—C(═O)-E-OH with an ω-bromo-alkane-carboxylic acid ester (or a synthetic equivalent) in the presence of a base such as sodium or potassium carbonate, sodium or potassium hydroxide, sodium hydride, sodium or potassium alkoxide in a solvent, such as DMF, NMP, DMSO, acetone, acetonitrile, ethyl acetate or isopropyl acetate. The reaction is performed at 20-160° C., usually at room temperature, but when the phenol moiety has one or more substituents heating to 50° C. or more can be beneficial, especially when the substituents are in the ortho position relatively to the phenol. This will readily be recognised by those skilled in the art.

Step 2 is a hydrolysis of the product from step 1.

Step 3 is similar to general procedure (B) and (C).

This general procedure (D) is further illustrated in the following examples:

Example 460

General Procedure (D)

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

Step 1:

A mixture of 4-hydroxybenzaldehyde (9.21 g, 75 mmol), potassium carbonate (56 g, 410 mmol) and 4-bromobutyric acid ethyl ester (12.9 mL, 90 mmol) in N,N-dimethylformamide (250 mL) was stirred vigorously for 16 hours at room temperature. The mixture was filtered and concentrated in vacuo to afford 19.6 g (100%) of 4-(4-formylphenoxy)butyric acid ethyl ester as an oil. ¹H-NMR (DMSO-d₆): δ 1.21 (3H, t), 2.05 (2H, p), 2.49 (2H, t), 4.12 (4H, m), 7.13 (2H, d), 7.87 (2H, d), 9.90 (1H, s). HPLC-MS (Method A): m/z=237 (M+1); R_t=3.46 min.

Step 2:

4-(4-Formylphenoxy)butyric acid ethyl ester (19.6 g, 75 mmol) was dissolved in methanol (250 mL) and 1 N sodium hydroxide (100 mL) was added and the resulting mixture was stirred at room temperature for 16 hours. The organic solvent was evaporated in vacuo (40° C., 120 mBar) and the residue was acidified with 1N hydrochloric acid (110 mL). The mixture was filtered and washed with water and dried in vacuo to afford 14.3 g (91%) 4-(4-formylphenoxy)butyric acid as a solid. ¹H-NMR (DMSO-d₆): δ 1.99 (2H, p), 2.42 (2H, t), 4.13 (2H, t), 7.14 (2H, d), 7.88 (2H, d), 9.90 (1H, s), 12.2 (1H, bs). HPLC-MS (Method A): m/z=209 (M+1); R_t=2.19 min.

Step 3:

Thiazolidine-2,4-dione (3.55 g, 27.6 mmol), 4-(4-formylphenoxy)butyric acid (5.74 g, 27.6 mmol), anhydrous sodium acetate (11.3 g, 138 mmol) and acetic acid (100 mL) was refluxed for 16 h. After cooling, the mixture was filtered and washed with acetic acid and water. Drying in vacuo afforded 2.74 g (32%) of 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid as a solid.

¹H-NMR (DMSO-d₆): δ 1.97 (2H, p), 2.40 (2H, t), 4.07 (2H, t), 7.08 (2H, d), 7.56 (2H, d), 7.77 (1H, s), 12.2 (1H, bs), 12.5 (1H, bs); HPLC-MS (Method A): m/z: 308 (M+1); Rt=2.89 min.

Example 461

General Procedure (D)

[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

Step 3:

Thiazolidine-2,4-dione (3.9 g, 33 mmol), 3-formylphenoxyacetic acid (6.0 g, 33 mmol), anhydrous sodium acetate (13.6 g, 165 mmol) and acetic acid (100 mL) was refluxed for 16 h. After cooling, the mixture was filtered and washed with acetic acid and water. Drying in vacuo afforded 5.13 9 (56%) of [3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid as a solid.

¹H-NMR (DMSO-d₆): δ 4.69 (2H, s), 6.95 (1H, dd), 7.09 (1H, t), 7.15 (1H, d), 7.39 (1H, t),7.53 (1H, s); HPLC-MS (Method A): m/z=280 (M+1) (poor ionisation); R_t=2.49 min.

The compounds in the following examples were similarly prepared.

Example 462

General Procedure (D)

3-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenyl]acrylic acid

¹H-NMR (DMSO-d₆): δ6.63 (1H, d), 7.59-7.64 (3H, m), 7.77 (1H, s), 7.83 (2H, m).

Example 463

General Procedure (D)

[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

Triethylamine salt: ¹H-NMR (DMSO-d₆): δ 4.27 (2H, s), 6.90 (2H, d), 7.26 (1H, s), 7.40 (2H, d).

Example 464

General Procedure (D)

4-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzoic acid

Example 465

General Procedure (D)

3-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzoic acid

¹H-NMR (DMSO-d₆): δ 7.57 (1H, s), 7.60 (1H, t), 7.79 (1H, dt), 7.92 (1H, dt), 8.14 (1H, t).

Example 466

General Procedure (D)

4-[2-Chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 2.00 (2H, p), 2.45 (2H, t), 4.17 (2H, t), 7.31 (1H, d), 7.54 (1H, dd), 7.69 (1H, d), 7.74 (1H, s), 12.2 (1H, bs), 12.6 (1H, bs). HPLC-MS (Method A): m/z: 364 (M+23); Rt=3.19 min.

Example 467

General Procedure (D)

4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 1.99 (2H, p), 2.46 (2H, t), 4.17 (2H, t), 7.28 (1H, d), 7.57 (1H, dd), 7.25 (1H, s), 7.85 (1H, d), 12.2 (1H, bs), 12.6 (1H, bs). HPLC-MS (Method A): m/z: 410 (M+23); Rt=3.35 min.

Example 468

General Procedure (D)

4-[2-Bromo-4-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 1.99 (2H, p), 2.45 (2H, t), 4.18 (2H, t), 7.28 (1H, d), 7.55 (1H, dd), 7.60 (1H, s), 7.86 (1H, d), 12.2 (1H, bs), 13.8 (1H, bs). HPLC-MS (Method A): m/z: 424 (M+23); Rt=3.84 min. HPLC-MS (Method A): m/z: 424 (M+23); Rt=3,84 min

Example 469

General Procedure (D)

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid

¹H-NMR (DMSO-d₆): δ 2.12 (2H, p), 2.5 (below DMSO), 4.28 (2H, t), 7.12 (1H, d), 7.6-7.7 (3H, m), 8.12 (1H, d), 8.31 (1H, d), 8.39 (1H, s), 12.2 (1H, bs), 12.6 (1H, bs). HPLC-MS (Method A): m/z: 380 (M+23); Rt=3.76 min.

Example 470

General Procedure (D)

5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentanoic acid

HPLC-MS (Method A): m/z: 394 (M+23); Rt=3.62 min. ¹H-NMR (DMSO-d₆): δ 1.78 (2H, m), 1.90 (2H, m), 2.38 (2H, t), 4.27 (2H, t), 7.16 (1H, d), 7.6-7.75 (3H, m), 8.13 (1H, d), 8.28 (1H, d), 8.39 (1H, s), 12.1 (1H, bs), 12.6 (1H, bs).

Example 471

5-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentanoic acid

5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]pentanoic acid (example 470, 185 mg, 0.5 mmol) was treated with an equimolar amount of bromine in acetic acid (10 mL). Stirring at RT for 14 days followed by evaporation to dryness afforded a mixture of the brominated compound and unchanged starting material. Purification by preparative HPLC on a C18 column using acetonitrile and water as eluent afforded 8 mg of the title compound.

HPLC-MS (Method C): m/z: 473 (M+23), Rt.=3.77 min

Example 472

4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid

Starting with 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyric acid (example 469, 0.5 mmol) using the same method as in example 471 afforded 66 mg of the title compound.

HPLC-MS (Method C): m/z: 459 (M+23); Rt.=3.59 min.

Example 473

General Procedure (D)

[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid

¹H-NMR (DMSO-d₆): δ 4.90 (2H, s), 7.12 (1H, d), 7.52 (1H, dd), 7.65 (1H, s) 7.84 (1H, d).HPLC-MS (Method A): m/z: not observed; Rt=2.89 min.

Example 474

General Procedure (D)

4-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid

¹H-NMR (DMSO-d₆): δ 1.98 (2H, p), 2.42 (2H, t), 4.04 (2H, t), 7.05 (1H, dd), 7.15 (2H, m), 7.45 (1H, t), 7.77 (1H, s), 12.1 (1H, bs), 12.6 (1H, bs). HPLC-MS (Method A): m/z: 330 (M+23); Rt=3.05 min.

Example 475

General Procedure (D)

[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-3-methoxyphenoxy]acetic acid

HPLC-MS (Method B): m/z: 310 (M+1); Rt=3.43 min.

Example 476

General Procedure (D)

[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]acetic acid

HPLC-MS (Method A): m/z: 330 (M+1); Rt=3.25 min.

Example 477

General Procedure (D)

8-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalene-1-carboxylic acid

HPLC-MS (Method A): m/z: 299 (M+1); Rt=2.49 min.

Example 478

General Procedure (D)

[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid

HPLC-MS (Method A): m/z: 303 (M+1); Rt=2.90 min.

Preparation of Starting Material:

3-Formylindol (10 g, 69 mmol) was dissolved in N,N-dimethylformamide (100 mL) and under an atmosphere of nitrogenand with external cooling, keeping the temperature below 15° C., sodium hydride (60% in mineral oil, 3.0 g, 76 mmol) was added in portions. Then a solution of ethyl bromoacetate (8.4 mL, 76 mmol) in N,N-dimethylformamide (15 mL) was added dropwise over 30 minutes and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between water (300 mL) and ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride (100 mL), dried (MgSO₄) and concentrated in vacuo to afford 15.9 g (quant.) of (3-formylindol-1-yl)acetic acid ethyl ester as an oil.

¹H-NMR (CDCl₃): δ_H=1.30 (3H, t), 4.23 (2H, q), 4.90 (2H, s), 7.3 (3H, m), 7.77 (1H, s), 8.32 (1H, d), 10.0 (1H, s).

(3-Formylindol-1-yl)acetic acid ethyl ester (15.9 g 69 mmol) was dissolved in 1,4-dioxane (100 mL) and 1N sodium hydroxide (10 mL) was added and the resulting mixture was stirred at room temperature for 4 days. Water (500 mL) was added and the mixture was washed with diethyl ether (150 mL). The aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (250+150 mL). The combined organic extracts were dried (MgSO₄) and concentrated in vacuo to afford 10.3 g (73%) of (3-formylindol-1-yl)acetic acid as a solid.

¹H-NMR (DMSO-d₆): δ_H=5.20 (2H, s), 7.3 (2H, m), 7.55 (1H, d), 8.12 (1H, d), 8.30 (1H, s), 9.95 (1H, s), 13.3 (1H, bs).

Example 479

General Procedure (D)

3-[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]propionic acid

HPLC-MS (Method A): m/z: 317 (M+1); Rt=3.08 min.

Preparation of Starting Material:

A mixture of 3-formylindol (10 g, 69 mmol), ethyl 3-bromopropionate (10.5 mL, 83 mmol) and potassium carbonate (28.5 g, 207 mmol) and acetonitrile (100 mL) was stirred vigorously at refux temperature for 2 days. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo to afford 17.5 g (quant.) of 3-(3-formylindol-1-yl)propionic acid ethyl ester as a solid.

¹H-NMR (DMSO-d₆): δ_H=1.10 (3H, t), 2.94 (2H, t), 4.02 (2H, q), 4.55 (2H, t), 7.3 (2H, m), 7.67 (1H, d), 8.12 (1H, d), 8.30 (1H, s), 9.90 (1H, s).

3-(3-Formylindol-1-yl)propionic acid ethyl ester (17.5 g 69 mmol) was hydrolysed as described above to afford 12.5 g (83%) of 3-(3-formylindol-1-yl)propionic acid as a solid.

¹H-NMR (DMSO-d₆): δ_H=2.87 (2H, t), 4.50 (2H, t), 7.3 (2H, m), 7.68 (1H, d), 8.12 (1H, d), 8.31 (1H, s), 9.95 (1H, s), 12.5 (1H, bs).

Example 480

General Procedure (D)

{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)benzylidenel-4-oxo-2-thioxothiazolidin-3-yl}acetic acid

HPLC-MS (Method A): m/z: 429 (M+23); Rt=3.89 min.

Example 481

General Procedure (D)

6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxyoctanoic acid

HPLC-MS (Method C): m/z: 436 (M+23); Rt.=4.36 min

The intermediate aldehyde for this compound was prepared by a slightly modified procedure: 6-Hydroxynaphthalene-2-carbaldehyde (1.0 g, 5.8 mmol) was dissolved in DMF (10 mL) and sodium hydride 60% (278 mg) was added and the mixture stirred at RT for 15 min. 8-Bromooctanoic acid (0.37 g, 1.7 mmol) was converted to the sodium salt by addition of sodium hydride 60% and added to an aliquot (2.5 mL) of the above naphtholate solution and the resulting mixture was stirred at RT for 16 hours. Aqueous acetic acid (10%) was added and the mixture was extracted 3 times with diethyl ether. The combined organic phases were dried with MgSO₄ and evaporated to dryness affording 300 mg of 8-(6-formylnaphthalen-2-yloxy)octanoic acid.

HPLC-MS (Method C): m/z 315 (M+1); Rt.=4.24 min.

Example 482

General Procedure (D)

12-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]dodecanoic acid

HPLC-MS (Method C): m/z: 492 (M+23); Rt.=5.3 min.

The intermediate aldehyde was prepared similarly as described in example 481.

Example 483

General Procedure (D)

11-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]undecanoic acid

HPLC-MS (Method C): m/z:478 (M+23); Rt.=5.17 min.

The intermediate aldehyde was prepared similarly as described in example 481.

Example 484

General Procedure (D)

15-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]pentadecanoic acid

HPLC-MS (Method C): m/z: 534 (M+23); Rt.=6.07 min.

The intermediate aldehyde was prepared similarly as described in example 481.

Example 485

General Procedure (D)

6-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]hexanoic acid

HPLC-MS (Method C): m/z: 408 (M+23); Rt.=3.71 min.

Example 486

General Procedure (D)

4-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]butyric acid

HPLC-MS (Method C): m/z: 380 (M+23); Rt.=3.23 min.

Example 487

General Procedure (D)

6-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]hexanoic acid ethyl ester

HPLC-MS (Method C): m/z: 436 (M+23); Rt.=4.64 min.

Example 488

General Procedure (D)

4-[6-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-2-yloxy]butyric acid ethyl ester

HPLC-MS (Method C): m/z: 408 (M+23); Rt.=4.28 min.

Example 489

General Procedure (D)

2-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonic acid

HPLC-MS (Method C): m/z=444 (M+1); Rt=3.84 min.

Example 490

General Procedure (D)

2-{5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonic acid diethyl ester

HPLC-MS (Method C): m/z=500 (M+1); Rt=5.18 min.

Example 491

General Procedure (D)

4-[4-(2,4,6-Trioxotetrahydropyrimidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid

HPLC-MS (Method C): m/z=369 (M+1); Rt=2.68 min.

Example 492

N-(3-Aminopropyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyramide

To a mixture of 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyric acid (example 469, 5.9 g, 16.5 mmol) and 1-hydroxybenzotriazole (3.35 g, 24.8 mmol) in DMF (60 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.75 g, 24.8 mmol) and the resulting mixture was stirred at room temperature for 2 hours. N-(3-amino-propylcarbamic acid tert-butyl ester (3.45 g, 19.8 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and ethyl acetate and dichloromethane were added to the residue. The mixture was filtered, washed with water and dried in vacuo to afford 4.98 g (59%) of (3-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylamino}propyl)carbamic acid tert-butyl ester.

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.79 min.

(3-{4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylamino}-propyl)carbamic acid tert-butyl ester (4.9 g, 9.5 mmol) was added dichloromethane (50 mL) and trifluoroacetic acid (50 mL) and the resulting mixture was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo and co-evaporated with toluene. To the residue was added ethyl acetate (100 mL) and the mixture was filtered and dried in vacuo to afford the title compound as the trifluoroacetic acid salt.

HPLC-MS (Method C): m/z: 414 (M+1); Rt=2.27 min.

Compounds of the Invention Includes:

Example 493
Example 494
Example 495
Example 496
Example 497
Example 498
Example 499
Example 500
Example 501
Example 502
Example 503

Example 504

Prepared Analogously to General Procedure (D)

2-{5-[4-(2,4-Thiazolidindion-5-ylidenemethyl)naphthalen-1-yloxy]pentyl}malonic acid

A solution of 4-hydroxy-1-naphtaldehyde (1.0 g, 5.81 mmol), 2-(5-bromopentyl)malonic acid diethyl ester (2.07 g, 6.68 mmol) and potassium carbonate (4.01 g, 29 mmol) in DMF (50 mL) was stirred at 100° C. for 3 hours. The mixture was cooled and the salt was filtered off. The solvent was then removed under reduced pressure to afford 2.9 g of crude 2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonic acid diethyl ester which was used for the next reaction without further purification.

HPLC-MS (Method C): m/z: 401 (M+1); Rt=5.16 min. ¹H-NMR (DMSO-d6): δ=1.18 (t, 6 H), 1.39 (m, 2 H), 1.55 (m, 2 H), 1.87 (m, 4 H), 3.48 (t, 1 H), 4.13 (m, 4 H), 4.27 (t, 2 H), 7.17 (d, 1 H), 7.64(t, 1 H), 7.75 (t, 1 H), 8.13 (d, 1 H), 8.29 (d, 1 H), 9.24 (d, 1 H), 10.19 (s, 1 H).

1.4 g (3.5 mmol) of crude 2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonic acid diethyl ester was treated with aqueous sodium hydroxide (1N, 8.75 mL, 8.75 mmol) and methanol (50 mL). The solution was stirred at 70° C. for 5 hours and the mixture was concentrated under reduced pressure. Hydrochloric acid (6 N) was added until pH<2. The resulting slurry was stirred untill it solidified. The crystals were filtered off, washed with water and then dried in vacuo to afford 1.1 g (92%) of 2-[5-(4-formylnaphtalen-1-yloxy)pentyl]malonic acid. The product was used in the next step without further purification.

HPLC-MS (Method C): m/z: 345 (M+1); Rt=3.52 min. ¹H-NMR(DMSO-d6): δ=1.40 (m, 2 H), 1.55 (m, 2 H), 1.80 (m, 2 H), 1.90 (m, 2 H), 3.24 (t, 1 H), 4.29 (t, 2 H), 7.19 (d, 1 H), 7.64(t, 1 H), 7.75 (t, 1 H), 8.14 (d, 1 H), 8.30 (d, 1 H), 9.23 (d, 1 H), 10.18 (s, 1 H), 12.69 (s, 2 H).

To a solution of 2-[5-(4-formylnaphtalen-1-yloxy) pentyl]malonic acid (0.36 g, 1.05 mmol) in acetic acid (10 mL) was added 2,4-thiazolidindione (0.16 g,1.36 mmol) and piperidine (0.52 mL, 5.25 mmol). The solution was heated to 105° C. for 24 hours. After cooling to room temperature, the solvents were removed in vacuo. Water was added to the residue. The precipitate was filtered off and washed with water. Recrystalisation from acetonitrile afforded 200 mg (43%) of the title compound as a solid.

HPLC-MS (Method C): m/z: 422 (M-CO₂+Na); Rt=4.08 min. ¹H-NMR(DMSO-d₆): δ=1.41 (m, 2 H), 1.55 (m, 4 H), 1.88 (m, 2 H), 2.23 (t, 1 H), 4.24 (t, 2 H), 7.61-7.74 (m, 3 H), 8.12 (d, 1 H), 8.28 (d, 1 H), 8.38 (s, 1 H), 12.00 (s, 1 H), 12.59 (s, 2 H).

The following compounds are commercially available and may be prepared according to general procedure (D):

Example 505

Example 506

Example 507

Example 508

Example 509

Example 510

Example 511

The following salicylic acid derivatives do all bind to the His B10 Zn²⁺ site of the insulin hexamer:

Example 512

Salicylic acid

Example 513

Thiosalicylic acid (or: 2-Mercaptobenzoic acid)

Example 514

2-Hydroxy-5-nitrobenzoic acid

Example 515

3-Nitrosalicyclic acid

Example 516

5,5′-Methylenedisalicylic acid

Example 517

2-Amino-5-trifluoromethylbenzoesyre

Example 518

2-Amino4-chlorobenzoic acid

Example 519

2-Amino-5-methoxybenzoesyre

Example 520

Example 521

Example 522

Example 523

Example 524

Example 525

Example 526

5-Iodosalicylic acid

Example 527

5-Chlorosalicylic acid

Example 528

1-Hydroxy-2-naphthoic acid

Example 529

3,5-Dihydroxy-2-naphthoic acid

Example 530

3-Hydroxy-2-naphthoic acid

Example 531

3,7-Dihydroxy-2-naphthoic acid

Example 532

2-Hydroxybenzo[a]carbazole-3-carboxylic acid

Example 533

7-Bromo-3-hydroxy-2-naphthoic acid

This compound was prepared according to Murphy et al., J. Med. Chem. 1990, 33, 171-8.

HPLC-MS (Method A): m/z: 267 (M+1); Rt:=3.78 min.

Example 534

1,6-Dibromo-2-hydroxynaphthalene-3-carboxylic acid

This compound was prepared according to Murphy et al., J. Med. Chem. 1990, 33, 171-8.

HPLC-MS (Method A): m/z: 346 (M+1); Rt:=4.19 min.

Example 535

7-Formyl-3-hydroxynaphthalene-2-carboxylic Acid

A solution of 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (15.0 g, 56.2 mmol) (example 533) in tetrahydrofuran (100 mL) was added to a solution of lithium hydride (893 mg, 112 20 mmol) in tetrahydrofuran (350 mL). After 30 minutes stirring at room temperature, the resulting solution was heated to 50° C. for 2 minutes and then allowed to cool to ambient temperature over a period of 30 minutes. The mixture was cooled to −78° C., and butyllithium (1.6 M in hexanes, 53 mL, 85 mmol) was added over a period of 15 minutes. N,N-Dimethylformamide (8.7 mL, 8.2 g, 112 mmol) was added after 90 minutes additional stirring. The cooling was discontinued, and the reaction mixture was stirred at room temperature for 17 hours before it was poured into 1 N hydrochloric acid (aq.) (750 mL). The organic solvents were evaporated in vacuo, and the resulting precipitate was filtered off and rinsed with water (3×100 mL) to yield the crude product (16.2 g). Purification on silica gel (dichloromethane/methanol/acetic acid=90:9:1) furnished the title compound as a solid.

¹H-NMR (DMSO-d6): δ 11.95 (1H, bs), 10.02 (1H, s), 8.61 (1H, s), 8.54 (1H, s), 7.80 (2H, bs), 7.24 (1H, s); HPLC-MS (Method (A)): m/z: 217 (M+1); Rt=2.49 min.

Example 536

3-Hydroxy-7-methoxy-2-naphthoic acid

Example 537

4-Amino-2-hydroxybenzoic acid

Example 538

5-Acetylamino-2-hydroxybenzoic acid

Example 539

2-Hydroxy-5-methoxybenzoic acid

The following compounds were prepared as described below:

Example 540

4-Bromo-3-hydroxynaphthalene-2-carboxylic acid

3-Hydroxynaphthalene-2-carboxylic acid (3.0 g, 15.9 mmol) was suspended in acetic acid (40 mL) and with vigorous stirring a solution of bromine (817 μL, 15.9 mmol) in acetic acid (10 mL) was added drop wise during 30 minutes. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying in vacuo afforded 3.74 g (88%) of 4-bromo-3-hydroxynaphthalene-2-carboxylic acid as a solid.

¹H-NMR (DMSO-d₆): δ 7.49 (1H, t), 7.75 (1H, t), 8.07 (2H, “t”), 8.64 (1H, s). The substitution pattern was confirmed by a COSY experiment, showing connectivities between the 3 (4 hydrogen) “triplets”. HPLC-MS (Method A): m/z: 267 (M+1); Rt=3.73 min.

