Patent Application
20050176762
The present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine.
The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NK1, NK2 and NK3) and NKB binds preferentially to the NK3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23-93).
Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Physiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J. Neurosci., 11, 2332-8). However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.
International Patent Application, Publication Number WO 00/58307 describes a series of aryl fused 2,4-disubstituted pyridines, such as naphthyridine derivatives, which are stated to exhibit biological activity as NK3 receptor antagonists.
The compounds of the present invention are quinoline derivatives. Other quinoline derivatives have been described previously as selective NK3 antagonists. For example, International Patent Application, Publication Numbers, WO 95/32948 and WO 96/02509 describe a series of selective and potent NK3 receptor antagonists.
International Patent Application, Publication Number WO 00/64877 describes a series of 2-aminoquinolinecarboxamides as neurokinin receptor ligands.
International Patent Application, Publication Number, WO 00/58303 describes a series of 4-substituted quinoline derivatives which are stated to be NK3 and/or GABA(A) receptor ligands. Such compounds are characterised by the presence of a nitrogen-containing heterocyclic moiety at the C(4) position of the quinoline ring.
International Patent Application, Publication Numbers, WO 97/21680, WO 98/52942, WO 00/31037 and WO 00/31038 describe compounds which have biological activity as combined NK3 and NK2 receptor antagonists.
Copending International Patent Application Numbers, PCT/EP01/13833, PCT/EP01/14140 and PCT/EP01/13832 also describe compounds that have biological activity as combined NK3 and NK2 receptor antagonists.
We have now discovered a further novel class of non-peptide NK3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK2 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions, which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2.
These conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyper-reactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), gastro-exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders; increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema following pre-eclampsia in pregnancies (hereinafter referred to as the ‘Primary Conditions’).
Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (hereinafter referred to as the ‘Secondary Conditions’).
The compounds of formula (I) are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.
Certain compounds of the present invention have also been found to exhibit surprisingly advantageous pharmacochemical properties.
According to the present invention, there is provided a compound of formula (I) below or a pharmaceutically acceptable salt or solvate thereof:
wherein:
not being a compound wherein R5 is unsubstituted phenyl, and R1, R2, R3, R4, R6, R7 and a are selected from the following:
Preferably, R1 is H.
Suitably, R2 is aryl or cycloalkyl. Preferably, R2 is cyclohexyl.
Suitably, R3 is alkyl. Preferably, R3 is methyl.
Suitably, R4 is NR8R9 wherein R8 and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and optionally substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and —C(═O)NHR15, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl. Preferably R4 is NR8R9 wherein R8 and R9 together with the N atom to which they are attached form a heterocyclic ring comprising 4-8 ring members, said ring members optionally including in addition to said N atom one or more further heteroatoms selected from N, O or S; said heterocyclic ring being saturated or unsaturated and being substituted one or more times by hydroxy, oxo, alkyl, aminoalkyl, di-alkylaminoalkyl and —C(═O)NHR15, and wherein said ring may be optionally fused or linked by a single bond or an alkyl chain to one or more cycloalkyl, heterocyclyl or aryl groups, which cycloalkyl, heterocyclyl or aryl groups are unsubstituted or are substituted one or more times by halo, haloalkyl, oxo and aryl.
Suitably, R5 is aryl or an aromatic heterocyclic group. Preferably, R5 is phenyl or 3-thienyl.
Suitably, R6 is H or fluoro.
Suitably, R7 is H or fluoro.
Suitably, a is 1, 2 or 3. Preferably, a is 1.
In some embodiments of the invention, R8 is H or R11R12 where R12 is H or OH. R11 may be C1-3 allyl. Alternatively, R11 may be 3°-alkylaminoalkyl, such as R15NR16R17 where each of R15, R16 and R17 is independently selected from