Example 541

3-Hydroxy-4-iodonaphthalene-2-carboxylic acid

3-Hydroxynaphthalene-2-carboxylic acid (0.5 g, 2.7 mmol) was suspended in acetic acid (5 mL) and with stirring iodine monochloride (135 μL, 2.7 mmol) was added. The suspension was stirred at room temperature for 1 hour, filtered and washed with water. Drying afforded 0.72 g (85%) of 4-iodo-3-hydroxynaphthalene-2-carboxylic acid as a solid.

¹H-NMR (DMSO-d₆): δ 7.47 (1H, t), 7.73 (1H, t), 7.98 (1H, d), 8.05 (1H, d), 8.66 (1H, s). HPLC-MS (Method A): m/z: 315 (M+1); Rt=3.94 min.

Example 542

2-Hydroxy-5-[(4-methoxyphenylamino)methyl]benzoic acid

p-Anisidine (1.3 g, 10.6 mmol) was dissolved in methanol (20 mL) and 5-formylsalicylic acid (1.75 g, 10.6 mmol)was added and the resulting mixture was stirred at room temperature for 16 hours. The solid formed was isolated by filtration, re-dissolved in N-methyl pyrrolidone (20 mL) and methanol (2 mL). To the mixture was added sodium cyanoborohydride (1.2 g) and the mixture was heated to 70° C. for 3 hours. To the cooled mixture was added ethyl acetate (100 mL) and the mixture was extracted with water (100 mL) and saturated aqueous ammonium chloride (100 mL). The combined aqueous phases were concentrated in vacuo and a 2 g aliquot was purified by SepPac chromatography eluting with mixtures of aetonitrile and water containing 0.1% trifluoroacetic acid to afford the title compound.

HPLC-MS (Method A): m/z: 274 (M+1); Rt=1.77 min. ¹H-NMR (methanol-d₄): δ 3.82 (3H, s), 4.45 (2H, s), 6.96 (1H, d), 7.03 (2H, d), 7.23 (2H, d), 7.45 (1 H, dd), 7.92 (1 H, d).

Example 543

2-Hydroxy-5-(4-methoxyphenylsulfamoyl)benzoic acid

A solution of 5-chlrosulfonylsalicylic acid (0.96 g, 4.1 mmol) in dichloromethane (20 mL) and triethylamine (1.69 mL, 12.2 mmol) was added p-anisidine (0.49 g, 4.1 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was added dichloromethane (50 mL) and was washed with water (2×100 mL). Drying (MgSO₄) of the organic phase and concentration in vacuo afforded 0.57 g crude product. Purification by column chromatography on silica gel eluting first with ethyl acetate:heptane (1:1) then with methanol afforded 0.1 g of the title compound.

HPLC-MS (Method A): m/z: 346 (M+23); Rt=2.89 min. ¹H-NMR (DMSO-d₆): δ 3.67 (3H, s), 6.62 (1H, d), 6.77 (2H, d), 6.96 (2H, d), 7.40 (1H, dd), 8.05 (1H, d), 9.6 (1H, bs). General Procedure (E) for Preparation of Compounds of General Formula I₄: wherein Lea is a leaving group such as Cl, Br, I or OSO₂CF₃, R is hydrogen or C₁-C₆-alkyl, optionally the two R-groups may together form a 5-8 membered ring, a cyclic boronic acid ester, and J is as defined above.

An analogous chemical transformation has previously been described in the literature (Bumagin et al., Tetrahedron, 1997, 53, 14437-14450). The reaction is generally known as the Suzuki coupling reaction and is generally performed by reacting an aryl halide or triflate with an arylboronic acid or a heteroarylboronic acid in the presence of a palladium catalyst and a base such as sodium acetate, sodium carbonate or sodium hydroxide. The solvent can be water, acetone, DMF, NMP, HMPA, methanol, ethanol toluene or a mixture of two or more of these solvents. The reaction is performed at room temperature or at elevated temperature. The general procedure (E) is further illustrated in the following example:

Example 544

General Procedure (E)

7-(4-Acetylphenyl)-3-hydroxynaphthalene-2-carboxylic Acid

To 7-bromo-3-hydroxynaphthalene-2-carboxylic acid (100 mg, 0.37 mmol) (example 533) was added a solution of 4-acetylphenylboronic acid (92 mg, 0.56 mmol) in acetone (2.2 mL) followed by a solution of sodium carbonate (198 mg, 1.87 mmol) in water (3.3 mL). A suspension of palladium(II) acetate (4 mg, 0.02 mmol) in acetone (0.5 mL) was filtered and added to the above solution. The mixture was purged with N₂ and stirred vigorously for 24 hours at room temperature. The reaction mixture was poured into 1 N hydrochloric acid (aq.) (60 mL) and the precipitate was filtered off and rinsed with water (3×40 mL). The crude product was dissolved in acetone (25 mL) and dried with magnesium sulfate (1 h). Filtration followed by concentration furnished the title compound as a solid (92 mg).

¹H-NMR (DMSO-d₆): δ 12.60 (1H, bs), 8.64 (1H, s), 8.42 (1H, s), 8.08 (2H, d), 7.97 (2H, d), 7.92 (2H, m), 7.33 (1H, s), 2.63 (3H, s); HPLC-MS (Method (A): m/z: 307 (M+1); Rt=3.84 min.

The compounds in the following examples were prepared in a similar fashion. Optionally, the compounds can be further purified by recrystallization from e.g. ethanol or by chromatography.

Example 545

General Procedure (E)

3-Hydroxy-7-(3-methoxyphenyl)naphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 295 (M+1); Rt=4.60 min.

Example 546

General Procedure (E)

3-Hydroxy-7-phenylnaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 265 (M+1); Rt=4.6 min.

Example 547

General Procedure (E)

3-Hydroxy-7-p-tolylnaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 279 (M+1); Rt=4.95 min.

Example 548

General Procedure (E)

7-(4-Formylphenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 293 (M+1); Rt=4.4 min.

Example 549

General Procedure (E)

6-Hydroxy-[1,2]binaphthalenyl-7-carboxylic acid

HPLC-MS (Method (A)): m/z: 315 (M+1); Rt=5.17 min.

Example 550

General Procedure (E)

7-(4-Carboxy-phenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=3.60 min.

Example 551

General Procedure (E)

7-Benzofuran-2-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 305 (M+1); Rt=4.97 min.

Example 552

General Procedure (E)

3-Hydroxy-7-(4-methoxyphenyl)-naphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 295 (M+1); Rt=4.68 min.

Example 553

General Procedure (E)

7-(3-Ethoxyphenyl)-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=4.89 min.

Example 554

General Procedure (E)

7-Benzo[1,3]dioxol-5-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 309 (M+1); Rt=5.61 min.

Example 555

General Procedure (E)

7-Biphenyl-3-yl-3-hydroxynaphthalene-2-carboxylic acid

HPLC-MS (Method (A)): m/z: 341 (M+1); Rt=5.45 min. General Procedure (F) for Preparation of Compounds of General Formula I₅: wherein R³⁰ is hydrogen or C₁-C₆-alkyl and T is as defined above

This general procedure (F) is further illustrated in the following example:

Example 556

General Procedure (F)

3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic Acid

7-Formyl-3-hydroxynaphthalene-2-carboxylic acid (40 mg, 0.19 mmol) (example 535) was suspended in methanol (300 μL). Acetic acid (16 μL, 17 mg, 0.28 mmol) and 4-2-propyl)aniline (40 μL, 40 mg, 0.30 mmol) were added consecutively, and the resulting mixture was stirred vigorously at room temperature for 2 hours. Sodium cyanoborohydride (1.0 M in tetrahydrofuran, 300 μL, 0.3 mmol) was added, and the stirring was continued for another 17 hours. The reaction mixture was poured into 6 N hydrochloric acid (aq.) (6 mL), and the precipitate was filtered off and rinsed with water (3×2 mL) to yield the title compound (40 mg) as its hydrochloride salt. No further purification was necessary.

¹H-NMR (DMSO-d₆): δ 10.95 (1H, bs), 8.45 (1H, s), 7.96 (1H, s), 7.78 (1H, d), 7.62 (1H, d), 7.32 (1H, s), 7.13 (2H, bd), 6.98 (2H, bd), 4.48 (2H, s), 2.79 (1H, sept), 1.14 (6H, d); HPLC-MS (Method (A)): m/z: 336 (M+1); Rt=3.92 min.

The compounds in the following examples were made using this general procedure (F).

Example 557

General Procedure (F)

7-{[(4-Bromophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 372 (M+1); Rt=4.31 min.

Example 558

General Procedure (F)

7-{[(3,5-Dichlorophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 362 (M+1); Rt=4.75 min.

Example 559

General Procedure (F)

7-{[(Benzothiazol-6-yl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.43 min.

Example 560

General Procedure (F)

3-Hydroxy-7-{[(quinolin-6-yl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 345 (M+1); Rt=2.26 min.

Example 561

General Procedure (F)

3-Hydroxy-7-{[(4-methoxyphenyl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 324 (M+1); Rt=2.57 min.

Example 562

General Procedure (F)

7-{[(2,3-Dihydrobenzofuran-5-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 350 (M+1); Rt=2.22 min.

Example 563

General Procedure (F)

7-{[(4-Chlorobenzyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 342 (M+1); Rt=2.45 min.

Example 564

General Procedure (F)

3-Hydroxy-7-{[(naphthalen-1-ylmethyl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 357 (M+1); Rt=2.63 min.

Example 565

General Procedure (F)

7-{[(Biphenyl-2-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 384 (M+1); Rt=2.90 min.

Example 566

General Procedure (F)

3-Hydroxy-7-{[(4-phenoxybenzyl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 400 (M+1); Rt=3.15 min.

Example 567

General Procedure (F)

3-Hydroxy-7-{[(4-methoxybenzyl)amino]methyl}naphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 338 (M+1); Rt=2.32 min. General Procedure (G) for Preparation of Compounds of General Formula I₆: wherein J is as defined above and the moiety (C₁-C₆-alkanoyl)₂O is an anhydride.

The general procedure (G) is illustrated by the following example:

Example 568

General Procedure (G)

N-Acetyl-3-hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic Acid

3-Hydroxy-7-[(4-(2-propyl)phenylamino)methyl]naphthalene-2-carboxylic acid (25 mg, 0.07 mmol) (example 556) was suspended in tetrahydrofuran (200 μL). A solution of sodium hydrogencarbonate (23 mg, 0.27 mmol) in water (200 μL) was added followed by acetic anhydride (14 μL, 15 mg, 0.15 mmol). The reaction mixture was stirred vigorously for 65 hours at room temperature before 6 N hydrochloric acid (4 mL) was added. The precipitate was filtered off and rinsed with water (3×1 mL) to yield the title compound (21 mg). No further purification was necessary.

¹H-NMR (DMSO-d₆): δ 10.96 (1H, bs), 8.48 (1H, s), 7.73 (1H, s), 7.72 (1H, d), 7.41 (1H, dd), 7.28 (1H, s), 7.23 (2H, d), 7.18 (2H, d), 4.96 (2H, s), 2.85 (1H, sept), 1.86 (3H, s), 1.15 (6H, d); HPLC-MS (Method (A)): m/z: 378 (M+1); Rt=3.90 min.

The compounds in the following examples were prepared in a similar fashion.

Example 569

General Procedure (G)

N-Acetyl-7-{[(4-bromophenyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 414 (M+1); Rt=3.76 min.

Example 570

General Procedure (G)

N-Acetyl-7-{[(2,3-dihydrobenzofuran-5-ylmethyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 392 (M+1); Rt=3.26 min.

Example 571

General Procedure (G)

N-Acetyl-7-{[(4-chlorobenzyl)amino]methyl}-3-hydroxynaphthalene-2-carboxylic Acid

HPLC-MS (Method C): m/z: 384 (M+1); Rt=3.67 min.

Compounds of the invention may also include tetrazoles:

Example 572

5-(3-(Naphthalen-2-yloxymethyl)-phenyl)-1H-tetrazole

To a mixture of 2-naphthol (10 g, 0.07 mol) and potassium carbonate (10 g, 0.073 mol) in acetone (150 mL), alpha-bromo-m-tolunitril (13.6 g, 0.07 mol) was added in portions. The reaction mixture was stirred at reflux temperature for 2.5 hours. The cooled reaction mixture was filtered and evaporated in vacuo affording an oily residue (19 g) which was dissolved in diethyl ether (150 mL) and stirred with a mixture of active carbon and MgSO₄ for 16 hours. The mixture was filtered and evaporated in vacuo affording crude 18.0 g (100%) of 3-(naphthalen-2-yloxymethyl)-benzonitrile as a solid.

12 g of the above benzonitrile was recrystallised from ethanol (150 mL) affording 8.3 g (69%) of 3-(naphthalen-2-yloxymethyl)-benzonitrile as a solid.

M.p. 60-61° C. Calculated for C₁₈H₁₃NO: C, 83.37%; H, 5.05%; N, 5.40%; Found C, 83.51%; H, 5.03%; N, 5.38%.

To a mixture of sodium azide (1.46 g, 22.5 mmol) and ammonium chloride (1.28 g, 24.0 mmol) in dry dimethylformamide (20 mL) under an atmosphere of nitrogen, 3-(naphthalen-2-yloxymethyl)-benzonitrile (3.9 g, 15 mmol) was added and the reaction mixture was stirred at 125° C. for 4 hours. The cooled reaction mixture was poured on to ice water (300 mL) and acidified to pH=1 with 1 N hydrochloric acid. The precipitate was filtered off and washed with water, dried at 100° C. for 4 hours affording 4.2 g (93%) of the title compound.

M.p. 200-202° C. Calculated for C₁₈H₁₄N₄O: C, 71.51%; H, 4.67%; N, 18.54%; Found C, 72.11%; H, 4.65%; N, 17.43%. ¹H NMR (400 MHz, DMSO-d₆) δ_H 5.36 (s, 2H), 7.29 (dd, 1H), 7.36 (dt, 1H), 7.47 (m, 2H), 7.66 (t, 1H), 7.74 (d, 1H), 7.84 (m, 3H), 8.02 (d, 1H), 8.22 (s, 1H).

Example 573

N-(3-(Tetrazol-5-yl)phenyl)-2-naphtoic acid amide

2-Naphtoic acid (10 g, 58 mmol) was dissolved in dichloromethane (100 mL) and N,N-dimethylformamide (0.2 mL) was added followed by thionyl chloride (5.1 ml, 70 mmol). The mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, the mixture was added dropwise to a mixture of 3-aminobenzonitril (6.90 g, 58 mmol) and triethyl amine (10 mL) in dichloromethane (75 mL). The resulting mixture was stirred at room temperature for 30 minutes. Water (50 mL) was added and the volatiles was exaporated in vacuo. The resulting mixture was filtered and the filter cake was washed with water followed by heptane (2×25 mL). Drying in vacuo at 50° C. for 16 hours afforded 15.0 g (95%) of N-(3-cyanophenyl)-2-naphtoic acid amide.

M.p. 138-140° C.

The above naphthoic acid amide (10 g, 37 mmol) was dissolved in N,N-dimethylformamide (200 mL) and sodium azide (2.63 g, 40 mmol) and ammonium chloride (2.16 g, 40 mmol) were added and the mixture heated at 125° C. for 6 hours. Sodium azide (1.2 g) and ammonium chloride (0.98 g) were added and the mixture heated at 125° C. for 16 hours. After cooling, the mixture was poured into water (1.5 l) and stirred at room temperature for 30 minutes. The solid formed was filtered off, washed with water and dried in vacuo at 50° C. for 3 days affording 9.69 g (84%) of the title compound as a solid which could be further purified by treatment with ethanol at reflux temperature.

¹H NMR (200 MHz, DMSO-d₆): δ_H 7.58-7.70 (m, 3H), 7.77 (d, 1H), 8.04-8.13 (m, 5H), 8.65 d, 1H), 10.7 (s, 1H).

Calculated for C₁₈H₁₃N₅O, 0.75 H₂O: C, 65.74%; H, 4.44%; N, 21.30%. Found: C, 65.58%; H, 4.50%; N, 21.05%.

Example 574

5-[3-(Biphenyl4-yloxymethyl)phenyl]-1H-tetrazole

To a solution of 4-phenylphenol (10.0 g, 59 mmol) in dry N,N-dimethyl-formamide (45 mL) kept under an atmosphere of nitrogen, sodium hydride (2.82 g, 71 mmol, 60% dispersion in oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. A solution of m-cyanobenzyl bromide (13 g, 65 mmol) in dry N,N-dimethylformamide (45 mL) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured on to ice water (150 mL). The precipitate was filtered of and washed with 50% ethanol

(3×50 mL), ethanol (2×50 mL), diethyl ether (80 mL), and dried in vacuo at 50° C. for 18 hours affording crude 17.39 g of 3-(biphenyl-4-yloxymethyl)-benzonitrile as a solid.

¹H NMR (200 MHz, CDCl₃) δ_H 5.14 (s, 2H), 7.05 (m, 2H), 7.30-7.78 (m, 11H).

To a mixture of sodium azide (2.96 g, 45.6 mmol) and ammonium chloride (2.44 g, 45.6 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-yloxymethyl)-benzonitrile (10.0 g, 35.0 mmol) was added and the reaction mixture was stirred at 125° C. for 18 hours. The cooled reaction mixture was poured on to a mixture of 1N hydrochloric acid (60 mL) and ice water (500 mL). The precipitate was filtered off and washed with water (3×100 mL), 50% ethanol (3×100 mL), ethanol (50 mL), diethyl ether (50 mL), ethanol (80 mL), and dried in vacuo at 50° C. for 18 hours affording 8.02 g (70%) of the title compound.

¹H NMR (200 MHz, DMSO-d₆) δ_H 5.31 (s, 2H), 7.19 (m, 2H), 7.34 (m, 1H), 7.47 (m, 2H), 7.69 (m, 6H), 8.05 (dt, 1H), 8.24 (s, 1H).

Example 575

5-(3-Phenoxymethyl)-phenyl)-tetrazole

3-Bromomethylbenzonitrile (5.00 g, 25.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), phenol (2.40 g, 25.5 mmol) and potassium carbonate (10.6 g, 77 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried (MgSO₄) and evaporated in vacuo to afford 5.19 g (97%) 3-(phenoxymethyl)benzonitrile as an oil.

TLC: R_f=0.38 (Ethyl acetate/heptane=1:4)

The above benzonitrile (5.19 g, 24.8 mmol) was dissolved in N,N-dimethylformamide (100 mL) and sodium azide (1.93 g, 30 mmol) and ammonium chloride (1.59 g, 30 mmol) were added and the mixture was heated at 140° C. for 16 hours. After cooling, the mixture was poured into water (800 mL). The aqeous mixture was washed with ethyl acetate (200 mL). The pH of the aqueous phase was adjusted to 1 with 5 N hydrochloric acid and stirred at room temperature for 30 minutes. Filtration, washing with water and drying in vacuo at 50° C. afforded 2.06 g (33%) of the title compound as a solid.

¹H NMR (200 MHz, CDCl₃+DMSO-d₆) δ_H 5.05 (s, 2H), 6.88 (m, 3H), 7.21 (m, 2H), 7.51 (m, 2H), 7.96 (dt, 1H), 8.14 (s, 1H).

Example 576

5-[3-(Biphenyl-4-ylmethoxy)phenyl]-1H-tetrazole

To a solution of 3-cyanophenol (5.0 g, 40.72 mmol) in dry N,N-dimethylformamide (100 mL) kept under an atmosphere of nitrogen, sodium hydride (2 g, 48.86 mmol, 60% dispersion in oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. p-Phenylbenzyl chloride (9.26 g, 44.79 mmol) and potassium iodide (0.2 g, 1.21 mmol) were added and the reaction mixture was stirred at room temperature for 60 hours. The reaction mixture was poured on to a mixture of saturated sodium carbonate (100 mL) and ice water (300 mL). The precipitate was filtered of and washed with water (3×100 mL), n-hexane (2×80 mL) and dried in vacuo at 50° C. for 18 hours affording 11.34 g (98%) of 3-(biphenyl-4-ylmethoxy)-benzonitrile as a solid.

To a mixture of sodium azide (2.37 g, 36.45 mmol) and ammonium chloride (1.95 g, 36.45 mmol) in dry N,N-dimethylformamide (100 mL) under an atmosphere of nitrogen, 3-(biphenyl-4-ylmethoxy)-benzonitrile (8.0 g, 28.04 mmol) was added and the reaction mixture was stirred at

125° C. for 18 hours. To the cooled reaction mixture water (100 mL) was added and the reaction mixture stirred for 0.75 hour. The precipitate was filtered off and washed with water, 96% ethanol (2×50 mL), and dried in vacuo at 50° C. for 18 hours affording 5.13 g (56%) of the title compound.

¹H NMR (200 MHz, DMSO-d₆) δ_H 5.29 (s, 2H), 7.31 (dd, 1H), 7.37-7.77 (m, 12H).

Example 577

5-[4-(Biphenyl-4-ylmethoxy)-3-methoxyphenyl]-1H-tetrazol

This compound was made similarly as described in example 576.

Example 578

Example 579

5-(2-Naphtylmethyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step 2.

Example 580

5-(1-Naphtylmethyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step 2.

Example 581

5-[4-(Biphenyl-4-yloxymethyl)phenyl]-1H-tetrazole

A solution of alpha-bromo-p-tolunitrile (5.00 g, 25.5 mmol), 4-phenylphenol (4.56 g, 26.8 mmol), and potassium carbonate (10.6 g, 76.5 mmol) in N,N-dimethylformamide (75 mL) was stirred vigorously for 16 hours at room temperature. Water (75 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with thoroughly with water. Drying in vacuo over night at 50° C. afforded 7.09 g (97%) of 4-(biphenyl-4-yloxymethyl)benzonitrile as a solid.

The above benzonitrile (3.00 g, 10.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium azide (1.03 g, 15.8 mmol) and ammonium chloride (0.84 g, 15.8 mmol) were added and the mixture was stirred 16 hours at 125° C. The mixture was cooled to room temperature and water (50 mL) was added. The suspension was stirred overnight, filtered, washed with water and dried in vacuo at 50° C. for 3 days to give crude 3.07 g (89%) of the title compound. From the mother liquor crystals were colected and washed with water, dried by suction to give 0.18 g

(5%) of the title compound as a solid.

¹H NMR (200 MHz, DMSO-d₆): δ_H 5.21 (s, 2H), 7.12 (d, 2H), 7.30 (t, 1H), 7.42 (t, 2H), 7.56-7.63 (m, 6H), 8.03 (d, 2H).

Calculated for C₂₀H₁₆N₄O, 2H₂O: C, 65.92%; H, 5.53%; N, 15.37%. Found: C, 65.65%; H, 5.01%; N, 14.92%.

Example 582

This compound was prepared similarly as described in example 576.

Example 583

Example 584

Example 585

Example 586

5-(3-(Biphenyl-4-yloxymethyl)-benzyl)-1H-tetrazole

Example 587

5-(1-Naphthyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step 2.

Example 588

5-[3-Methoxy-4-(4-methylsulfonylbenzyloxy)phenyl]-1H-tetrazole

This compound was made similarly as described in example 576.

Example 589

5-(2-Naphthyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step 2.

Example 590

2-Amino-N-(1H-tetrazol-5-yl)-benzamide

Example 591

5-(4-Hydroxy-3-methoxyphenyl)-1H-tetrazole

This compound was prepared similarly as described in example 572, step 2.

Example 592

4-(2H-Tetrazol-5-ylmethoxy)benzoic acid

To a mixture of methyl 4-hydroxybenzoate (30.0 9, 0.20 mol), sodium iodide (30.0 g, 0.20 mol) and potassium carbonate (27.6 g, 0.20 mol) in acetone (2000 mL) was added chloroacetonitrile (14.9 g, 0.20 mol). The mixture was stirred at RT for 3 days. Water was added and the mixture was acidified with 1N hydrochloric acid and the mixture was extracted with diethyl ether. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The residue was dissolved in acetone and chloroacetonitrile (6.04 g,0.08 mol), sodium iodide (12.0 g, 0.08 mol) and potassium carbonate (11.1 g, 0.08 mol) were added and the mixture was stirred for 16 hours at RT and at 60° C. More chloroacetonitrile was added until the conversion was 97%. Water was added and the mixture was acidified with 1N hydrochloric acid and the mixture was extracted with diethyl ether. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to afford methyl 4-cyanomethyloxybenzoate in quantitative yield. This compound was used without further purification in the following step.

A mixture of methyl 4-cyanomethyloxybenzoate (53.5 g,0.20 mol), sodium azide (16.9 g, 0.26 mol) and ammonium chloride (13.9 g, 0.26 mol) in DMF 1000 (mL) was refluxed overnight under N₂. After cooling, the mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated in vacuo, to afford methyl 4-(2H-tetrazol-5-ylmethoxy)benzoate. This compound was used as such in the following step.

Methyl 4-(2H-Tetrazol-5-ylmethoxy)-benzoate was refluxed in 3N sodium hydroxide. The reaction was followed by TLC (DCM:MeOH=9:1). The reaction mixture was cooled, acidified and the product filtered off. The impure product was washed with DCM, dissolved in MeOH, filtered and purified by column chromatography on silica gel (DCM:MeOH=9:1).The resulting product was recrystallised from DCM:MeOH=95:5. This was repeated until the product was pure. This afforded 13.82 g (30%) of the title compound.

¹H-NMR (DMSO-d₆): 4.70 (2H, s), 7.48 (2H, d), 7.73 (2H, d), 13 (1H, bs).

Example 593

4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoic acid

To a solution of sodium hydroxide (10.4 g, 0.26 mol) in degassed water (600 mL) was added 4-mercaptobenzoic acid (20.0 g, 0.13 mol). This solution was stirred for 30 minutes. To a solution of potassium carbonate (9.0 g, 65 mmol) in degassed water (400 mL) was added chloroacetonitrile (9.8 g, (0.13 mol) portion-wise. These two solutions were mixed and stirred for 48 hours at RT under N₂. The mixture was filtered and washed with heptane. The aqueous phase was acidified with 3N hydrochloric acid and the product was filtered off, washed with water and dried, affording 4-cyanomethylsulfanylbenzoic acid (27.2 g, 88%). This compound was used without further purification in the following step.

A mixture of 4-cyanomethylsulfanylbenzoic acid (27.2 g, 0.14 mol), sodium azide (11.8 g, 0,18 mol) and ammonium chloride (9.7 g, 0.18 mol) in DMF (1000 mL) was refluxed overnight under N₂. The mixture was concentrated in vacuo. The residue was suspended in cold water and extracted with diethyl ether. The combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Water was added and the precipitate was filtered off. The aqueous layer was concentrated in vacuo, water was added and the precipitate filtered off. The combined impure products were purified by column chromatography using DCM:MeOH=9:1 as eluent, affording the title compound (5.2 g, 16%).

¹H-NMR (DMSO-d₆): 5.58 (2H, s), 7.15 (2H, d), 7.93 (2H, d), 12.7 (1H, bs).

Example 594

3-(2H-Tetrazol-5-yl)-9H-carbazole

3-Bromo-9H-carbazole was prepared as described by Smith et al. in Tetrahedron 1992, 48, 7479-7488.

A solution of 3-bromo-9H-carbazole (23.08 g, 0.094 mol) and cuprous cyanide (9.33 g, 0.103 mol) in N-methyl-pyrrolidone (300 ml) was heated at 200° C. for 5 h. The cooled reaction mixture was poured on to water (600 ml) and the precipitate was filtered off and washed with ethyl acetate (3×50 ml). The filtrate was extracted with ethyl acetate (3×250 ml) and the combined ethyl acetate extracts were washed with water (150 ml), brine (150 ml), dried (MgSO₄) and concentrated in vacuo. The residue was crystallised from heptanes and recrystallised from acetonitrile (70 ml) affording 7.16 g (40%) of 3-cyano-9H-carbazole as a solid. M.p. 180-181° C.

3-Cyano-9H-carbazole (5.77 g, 30 mmol) was dissolved in N,N-dimethylformamide (150 ml), and sodium azide (9.85 g, 152 mmol), ammonium chloride (8.04 g, 150 mmol) and lithium chloride (1.93 g, 46 mmol) were added and the mixture was stirred for 20 h at 125° C. To the reaction mixture was added an additional portion of sodium azide (9.85 g, 152 mmol) and ammonium chloride (8.04 g, 150 mmol) and the reaction mixture was stirred for an additional 24 h at 125° C. The cooled reaction mixture was poured on to water (500 ml). The suspension was stirred for 0.5 h, and the precipitate was filtered off and washed with water (3×200 ml) and dried in vacuo at 50° C. The dried crude product was suspended in diethyl ether (500 ml) and stirred for 2 h, filtered off and washed with diethyl ether (2×200 ml) and dried in vacuo at 50° C. affording 5.79 g (82%) of the title compound as a solid.

¹H-NMR (DMSO-d₆): δ 11.78 (1H, bs), 8.93 (1H, d), 8.23 (1H, d), 8.14 (1H, dd), 7.72 (1H, d), 7.60 (1H, d), 7.49 (1H, t), 7.28 (1H, t); HPLC-MS (Method C): m/z: 236 (M+1); Rt=2.77 min.

The following commercially available tetrazoles do all bind to the His B10 Zn²⁺ site of the insulin hexamer:

Example 595

5-(3-Tolyl)-1H-tetrazole

Example 596

5-(2-Bromophenyl)tetrazole

Example 597

5-(4-Ethoxalylamino-3-nitrophenyl)tetrazole

Example 598

Example 599

Example 600

Example 601

Example 602

Tetrazole

Example 603

5-Methyltetrazole

Example 604

5-Benzyl-2H-tetrazole

Example 605

4-(2H-Tetrazol-5-yl)benzoic acid

Example 606

5-Phenyl-2H-tetrazole

Example 607

5-(4-Chlorophenylsulfanylmethyl)-2H-tetrazole

Example 608

5-(3-Benzyloxyphenyl)-2H-tetrazole

Example 609

2-Phenyl-6-(1H-tetrazol-5-yl)-chromen-4-one

Example 610

Example 611

Example 612

Example 613

Example 614

Example 615

5-(4-Bromo-phenyl)-1H-tetrazole

Example 616

Example 617

Example 618

Example 619

Example 620

Example 621

Example 622

Example 623

Example 624

Example 625

Example 626

Example 627

Example 628

Example 629

Example 630

Example 631

Example 632

Example 633

Example 634

Example 635

Example 636

Example 637

Example 638

Example 639

Example 640

Example 641

Example 642

Example 643

Example 644

Example 645

Example 646

5-(2,6-Dichlorobenzyl)-2H-tetrazole

General Procedure (H) for Preparation of Compounds of General Formula I₇: wherein K, M, and T are as defined above.

The reaction is generally known as a reductive alkylation reaction and is generally performed by stirring an aldehyde with an amine at low pH (by addition of an acid, such as acetic acid or formic acid) in a solvent such as THF, DMF, NMP, methanol, ethanol, DMSO, dichloromethane, 1,2-dichloroethane, trimethyl orthoformate, triethyl orthoformate, or a mixture of two or more of these. As reducing agent sodium cyano borohydride or sodium triacetoxy borohydride may be used. The reaction is performed between 20° C. and 120° C., preferably at room temperature.

When the reductive alkylation is complete, the product is isolated by extraction, filtration, chromatography or other methods known to those skilled in the art.

The general procedure (H) is further illustrated in the following example 647:

Example 647

General Procedure (H)

Biphenyl-4-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

A solution of 5-(3-aminophenyl)-2H-tetrazole (example 874, 48 mg, 0.3 mmol) in DMF (250 μL) was mixed with a solution of 4-biphenylylcarbaldehyde (54 mg, 0.3 mmol) in DMF (250 μL) and acetic acid glacial (250 μL) was added to the mixture followed by a solution of sodium cyano borohydride (15 mg, 0.24 mmol) in methanol (250 μL). The resulting mixture was shaken at room temperature for 2 hours. Water (2 mL) was added to the mixture and the resulting mixture was shaken at room temperature for 16 hours. The mixture was centrifugated (6000 rpm, 10 minutes) and the supernatant was removed by a pipette. The residue was washed with water (3 mL), centrifugated (6000 rpm, 10 minutes) and the supernatant was removed by a pipette. The residue was dried in vacuo at 40° C. for 16 hours to afford the title compound as a solid.

HPLC-MS (Method C): m/z: 328 (M+1), 350 (M+23); Rt=4.09 min.

Example 648

General Procedure (H)

Benzyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 252 (M+1); Rt=3.74 min.

Example 649

General Procedure (H)

(4-Methoxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 282.2 (M+1); Rt=3.57 min.

Example 650

General Procedure (H)

4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenol

HPLC-MS (Method D): m/z: 268,4 (M+1); Rt=2.64 min.

Example 651

General Procedure (H)

(4-Nitrobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 297.4 (M+1); Rt=3.94 min.

Example 652

General Procedure (H)

(4-Chlorobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 287.2 (M+1); Rt=4.30 min.

Example 653

General Procedure (H)

(2-Chlorobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 286 (M+1); Rt=4.40 min.

Example 654

General Procedure (H)

(4-Bromobenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z:332 (M+1); Rt=4.50 min.

Example 655

General Procedure (H)

(3-Benzyloxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.94 min.

Example 656

General Procedure (H)

Naphthalen-1-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 657

General Procedure (H)

Naphthalen-2-ylmethyl-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.60 min.

Example 658

General Procedure (H)

4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.24 min.

Example 659

General Procedure (H)

[3-(2H-Tetrazol-5-yl)-phenyl]-[3-(3-trifluoromethyl-phenoxy)benzyl]amine

HPLC-MS (Method D): m/z: 412 (M+1); Rt=5.54 min.

Example 660

General Procedure (H)

(3-Phenoxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.04 min.

Example 661

General Procedure (H)

(4-Phenoxy-benzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.00 min.

Example 662

General Procedure (H)

(4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenoxy)acetic acid

HPLC-MS (Method D): m/z: 326 (M+1); Rt=3.10 min.

Example 663

General Procedure (H)

(4-Benzyloxybenzyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.97 min.

Example 664

General Procedure (H)

3-(4-{[3-(2H-Tetrazol-5-yl)phenylamino]methyl}phenyl)acrylic acid

HPLC-MS (Method D): m/z: 322 (M+1); Rt=3.60 min.

Example 665

General Procedure (H)

Dimethyl-(4-{[3-(2H-tetrazol-5-yl)phenylamino]methyl}naphthalen-1-yl)amine

HPLC-MS (Method D): m/z: 345 (M+1); Rt=3.07 min.

Example 666

General Procedure (H)

(4′-Methoxybiphenyl-4-ylmethyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.97 min.

Example 667

General Procedure (H)

(2′-Chlorobiphenyl-4-ylmethyl)-[3-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 362 (M+1); Rt=5.27 min.

Example 668

General Procedure (H)

Benzyl-[4-(2H-tetrazol-5-yl)phenyl]amine

For preparation of starting material, see example 875.

HPLC-MS (Method D): m/z: 252 (M+1); Rt=3.97 min.

Example 669

General Procedure (H)

(4-Methoxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 282 (M+1); Rt=3.94 min.

Example 670

General Procedure (H)

4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenol

HPLC-MS (Method D): m/z: 268 (M+1); Rt=3.14 min.

Example 671

General Procedure (H)

(4-Nitrobenzyl)-[4-2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: (M+1); Rt=3.94 min.

Example 672

General Procedure (H)

(4-Chlorobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: (M+1); Rt=4.47 min.

Example 673

General Procedure (H)

(2-Chlorobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 286 (M+1); Rt=4.37 min.

Example 674

General Procedure (H)

(4-Bromobenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 331 (M+1); Rt=4.57 min.

Example 675

General Procedure (H)

(3-Benzyloxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.07 min.

Example 676

General Procedure (H)

Naphthalen-1-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 677

General Procedure (H)

Naphthalen-2-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 302 (M+1); Rt=4.70 min.

Example 678

General Procedure (H)

Biphenyl-4-ylmethyl-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 328 (M+1); Rt=5.07 min.

Example 679

General Procedure (H)

4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.34 min.

Example 680

General Procedure (H)

[4-(2H-Tetrazol-5-yl)phenyl]-[3-(3-trifluoromethylphenoxy)benzyl]amine

HPLC-MS (Method D): m/z: 412 (M+1); Rt=5.54 min.

Example 681

General Procedure (H)

(3-Phenoxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.07 min.

Example 682

General Procedure (H)

(4-Phenoxybenzyl)-[4-(2H-tetrazol-5-yl)-phenyl]-amine

HPLC-MS (Method D): m/z: 344 (M+1); Rt=5.03 min.

Example 683

General Procedure (H)

3-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}benzoic acid

HPLC-MS (Method D): m/z: 286 (M+1); Rt=3.47 min.

Example 684

General Procedure (H)

(4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenoxy)acetic acid

HPLC-MS (Method D): m/z: 326 (M+1); Rt=3.40 min.

Example 685

General Procedure (H)

(4-Benzyloxybenzyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.14 min.

Example 686

General Procedure (H)

3-(4-{[4-(2H-Tetrazol-5-yl)phenylamino]methyl}phenyl)acrylic acid

HPLC-MS (Method D): m/z: 322 (M+1); Rt=3.66 min.

Example 687

General Procedure (H)

Dimethyl-(4-{[4-(2H-tetrazol-5-yl)phenylamino]methyl}naphthalen-1-yl)amine

HPLC-MS (Method D): m/z: 345 (M+1); Rt=3.10 min.

Example 688

General Procedure (H)

(4′-Methoxybiphenyl-4-ylmethyl)-[4-(2H-tetrazol-5-yl)phenyl]amine

HPLC-MS (Method D): m/z: 358 (M+1); Rt=5.04 min.

Example 689

General Procedure (H)

(2′-Chlorobiphenyl-4-ylmethyl)-[4-(2H-tetrazol-5-yl)-phenyl]-amine

HPLC-MS (Method D): m/z: 362 (M+1); Rt=5.30 min.

General Procedure (I) for Preparation of Compounds of General Formula I₈:

wherein K, M and T are as defined above.

This procedure is very similar to general procedure (A), the only difference being the carboxylic acid is containing a tetrazole moiety. When the acylation is complete, the product is isolated by extraction, filtration, chromatography or other methods known to those skilled in the art.

The general procedure (I) is further illustrated in the following example 690:

Example 690

General Procedure (I)

4-[4-(2H-Tetrazol-5-yl)benzoylamino]benzoic acid

To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 605, 4 mmol) and HOAt (4.2 mmol) in DMF (6 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol) and the resulting mixture was stirred at room temperature for 1 hour. An alquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of a solution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines as hydrochlorides can also be utilised, a slight excess of triethylamine was added to the hydrochloride suspension in DMF prior to mixing with the HOAt-ester.) The resulting mixture was shaken for 3 days at room temperature. 1 N hydrochloric acid (2 mL) was added and the mixture was shaken for 16 hours at room temperature. The solid was isolated by centrifugation (alternatively by filtration or extraction) and was washed with water (3 mL). Drying in vacuo at 40° C. for 2 days afforded the title compound.

HPLC-MS (Method D): m/z: 310 (M+1); Rt=2.83 min.

Example 691

General Procedure (I)

3-[4-(2H-Tetrazol-5-yl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 310 (M+1); Rt=2.89 min.

Example 692

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-yl)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 336 (M+1); Rt=3.10 min.

Example 693

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-yl)benzoylamino]phenyl}propionic acid

HPLC-MS (Method D): m/z: 338 (M+1); Rt=2.97 min.

Example 694

General Procedure (I)

3-Methoxy-4-[4-(2H-tetrazol-5-yl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 340 (M+1); Rt=3.03 min.

Example 695

General Procedure (I)

N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 372 (M+1); Rt=4.47 min.

Example 696

General Procedure (I)

N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 358 (M+1); Rt=4.50 min.

Example 697

General Procedure (I)

N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 354 (M+1); Rt=4.60 min.

Example 698

General Procedure (I)

N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 383 (M+1); Rt=4.60 min.

Example 699

General Procedure (I)

N-Phenyl-4-(2H-tetrazol-5-yl)benzamide

HPLC-MS (Method D): m/z: 266 (M+1); Rt=3.23 min.

Example 700

General Procedure (I)

4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

The starting material was prepared as described in example 592.

HPLC-MS (Method D): m/z: 340 (M+1); Rt=2.83 min.

Example 701

General Procedure (I)

3-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 340 (M+1); Rt=2.90 min.

Example 702

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 366 (M+1); Rt=3.07 min.

Example 703

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-ylmethoxy)benzoylamino]phenyl}propionic acid

HPLC-MS (Method D): m/z: 368 (M+1); Rt=2.97 min.

Example 704

General Procedure (I)

3-Methoxy-4-[4-(2H-tetrazol-5-ylmethoxy)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 370 (M+1); Rt=3.07 min.

Example 705

General Procedure (I)

N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 402 (M+1); Rt=4.43 min.

Example 706

General Procedure (I)

N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 388 (M+1); Rt=4.50 min.

Example 707

General Procedure (I)

N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 384 (M+1); Rt=4.57 min.

Example 708

General Procedure (I)

N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 413 (M+1); Rt=4.57 min.

Example 709

General Procedure (I)

N-Phenyl-4-(2H-tetrazol-5-ylmethoxy)benzamide

HPLC-MS (Method D): m/z: 296 (M+1); Rt=3.23 min.

Example 710

General Procedure (I)

4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

The starting material was prepared as described in example 593.

HPLC-MS (Method D): m/z: 356 (M+1); Rt=2.93 min.

Example 711

General Procedure (I)

3-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 356 (M+1); Rt=3.00 min.

Example 712

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]phenyl}acrylic acid

HPLC-MS (Method D): m/z: 382 (M+1); Rt=3.26 min.

Example 713

General Procedure (I)

3-{4-[4-(2H-Tetrazol-5-ylmethylsulfanyl)benzoylamino]phenyl}propionic acid

HPLC-MS (Method D): m/z: 384 (M+1); Rt=3.10 min.

Example 714

General Procedure (I)

3-Methoxy-4-[4-(2H-tetrazol-5-ylmethylsulfanyl)benzoylamino]benzoic acid

HPLC-MS (Method D): m/z: 386 (M+1); Rt=3.20 min.

Example 715

General Procedure (I)

N-(4-Benzyloxyphenyl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 418 (M+1); Rt=4.57 min.

Example 716

General Procedure (I)

N-(4-Phenoxyphenyl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 404 (M+1); Rt=4.60 min.

Example 717

General Procedure (I)

N-(9H-Fluoren-2-yl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 400 (M+1); Rt=4.67 min.

Example 718

General Procedure (I)

N-(9-Ethyl-9H-carbazol-2-yl)-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 429 (M+1); Rt=4.67 min.

Example 719

General Procedure (I)

N-Phenyl-4-(2H-tetrazol-5-ylmethylsulfanyl)benzamide

HPLC-MS (Method D): m/z: 312 (M+1); Rt=3.40 min.

General Procedure (J) for Solution Phase Preparation of Amides of General Formula I₉:

wherein T is as defined above.

This general procedure (J) is further illustrated in the following example.

Example 720

General Procedure (J)

9-(3-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3-(2H-Tetrazol-5-yl)-9H-carbazole (example 594, 17 g, 72.26 mmol) was dissolved in N,N-dimethylformamide (150 mL). Triphenylmethyl chloride (21.153 g, 75.88 mmol) and triethylamine (20.14 mL, 14.62 g, 144.50 mmol) were added consecutively. The reaction mixture was stirred for 18 hours at room temperature, poured into water (1.5 L) and stirred for an additional 1 hour. The crude product was filtered off and dissolved in dichloromethane (500 mL). The organic phase was washed with water (2×250 mL) and dried with magnesium sulfate (1 h). Filtration followed by concentration yielded a solid which was triturated in heptanes (200 mL). Filtration furnished 3-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (31.5 g) which was used without further purification.

¹H-NMR (CDCl₃): δ8.87 (1H, d), 8.28 (1H, bs), 8.22 (1H, dd), 8.13 (1H, d), 7.49 (1H, d), 7.47-7.19 (18H, m); HPLC-MS (Method C): m/z: 243 (triphenylmethyl); Rt=5.72 min.

3-[2-(Triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (200 mg, 0.42 mmol) was dissolved in methyl sulfoxide (1.5 mL). Sodium hydride (34 mg, 60%, 0.85 mmol) was added, and the resulting suspension was stirred for 30 min at room temperature. 3-Chlorobenzyl chloride (85 μL, 108 mg, 0.67 mmol) was added, and the stirring was continued at 40° C. for 18 hours. The reaction mixture was cooled to ambient temperature and poured into 0.1 N hydrochloric acid (aq.) (15 mL). The precipitated solid was filtered off and washed with water (3×10 mL) to furnish 9-(3-chlorobenzyl)-3-[2-triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole, which was dissolved in a mixture of tetrahydrofuran and 6 N hydrochloric acid (aq.) (9:1) (10 mL) and stirred at room temperature for 18 hours. The reaction mixture was poured into water (100 mL). The solid was filtered off and rinsed with water (3×10 mL) and dichloromethane (3×10 mL) to yield the title compound (127 mg). No further purification was necessary.

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.12 (1H, dd), 7.90 (1H, d), 7.72 (1H, d), 7.53 (1H, t), 7.36-7.27 (4H, m), 7.08 (1H, bt), 5.78 (2H, s); HPLC-MS (Method B): m/z: 360 (M+1); Rt=5.07 min.

The compounds in the following examples were prepared in a similar fashion. Optionally, the compounds can be further purified by recrystallization from e.g. aqueous sodium hydroxide (1 N) or by chromatography.

Example 721

General Procedure (J)

9-(4-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 360 (M+1); Rt=4.31 min.

Example 722

General Procedure (J)

9-(4-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.26 min.

Example 723

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-(4-trifluoromethylbenzyl)-9H-carbazole

HPLC-MS (Method C): m/z: 394 (M+1); Rt=4.40 min.

Example 724

General Procedure (J)

9-(4-Benzyloxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 432 (M+1); Rt=4.70 min.

Example 725

General Procedure (J)

9-(3-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.25 min.

Example 726

General Procedure (J)

9-Benzyl-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.91 (1H, dd), 8.30 (1H, d), 8.13 (1H, dd), 7.90 (1H, d), 7.73 (1H, d), 7.53 (1H, t), 7.36-7.20 (6H, m), 5.77 (2H, s).

Example 727

General Procedure (J)

9-(4-Phenylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.94 (1H, s), 8.33 (1H, d), 8.17 (1H, dd), 7.95 (1H, d), 7.77 (1H, d), 7.61-7.27 (11H, m), 5.82 (2H, s).

Example 728

General Procedure (J)

9-(3-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 356 (M+1); Rt=3.99 min.

Example 729

General Procedure (J)

9-(Naphthalen-2-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 376 (M+1); Rt=4.48 min.

Example 730

General Procedure (J)

9-(3-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.33 min.

Example 731

General Procedure (J)

9-(Biphenyl-2-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 402 (M+1); Rt=4.80 min.

Example 732

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-[4-(1,2,3-thiadiazol-4-yl)benzyl]-9H-carbazole

Example 733

General Procedure (J)

9-(2′-Cyanobiphenyl-4-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.91 (1H, d), 8.31 (1H, d), 8.13 (1H, dd), 7.95 (1H, d), 7.92 (1H, d), 7.78 (1H, d), 7.75 (1H, dt), 7.60-7.47 (5H, m), 7.38-7.28 (3H, m), 5.86 (2H, s); HPLC-MS (Method C): m/z: 427 (M+1); Rt=4.38 min.

Example 734

General Procedure (J)

9-(4-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 452 (M+1); Rt=4.37 min.

Example 735

General Procedure (J)

9-(3,5-Bis(trifluoromethyl)benzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 462 (M+1); Rt=4.70 min.

Example 736

General Procedure (J)

9-(4-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.88 (1H, d), 7.70 (1H, d), 7.52 (1H, t), 7.49 (2H, d), 7.31 (1H, t), 7.14 (2H, d), 5.74 (2H, s); HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.40 min.

Example 737

General Procedure (J)

9-(Anthracen-9-ylmethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 426 (M+1); Rt=4.78 min.

Example 738

General Procedure (J)

9-(4-Carboxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3.6 fold excess sodium hydride was used.

¹H-NMR (DMSO-d₆): δ12.89 (1H, bs), 8.89 (1H, d), 8.30 (1H, d), 8.10 (1H, dd), 7.87 (1H, d), 7.86 (2H, d), 7.68 (1H, d), 7.51 (1H, t), 7.32 (1H, t), 7.27 (2H, d), 5.84 (2H, s); HPLC-MS (Method C): m/z: 370 (M+1); Rt=3.37 min.

Example 739

General Procedure (J)

9-(2-Chlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 360 (M+1); Rt=5.30 min.

Example 740

General Procedure (J)

9-(4-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.88 (1H, d), 8.28 (1H, d), 8.10 (1H, dd), 7.89 (1H, d), 7.72 (1H, d), 7.52 (1H, t), 7.31 (1H, t), 7.31-7.08 (4H, m), 5.74 (2H, s); HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.10 min.

Example 741

General Procedure (J)

9-(3-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.12 (1H, dd), 7.90 (1H, d), 7.72 (1H, d), 7.53 (1H, t), 7.37-7.27 (2H, m), 7.12-7.02 (2H, m), 6.97 (1H, d), 5.78 (2H, s); HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.10 min.

Example 742

General Procedure (J)

9-(2-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 452 (M+1); Rt=4.58 min.

Example 743

General Procedure (J)

9-(3-Carboxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3.6 fold excess sodium hydride was used.

¹H-NMR (DMSO-d₆): δ12.97 (1H, bs), 8.90 (1H, bs), 8.30 (1H, d), 8.12 (1H, bd), 7.89 (1H, d), 7.82 (1H, m), 7.77 (1H, bs), 7.71 (1H, d), 7.53 (1H, t), 7.46-7.41 (2H, m), 7.32 (1H, t), 5.84 (2H, s); HPLC-MS (Method C): m/z: 370 (M+1); Rt=3.35 min.

Example 744

General Procedure (J)

9-[4-(2-Propyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.27 (1H, d), 8.10 (1H, dd), 7.87 (1H, d), 7.71 (1H, d), 7.51 (1H, t), 7.31 (1H, t), 7.15 (2H, d), 7.12 (2H, d), 5.69 (2H, s), 2.80 (1h, sept), 1.12 (6H, d); HPLC-MS (Method C): m/z: 368 (M+1); Rt=4.73 min.

Example 745

General Procedure (J)

9-(3,5-Dimethoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 386 (M+1); Rt=4.03 min.

Example 746

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-(2,4,5-trifluorobenzyl)-9H-carbazole

HPLC-MS (Method B): m/z: 380 (M+1); Rt=5.00 min.

Example 747

General Procedure (J)

N-Methyl-N-phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 383 (M+1); Rt=4.30 min.

Example 748

General Procedure (J)

9-(4-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.86 (1H, d), 8.26 (1H, d), 8.10 (1H, dd), 7.90 (1H, d), 7.73 (1H, d), 7.51 (1H, t), 7.30 (1H, t), 7.18 (2H, d), 6.84 (2H, d), 5.66 (2H, s), 3.67 (3H, s); HPLC-MS (Method B): m/z: 356 (M+1); Rt=4.73 min.

Example 749

General Procedure (J)

9-(2-Methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.27 (1H, d), 8.09 (1H, dd), 7.77 (1H, d), 7.60 (1H, d), 7.49 (1H, t), 7.29 (1H, t), 7.23 (1H, bt), 7.07 (1H, bd), 6.74 (1H, bt), 6.61 (1H, bd), 5.65 (2H, s), 3.88 (3H, s); HPLC-MS (Method B): m/z: 356 (M+1); Rt=4.97 min.

Example 750

General Procedure (J)

9-(4-Cyanobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.74 min.

Example 751

General Procedure (J)

9-(3-Cyanobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 351 (M+1); Rt=3.73 min.

Example 752

General Procedure (J)

9-(5-Chloro-2-methoxybenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.87 (1H, d), 8.35 (1H, d), 8.10 (1H, dd), 7.73 (1H, d), 7.59 (1H, d), 7.49 (1H, t), 7.29 (1H, t), 7.27 (1H, dd), 7.11 (1H, d), 6.51 (1H, d), 5.63 (2H, s), 3.88 (3H, s); HPLC-MS (Method C): m/z: 390 (M+1); Rt=4.37 min.

Example 753

General Procedure (J)

N-Phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

¹H-NMR (DMSO-d₆): δ10.54 (1H, s), 8.87 (1H, bs), 8.27 (1H, d), 8.12 (1H, bd), 7.83 (1H, d), 7.66 (1H, d), 7.61 (2H, d), 7.53 (1H,t), 7.32 (1H, t), 7.32 (2H, t), 7.07 (1H, t), 5.36 (2H, s); HPLC-MS (Method C): m/z: 369 (M+1); Rt=3.44 min.

Example 754

General Procedure (J)

N-Butyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

¹H-NMR (DMSO-d₆): δ8.85 (1H, d), 8.31 (1H, t), 8.25 (1H, d), 8.10 (1H, dd), 7.75 (1H, d), 7.58 (1H, d), 7.52 (1H, t), 7.30 (1H, t), 5.09 (2H, s), 3.11 (2H, q), 1.42 (2H, quint), 1.30 (2H, sext), 0.87 (3H, t); HPLC-MS (Method C): m/z: 349 (M+1); Rt=3.20 min.

Example 755

General Procedure (J)

9-(2,4-Dichlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.92 (1H, d), 8.32 (1H, d), 8.09 (1H, dd), 7.76 (1H, d), 7.74 (1H, d), 7.58 (1H, d), 7.51 (1H, t), 7.33 (1H, t), 7.23 (1H, dd), 6.42 (1H, d), 5.80 (2H, s); HPLC-MS (Method B): m/z: 394 (M+1); Rt=5.87 min.

Example 756

General Procedure (J)

9-(2-Methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.92 (1H, d), 8.32 (1H, d), 8.08 (1H, dd), 7.72 (1H, d), 7.55 (1H, d), 7.48 (1H, t), 7.32 (1H, t), 7.26 (1H, d), 7.12 (1H, t), 6.92 (1H, t), 6.17 (1H, d), 5.73 (2H, s), 2.46 (3H, s); HPLC-MS (Method B): m/z: 340 (M+1); Rt=5.30 min.

Example 757

General Procedure (J)

9-(3-Nitrobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 371 (M+1); Rt=3.78 min.

Example 758

General Procedure (J)

9-(3,4-Dichlorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 394 (M+1); Rt=5.62 min.

Example 759

General Procedure (J)

9-(2,4-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.88 (1H, d), 7.69 (1H, d), 7.52 (1H, t), 7.36-7.24 (2H, m), 7.06-6.91 (2H, m), 5.78 (2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 760

General Procedure (J)

9-(3,5-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.90 (1H, bs), 8.31 (1H, d), 8.13 (1H, bd), 7.90 (1H, d), 7.73 (1H, d), 7.54 (1H, t), 7.34 (1H, t), 7.14 (1H, t), 6.87 (2H, bd), 5.80 (2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 761

General Procedure (J)

9-(3,4-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, bs), 8.29 (1H, d), 8.12 (1H, bd), 7.92 (1H, d), 7.74 (1H, d), 7.54 (1H, t), 7.42-7.25 (3H, m), 6.97 (1H, bm), 5.75 (2H, s); HPLC-MS (Method B): m/z: 362 (M+1); Rt=5.17 min.

Example 762

General Procedure (J)

9-(3-Iodobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method B): m/z: 452 (M+1); Rt=5.50 min.

Example 763

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-[3-(trifluoromethyl)benzyl]-9H-carbazole

¹H-NMR (DMSO-d₆): δ8.89 (1H, d), 8.30 (1H, d), 8.11 (1H, dd), 7.90 (1H, d), 7.72 (1H, d), 7.67 (1H, bs), 7.62 (1H, bd), 7.53 (1H, t), 7.50 (1H, bt), 7.33 (1H, bd), 7.32 (1H, t), 5.87 (2H, s); HPLC-MS (Method B): m/z: 394 (M+1); Rt=5.40 min.

Example 764

General Procedure (J)

N-(4-Carboxyphenyl)-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

3.6 fold excess sodium hydride was used.

HPLC-MS (Method B): m/z: 413 (M+1); Rt=3.92 min.

Example 765

General Procedure (J)

N-(2-Propyl)-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 335 (M+1); Rt=3.70 min.

Example 766

General Procedure (J)

N-Benzyl-N-phenyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 459 (M+1); Rt=5.37 min.

Example 767

General Procedure (J)

N-[4-(2-Methyl-2-propyl)phenyl]-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method B): m/z: 425 (M+1); Rt=5.35 min.

Example 768

General Procedure (J)

N-Phenethyl-2-[3-(2H-tetrazol-5-yl)carbazol-9-yl]acetamide

HPLC-MS (Method C): m/z: 397 (M+1); Rt=3.43 min.

Example 769

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-[2-(trifluoromethyl)benzyl]-9H-carbazole

HPLC-MS (Method C): m/z: 394 (M+1); Rt=4.44 min.

Example 770

General Procedure (J)

9-[2-Fluoro-6-(trifluoromethyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 412 (M+1); Rt=4.21 min.

Example 771

General Procedure (J)

9-[2,4-Bis(trifluoromethyl)benzyl)]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 462 (M+1); Rt=4.82 min.

Example 772

General Procedure (J)

3-(2H-Tetrazol-5-yl)-9-(2,4,6-trimethylbenzyl)-9H-carbazole

HPLC-MS (Method C): m/z: 368 (M+1); Rt=4.59 min.

Example 773

General Procedure (J)

9-(2,3,5,6-Tetramethylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 382 (M+1); Rt=4.47 min.

Example 774

General Procedure (J)

9-[(Naphthalen-1-yl)methyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 376 (M+1); Rt=4.43 min.

Example 775

General Procedure (J)

9-[Bis(4-fluorophenyl)methyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 438 (M+1); Rt=4.60 min.

Example 776

General Procedure (J)

9-(2-Bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 404 (M+1); Rt=4.50 min.

Example 777

General Procedure (J)

9-(2-Fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 344 (M+1); Rt=4.09 min.

Example 778

General Procedure (J)

9-(4-Carboxy-2-methylbenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 384 (M+1); Rt=3.56 min.

Example 779

General Procedure (J)

9-(2-Phenylethyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 340 (M+1); Rt=4.08 min.

Example 780

General Procedure (J)

9-[2-Fluoro-5-(trifluoromethyl)benzyl]-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z: 412 (M+1); Rt=4.34 min.

Example 781

General Procedure (J)

9-(4-Carboxy-2-fluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

3-Fluoro-4-methylbenzoic acid (3.0 g, 19.5 mmol) and benzoyl peroxide (0.18 g, 0.74 mmol) were suspended in benzene. The mixture was purged with N₂ and heated to reflux. N-Bromosuccinimide (3.47 g, 19.5 mmol) was added portionwise, and reflux was maintained for 18 hours. The reaction mixture was concentrated, and the residue was washed with water (20 mL) at 70° C. for 1 hour. The crude product was isolated by filtration and washed with additional water (2×10 mL). The dry product was recrystallized from heptanes. Filtration furnished 4-bromomethyl-3-fluorobenzoic acid (1.92 g) which was used in the following step according to General Procedure (J).

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 388 (M+1); Rt=3.49 min.

Example 782

General Procedure (J)

5-{4-[[(3-(2H-Tetrazol-5-yl)carbazol-9-yl)methyl]naphthalen-1-yl]oxy}pentanoic Acid

5-[(4-Formylnaphthalen-1-yl)oxy]pentanoic acid intermediate obtained in example 470(3.0 g, 11.0 mmol) was dissolved in a mixture of methanol and tetrahydrofuran (9:1) (100 mL), and sodium borohydride (1.67 g, 44.1 mmol) was added portionwise at ambient temperature. After 30 minutes, the reaction mixture was concentrated to 50 mL and added to hydrochloric acid (0.1 N, 500 mL). Additional hydrochloric acid (1 N, 40 mL) was added, and 5-[(4-hydroxymethyl-naphthalen-1-yl)oxy]pentanoic acid (2.90 g) was collected by filtration. To the crude product was added concentrated hydrochloric acid (100 mL), and the suspension was stirred vigorously for 48 hours at room temperature. The crude product was filtered off and washed with water, until the pH was essentially neutral. The material was washed with heptanes to furnish 5-[(4-chloromethylnaphthalen-1-yl)oxy]pentanoic acid (3.0 g) which was used in the following step according to General Procedure (J).

In this preparation, a 3.6-fold excess of sodium hydride was used.

HPLC-MS (Method C): m/z: 492 (M+1); Rt=4.27 min.

Example 783

General Procedure (J)

9-(2,3-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=4.13 min.

Example 784

General Procedure (J)

9-(2,5-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=4.08 min.

Example 785

General Procedure (J)

9-Pentafluorophenylmethyl-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=416 (M+1); Rt=4.32 min.

Example 786

General Procedure (J)

9-(2,6-Difluorobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole

HPLC-MS (Method C): m/z=362 (M+1); Rt=3.77 min.

Further compounds of the invention that may be prepared according to general procedure (J), and includes:

Example 787
Example 788
Example 789
Example 790
Example 791
Example 792
Example 793
Example 794
Example 795
Example 796
Example 797
Example 798
Example 799

The following compounds of the invention may be prepared eg. from 9-(4-bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole (example 736) or from 9-(3-bromobenzyl)-3-(2H-tetrazol-5-yl)-9H-carbazole (example 730) and aryl boronic acids via the Suzuki coupling reaction eg as described in Littke, Dai & Fu J. Am. Chem. Soc., 2000, 122, 4020-8 (or references cited therein), or using the methodology described in general procedure (E), optionally changing the palladium catalyst to bis(tri-tert-butylphosphine)palladium (0).

Example 800
Example 801
Example 802
Example 803
Example 804
Example 805

General Procedure (K) for Preparation of Compounds of General Formula I₁₀:

wherein T is as defined above.

The general procedure (K) is further illustrated by the following example:

Example 806

General Procedure (K)

1-Benzyl-5-(2H-tetrazol-5-yl)-1H-indole

5-Cyanoindole (1.0 g, 7.0 mmol) was dissolved in N,N-dimethylformamide (14 mL) and cooled in an ice-water bath. Sodium hydride (0.31 g, 60 %, 7.8 mmol) was added, and the resulting suspension was stirred for 30 min. Benzyl chloride (0.85 mL, 0.94 g, 7.4 mmol) was added, and the cooling was discontinued. The stirring was continued for 65 hours at room temperature. Water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (30 mL) and dried with sodium sulfate (1 hour). Filtration and concentration yielded the crude material. Purification by flash chromatography on silica gel eluting with ethyl acetate/heptanes=1:3 afforded 1.60 g 1-benzyl-1H-indole-5-carbonitrile.

HPLC-MS (Method C): m/z: 233 (M+1); Rt=4.17 min.

1-Benzyl-1H-indole-5-carbonitrile was transformed into 1-benzyl-5-(2H-tetrazol-5-yl)-1H-indole by the method described in general procedure (J) and in example 594. Purification was done by flash chromatography on silica gel eluting with dichloromethane/methanol=9:1.

HPLC-MS (Method C): m/z: 276 (M+1); Rt=3.35 min.

The compounds in the following examples were prepared by the same procedure.

Example 807

General Procedure (K)

1-(4-Bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method C): m/z: 354 (M+1); Rt=3.80 min.

Example 808

General Procedure (K)

1-(4-Phenylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

¹H-NMR (200 MHz, DMSO-d₆): δ=5.52 (2H, s), 6.70 (1H, d), 7.3-7.45 (6H, m), 7.6 (4H, m), 7.7-7.8 (2H, m), 7.85(1H, dd), 8.35 (1H, d). Calculated for C₂₂H₁₇N₅, H₂O: 73.32% C; 5.03% H; 19.43% N. Found: 73.81% C; 4.90% H; 19.31% N.

Example 809

4′-[5-(2H-Tetrazol-5-yl)indol-1-ylmethyl]biphenyl-4-carboxylic acid

5-(2H-Tetrazol-5-yl)-1H-indole (Syncom BV, Groningen, NL) (1.66 g, 8.9 mmol) was treated with trityl chloride (2.5 g, 8.9 mmol) and triethyl amine (2.5 mL, 17.9 mmol) in DMF(25 mL) by stirring at RT overnight. The resulting mixture was treated with water. The gel was isolated, dissolved in methanol, treated with activated carbon; filtered and evaporated to dryness in vacuo. This afforded 3.6 g (94%) of crude 5-(2-trityl-2H-tetrazol-5-yl)-1H-indole.

HPLC-MS (Method C): m/z=450 (M+23); Rt.=5.32 min.

4-Methylphenylbenzoic acid (5 g, 23.5 mmol) was mixed with CCl₄ (100 mL) and under an atmosphere of nitrogen, the slurry was added N-Bromosuccinimide (4.19 g, 23.55 mmol) and dibenzoyl peroxide (0.228 g, 0.94 mmol). The mixture was subsequently heated to reflux for 0.5 hour. After cooling, DCM and water (each 30 mL) were added. The resulting precipitate was isolated, washed with water and a small amount of methanol. The solid was dried in vacuo to afford 5.27 g (77%) of 4′-bromomethylbiphenyl-4-carboxylic acid.

HPLC-MS (Method C): m/z=291 (M+1); Rt.=3.96 min.

5-(2-Trityl-2H-tetrazol-5-yl)-1H-indole (3.6 g, 8.4 mmol) was dissolved in DMF (100 mL). Under nitrogen, NaH (60% suspension in mineral oil, 34 mmol) was added slowly. 4′-Bromomethylbiphenyl-4-carboxylic acid (2.7 g, 9.2 mmol) was added over 5 minutes and the resulting slurry was heated at 40° C. for 16 hours. The mixture was poured into water (100 mL) and the precipitate was isolated by filtration and treated with THF/6N HCl (9/1) (70 mL) at room temperature for 16 hours. The mixture was subsequently evaporated to dryness in vacuo, the residue was treated with water and the solid was isolated by filtration and washed thoroughly 3 times with DCM. The solid was dissolved in hot THF (400 mL) treated with activated carbon and filtered. The filtrate was evaporated in vacuo to dryness. This afforded 1.6 g (50%) of the title compound.

HPLC-MS (Method C): m/z=396 (M+1); Rt.=3.51 min.

Example 810

General Procedure (K)

5-(2H-Tetrazol-5-yl)-1H-indole

5-(2H-Tetrazol-5-yl)-1H-indole was prepared from 5-cyanoindole according to the method described in example 594.

HPLC-MS (Method C): m/z: 186 (M+1); Rt=1.68 min.

Example 811

General Procedure (K)

1-Benzyl-4-(2H-tetrazol-5-yl)-1H-indole

1-Benzyl-1H-indole-4-carbonitrile was prepared from 4-cyanoindole according to the method described in example 806.

HPLC-MS (Method C): m/z: 233 (M+1); Rt=4.24 min.

1-Benzyl-4-(2H-tetrazol-5-yl)-1H-indole was prepared from 1-benzyl-1H-indole-4-carbonitrile according to the method described in example 594.

HPLC-MS (Method C): m/z: 276 (M+1); Rt=3.44 min.

General Procedure (L) for Preparation of Compounds of General Formula I₁₁:

wherein T is as defined above and

• • Pol—is a polystyrene resin loaded with a 2-chlorotrityl linker, graphically shown below:

This general procedure (L) is further illustrated by the following example:

Example 812

General Procedure (L)

5-(2H-Tetrazol-5-yl)-1-[3-(trifluoromethyl)benzyl]-1H-indole

2-Chlorotritylchloride resin (100 mg, 0.114 mmol active chloride) was swelled in dichloromethane (2 mL) for 30 min. The solvent was drained, and a solution of 5-(2H-tetrazol-5-yl)-1H-indole (example 810) (63 mg, 0.34 mmol) in a mixture of N,N-dimethylformamide, dichloromethane and N,N-di(2-propyl)ethylamine (DIPEA) (5:5:2) (1.1 mL) was added. The reaction mixture was shaken at room temperature for 20 hours. The solvent was removed by filtration, and the resin was washed consecutively with N,N-dimethylformamide (2×4 mL), dichloromethane (6×4 mL) and methyl sulfoxide (2×4 mL). Methyl sulfoxide (1 mL) was added, followed by the addition of a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 0.57 mL, 0.57 mmol). The mixture was shaken for 30 min at room temperature, before 3-(trifluoromethyl)benzyl bromide (273 mg, 1.14 mmol) was added as a solution in methyl sulfoxide (0.2 mL). The reaction mixture was shaken for 20 hours at room temperature. The drained resin was washed consecutively with methyl sulfoxide (2×4 mL), dichloromethane (2×4 mL), methanol (2×4 mL), dichloromethane (2×4 mL) and tetrahydrofuran (4 mL). The resin was treated with a solution of hydrogen chloride in tetrahydrofuran, ethyl ether and ethanol=8:1:1 (0.1 M, 3 mL) for 6 hours at room temperature. The resin was drained and the filtrate was concentrated in vacuo. The crude product was re-suspended in dichloromethane (1.5 mL) and concentrated three times to afford the title compound (35 mg). No further purification was necessary.

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.35 min. ¹H-NMR (DMSO-d₆): δ8.29 (1H, s), 7.80 (1H, dd), 7.72 (2H, m), 7.64 (2H, bs), 7.56 (1H, t), 7.48 (1H, d), 6.70 (1H, d), 5.62 (2H, s).

The compounds in the following examples were prepared in a similar fashion. Optionally, the compounds can be further purified by recrystallization or by chromatography.

Example 813

General Procedure (L)

1-(4-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.11 min.

Example 814

General Procedure (L)

1-(2-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.05 min.

Example 815

General Procedure (L)

1-(4-Methoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 306 (M+1); Rt=3.68 min.

Example 816

General Procedure (L)

1-(4-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Example 817

General Procedure (L)

5-(2H-Tetrazol-5-yl)-1-[4-(trifluoromethyl)benzyl]-1H-indole

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.18 min.

Example 818

General Procedure (L)

1-(3-Chlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 310 (M+1); Rt=4.01 min.

Example 819

General Procedure (L)

1-(3-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Example 820

General Procedure (L)

1-(2,4-Dichlorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 344 (M+1); Rt=4.41 min.

Example 821

General Procedure (L)

1-(3-Methoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 306 (M+1); Rt=3.64 min.

Example 822

General Procedure (L)

1-(4-Fluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 294 (M+1); Rt=3.71 min.

Example 823

General Procedure (L)

1-(3-Fluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 294 (M+1); Rt=3.68 min.

Example 824

General Procedure (L)

1-(2-Iodobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 402 (M+1); Rt=4.11 min.

Example 825

General Procedure (L)

1-[(Naphthalen-2-yl)methyl]-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 326 (M+1); Rt=4.18 min.

Example 826

General Procedure (L)

1-(3-Bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 354 (M+1); Rt=4.08 min.

Example 827

General Procedure (L)

1-(4-Carboxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

In this preparation, a larger excess of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) was used.

HPLC-MS (Method B): m/z: 320 (M+1); Rt=2.84 min.

Example 828

General Procedure (L)

1-(3-Carboxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

In this preparation, a larger excess of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.7 mL, 1.7 mmol) was used.

HPLC-MS (Method B): m/z: 320 (M+1); Rt=2.91 min.

Example 829

General Procedure (L)

1-(2,4-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.78 min.

Example 830

General Procedure (L)

1-(3,5-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.78 min.

Example 831

General Procedure (L)

1-(3,4-Difluorobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 312 (M+1); Rt=3.81 min.

Example 832

General Procedure (L)

1-[4-(2-Propyl)benzyl]-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 318 (M+1); Rt=4.61 min.

Example 833

General Procedure (L)

1-(3,5-Dimethoxybenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 336 (M+1); Rt=3.68 min.

Example 834

General Procedure (L)

1-(2′-Cyanobiphenyl-4-yl methyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 377 (M+1); Rt=4.11 min.

Example 835

General Procedure (L)

1-(2-Methylbenzyl)-5-(2H-tetrazol-5-yl)-1H-indole

HPLC-MS (Method B): m/z: 290 (M+1); Rt=3.98 min.

Further compounds of the invention that may be prepared according to general procedure (K) and/or (L) includes:

Example 836
Example 837
Example 838
Example 839
Example 840
Example 841
Example 842
Example 843
Example 844
Example 845
Example 846
Example 847
Example 848
Example 849
Example 850
Example 851
Example 852
Example 853
Example 854
Example 855
Example 856
Example 857
Example 858
Example 859

The following compounds of the invention may be prepared eg. from 1-(4-bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole (example 807) or from the analogue 1-(3-bromobenzyl)-5-(2H-tetrazol-5-yl)-1H-indole and aryl boronic acids via the Suzuki coupling reaction eg as described in Littke, Dai & Fu J. Am. Chem. Soc., 2000, 122, 4020-8 (or references cited therein), or using the methodology described in general procedure (E), optionally changing the palladium catalyst to bis(tri-tert-butylphosphine)palladium (0).

Example 860
Example 861
Example 862
Example 863
Example 864

General Procedure (M) for Preparation of Compounds of General Formula I₁₂:

wherein T is as defined above.

The general procedure (M) is further illustrated by the following example:

Example 865

General Procedure (M)

1-Benzoyl-5-(2H-tetrazol-5-yl)-1H-indole

To a solution of 5-cyanoindole (1.0 g, 7.0 mmol) in dichloromethane (8 mL) was added 4-(dimethylamino)pyridine (0.171 g, 1.4 mmol), triethylamine (1.96 mL, 1.42 g, 14 mmol) and benzoyl chloride (0.89 mL, 1.08 g, 7.7 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture was diluted with dichloromethane (80 mL) and washed consecutively with a saturated solution of sodium hydrogencarbonate (40 mL) and brine (40 mL). The organic phase was dried with magnesium sulfate (1 hour). Filtration and concentration furnished the crude material which was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes=2:3. 1-Benzoyl-1H-indole-5-carbonitrile was obtained as a solid.

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.07 min.

1-Benzoyl-1H-indole-5-carbonitrile was transformed into 1-benzoyl-5-(2H-tetrazol-5-yl)-1H-indole by the method described in example 594.

HPLC (Method C): Rt=1.68 min.

The compound in the following example was prepared by the same procedure.

Example 866

General Procedure (M)

1-Benzoyl-4-(2H-tetrazol-5-yl)-1H-indole

1-Benzoyl-1H-indole-4-carbonitrile was prepared from 4-cyanoindole according to the method described in example 865.

HPLC-MS (Method C): m/z: 247 (M+1); Rt=4.24 min.

1-Benzoyl-4-(2H-tetrazol-5-yl)-1H-indole was prepared from 1-benzoyl-1H-indole-4-carbonitrile according to the method described in example 594.

HPLC (Method C): Rt=1.56 min.

Example 867

General Procedure (M)

(2-Fluoro-3-trifluoromethylphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=376 (M+1); Rt=4.32 min.

Example 868

General Procedure (M)

(4-Methoxyphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=320 (M+1); Rt=3.70 min.

Example 869

General Procedure (M)

(3-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.72 min.

Example 870

General Procedure (M)

(4-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.71 min.

Example 871

General Procedure (M)

Naphthalen-2-yl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z=340 (M+1); Rt=4.25 min.

Example 872

General Procedure (M)

(2,3-Difluorophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B: m/z=326 (M+1); Rt=3.85 min.

The following known and commercially available compounds do all bind to the His B10 Zn²⁺ site of the insulin hexamer:

Example 873

1-(4-Fluorophenyl)-5-(2H-tetrazol-5-yl)-1H-indole

Example 874

1-Amino-3-(2H-tetrazol-5-yl)benzene

Example 875

1-Amino-4-(2H-tetrazol-5-yl)benzene

A mixture of 4-aminobenzonitrile (10 g, 84.6 mmol), sodium azide (16.5 g, 254 mmol) and ammonium chloride (13.6 g, 254 mmol) in DMF was heated at 125° C. for 16 hours. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residue was added water (200 mL) and diethyl ether (200 mL) which resulted in crystallisation. The mixture was filtered and the solid was dried in vacuo at 40° C. for 16 hours to afford 5-4-aminophenyl)-2H-tetrazole.

¹H NMR DMSO-d₆): δ=5.7 (3H, bs), 6.69 (2H, d), 7.69 (2H, d). HPLC-MS (Method C): m/z: 162 (M+1); Rt=0.55 min.

Example 8761

Nitro-4-(2H-tetrazol-5-yl)benzene

Example 8771

Bromo-4-(2H-tetrazol-5-yl)benzene

General Procedure (N) for Solution Phase Preparation of Amides of General Formula I₁₃:

wherein Frag is any fragment carrying a carboxylic acid group, R is hydrogen, optionally substituted aryl or C_1-8-alkyl and R′ is hydrogen or C_1-4-alkyl.

Frag-CO₂H may be prepared eg by general procedure (D) or by other similar procedures described herein, or may be commercially available.

The procedure is further illustrated in the following example 878:

Example 878

General Procedure (N)

N-(4-Chlorobenzyl)-2-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)-1H-indol-1-yl]acetamide

[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indol-1-yl]acetic acid (example 478, 90.7 mg, 0.3 mmol) was dissolved in NMP (1 mL) and added to a mixture of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide, hydrochloride (86.4 mg, 0.45 mmol) and 1-hydroxybenzotriazol (68.8 mg, 0.45 mmol) in NMP (1 mL). The resulting mixture was shaken at RT for 2 h. 4-Chlorobenzylamine (51 mg, 0.36 mmol) and DIPEA (46.4 mg, 0.36 mmol) in NMP (1 mL) were added to the mixture and the resulting mixture shaken at RT for 2 days. Subsequently ethyl acetate (10 mL) was added and the resulting mixture washed with 2×10 mL water followed by saturated ammonium chloride (5 mL). The organic phase was evaporated to dryness giving 75 mg (57%) of the title compound.

HPLC-MS (Method C): m/z: 426 (M+1); Rt.=3.79 min.

Example 879

General Procedure (N)

N-(4-Chlorobenzyl)-4-[2-chloro-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 465 (M+1); Rt=4.35 min.

Example 880

General Procedure (N)

N-(4-Chlorobenzyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 431 (M+1); Rt=3.68 min.

Example 881

General Procedure (N)

2-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]-N-(4-chlorobenzyl)acetamide

HPLC-MS (Method A): m/z: 483 (M+1); Rt=4.06 min.

Example 882

General Procedure (N)

N-(4-Chlorobenzyl)-2-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetamide

HPLC-MS (Method A): m/z: 403 (M+1); Rt=4.03 min.

Example 883

General Procedure (N)

N-(4-Chlorobenzyl)-3-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]acrylamide

HPLC-MS (Method A): m/z: 399 (M+1); Rt=3.82.

Example 884

General Procedure (N)

N-(4-Chlorobenzyl)-4-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyramide

HPLC-MS (Method A): m/z: 431 (M+1); Rt=3.84 min.

Example 885

General Procedure (N)

4-[2-Bromo-4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]-N-(4-chlorobenzyl)butyramide

HPLC-MS (Method A): m/z: 511 (M+1); Rt=4.05 min.

Example 886

General Procedure (N)

4-[2-Bromo-4-(4-oxo-2-thioxothiazolidin-5-ylidenemethyl)-phenoxy]-N-(4-chlorobenzyl)-butyramide

HPLC-MS (Method A): m/z: 527 (M+1); Rt=4.77 min.

Example 887

General Procedure (N)

N-(4-Chlorobenzyl)-2-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]acetamide

HPLC-MS (Method C): m/z: 431 (M+1); Rt.=4.03 min.

Example 888

General Procedure (N)

N-(4-Chlorobenzyl)-3-[3-(2,4-dioxothiazolidin-5-ylidenemethyl)-1H-indol-1-yl]propionamide

HPLC-MS (Method C): m/z: 440 (M+1); Rt.=3.57 min.

Example 889

General Procedure (N)

N-(4-Chlorobenzyl)-4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyramide

HPLC-MS (Method C): m/z: 481 (M+1); Rt=4.08 min.

Example 890

General Procedure (N)

4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-N-hexylbutyramide

HPLC-MS (Method C): m/z: 441 (M+1); Rt=4.31 min.

Example 891

General Procedure (N)

4-({[3-(2,4-Dioxothiazolidin-5-ylidenemethyl)indole-7-carbonyl]amino}methyl)benzoic acid methyl ester

HPLC-MS (Method C): m/z: 436 (M+1); Rt.=3.55 min.

Example 892

General Procedure (N)

N-(4-Chlorobenzyl)-4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z:493 (M+1); Rt=4.19 min.

Example 893

General Procedure (N)

N-(4-Chlorobenzyl)-3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z: 493 (M+1); Rt=4.20 min.

Example 894

General Procedure (N)

N-(4-Chlorobenzyl)-3-methyl-4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]benzamide

HPLC-MS (Method C): m/z: 507 (M+1); Rt=4.37 min.

Example 895

General Procedure (N)

5-{2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-acetylamino}-isophthalic acid dimethyl ester

HPLC-MS (Method C): m/z=521 (M+1); Rt.=4.57 min.

Example 896

General Procedure (N)

5-2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-acetylamino)isophthalic acid

HPLC-MS (Method C): m/z=515 (M+23); Rt.=3.09 min.

Example 897

General Procedure (N)

5-(3-2-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-ethyl}-ureido)-isophthalic acid monomethyl ester

HPLC-MS (Method C): m/z=536 (M+1); Rt=3.58 min.

Example 898

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic acid dimethyl ester

4-[3-(1H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid (2.00 g, 5.41 mmol), 1-hydroxybenzotriazole (1.46 g, 10.8 mmol) and N,N-di(2-propyl)ethylamine (4.72 mL, 3.50 g, 27.1 mmol) were dissolved in dry N,N-dimethylformamide (60 mL). The mixture was cooled in an ice-water bath, and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.45 g, 7.56 mmol) and (S)-aminosuccinic acid dimethyl ester hydrochloride (1.28 g, 6.48 mmol) were added. The cooling was discontinued, and the reaction mixture was stirred at room temperature for 18 hours before it was poured into hydrochloric acid (0.1 N, 600 mL). The solid was collected by filtration and washed with water (2×25 mL) to furnish the title compound.

HPLC-MS (Method C): m/z: 513 (M+1); Rt=3.65 min. ¹H-NMR (DMSO-d₆): δ 8.90 (1H, d), 8.86 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.87 (1H, d), 7.75 (2H, d), 7.69 (1H, d), 7.51 (1H, t), 7.32 (1H, t), 7.28 (2H, d), 5.82 (2H, s), 4.79 (1H, m), 3.61 (3H, s), 3.58 (3H, s), 2.92 (1H, dd), 2.78 (1H, dd).

Example 899

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic acid

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic acid dimethyl ester (1.20 g, 2.34 mmol) was dissolved in tetrahydrofuran (30 mL). Aqueous sodium hydroxide (1 N, 14 mL) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into hydrochloric acid (0.1 N, 500 mL). The solid was collected by filtration and washed with water (2×25 mL) and diethyl ether (2×25 mL) to furnish the title compound.

HPLC-MS (Method C): m/z: 485 (M+1); Rt=2.94 min. ¹H-NMR (DMSO-d₆): δ 12.44 (2H, s (br)), 8.90 (1H, d), 8.68 (1H, d), 8.29 (1H, d), 8.11 (1H, dd), 7.87 (1H, d), 7.75 (2H, d), 7.68 (1H, d), 7.52 (1H, t), 7.32 (1H, t), 7.27 (2H, d), 5.82 (2H, s), 4.70 (1H, m), 2.81 (1H, dd), 2.65 (1H, dd).

The compounds in the following examples were prepared in a similar fashion.

Example 900

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino}-succinic acid dimethyl ester

HPLC-MS (Method C): m/z=513 (M+l); Rt=3.65 min.

Example 901

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.57 min.

Example 902

General Procedure (N)

(Methoxycarbonylmethyl-{4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-acetic acid methyl ester

HPLC-MS (Method C): m/z=513 (M+1); Rt=3.55 min.

Example 903

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid

HPLC-MS (Method C): m/z=499 (M+1); Rt=2.87 min.

Example 904

General Procedure (N)

(Ethoxycarbonylmethyl-{4-[3-(2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-acetic acid ethyl ester

HPLC-MS (Method C): m/z=541 (M+1); Rt=3.91 min.

Example 905

General Procedure (N)

3-(3-{4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-hexanedioic acid dimethyl ester

HPLC-MS (Method C: m/z=585 (M+1); Rt=2.81 min.

Example 906

General Procedure (N)

3-(3-{4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-hexanedioic acid

HPLC-MS (Method C): m/z=554 (M−3); Rt=3.19 min.

Example 907

General Procedure (N)

(Carboxymethyl-{4-[3-2H-tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoyl}-amino)-acetic acid

HPLC-MS (Method C): m/z=485 (M+1); Rt=3.04 min.

Example 908

General Procedure (N)

4-(3-{4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]-butyrylamino}-propylamino)-cyclohexane-1,3-dicarboxylic acid dimethyl ester

HPLC-MS (Method C): m/z=612 (M+1); Rt=3.24 min.

Example 909

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 910

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 911

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid dimethyl ester

HPLC-MS (Method C): m/z=527 (M+1); Rt=3.65 min.

Example 912

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid

HPLC-MS (Method C): m/z=499 (M+1); Rt=3.00 min.

Example 913

General Procedure (N)

(Methoxycarbonylmethyl-{3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoyl}amino)acetic acid methyl ester

¹H-NMR (DMSO-d₆): δ 8.88 (1H, d), 8.29 (1H, d), 8.10 (1H, dd), 7.85 (1H, d), 7.67 (1H, d), 7.52 (1H, t), 7.39 (1H, t), 7.30 (2H, m), 7.17 (2H, m), 5.79 (2H, s), 4.17 (2H, s), 4.02 (2H, s), 3.62 (3H, s), 3.49 (3H, s).

Example 914

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}succinic acid dimethyl ester

HPLC-MS (Method C): m/z=513 (M+1); Rt=3.70 min.

Example 915

General Procedure (N)

2-{3-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino}-succinic acid

HPLC-MS (Method C): m/z=485 (M+1); Rt=2.96 min.

Example 916

General Procedure (N)

(Carboxymethyl-{3-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoyl}amino)acetic acid

HPLC-MS (Method C): m/z=485 (M+1); Rt=2.87 min.

Example 917

General Procedure (N)

4-(4-(3-Carboxy-propylcarbamoyl)4-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]-benzoylamino}-butyrylamino)-butyric acid

The title compound was prepared by coupling of (S)-2-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino)pentanedioic acid bis-(2,5-dioxopyrrolidin-1-yl) ester (prepared from (S)-2-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}pentanedioic acid by essentially the same procedure as described for the synthesis of 4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid 2,5-dioxopyrrolidin-1-yl ester) with 4-aminobutyric acid according to the procedure described for the preparation of 4-{4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}butyric acid.

HPLC-MS (Method C): m/z: 669 (M+1); Rt=2.84 min.

Example 918

General Procedure (N)

[2-(2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]benzoylamino}ethoxy)ethoxy]acetic acid

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.10 min.

Example 919

General Procedure (N)

2-{4-[3-(2H-Tetrazol-5-yl)-carbazol-9-ylmethyl]-benzoylamino-pentanedioic acid di-tert-butyl ester

HPLC-MS (Method C): m/z=611 (M+1); Rt=4.64 min.

Example 920

General Procedure (N)

4-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}butyric Acid

HPLC-MS (Method C): m/z: 455 (M+1); Rt=3.13 min.

Example 921

General Procedure (N)

[2-(2-{4-[3-(2H-Tetrazol-5-yl)carbazol-9-ylmethyl]benzoylamino}ethoxy)ethoxy]acetic acid

The title compound was prepared by coupling of 4-[3-(2H-tetrazol-5-yl)carbazol-9-ylmethyl]benzoic acid 2,5-dioxopyrrolidin-1-yl ester with [2-(2-aminoethoxy)ethoxy]acetic acid (prepared from [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid by treatment with PS-Trisamine resin in DMF).

HPLC-MS (Method C): m/z: 515 (M+1); Rt=3.10 min.

The commercially available compounds in the following examples do all bind to the HisB10 Zn²⁺ site:

Example 922

1-(4-Bromo-3-methylphenyl)-1,4-dihydrotetrazole-5-thione

Example 923

1-(4-Iodophenyl)-1,4-dihydrotetrazole-5-thione

Example 924

1-(2,4,5-Trichlorophenyl)-1H-tetrazole-5-thiol

Example 925

1-(2,6-Dimethylphenyl)-1,4-dihydrotetrazole-5-thione

Example 926

1-(2,4,6-Trimethylphenyl)-1,4-dihydrotetrazole-5-thione

Example 927

1-(4-Dimethylaminophenyl)-1H-tetrazole-5-thiol

Example 928

1-(3,4-Dichlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 929

1-(4-Propylphenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 930

1-(3-Chlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 931

1-(2-Fluorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 932

1-(2,4-Dichlorophenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 933

1-(4-Trifluoromethoxyphenyl)-1,4-dihydro-1H-tetrazole-5-thione

Example 934

N-[4-(5-Mercaptotetrazol-1-yl)-phenyl]-acetamide

Example 935

1-(4-Chlorophenyl)-1,4-dihydrotetrazole-5-thione

Example 936

1-(4-Methoxyphenyl)-1,4-dihydrotetrazole-5-thione

Example 937

1-(3-Fluoro-4-pyrrolidin-1-ylphenyl)-1,4-dihydrotetrazole-5-thione

Example 938

N-[3-(5-Mercaptotetrazol-1-yl)phenyl]acetamide

Example 939

1-(4-Hydroxyphenyl)-5-mercaptotetrazole

Example 940

Preparation of 1-aryl-1,4-dihydrotetrazole-5-thiones (or the tautomeric 1-aryltetrazole-5-thiols) is described in the literature (eg. by Kauer & Sheppard, J. Org. Chem., 32, 3580-92 (1967)) and is generally performed eg. by reaction of aryl-isothiocyanates with sodium azide followed by acidification

1-Aryl-1,4-dihydrotetrazole-5-thiones with a carboxylic acid tethered to the aryl group may be prepared as shown in the following scheme:

Step 1 is a phenol alkylation and is very similar to steps 1 and 2 of general procedure (D) and may also be prepared similarly as described in example 481.

Step 2 is a reduction of the nitro group. SnCl₂, H₂ over Pd/C and many other procedures known to those skilled in the art may be utilised.

Step 3 is formation of an arylisothiocyanate from the corresponding aniline. As reagents CS₂, CSCl₂, or other reagents known to those skilled in the art, may be utilised.

Step 4 is a conversion to mercaptotetrazole as described above.

Compounds of the invention include:
Example 941
Example 942
Example 943
Example 944
Example 945
Example 946
Example 947

Example 948

4-(4-Hydroxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Phenylsulphonyl acetonitrile (2.0 g, 11.04 mmol) was mixed with 4-hydroxybenzaldehyde (1.35 g, 11.04 mmol) in DMF (10 mL) and toluene (20 mL). The mixture was refluxed for 3 hours and subsequently evaporated to dryness in vacuo. The residue was treated with diethyl ether and toluene. The solid formed was filtered to afford 2.08 g (66%) of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile.

HPLC-MS (Method C): m/z: 286 (M+1); Rt.=3.56 min.

A mixture of 2-benzenesulfonyl-3-(4-hydroxyphenyl)acrylonitrile (2.08 g, 7.3 mmol) and sodium azide (0.47 g, 7.3 mmol) in DMF (50 mL) was heated at reflux temperature 2 hours. After cooling, the mixture was poured on ice. The mixture was evaporated in vacuo to almost dryness and toluene was added. After filtration, the organic phase was evaporated in vacuo. The residue was purified by silicagel chromatography eluting with a mixture of ethyl acetate and heptane (1:2). This afforded 1.2 g (76%) of the title compound.

1H NMR (DMSO-d₆): 10.2 (broad,1H); 7.74 (d,2H); 6.99 (d,2H); 3.6-3.2 (broad,1H). HPLC-MS (Method C) m/z:=187 (M+1); Rt.=1.93 min

General Procedure (O) for Preparation of Compounds of General Formula I₁₄:

wherein

• • AA is as defined above,

Steps 1 and 2 are described in the literature (eg Beck & Gûnther, Chem. Ber., 106, 2758-66 (1973))

Step 1 is a Knoevenagel condensation of the aldehyde AA-CHO with phenylsulfonyl-acetonitrile and step 2 is a reaction of the vinylsulfonyl compound obtained in step 1 with sodium azide. This reaction is usually performed in DMF at 90-110° C.

This general procedure is further illustrated in the following example 949:

Example 949

General Procedure (O)

[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy]acetic acid

Phenylsulphonylacetonitrile (0.1 g, 0.55 mmol) was mixed with 4-formylphenoxyactic acid (0.099 g, 0.55 mmol) in DMF (3 mL) and heated to 110° C. for 3 h and subsequently cooled to RT. Sodium azide (0.036 g, 0.55 mmol) was added and the resulting mixture was heated to 110° C. for 3 h and cooled to RT. The mixture was poured into water (20 mL) and centrifuged. The supernatant was discarded, ethanol (5 mL) was added and the mixture was centrifuged again. After discarding the supernatant, the residue was dried in vacuo to afford 50 mg (37%) of [4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy]acetic acid.

HPLC-MS (Method C): m/z: 245 (M+1) Rt. 2.19 min.

Example 950

General Procedure (O)

5-(Naphthalen-1-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 221 (M+1); Rt. 3.43 min.

Example 951

General Procedure (O)

5-(Naphthalen-2-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 221 (M+1); Rt=3.66 min.

Example 952

General Procedure (O)

4-[3-(5-Cyano-[1,2,3]triazol-4-yl)-1,4-dimethylcarbazol-9-ylmethyl]-benzoic acid

HPLC-MS (Method C): m/z=422 (M+1); Rt=3.85 min.

Preparation of Intermediary Aldehyde:

1,4 Dimethylcarbazol-3-carbaldehyde (0.68 g, 3.08 mmol) was dissolved in dry DMF (15 mL), NaH (diethyl ether washed) (0.162 g, 6.7 mol) was slowly added under nitrogen and the mixture was stirred for 1 hour at room temperature. 4-Bromomethylbenzoic acid (0.73 g, 3.4 mmol) was slowly added and the resulting slurry was heated to 40° C. for 16 hours. Water (5 mL) and hydrochloric acid (6N, 3 mL) were added. After stirring for 20 min at room temperature, the precipitate was filtered off and washed twice with acetone to afford after drying 0.38 g (34%) of 4-(3-formyl-1,4-dimethylcarbazol-9-ylmethyl)benzoic acid.

HPLC-MS (Method C): m/z=358 (M+1), RT.=4.15 min.

Example 953

General Procedure (O)

5-(Anthracen-9-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 271 (M+1); Rt=3.87 min.

Example 954

General Procedure (O)

5-(4-Methoxynaphthalen-1-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 251 (M+1); Rt=3.57 min.

Example 955

General Procedure (O)

5-(1,4-Dimethyl-9H-carbazol-3-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z: 288 (M+1); Rt=3.67 min.

Example 956

General Procedure (O)

5-(4′-Methoxybiphenyl-4-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=277 (M+1); Rt=3.60 min.

Example 957

General Procedure (O)

5-(4-Styrylphenyl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=273 (M+1); Rt=4.12 min.

Example 958

General Procedure (O)

5-(2,6-Dichloro-4-dibenzylaminophenyl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C): m/z=434 (M+1); Rt=4.64 min.

Example 959

General Procedure (O)

5-(1-Bromonaphthalen-2-yl)-3H-[1,2,3]triazole-4-carbonitrile

HPLC-MS (Method C: m/z=300 (M+1); Rt.=3.79 min.

Example 960

4-(4-Bromophenyl)-1H-[1,2,3]triazole-5-carbonitrile

This compound is commercially available (MENAI).

Example 961

N-[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)-phenyl]-acetamide

This compound is commercially available (MENAI).

Example 962

General Procedure (O)

5-(4′-Chlorobiphenyl-4-yl)-3H-[1,2,3]triazole4-carbonitrile

HPLC-MS (Method C): m/z=281 (M+1); Rt=4.22 min.

The compounds in the following examples are commercially available and may be prepared using a similar methodology:

Example 963

4-(4-Trifluoromethoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 964

4-Benzo[1,3]dioxol-5-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 965

4-(3-Trifluoromethylphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 966

4-Pyridin-3-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 967

4-(2,6-Dichlorophenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 968

4-Thiophen-2-yl-1H-[1,2,3]triazole-5-carbonitrile

Example 969

3,5-Dimethylisoxazole-4-carboxylic acid 4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 970

3,3-Dimethyl-butyric acid 4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 971

4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid 4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 972

4-Chlorobenzoic acid 4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl ester

Example 973

4-(3-Phenoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 974

4-(5-Bromo-2-methoxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile

Example 975

4-(2-Chloro-6-fluorophenyl)-1H-[1,2,3]triazole-5-carbonitrile

The following cyanotriazoles are also compounds of the invention:

• 4-(2-Chloro-6-fluorophenyl)-1H-[1,2,3]triazole-5-carbonitrile.
• Terephthalic acid mono[4-(5-cyano-1H-[1,2,3]triazol-4-yl)phenyl]ester.
• N-[4-(5-cyano-1H-[1,2,3]triazol-4-yl)-phenyl]terephthalamic acid
• 4-(4-Octyloxyphenyl)-1H-[1,2,3]triazole-5-carbonitrile
• 4-(4-Styrylphenyl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(4′-Trifluoromethylbiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(4′-Chlorobiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(4′-Methoxybiphenyl-4-yl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(1-Naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(9-Anthranyl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(4-Methoxy-1-naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(4-Aminophenyl)-1H-[1,2,3]triazole-5-carbonitrile.
• 4-(2-Naphthyl)-1H-[1,2,3]triazole-5-carbonitrile.

General Procedure (P) for Preparation of Compounds of General Formula I₁₅:

wherein

• • n is 1 or 3-20,
  • AA is as defined above,
  • R″ is a standard carboxylic acid protecting group, such as C₁-C₆-alkyl or benzyl and Lea is a leaving group, such as chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy or the like.

This procedure is very similar to general procedure (D), steps 1 and 2 are identical.

Steps 3 and 4 are described in the literature (eg Beck & Gûnther, i Chem. Ber., 106, 2758-66 (1973))

Step 3 is a Knoevenagel condensation of the aldehyde obtained in step 2 with phenylsulfonylacetonitrile and step 4 is a reaction of the vinylsulfonyl compound obtained in step 3 with sodium azide. This reaction is usually performed in DMF at 90-110° C.

This General procedure (P) is further illustrated in the following two examples

Example 976

General Procedure (P)

5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentanoic acid ethyl ester

6-Hydroxynaphthalene-2-carbaldehyde (Syncom BV. NL, 15.5 g, 90 mmol) and K₂CO₃ (62.2 g, 450 mmol) were mixed in DMF (300 mL) and stirred at room temperature for 1 hour. Ethyl 5-bromovalerate (21.65 g, 103.5 mmol) was added and the mixture was stirred at room temperature for 16 hours. Activated carbon was added and the mixture was filtered. The filtrate was evaporated to dryness in vacuo to afford 28.4 g of crude 5-(6-formylnaphthalen-2-yloxy)pentanoic acid ethyl ester, which was used without further purification.

HPLC-MS (Method C): m/z=301 (M+1); Rt.=4.39 min.

5-(6-Formylnaphthalen-2-yloxy)pentanoic acid ethyl ester (28.4 g, 94.5 mmol), phenylsulfonylacetonitrile (20.6 g, 113.5 mmol), and piperidine (0.94 mL) were dissolved in DMF (200 mL) and the mixture was heated at 50° C. for 16 hours. The resulting mixture was evaporated to dryness in vacuo and the residue was dried for 16 hours at 40° C. in vacuo. The solid was recrystallised from 2-propanol (800 mL) and dried again as described above. This afforded 35 g (80%) of 5-[6-(2-benzenesulfonyl-2-cyanovinyl)naphthalen-2-yloxy]pentanoic acid ethyl ester.

HPLC-MS (Method C): m/z=486 (M+23); Rt.=5.09 min.

5-[6-(2-Benzenesulfonyl-2-cyanovinyl)naphthalen-2-yloxy]pentanoic acid ethyl ester (35 g, 74.6 mmol) and sodium azide (4.9 g, 75.6 mmol) were dissolved in DMF (100 mL) and stirred for 16 hours at 50° C. The mixture was evaporated to dryness in vacuo, redissolved in THF/ethanol and a small amount of precipitate was filtered off. The resulting filtrate was poured into water (2.5 L). Filtration afforded after drying 24.5 g (88%) of 5-[6-(5-cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]pentanoic acid ethyl ester (24.5 g, 88%).

HPLC-MS (Method C): m/z=365 (M+1); Rt.=4.36 min.

Example 977

General Procedure (B)

5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentanoic acid

5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]pentanoicacid ethyl ester (24.5 g, 67.4 mmol) was dissolved in THF (150 mL) and mixed with sodium hydroxide (8.1 g, 202 mmol) dissolved in water (50 mL). The mixture was stirred for 2 days and the volatiles were evaporated in vacuo. The resulting aqueous solution was poured into a mixture of water (1 L) and hydrochloric acid (1 N, 250 mL). The solid was isolated by filtration, dissolved in sodium hydroxide (1 N, 200 mL), and the solution was washed with DCM and then ethyl acetate, the aquous layer was acidified with hydrochloric acid (12N). The precipitate was isolated by filtration, dissolved in THF/diethyl ether, the solution was treated with MgSO₄ and activated carbon, filtrated and evaporated in vacuo to almost dryness followed by precipitation by addition of pentane (1 L). This afforded after drying in vacuo 17.2 g (76%) of the title compound.

HPLC-MS (Method C): m/z=337 (M+1); Rt.=3.49 min.

Example 978

General Procedure (P)

6-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)naphthalen-2-yloxy]hexanoic acid

HPLC-MS (Method C): m/z=351 (M+1); Rt=3.68 min.

Example 979

General Procedure (P)

11-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-undecanoic acid

HPLC-MS (Method C): m/z=443 (M+23); Rt=4.92 min.

Example 980

General Procedure (P)

2-{3-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-propyl}-malonic acid

HPLC-MS (Method C): m/z=465 (M+1); Rt.=4.95 min.

Example 981

General Procedure (P)

2-{5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentyl}-malonic acid diethyl ester

HPLC-MS (Method C): m/z=465 (M+1); Rt.=4.95 min.

Example 982

General Procedure (P)

2-{3-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-propyl}-malonic acid

HPLC-MS (Method C): m/z=381 (M+1); Rt.=3.12 min.

Example 983

General Procedure (P)

2-{5-[6-(5-Cyano-1H-[1,2,3]triazol-4-yl)-naphthalen-2-yloxy]-pentyl}-malonic acid

HPLC-MS (Method C): m/z 0 409 (M+1); Rt.=3.51 min.

Example 984

General Procedure (P)

4-[4-(5-Cyano-1H-[1,2,3]triazol-4-yl)-phenoxy]butyric acid

HPLC-MS (Method C): m/z=273 (M+1); Rt=2.44 min.

The following compounds may be prepared according to this general procedure (P):

• 4-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)butyric acid:
• 2-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)acetic acid:
• 4-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)butyric acid ethyl ester
• 5-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)pentanoic acid
• 8-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)octanoic acid
• 10-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)decanoic acid
• 12-(4-(5-Cyano-1H-[1,2,3]triazol-4-yl)phenoxy)dodecanoic acid

General Procedure (R) for Preparation of Compounds of General Formula I₁₂:

wherein T is as defined above and R² and R³ are hydrogen, aryl or lower alkyl, both optionally substituted.

The general procedure (R) is further illustrated by the following example:

Example 985

General Procedure (R)

Phenyl-[3-(2H-tetrazol-5-yl)-carbazol-9-yl]-methanone

2-Chlorotritylchloride resin (100 mg, 0.114 mmol active chloride) was swelled in dichloromethane (4 mL) for 30 minutes. The solvent was drained, and a solution of 3-(2H-tetrazol-5-yl)-9H-carbazole (80 mg, 0.34 mmol) in a mixture of N,N-dimethylformamide/dichloromethane/N,N-di(2-propyl)ethylamine (5:5:1) (3 mL) was added. The reaction mixture was shaken at room temperature for 20 hours. The solvent was removed by filtration, and the resin was washed thoroughly with N,N-dimethylformamide (2×4 mL) and dichloromethane (6×4 mL). A solution of 4-(dimethylamino)pyridine (14 mg, 0.11 mmol) and N,N-di(2-propyl)ethylamine (0.23 mL, 171 mg, 1.32 mmol) in N,N-dimethylformamide (2 mL) was added followed by benzoyl chloride (0.13 mL, 157 mg, 1.12 mmol). The mixture was shaken for 48 hours at room temperature. The drained resin was washed consecutively with dichloromethane (2×4 mL), methanol (2×4 mL) and tetrahydrofuran (4 mL). The resin was treated for 2 hours at room temperature with a solution of dry hydrogen chloride in tetrahydrofuran/ethyl ether/ethanol=8:1:1 (0.1 M, 3 mL). The reaction mixture was drained and concentrated. The crude product was stripped with dichloromethane (1.5 mL) three times to yield the title compound.

HPLC-MS (Method C): m/z: 340 (M+1); Rt=3.68 min. ¹H-NMR (DMSO-d₆): δ 8.91 (1H, s), 8.34 (1H, d), 8.05 (1H, d), 7.78 (3H, m), 7.63 (3H, m), 7.46 (2H, m), 7.33 (1H, dd).

The compounds in the following examples were prepared in a similar fashion.

Example 986

General Procedure (R)

Phenyl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z: 290 (M+1); Rt=3.04 min. ¹H-NMR (DMSO-d₆): δ 8.46 (1H, d), 8.42 (1H, d), 8.08 (1H, dd), 7.82 (2H, d), 7.74 (1H, t), 7.64 (2H, t), 7.55 (1H, d), 6.93 (1H, d).

Example 987

General Procedure (R)

(2,3-Difluorophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=326 (M+1); Rt=3.85 min.

Example 988

General Procedure (R)

(2-Fluoro-3-trifluoromethylphenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=376 (M+1); Rt=4.32 min.

Example 989

General Procedure (R)

(3-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.72 min.

Example 990

General Procedure (R)

(4-Nitrophenyl)-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method B): m/z=335 (M+1); Rt=3.71 min.

Example 991

General Procedure (R)

Naphthalen-2-yl-[5-(2H-tetrazol-5-yl)-indol-1-yl]-methanone

HPLC-MS (Method C): m/z=340 (M+1); Rt=4.25 min.

Example 992

General Procedure (R)

HPLC-MS (Method C): m/z: 354 (M+1); Rt=3.91 min.

Example 993

General Procedure (R)

HPLC-MS (Method C): m/z: 418 (M+1); Rt=4.39 min.

Example 994

General Procedure (R)

HPLC-MS (Method C): m/z: 370 (M+1); Rt=4.01 min.

Example 995

General Procedure (R)

HPLC-MS (Method C): m/z: 374 (M+1); Rt=4.28 min.

Example 996

General Procedure (R)

HPLC-MS (Method C): m/z: 416 (M+1); Rt=4.55 min.

Example 997

General Procedure (R)

HPLC-MS (Method C): m/z: 354 (M+1); Rt=4.22 min.

Example 998

General Procedure (R)

HPLC-MS (Method C): m/z: 358 (M+1); Rt=3.91 min.

Example 999

General Procedure (R)

HPLC-MS (Method C): m/z: 390 (M+1); Rt=4.38 min.

Example 1000

General Procedure (R)

HPLC-MS (Method C): m/z: 418 (M+1); Rt=4.36 min.

Example 1001

General Procedure (R)

HPLC-MS (Method C): m/z: 304 (M+1); Rt=3.32 min.

Example 1002

General Procedure (R)

HPLC-MS (Method C): m/z: 368 (M+1); Rt=3.84 min.

Example 1003

General Procedure (R)

HPLC-MS (Method C): m/z: 320 (M+1); Rt=3.44 min.

Example 1004

General Procedure (R)

HPLC-MS (Method C): m/z: 324 (M+1); Rt=3.73 min.

Example 1005

General Procedure (R)

HPLC-MS (Method C): m/z: 304 (M+1); Rt=3.64 min.

Example 1006

General Procedure (R)

HPLC-MS (Method A): m/z: 308 (M+1); Rt=3.61 min.

Example 1007

General Procedure (R)

HPLC-MS (Method C): m/z: 368 (M+1); Rt=3.77 min.

Example 1008

General Procedure (R)

HPLC-MS (Method A): (sciex) m/z: 326 (M+1); Rt=3.73 min. HPLC-MS (Method C): m/z: 326 (M+1); Rt=3.37 min.

Example 1009

General Procedure (R)

HPLC-MS (Method C): m/z: 374 (M+1); Rt=4.03 min.

Example 1010

Characterization of Ligand Effects on Physical Stability of Formulations by the Thioflavine T Fluorescence Assay

Low physical stability of insulin formulations may lead to amyloid fibril formation, which is observed as well-ordered, thread-like macromolecular structures in the sample eventually resulting in gel formation. This has traditionally been measured by visual inspection of the sample. However, the application of a small molecule indicator probe is much more preferable. Thioflavin T is such a probe and has a distinct fluorescence signature when binding to fibrils (or rather β-sheet rich proteins) [Naiki et al. (1989) Anal. Biochem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284]. Its application to insulin fibrillation has recently been validated [Nielsen et al. (2001) Biochemistry 40, 6036-6046].

The time course for fibril formation can be described by a sigmoidal curve with the following expression: $\begin{array}{cc}F=f_i+m_{i}t+\frac{f_f+m_{f}t}{1+e^{-\left[\left(t-t_0\right)/\tau \right]}}& \mathrm{Eq}.\left(2\right)\end{array}$ Here, F is the ThT fluorescence at the time t. The constant t₀ is the time needed to reach 50% of maximum fluorescence. The minimum and maximum fluorescence is denoted f_i and f_f, respectively, and the expressions m_it and m_fg describe the linear development of the bottom and top base lines. The two important parameters describing fibril formation are the lag-time calculated by t₀-2τ and the apparent rate constant k_app=1/τ.

Formation of a partially folded intermediate of the protein is suggested as a general initiating mechanism for fibrillation. Few of those intermediates nucleate to form a template onto which further intermediates may assembly and the fibrillation is initiated. The lag-time corresponds to the interval in which the critical mass of nucleus is built up and the apparent rate constant is the rate with which the fibril itself is formed.

In accordance with this mechanism, insulin needs to dissociate to its monomeric form before a partially folded intermediate may be formed. Keeping insulin on a multimeric form may therefore result in increased physical stability. Ligands binding to the insulin hexamer zinc site should stabilize the hexameric form and draw the equilibrium even further away from the monomeric form. Hence, an increased physical stability could be achieved.

Sample Preparation

Insulin formulations were prepared freshly before each assay from appropriate stock solutions. Typical final concentrations were 0.6 mM human insulin or insulin aspart analogue, 0.2 mM ZnAc, 30 mM phenol, 10 mM Tris pH 8. ThT was added from a 1 mM stock solution in water to a final concentration of 1 μM. The formulations were typically prepared in double concentration and mixed with an equal volume of test compound in appropriate concentration in 4% DMSO, 10 mM Tris pH 8.

Alternatively, insulin aspart formulations (100 U/ml) from the production line were used directly. ThT was added to 1 μM and DMSO containing test compound in appropriate concentration to 2%.

Sample aliquots of 200 μl were placed in a 96 well microtiter plate (Packard OptiPlate™-96, white polystyrene). Usually, eight replica of each sample (corresponding to one test 373 compound concentration) was placed in one column of wells. The plate was sealed with Scotch Pad (Qiagen).

Control experiments for possible test compound quenching of the ThT emission were carried out using human insulin without Zn²⁺ and phenol i.e. in a non-hexameric configuration. Hence, the fibrillation process as well as the ThT emission should be unaffected by the presence of test compound, unless it quenched the ThT signal.

Incubation and Fluorescence Measurement

Temperature incubation, shaking and measurement of the ThT fluorescence were done in a Fluoroskan Ascent FL fluorescence platereader (Thermo Labsystems). Temperature setting is possible up till 45° C., but usually sat at 30° C. Heating was initiated at first measurement. The orbital shaking is selectable up till 1200 rpm, but adjusted to 960 rpm in all the presented data with an amplitude of 1 mm.

Fluorescence measurement was done using excitation trough a 444 nm filter and measurement of emission through a 485 nm filter. Each run was initiated by a measurement and intervals between measurements were usually 20 min. The plate was shaken and heated as adjusted between each measurement. The assay time was regulated by the number of measurements and the interval in between. Usually the plate was measured 46 times with 20 min between, i.e. over 15 hours.

Data Handling

The measurement points were saved in Microsoft Excel format for further processing and curve drawing and fitting was performed using GraphPad Prism. The background emission from ThT in the absence of fibrils was negligible. Some test compounds had background fluorescence under the applied experimental conditions. This was eliminated by subtracting the mean value of the first measurement from the data set for this test compound. The data points are shown with standard deviation.

The data set may be fitted to Eq. (2). However, since the stabilizing effect of the test compounds/ligands were so significant that a full sigmoid curve was not obtained during the usual assay time, curve fitting to such a data set would be imprecise and hence meaningless.

Only data obtained in the same experiment (i.e. samples on the same plate) are presented in the same graph.

Examples & Results

The various ligands are shown below with structure and affinity towards the zinc site as measured by the TZD-assay described in “Analytical Methods”.

			Kd(app)
Reference	Example	Compound	(nM)
A	533		383
C	462		58
D	738		171
E	68		23
F	756		3
G	1		3879
H	76		82
I	759		23

The ThT assays of various combinations of insulin formulations and ligands are shown in FIG. 1-8.

Addition of ligands improves the physical stability of insulin formulations. This holds for human insulin formulations (see FIG. 1) as well as insulin aspart formulations (rest of data set).

The improved stability can be obtained by using various compound classes as zinc site anchor, e.g. benzothriazoles (G, FIG. 1), naphthosalicylic acids (A, FIG. 2), thiazolidine-diones (E, FIGS. 4, 7; C, FIG. 2; H, FIGS. 6, 8) and tetrazoles (D, FIG. 3; F, FIG. 8; I, FIG. 5).

Increased affinity of the ligand results in higher stability of the formulation. Compare the effect of the weakest binding ligand in 2 mM (G, FIG. 1) with the effect on an insulin aspart formulation of 0.5 mM E (FIG. 4). Also compare the effects of similar concentrations of A and C (FIG. 2); and of D (FIG. 3) and E (FIG. 4) on insulin aspart formulations.

Increasing the concentration of ligand tends to improve the stabilization (see FIGS. 1, 3, 4, 5, 6). In some instants, more pronounced effects are seen with the ligand in slight molar excess to the zinc sites, see FIGS. 4, 6, whereas it seems to plateau around the stoichiometric concentration in other instances (FIGS. 3, 5).

Of the presented ligands, A, C, D, E, F were tested in a disappearance assay for the effect on release of insulin aspart from a subcutaneous inject site. Surprisingly, the ligands had no effect on the insulin aspart disappearance. In a very limited way, this can be mimicked in the ThT assay by increasing the assay temperature to 37° C. (see FIGS. 7, 8). The stabilizing effect is somewhat attenuated, e.g. compare E at 30° C. (FIG. 4) and 37° C. (FIG. 7), and H (FIG. 6 and 8). The ligand with highest affinity (F) has the most stabilizing effect at 37° C. (FIG. 8).

Example 1011

Retention of Fast Absorption Characteristics of Formulations Stabilized by Addition of His^B10 Zn²⁺-Site Ligands

Formulations of the present invention were characterized by the disappearance rate from the subcutaneous depot following injection in pigs. Formulations of B28 Asp human insulin containing A14Tyr(¹²⁵I) B28 Asp human insulin were followed with an external γ-counter (Ribel et al., The pig as a model for subcutaneous absorption in man. In: Serrano-Ritos & Lefebre (Eds.): Diabetes (1985) proceedings ot the 12^th congress of the international diabetes federation, Madrid, Spain, 1985 (Excerpta Medica, Amsterdam (1986) 891-896. Formulations of Insulin Aspart (0.6 mM, U100) containing 0.3 mM Zn²⁺, 30 mM phenol, 2 mM phosphate buffer, and 1.6% glycerol, pH 7.4, were compared with the corresponding formulations containing 0.3 mM of the ligands shown below: where T_50% is the time when 50% ot the A14Tyr(¹²⁵I) B28 Asp insulin has disappeared from the site of injection and K_d is the affinity of the ligand as measured by the TZD-assay described in “Analytical methods” below. It is evident that the stabilizing ligands do not affect the fast absorption properties of the formulations

				Kd (app)
	Example #	Compound	T50%	(nM)
reference			1.3 ± 0.3
A	533		1.0 ± 0.23	383
B	476		1.1 ± 0.37	68
C	462		0.9 ± 0.19	58
D	738		1.3 ± 0.36	171
E	68		1.2 ± 0.41	23
F	756		1.2 ± 0.27	3

Example 1012

Reference Experiment

The chemical stability of insulin formulations of the invention was characterised by HPLC (RPC, reverse phase chromatography and SEC, size exclusion chromatography). As reference, insulin formulated without ligands of the invention but with 0.3% DMSO was also investigated and shown below:

FIG. 10. Reverse phase chromatography of formulated human insulin with 3 Zn²⁺ per hexamer, 30 mM phenol, 150 mM mannitol, 3 mM phosphoric acid, sodium hydroxide to pH 7.4 and 0.3% DMSO corresponding to 3 ligands per hexamer at start (upper panel) and after storage for 2 weeks at 37° C. (lower panel): Preservatives before 20 min., “hydrophilic derivatives” (desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives 1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w), 25° C. (10 w), 15° C. (30 w) gave about the same increase of transformation products correlating to an increase in reactions constants of a factor 3-4 per 10 degree.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column, 150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodium phosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient (g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(sudden change), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9 mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column, 300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile: arginine 1 g/L at flow of 1 mL/min and ambient temperature.

	RPC	SEC
% formed/year	hphil	hphob1	hphob2	dimer
45° C.	153.3	47.5	23.4	21.9
37° C.	57.2	15.6	5.20	6.24
30° C.	24.5	4.16	1.30	2.08
25° C.	14.2	2.13	0.68	1.09
15° C.	4.12	0.43	0.22	0.31
5° predicted	(1.001)	(0.066)	(0.027)	(0.052)

The chemical stability of insulin formulations of the invention was likewise characterised by HPLC (RPC, reverse phase chromatography and SEC, size exclusion chromatography). Compared to the reference the formulations of the invention were shown to be more chemically stable.

Example 1013

Chemical stability of insulin formulated with the compound of example 533, 7-bromo-3-hydroxy-2-naphthoic acid:

FIG. 11. Reverse phase chromatography of formulated human insulin as described for the reference example and added 3 ligands of Example 533 and 3 Zn²⁺ per hexamer at start (upper panel) and after storage for 2 weeks at 37° C. (lower panel): Preservatives before 20 min., “hydrophilic derivatives” (desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives 1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w), 25° C. (10 w), 15° C. (30 w) will give about the same increase in transformation products correlating to an increase in reaction constants of a factor 3-4 per 10 degrees.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column, 150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodium phosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient (g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(sudden change), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9 mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column, 300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1 g/L at flow of 1 mL/min and ambient temperature.

	RPC	SEC
% formed/year	hphil	hphob1	hphob2	dimer
45° C.	30.7	62.1	23.4	26.3
37° C.	12.5	22.4	7.02	7.02
30° C.	6.76	6.42	2.25	2.86
25° C.	4.06	5.67	1.46	1.61
15° C.	1.80	0.85	0.42	0.45
5° predicted	(0.55)	(0.19)	(0.079)	(0.087)

Example 1014

Chemical stability of insulin formulated with the compound of Example 462, 3-[4-2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]acrylic acid:

FIG. 12. Reverse phase chromatography of formulated human insulin as described for the reference example and added 3 ligands of example 462 and 3 Zn²⁺ per hexamer at start (upper panel) and after storage for 2 weeks at 37° C. (lower panel): Preservatives before 20 min., “hydrophilic derivatives” (desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives 1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w), 25° C. (10 w), 15° C. (30 w) will give about the same increase in transformation products correlating to an increase in reaction constants of a factor 3-4 per 10 degrees.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column, 150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodium phosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient (g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(sudden change), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9 mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column, 300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1 g/L at flow of 1 mL/min and ambient temperature.

	RPC	SEC
% formed/year	hphil	hphob1	hphob2	Dimer
45° C.	20.4	43.8	17.5	21.2
37° C.	9.88	19.5	4.68	6.24
30° C.	4.07	4.42	1.65	2.17
25° C.	2.60	6.14	0.78	1.09
15° C.	1.02	1.28	0.38	0.28
5° predicted	(0.293)	(0.336)	(0.062)	(0.048)

Example 1015

Chemical stability of insulin formulated with the compound of example 461, [3-(2,4-Dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid:

FIG. 13. Reverse phase chromatography of formulated human insulin added 3 ligands (#) and 3 Zn per hexamer at start and storage of 2 w 37° C.: Preservatives before 20 min., “hydrophilic derivatives” (desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives 1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w), 25° C. (10 w), 15° C. (30 w) will give about the same increase of 0.7% hfil, 0.6% hfob1, 0.3% hfob2 and 0.3% dimer solution 1, correlating to Q₁₀ of 3 below 30° C. and 4 at higher temperature for ref.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column, 150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodium phosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient (g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(sudden change), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9 mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column, 300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1 g/L at flow of 1 mL/min and ambient temperature.

	RPC	SEC
% formed/year	hphil	hphob1	hphob2	dimer
45° C.	29.9	52.6	23.4	23.4
37° C.	11.2	20.0	7.02	6.50
30° C.	5.12	7.11	1.99	2.34
25° C.	2.86	4.78	0.99	1.20
15° C.	1.14	0.67	0.29	0.33
5° predicted	(0.287)	(0.153)	(0.044)	(0.057)

Example 1016

Chemical stability of insulin formulated with the compound of example 70, 5-(4-Diethylaminobenzylidene)thiazolidine-2,4-dione

FIG. 14. Reverse phase chromatography of formulated human insulin added 3 ligands (#) and 3 Zn per hexamer at start and storage of 2 w 37° C.: Preservatives before 20 min., “hydrophilic derivatives” (desamido-insulins) 20 min to main top insulin, “hydrophobic derivatives 1” main top to 64 min., and “hydrophobic derivatives 2” (insulin dimers) after 64 min.

Storage in HPLC 1 ml vials at 45° C. (5 d), 37° C. (2 w), 30° C. (6 w), 25° C. (10 w), 15° C. (30 w) will give about the same increase of 0.7% hfil, 0.6% hfob1, 0.3% hfob2 and 0.3% dimer solution 1, correlating to Q₁₀ of 3 below 30° C. and 4 at higher temperature for ref.

RPC (reverse phase chromatography) on Waters SymmetryShield RP₈ column, 150×4.6 mm and 3.5 μm, eluted by A: 0.2 M sodium sulfate+0.04 M sodium phosphate pH 7.2+10% acetonitrile and isocratically (i) or a gradient (g) of B: 70% acetonitrile [minutes/% B(i/g): 0/19, 21/24(i)(sudden change), 51/24(i), 81/39(g), 81.1/0(i), 82.3/19(i)] at flow of 0.9 mL/min and 30° C.

SEC (size exclusion chromatography) on Waters insulin HMWP column, 300×7.8 mm, eluted by 15:20:65 of acetic acid: acetonitrile:arginine 1 g/L at flow of 1 mL/min and ambient temperature.

	RPC	SEC
% formed/year	hphil	hphob1	hphob2	dimer
45° C.	56.2	78.8	27.0	29.2
37° C.	23.7	14.8	6.50	8.84
30° C.	12.1	6.94	3.03	3.55
25° C.	6.08	4.99	0.94	2.24
15° C.	1.95	1.09	0.42	0.69
5° predicted	(0.54)	(0.22)	(0.064)	(0.15)

Analytical Methods

Assays to quantify the binding affinity of ligands to the metal site of the insulin R₆ hexamers:

4H3N-Assay:

The binding affinity of ligands to the metal site of insulin R₆ hexamers are measured in a UV/vis based displacement assay. The UV/vis spectrum of 3-hydroxy-4-nitro benzoic acid (4H3N) which is a known ligand for the metal site of insulin R₆ shows a shift in absorption maximum upon displacement from the metal site to the solution (Huang et al., 1997, Biochemistry 36, 9878-9888). Titration of a ligand to a solution of insulin R₆ hexamers with 4H3N mounted in the metal site allows the binding affinity of these ligands to be determined following the reduction of absorption at 444 nm.

A stock solution with the following composition 0.2 mM human insulin, 0.067 mM Zn-acetate, 40 mM phenol, 0.101 mM 4H3N is prepared in a 10 mL quantum as described below. Buffer is always 50 mM tris buffer adjusted to pH=8.0 with NaOH/ClO₄⁻.

• • 1000 μL of 2.0 mM human insulin in buffer
  • 66.7 μL of 10 mM Zn-acetate in buffer
  • 800 μL of 500 mM phenol in H₂O
  • 201 μL of 4H3N in H₂O
  • 7.93 ml buffer

The ligand is dissolved in DMSO to a concentration of 20 mM.

The ligand solution is titrated to a cuvette containing 2 mL stock solution and after each addition the UV/vis spectrum is measured. The titration points are listed in Table 3 below.

TABLE 3

ligand	ligand
addition	conc.	dilution
(μl)	(mM)	factor
1	0.010	1.0005
1	0.020	1.0010
1	0.030	1.0015
2	0.050	1.0025
5	0.100	1.0050
10	0.198	1.0100
20	0.392	1.0200
20	0.583	1.0300
20	0.769	1.0400
20	0.952	1.0500

The UV/vis spectra resulting from a titration of the compound 3-hydroxy-2-naphthoic acid is shown in FIG. 5. Inserted in the upper right corner is the absorbance at 444 nm vs. the concentration of ligand.

The following equation is fitted to these datapoints to determine the two parameters K_D(obs), the observed dissociation constant, and abs_max the absorbance at maximal ligand concentration. abs([ligand]_free)=(abs_max*[ligand]_free)/(K_D(obs)+[ligand]_free)

The observed dissociation constant is recalculated to obtain the apparent dissociation constant K_D(app)=K_D(obs)/(1+[4H3N]/K_4H3N) The value of K_4H3N=50 μM is taken from Huang et al., 1997, Biochemistry 36, 9878-9888. TZD-Assay:

The binding affinity of ligands to the metal site of insulin R₆ hexamers are measured in a fluorescense based displacement assay. The fluorescence of 5-(4-dimethylaminobenzylidene)thiazolidine-2,4-dione (TZD) which is a ligand for the metal site of insulin R₆ is quenched upon displacement from the metal site to the solution. Titration of a ligand to a stock solution of insulin R₆ hexamers with this compound mounted in the metal site allows the binding affinity of these ligands to be determined measuring the fluorescence at 455 nm upon excitation at 410 nm.

Preparation

Stock solution: 0.02 mM human insulin, 0.007 mM Zn-acetate, 40 mM phenol, 0.01 mM TZD in 50 mM tris buffer adjusted to pH=8.0 with NaOH/ClO₄⁻.

The ligand is dissolved in DMSO to a concentration of 5 mM and added in aliquots to the stock solution to final concentrations of 0-250 □M.

Measurements

Fluorescence measurements were carried out on a Perkin Elmer Spectrofluorometer LS50B. T main absorption band was excited at 410 nm and emission was detected at 455 nm. The resolution was 10 nm and 2.5 nm for excitation and emission, respectively.

Data Analysis

This equation is fitted to the datapoints ΔF(455 nm))=ΔF_max* [ligand]_free/(K_D(app)*(1+[TZD]/K_TZD)+[ligand]_free)) K_D(app) is the apparent dissociation constant and F_max is the fluorescence at maximal ligand concentration. The value of K_TZD is measured separately to 230 nM

Two different fitting-procedures can be used. One in which both parameters, K_D(app) and F_max, are adjusted to best fit the data and a second in which the value of F_max is fixed (F_max=1) and only K_D(app) is adjusted. The given data are from the second fitting procedure. The Solver module of Microsoft Excel can be used to generate the fits from the data points.

Claims

1. A pharmaceutical composition comprising insulin and a zinc-binding ligand which reversibly binds to a HisB10 Zn2+ site of an insulin hexamer, wherein the ligand is selected from the group consisting of benzotriazoles, 3-hydroxy 2-naphthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, pyrimidinetriones, or 4-cyano-1,2,3-triazoles, or enantiomers, diastereomers, racemic mixtures, tautomers, or salts thereof with a pharmaceutically acceptable acid or base.

2. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is

3. A pharmaceutical composition according to claim 2 wherein X is ═O or ═S.

4. A pharmaceutical composition according to claim 3 wherein X is ═O.

5. A pharmaceutical composition according to claim 3 wherein X is ═S.

6. A pharmaceutical composition according to claim 2 wherein Y is —O— or —S—.

7. A pharmaceutical composition according to claim 6 wherein Y is —O—.

8. A pharmaceutical composition according to claim 6 wherein Y is —NH—.

9. A pharmaceutical composition according to claim 6 wherein Y is —S—.

10. A pharmaceutical composition according to claim 2 wherein A is aryl optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

11. A pharmaceutical composition according to claim 10 wherein A is selected from ArG1 optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

12. A pharmaceutical composition according to claim 11 wherein A is phenyl or naphtyl optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

13. A pharmaceutical composition according to claim 12 wherein A is

14. A pharmaceutical composition according to claim 12 wherein A is phenyl.

15. A pharmaceutical composition according to claim 2 wherein A is heteroaryl optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

16. A pharmaceutical composition according to claim 15 wherein A is selected from Het1 optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

17. A pharmaceutical composition according to claim 16 wherein A is selected from Het2 optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

18. A pharmaceutical composition according to claim 17 wherein A is selected from Het3 optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

19. A pharmaceutical composition according to claim 18 wherein A is selected from the group consisting of indolyl, benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein each heteroaryl may optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

20. A pharmaceutical composition according to claim 18 wherein A is benzofuranyl optionally substituted with up to four substituents R7, R8, R9, and R10 which may be the same or different.

21. A pharmaceutical composition according to claim 20 wherein A is

22. A pharmaceutical composition according to claim 18 wherein A is carbazolyl optionally substituted with up to four substituents R7, R8, R9, and R10 which may be the same or different.

23. A pharmaceutical composition according to claim 22 wherein A is

24. A pharmaceutical composition according to claim 18 wherein A is quinolyl optionally substituted with up to four substituents R7, R8, R9, and R10 which may be the same or different.

25. A pharmaceutical composition according to claim 24 wherein A is

26. A pharmaceutical composition according to claim 18 wherein A is indolyl optionally substituted with up to four substituents R7, R8, R9, and R10 which may be the same or different.

27. A pharmaceutical composition according to claim 26 wherein A is

28. A pharmaceutical composition according to claim 2 wherein R1 is hydrogen.

29. A pharmaceutical composition according to claim 2 wherein R2 is hydrogen.

30. A pharmaceutical composition according to claim 2 wherein R1 and R2 are combined to form a double bond.

31. A pharmaceutical composition according to claim 2 wherein R3 is C1-C6-alkyl, halogen, or C(O)NR16R17.

32. A pharmaceutical composition according to claim 31 wherein R3 is C1-C6-alkyl or C(O)NR16R17.

33. A pharmaceutical composition according to claim 32 wherein R3 is methyl.

34. A pharmaceutical composition according to claim 2 wherein B is phenyl optionally substituted with up to four substituents, R7, R8, R9, and R10 which may be the same or different.

35. A pharmaceutical composition according to claim 2 wherein R4 is hydrogen.

36. A pharmaceutical composition according to claim 2 wherein R5 is hydrogen.

37. A pharmaceutical composition according to claim 2 wherein R6 is aryl.

38. A pharmaceutical composition according to claim 37 wherein R6 is phenyl.

39. A pharmaceutical composition according to claim 2 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —NO2, —R11, —NR11R12, —SR11, —NR11S(O)2R12, —S(O)2NR11R12, —S(O)NR11R12, —S(O)R11, —S(O)2R11, —OS(O)2 R11, —NR11C(O)R12, —CH2OR11, —CH2OC(O)R11, —CH2NR11R12, —OC(O)R11, —OC1-C6-alkyl-C(O)OR11, —OC1-C6-alkyl-C(O)NR11R12, —OC1-C6-alkyl-OR11, —SC1-C6-alkyl-C(O)OR11, —C2-C6-alkenyl-C(═O)OR11, —C(O)OR11, or —C2-C6-alkenyl-C(═O)R11, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may each optionally be substituted with one or more substituents independently selected from R13 aryl, aryloxy, aroyl, arylsulfanyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, aroyl-C2-C6-alkenyl, aryl-C2-C6-alkynyl, heteroaryl, heteroaryl-C1-C6-alkyl, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14

40. A pharmaceutical composition according to claim 39 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —NO2, —OR11, —NR11R12, —SR11, —S(O)2R11, —OS(O)2 R11, —CH2OC(O)R11, —OC(O)R11, —OC1-C6-alkyl-C(O)OR11, —OC1-C6-alkyl-OR11, —SC1-C6-alkyl-C(O)OR11, —C(O)OR11, or —C2-C6-alkenyl-C(═O)R11, C1-C6-alkyl or C1-C6-alkenyl which may each optionally be substituted with one or more substituents independently selected from R13 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14

41. A pharmaceutical composition according to claim 40 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —NO2, —OR11, —NR11R12, —SR11, —S(O)2R11, —OS(O)2 R11, —CH2OC(O)R11, —OC(O)R11, —OC1-C6-alkyl-C(O)OR11, —OC1-C6-alkyl-OR11, —SC1-C6-alkyl-C(O)OR11, —C(O)OR11, or —C2-C6-alkenyl-C(═O)R11, C1-C6-alkyl or C1-C6— which may each optionally be substituted with one or more substituents independently selected from R13 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14

42. A pharmaceutical composition according to claim 41 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —OR11, —OC1-C6-alkyl-C(O)OR11, or —C(O)OR11, C1-C6-alkyl which may each optionally be substituted with one or more substituents independently selected from R13 aryl, aryloxy, aryl-C1-C6-alkoxy, of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14.

43. A pharmaceutical composition according to claim 42 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —OR11, —OC1-C6-alkyl-C(O)OR11, or —C(O)OR11, C1-C6-alkyl which may each optionally be substituted with one or more substituents independently selected from R13 ArG1, ArG1oxy, ArG1-C1-C6-alkoxy, of which each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14.

44. A pharmaceutical composition according to claim 43 wherein R7, R8, R9 and R10 are independently selected from hydrogen, halogen, —OR11, —OC1-C6-alkyl-C(O)OR11, or —C(O)OR11, C1-C6-alkyl which may optionally be substituted with one or more substituents independently selected from R13 phenyl, phenyloxy, phenyl-C1-C6-alkoxy, wherein each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R14.

45. A pharmaceutical composition according to claim 2 wherein R11 and R12 are independently selected from hydrogen, C1-C20-alkyl, aryl or aryl-C1-C6-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R15, and the aryl groups may optionally be substituted one or more substituents independently selected from R16; R11 and R12 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.

46. A pharmaceutical composition according to claim 45 wherein R11 and R12 are independently selected from hydrogen, C1-C20-alkyl, aryl or aryl-C1-C6-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R15, and the aryl groups may optionally be substituted one or more substituents independently selected from R16.

47. A pharmaceutical composition according to claim 46 wherein R11 and R12 are independently selected from phenyl or phenyl-C1-C6-alkyl.

48. A pharmaceutical composition according to claim 46 wherein one or both of R11 and R12 are methyl.

49. A pharmaceutical composition according to claim 2 wherein R13 is independently selected from halogen, CF3, OR11 or NR11R12.

50. A pharmaceutical composition according to claim 49 wherein R13 is independently selected from halogen or OR11.

51. A pharmaceutical composition according to claim 50 wherein R13 is OR11.

52. A pharmaceutical composition according to claim 2 wherein R14 is independently selected from halogen, —C(O)OR11, —CN, —CF3, —OR11, S(O)2R11, and C1-C6-alkyl.

53. A pharmaceutical composition according to claim 52 wherein R14 is independently selected from halogen, —C(O)OR11, or —OR11.

54. A pharmaceutical composition according to claim 2 wherein R15 is independently selected from halogen, —CN, —CF3, —C(O)OC1-C6-alkyl,and —COOH.

55. A pharmaceutical composition according to claim 54 wherein R15 is independently selected from halogen or —C(O)OC1-C6-alkyl.

56. A pharmaceutical composition according to claim 2 wherein R16 is independently selected from halogen, —C(O)OC1-C6-alkyl, —COOH, —NO2, —OC1-C6-alkyl, —NH2, C(═O) or C1-C6-alkyl.

57. A pharmaceutical composition according to claim 56 wherein R16 is independently selected from halogen, —C(O)OC1-C6-alkyl, —COOH, —NO2, or C1-C6-alkyl.

58. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is

59. A pharmaceutical composition according to claim 58 wherein D is a valence bond.

60. A pharmaceutical composition according to claim 58 wherein D is C1-C6-alkylene optionally substituted with one or more hydroxy, C1-C6-alkyl, or aryl.

61. A pharmaceutical composition according to claim 58 wherein E is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents independently selected from R21, R22 and R23.

62. A pharmaceutical composition according to claim 61 wherein E is aryl optionally substituted with up to three substituents independently selected from R21, R22 and R23.

63. A pharmaceutical composition according to claim 62 wherein E is selected from ArG1 and optionally substituted with up to three substituents independently selected from R21, R22 and R23.

64. A pharmaceutical composition according to claim 63 wherein E is phenyl optionally substituted with up to three substituents independently selected from R21, R22 and R23.

65. A pharmaceutical composition according to claim 64 wherein the zinc-binding ligand is

66. A pharmaceutical composition according to claim 58 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —NO2, —OR27, —NR27R28, —SR27, —C(O)NR27R28, —OC(O)NR27R28, —NR27C(O)R28, —NR27C(O)OR28, —CH2C(O)NR27R28, —OCH2C(O)NR27R28, —CH2OR27, —CH2NR27R28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —NR27—C(═O)—C1-C6-alkyl-C(═O)OR27, —NR27—C(═O)—C1-C6-alkenyl-C(═O)OR27—, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may optionally be substituted with one or more substituents independently selected from R29 aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, aryl-C2-C6-alkynyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryl-C2-C6-alkenyl or heteroaryl-C2-C6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

67. A pharmaceutical composition according to claim 66 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

68. A pharmaceutical composition according to claim 67 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

69. A pharmaceutical composition according to claim 68 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —C1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, Het3, Het3-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

70. A pharmaceutical composition according to claim 69 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)R28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R29 phenyl, phenyloxy, phenyl-C1-C6-alkoxy, phenyl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

71. A pharmaceutical composition according to claim 58 wherein R19 is hydrogen or methyl.

72. A pharmaceutical composition according to claim 71 wherein R19 is hydrogen.

73. A pharmaceutical composition according to claim 58 wherein R27 is Hydrogen, C1-C6-alkyl or aryl.

74. A pharmaceutical composition according to claim 73 wherein R27 is hydrogen or C1-C6-alkyl.

75. A pharmaceutical composition according to claim 58 wherein R28 is hydrogen or C1-C6-alkyl.

76. A pharmaceutical composition according to claim 58 wherein F is a valence bond.

77. A pharmaceutical composition according to claim 58 wherein F is C1-C6-alkylene optionally substituted with one or more hydroxy, C1-C6-alkyl, or aryl.

78. A pharmaceutical composition according to claim 58 wherein G is C1-C6-alkyl or aryl, wherein the aryl is optionally substituted with up to three substituents R24, R25 and R26.

79. A pharmaceutical composition according to claim 58 wherein G is C1-C6-alkyl or ArG1, wherein the aryl is optionally substituted with up to three substituents R24, R25 and R26.

80. A pharmaceutical composition according to claim 78 wherein G is C1-C6-alkyl.

81. A pharmaceutical composition according to claim 80 wherein G is phenyl optionally substituted with up to three substituents R24, R25 and R26.

82. A pharmaceutical composition according to claim 58 wherein R24, R25 and R26 are independently selected from hydrogen, halogen, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —SCF3, —NO2, —OR27, —NR27R28, —SR27, —C(O)NR27R28, —OC(O)NR27R28, —NR27C(O)R28, —NR27C(O)OR28, —CH2C(O)NR27R28, —OCH2C(O)NR27R28, —CH2OR27, —CH2NR27R28, —OC(O)R27, —C1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —NR27—C(═O)—C1-C6-alkyl-C(═O)OR27, —NR27-C(═O)-C1-C6-alkenyl-C(═O)OR27—, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may optionally be substituted with one or more substituents independently selected from R29 aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, aryl-C2-C6-alkynyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryl-C2-C6-alkenyl or heteroaryl-C2-C6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

83. A pharmaceutical composition according to claim 82 wherein R24, R25 and R26 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may optionally be substituted with one or more substituents independently selected from R29 aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, aryl-C2-C6-alkynyl, heteroaryl, heteroaryl-C1-C6-alkyl, heteroaryl-C2-C6-alkenyl or heteroaryl-C2-C6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

84. A pharmaceutical composition according to claim 83 wherein R24, R25 and R26 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C1-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

85. A pharmaceutical composition according to claim 84 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, Het3, Het3-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

86. A pharmaceutical composition according to claim 85 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27—C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, Het3, Het3-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

87. A pharmaceutical composition according to claim 86 wherein R21, R22 and R23 are independently selected from hydrogen, halogen, —OCF3, —OR27, —NR27R28, —SR27, —NR27C(O)R28, —NR27C(O)OR28, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, —C2-C6-alkenyl-C(═O)OR27, —C(═O)NR27, —C1-C6-alkyl-C(═O)OR27, —C1-C6-alkyl-C(═O)OR27, or —C(O)OR27, methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 ArG1, ArG1-O—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

88. A pharmaceutical composition according to claim 58 wherein R20 is hydrogen or methyl.

89. A pharmaceutical composition according to claim 88 wherein R20 is hydrogen.

90. A pharmaceutical composition according to claim 58 wherein R27 is hydrogen, C1-C6-alkyl or aryl.

91. A pharmaceutical composition according to claim 90 wherein R27 is hydrogen or C1-C6-alkyl or ArG1.

92. A pharmaceutical composition according to claim 91 wherein R27 is hydrogen or C1-C6-alkyl.

93. A pharmaceutical composition according to claim 58 wherein R28 is hydrogen or C1-C6-alkyl.

94. A pharmaceutical composition according to claim 58 wherein R17 and R18 are independently selected from hydrogen, halogen, —CN, —CF3, —OCF3, —NO2, —OR27, —NR27R28, —SR27, —S(O)R27, —S(O)2R27, —C(O)NR27R28, —CH2OR27, —OC(O)R27, —OC1-C6-alkyl-C(O)OR27, —SC1-C6-alkyl-C(O)OR27, or —C(O)OR27, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

95. A pharmaceutical composition according to claim 94 wherein R17 and R18 are independently selected from hydrogen, halogen, —CN, —CF3, —NO2, —OR27, —NR27R28, or —C(O)OR27, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

96. A pharmaceutical composition according to claim 95 wherein R17 and R18 are independently selected from hydrogen, halogen, —CN, —CF3, —NO2, —OR27, —NR27R28, or —C(O)OR27 methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 aryl, aryloxy, aroyl, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

97. A pharmaceutical composition according to claim 96 wherein R17 and R18 are independently selected from hydrogen, halogen, —CN, —CF3, —NO2, —OR2 , —NR27R28, or —C(O)OR27 methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R29 ArG1, ArG1-O—, ArG1-C(O)—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, Het3, Het3-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

98. A pharmaceutical composition according to claim 97 wherein R17 and R18 are independently selected from hydrogen, halogen, —CN, —CF3, —NO2, —OR2 , —NR27R28, or —C(O)OR27 C1-C6-alkyl optionally substituted with one or more substituents independently selected from R29 phenyl, phenyloxy, phenyl-C1-C6-alkoxy, phenyl-C1-C6-alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from R30.

99. A pharmaceutical composition according to claim 58 wherein R27 is hydrogen or C1-C6-alkyl.

100. A pharmaceutical composition according to claim 99 wherein R27 is hydrogen, methyl or ethyl.

101. A pharmaceutical composition according to claim 58 wherein R28 is hydrogen or C1-C6-alkyl.

102. A pharmaceutical composition according to claim 101 wherein R28 is hydrogen, methyl or ethyl.

103. A pharmaceutical composition according to claim 58 wherein R72 is —OH or phenyl.

104. A pharmaceutical composition according to claim 58 wherein the zinc-binding ligand is

105. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is of the form H—I-J wherein H is wherein the phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R31 I is selected from a valence bond, —CH2N(R32)— or —SO2N(R33)—, wherein Z1 is S(O)2 or CH2, Z2 is —NH—, —O— or —S—, and n is 1 or 2, J is C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may each optionally be substituted with one or more substituents selected from R34, Aryl, aryloxy, aryl-oxycarbonyl-, aroyl, aryl-C1-C6-alkoxy-, aryl-C1-C6-alkyl-, aryl-C2-C6-alkenyl-, aryl-C2-C6-alkynyl-, heteroaryl, heteroaryl-C1-C6-alkyl-, heteroaryl-C2-C6-alkenyl- or heteroaryl-C2-C6-alkynyl-, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R37, Hydrogen, R31 is independently selected from hydrogen, halogen, —CN, —CH2CN, —CHF2, —CF3, —OCF3, —OCHF2, —OCH2CF3, —OCF2CHF2, —S(O)2CF3, —SCF3, —NO2, —OR35, —C(O)R35, —NR35R36, —SR35, —NR35S(O)2R36, —S(O)2NR35R36, —S(O)NR35R36, —S(O)R35, —S(O)2R35, —C(O)R35R36, —OC(O)NR35R36, —NR35C(O)R36, —CH2C(O)NR35R36, —OCH2C(O)NR35R36, —CH2OR35, —CH2NR35R36, —OC(O)R35, —OC1-C6-alkyl-C(O)OR35, —SC1-C6-alkyl-C(O)OR35 —C2-C6-alkenyl-C(═O)OR35, —NR35—C(═O)—C1-C6-alkyl-C(═O)OR35, —NR35—C(═O)—C1-C6-alkenyl-C(═O)OR35—, C1-C6-alkyl, C1-C6-alkanoyl or —C(O)OR35, R32 and R33 are independently selected from hydrogen, C1-C6-alkyl or C1-C6-alkanoyl, R34 is independently selected from halogen, —CN, —CF3, —OCF3, —OR35, and —NR35R36, R35 and R36 are independently selected from hydrogen, C1-C6-alkyl, aryl-C1-C6-alkyl or aryl, or R35 and R36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds, R37 is independently selected from halogen, —C(O)OR35, —C(O)H, —CN, —CF3, —OCF3, —NO2, —OR35, —NR35R36, C1-C6-alkyl or C1-C6-alkanoyl, or any enantiomer, diastereomer, racemic mixture, tautomer, or salt thereof with a pharmaceutically acceptable acid or base.

106. A pharmaceutical composition according to claim 105 wherein the zinc-binding ligand is of the form H—I-J, wherein H is

107. A pharmaceutical composition according to claim 105 wherein H is

108. A pharmaceutical composition according to claim 107 wherein H is

109. A pharmaceutical composition according to claim 107 wherein H is

110. A pharmaceutical composition according to claim 105 wherein I is a valence bond, —CH2N(R32)—, or —SO2N(R33)—.

111. A pharmaceutical composition according to claim 110 wherein I is a valence bond.

112. A pharmaceutical composition according to claim 105 wherein J is hydrogen, C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen, —CN, —CF3, —OCF3, —OR35, and —NR35R36, aryl, or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R37.

113. A pharmaceutical composition according to claim 112 wherein J is hydrogen, aryl or heteroaryl, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R37.

114. A pharmaceutical composition according to claim 112 wherein J is hydrogen, ArG1 or Het3, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R37.

115. A pharmaceutical composition according to claim 114 wherein J is hydrogen, phenyl or naphthyl optionally substituted with one or more substituents independently selected from R37.

116. A pharmaceutical composition according to claim 115 wherein J is hydrogen.

117. A pharmaceutical composition according to claim 105 wherein R32 and R33 are independently selected from hydrogen or C1-C6-alkyl.

118. A pharmaceutical composition according to claim 105 wherein R34 is hydrogen, halogen, —CN, —CF3, —OCF3, —SCF3, —NO2, —OR35, —C(O)R35, —NR35R36, —SR35, —C(O)NR35R36, —OC(O)NR35R36, —NR35C(O)R36, —OC(O)R35, —OC1-C6-alkyl-C(O)OR35, —SC1-C6-alkyl-C(O)OR35 or —C(O)OR35.

119. A pharmaceutical composition according to claim 118 wherein R34 is hydrogen, halogen, —CF3, —NO2, —OR35, —NR35R36, —SR35, —NR35C(O)R36, or —C(O)OR35.

120. A pharmaceutical composition according to claim 119 wherein R34 is hydrogen, halogen, —CF3, —NO2, —OR35, —NR35R36, or —NR35C(O)R36.

121. A pharmaceutical composition according to claim 120 wherein R34 is hydrogen, halogen, or —OR35.

122. A pharmaceutical composition according to claim 105 wherein R35 and R36 are independently selected from hydrogen, C1-C6-alkyl, or aryl.

123. A pharmaceutical composition according to claim 122 wherein R35 and R36 are independently selected from hydrogen or C1-C6-alkyl.

124. A pharmaceutical composition according to claim 105 wherein R37 is halogen, —C(O)OR35, —CN, —CF3, —OR35, —NR35R36, C1-C6-alkyl or C1-C6-alkanoyl.

125. A pharmaceutical composition according to claim 124 wherein R37 is halogen, —C(O)OR35, —OR35, —NR35R36, C1-C6-alkyl or C1-C6-alkanoyl.

126. A pharmaceutical composition according to claim 125 wherein R37 is halogen, —C(O)OR35 or —OR35.

127. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is

128. A pharmaceutical composition according to claim 127 wherein K is a valence bond, C1-C6-alkylene, —NH—C(═O)—U—, —C1-C6-alkyl-S—, —C1-C6-alkyl-O—, or —C(═O)—, wherein any C1-C6-alkyl moiety is optionally substituted with R38.

129. A pharmaceutical composition according to claim 128 wherein K is a valence bond, C1-C6-alkylene, —NH—C(═O)—U—, —C1-C6-alkyl-S—, or —C1-C6-alkyl-O, wherein any C1-C6-alkyl moiety is optionally substituted with R38.

130. A pharmaceutical composition according to claim 129 wherein K is a valence bond, C1-C6-alkylene, or —NH—C(═O)—U, wherein any C1-C6-alkyl moiety is optionally substituted with R38.

131. A pharmaceutical composition according to claim 130 wherein K is a valence bond or C1-C6-alkylene, wherein any C1-C6-alkyl moiety is optionally substituted with R38.

132. A pharmaceutical composition according to claim 130 wherein K is a valence bond or —NH—C(═O)—U.

133. A pharmaceutical composition according to claim 131 wherein K is a valence bond.

134. A pharmaceutical composition according to claim 127 wherein U is a valence bond or —C1-C6-alkyl-O—.

135. A pharmaceutical composition according to claim 134 wherein U is a valence bond.

136. A pharmaceutical composition according to claim 127 wherein M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R40.

137. A pharmaceutical composition according to claim 136 wherein M is ArG1 or Het1, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R40.

138. A pharmaceutical composition according to claim 137 wherein M is ArG1 or Het2, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R40.

139. A pharmaceutical composition according to claim 138 wherein M is ArG1 or Het3, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R40.

140. A pharmaceutical composition according to claim 139 wherein M is phenylene optionally substituted with one or more substituents independently selected from R40.

141. A pharmaceutical composition according to claim 139 wherein M is indolylene optionally substituted with one or more substituents independently selected from R40.

142. A pharmaceutical composition according to claim 141 wherein M is

143. A pharmaceutical composition according to claim 139 wherein M is carbazolylene optionally substituted with one or more substituents independently selected from R40.

144. A pharmaceutical composition according to claim 143 wherein M is

145. A pharmaceutical composition according to claim 127 wherein R40 is selected from hydrogen, halogen, —CN, —CF3, —OCF3, —NO2, —OR4, —NR41R42, —SR41, —S(O)2R41, —NR4 C(O)R42, —OC1-C6-alkyl-C(O)NR41R42, —C2-C6-alkenyl-C(═O)OR41, —C(O)OR41, ═O, —NH—C(═O)—O—C1-C6-alkyl, or —NH—C(═O)—C(═O)—O—C1-C6-alkyl, C1-C6-alkyl or C2-C6-alkenyl which may each optionally be substituted with one or more substituents independently selected from R43, aryl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, heteroaryl, heteroaryl-C1-C6-alkyl, or heteroaryl-C2-C6-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R44.

146. A pharmaceutical composition according to claim 145 wherein R40 is selected from hydrogen, halogen, —CN, —CF3, —OCF3, —NO2, —OR41, —NR41R42, —SR41, —S(O)2R41, —NR41C(O)R42, —OC1-C6-alkyl-C(O)NR41R42, —C2-C6-alkenyl-C(═O)OR41, —C(O)OR41, ═O, —NH—C(═O)—O—C1-C6-alkyl, or —NH—C(═O)—C(═O)—O—C1-C6-alkyl, C1-C6-alkyl or C2-C6-alkenyl which may each optionally be substituted with one or more substituents independently selected from R43, ArG1, ArG1-O—, ArG1-C1-C6-alkoxy, ArG1-C1-C6-alkyl, ArG1-C2-C6-alkenyl, Het3, Het3-C1-C6-alkyl, or Het3-C2-C6-alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substituents selected from R44.

147. A pharmaceutical composition according to claim 146 wherein R40 is selected from hydrogen, halogen, —CF3, —NO2, —OR41, —NR41R42, —C(O)OR41, ═O, or —NR41C(O)R42, C1-C6-alkyl, and ArG1.

148. A pharmaceutical composition according to claim 147 wherein R40 is hydrogen.

149. A pharmaceutical composition according to claim 147 wherein R40 is selected from Halogen, —NO2, —OR41, —NR41R42, —C(O)OR41, or —NR41C(O)R42, Methyl, and Phenyl.

150. A pharmaceutical composition according to claim 127 wherein R41 and R42 are independently selected from hydrogen, C1-C6-alkyl, or aryl, wherein the aryl moieties may optionally be substituted with halogen or —COOH.

151. A pharmaceutical composition according to claim 150 wherein R41 and R42 are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or —COOH.

152. A pharmaceutical composition according to claim 127 wherein Q is a valence bond, C1-C6-alkylene, —C1-C6-alkyl-O—, —C1-C6-alkyl-NH—, —NH-C1-C6-alkyl, —NH—C(═O)—, —C(═O)—NH—, —O—C1-C6-alkyl, —C(═O)—, or —C1-C6-alkyl-C(═O)—N(R47)— wherein the alkyl moieties are optionally substituted with one or more substituents independently selected from R48.

153. A pharmaceutical composition according to claim 152 wherein Q is a valence bond, —CH2—, —CH2—CH2—, —CH2—O—, —CH2—CH2—O—, —CH2—NH—, —CH2—CH2—NH—, —NH—CH2—, —NH—CH2—CH2—, —NH—C(═O)—, —C(═O)—NH—, —O—CH2—, —O—CH2-CH2—, or —C(═O)—.

154. A pharmaceutical composition according to claim 127 wherein R47 and R48 are independently selected from hydrogen, methyl and phenyl.

155. A pharmaceutical composition according to claim 127 wherein T is Hydrogen, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R50, aryl, aryl-C1-C6-alkyl, heteroaryl, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R50.

156. A pharmaceutical composition according to claim 155 wherein T is hydrogen, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R50, ArG1, ArG1-C1-C6-alkyl, Het3, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R50.

157. A pharmaceutical composition according to claim 156 wherein T is hydrogen, C1-C6-alkyl, optionally substituted with one or more substituents independently selected from R50, phenyl, phenyl-C1-C6-alkyl, wherein the alkyl and phenyl moieties are optionally substituted with one or more substituents independently selected from R50.

158. A pharmaceutical composition according to claim 157 wherein T is phenyl substituted with R50.

159. A pharmaceutical composition according to claim 127 wherein R50 is C1-C6-alkyl, C1-C6-alkoxy, aryl, aryloxy, aryl-C1-C6-alkoxy, —C(═O)—NH—C1-C6-alkyl-aryl, —C(═O)—NR50A—C1-C6-alkyl, —C(═O)—NH—(CH2CH2O)mC1-C6-alkyl-COOH, heteroaryl, —C1-C6-alkyl-COOH, —O—C1-C6-alkyl-COOH, —S(O)2R51, —C2-C6-alkenyl-COOH, —OR51, —NO2, halogen, —COOH, —CF3, —CN, ═O, —N(R51R52), wherein the aryl or heteroaryl moieties are optionally substituted with one or more R53.

160. A pharmaceutical composition according to claim 159 wherein R50 is C1-C6-alkyl, C1-C6-alkoxy, aryl, aryloxy, —C(═O)—NR50A—C1-C6-alkyl, —C(═O)—NH—(CH2CH2O)mC1-C6-alkyl-COOH, aryl-C1-C6-alkoxy , —OR51, —NO2, halogen, —COOH, —CF3, wherein any aryl moiety is optionally substituted with one or more R53.

161. A pharmaceutical composition according to claim 160 wherein R50 is C1-C6-alkyl, aryloxy, —C(═O)—NR51A—C1-C6-alkyl, —C(═O)—NH—(CH2CH2O)mC1-C6-alkyl-COOH, aryl-C1-C6-alkoxy , —OR51, halogen, —COOH, —CF3, wherein any aryl moiety is optionally substituted with one or more R53.

162. A pharmaceutical composition according to claim 161 wherein R50 is C1-C6-alkyl, ArG1-O—, —C(═O)—NR50A—C1-C6-alkyl, —C(═O)—NH—(CH2CH2O)mC1-C6-alkyl-COOH, ArG1-C1-C6-alkoxy, —OR51, halogen, —COOH, —CF3, wherein any aryl moiety is optionally substituted with one or more R53.

163. A pharmaceutical composition according to claim 162 wherein R50 is —C(═O)—NR50ACH2, —C(═O)—NH—(CH2CH2O)2CH2I—COOH, or —C(═O)—NR50ACH2CH2.

164. A pharmaceutical composition according to claim 162 wherein R50 is phenyl, methyl or ethyl.

165. A pharmaceutical composition according to claim 164 wherein R50 is methyl or ethyl.

166. A pharmaceutical composition according to claim 127 wherein m is 1 or 2.

167. A pharmaceutical composition according to claim 127 wherein R51 is methyl.

168. A pharmaceutical composition according to claim 127 wherein R53 is C1-C6-alkyl, C1-C6-alkoxy, —OR51, halogen,or —CF3.

169. A pharmaceutical composition according to claim 127 wherein R50A is —C(O)OCH3, —C(O)OCH2CH3 —COOH, —CH2C(O)OCH3, —CH2C(O)OCH2CH3, —CH2CH2C(O)OCH3, —CH2CH2C(O)OCH2CH3, —CH2COOH, methyl, or ethyl.

170. A pharmaceutical composition according to claim 127 wherein R50B is —C(O)OCH3, —C(O)OCH2CH3 —COOH, —CH2C(O)OCH3, —CH2C(O)OCH2CH3, —CH2CH2C(O)OCH3, —CH2CH2C(O)OCH2CH3, —CH2COOH, methyl, or ethyl.

171. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is

172. A pharmaceutical composition according to claim 171 wherein V is aryl, heteroaryl, or aryl-C1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected R54, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R55.

173. A pharmaceutical composition according to claim 172 wherein V is aryl, Het1, or aryl-C1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R54, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R55.

174. A pharmaceutical composition according to claim 173 wherein V is aryl, Het2, or aryl-C1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R54, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R55.

175. A pharmaceutical composition according to claim 174 wherein V is aryl, Het3, or aryl-C1-6-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R54, and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R55.

176. A pharmaceutical composition according to claim 175 wherein V is aryl optionally substituted with one or more substituents independently selected from R55.

177. A pharmaceutical composition according to claim 176 wherein V is ArG1 optionally substituted with one or more substituents independently selected from R55.

178. A pharmaceutical composition according to claim 177 wherein V is phenyl, naphthyl or anthranyl optionally substituted with one or more substituents independently selected from R55.

179. A pharmaceutical composition according to claim 178 wherein V is phenyl optionally substituted with one or more substituents independently selected from R55.

180. A pharmaceutical composition according to claim 171 wherein R55 is independently selected from halogen, C1-C6-alkyl, —CN, —OCF3, —CF3, —NO2, —OR56, —NR56R57, —NR56C(O)R57—SR56, —OC1-C8-alkyl-C(O)OR56, or —C(O)OR56, C1-C6-alkyl optionally substituted with one or more substituents independently selected from R58 aryl, aryl-C1-C6-alkyl, heteroaryl, or heteroaryl-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R59.

181. A pharmaceutical composition according to claim 180 wherein R55 is independently selected from halogen, C-C6-alkyl, —CN, —OCF3, —CF3, —NO2, —OR56, —NR56R57, —NR56C(O)R57—SR56, —OC1-C8-alkyl-C(O)OR56, or —C(O)OR56 C1-C6-alkyl optionally substituted with one or more substituents independently selected from R58 ArG1, ArG1-C1-C6-alkyl, Het3, or Het3-C1-C6-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents independently selected from R59.

182. A pharmaceutical composition according to claim 181 wherein R55 is independently selected from halogen, —OR56, —NR56R57, —C(O)OR56, —OC1-C8-alkyl-C(O)OR56, —NR56C(O)R57 or C1-C6-alkyl.

183. A pharmaceutical composition according to claim 182 wherein R55 is independently selected from halogen, —OR56, —NR56R57, —C(O)OR56, —OC1-C8-alkyl-C(O)OR56, —NR56C(O)R57, methyl or ethyl.

184. A pharmaceutical composition according to claim 171 wherein R56 and R57 are independently selected from hydrogen, CF3, C1-C12-alkyl, or —C(═O)—C1-C6-alkyl; R56 and R57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the nitrogen atom.

185. A pharmaceutical composition according to claim 184 wherein R56 and R57 are independently selected from hydrogen or C1-C12-alkyl, R56 and R57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the nitrogen atom.

186. A pharmaceutical composition according to claim 185 wherein R56 and R57 are independently selected from hydrogen or methyl, ethyl, propyl butyl, R56 and R57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the nitrogen atom.

187. A pharmaceutical composition according to claim 1 wherein the zinc-binding ligand is

188. A pharmaceutical composition according to claim 187 wherein M is aryl, heteroaryl or aryl-C1-6alkyl-, wherein the alkyl is optionally substituted with one or more R63, and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R64.

189. A pharmaceutical composition according to claim 188 wherein M is aryl or heteroaryl optionally substituted with one or more substituents independently selected from R64.

190. A pharmaceutical composition according to claim 189 wherein M is ArG1 or Het1 optionally substituted with one or more substituents independently selected from R64.

191. A pharmaceutical composition according to claim 190 wherein M is ArG1 or Het2 optionally substituted with one or more substituents independently selected from R64.

192. A pharmaceutical composition according to claim 191 wherein M is ArG1 or Het3 optionally substituted with one or more substituents independently selected from R64.

193. A pharmaceutical composition according to claim 192 wherein AA is phenyl, naphtyl, anthryl, carbazolyl, thienyl, pyridyl, or benzodioxyl optionally substituted with one or more substituents independently selected from R64.

194. A pharmaceutical composition according to claim 193 wherein M is phenyl or naphtyl optionally substituted with one or more substituents independently selected from R64.

195. A pharmaceutical composition according to claim 187 wherein R64 is independently selected from hydrogen, halogen, —CF3, —OCF3, —OR65, —NR65R66, C1-C6-alkyl, —OC(O)R65, —OC1-C6-alkyl-C(O)OR65, aryl-C2-C6-alkenyl, aryloxy or aryl, wherein C1-C6-alkyl is optionally substituted with one or more substituents independently selected from R67, and the cyclic moieties optionally are substituted with one or more substituents independently selected from R68.

196. A pharmaceutical composition according to claim 195 wherein R64 is independently selected from halogen, —CF3, —OCF3, —OR65, —NR65R66, methyl, ethyl, propyl, —OC(O)R65, —OCH2—C(O)OR65, —OCH2—CH2—C(O)OR65, phenoxy optionally substituted with one or more substituents independently selected from R68.

197. A pharmaceutical composition according to claim 187 wherein R65 and R66 are independently selected from hydrogen, CF3, C1-C12-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R71.

198. A pharmaceutical composition according to claim 197 wherein R65 and R66 are independently hydrogen, C1-C12-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R71.

199. A pharmaceutical composition according to claim 198 wherein R65 and R66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionally substituted with one or more substituents independently selected from R71.

200. A pharmaceutical composition according to claim 199 wherein R65 and R66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents independently selected from R71.

201. A pharmaceutical composition according to claim 200 wherein R65 and R66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one or more substituents independently selected from R71.

202. A pharmaceutical composition according to claim 201 wherein R65 and R66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyl optionally substituted with one or more R71 independently; or isoxazolyl optionally substituted with one or more substituents independently selected from R71.

203. A pharmaceutical composition according to claim 187 wherein R71 is halogen or C1-C6-alkyl.

204. A pharmaceutical composition according to claim 203 wherein R71 is halogen or methyl.

205. A pharmaceutical composition according to claim 1 wherein the insulin is rapid acting insulin.

206. A pharmaceutical composition according to claim 1 wherein the insulin is selected from the group consisting of human insulin, an analogue thereof, a derivative thereof, and combinations of any of these.

207. A pharmaceutical composition according to claim 206 wherein the insulin is an analogue of human insulin selected from the group consisting of iii. An analogue wherein position B28 is Asp, Lys, Leu, Val, or Ala and position B29 is Lys or Pro; and iv. des(B28-B30), des(B27) or des(B30) human insulin.

208. A pharmaceutical composition according to claim 207, wherein the insulin is an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro.

209. A pharmaceutical composition according to claim 207 wherein the insulin is des(B30) human insulin.

210. A pharmaceutical composition according to claim 207 wherein the insulin is is an analogue of human insulin wherein position B3 is Lys and position B29 is Glu or Asp.

211. A pharmaceutical composition according to claim 206 wherein the insulin is a derivative of human insulin having one or more lipophilic substituents.

212. A pharmaceutical composition according to claim 211 wherein the insulin derivative is selected from the group consisting of B29-Nε-myristoyl-des(B30) human insulin, B29-Nε-palmitoyl-des(B30) human insulin, B29-Nε-myristoyl human insulin, B29-Nε-palmitoyl human insulin, B28-Nε-myristoyl LysB28 ProB29 human insulin, B28-Nε-palmitoyl LysB28 ProB29 human insulin, B30-Nε-myristoyl-ThrB29LysB30 human insulin, B30-Nε-palmitoyl-ThrB29LysB30 human insulin, B29-Nε—(N-palmitoyl-γ-glutamyl)-des(B30) human insulin, B29-Nε—(N-lithocholyl-γ-glutamyl)-des(B30) human insulin, B29-Nε-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-Nε-(ω-carboxyheptadecanoyl) human insulin.

213. A pharmaceutical composition according to claim 212 wherein the insulin derivative is B29-Nε-myristoyl-des(B30) human insulin.

214. A pharmaceutical composition according to claim 1 comprising 2-6 moles zinc2+ ions per mole insulin.

215. A pharmaceutical composition according to claim 214 comprising 2-3 moles zinc2+ ions per mole insulin.

216. A pharmaceutical composition according to claim 1 further comprising at least 3 molecules of a phenolic compound per insulin hexamer.

217. A pharmaceutical composition according to claim 1 further comprising an isotonicity agent.

218. A pharmaceutical composition according to claim 1 further comprising a buffer substance.

219. A method of stabilising an insulin composition comprising adding a zinc-binding ligand according to claim 1 to the insulin composition.

220. A method of treating type 1 or type 2 diabetes comprising administering to a patient in need thereof a pharmaceutically effective dose of an insulin composition according to claim 1.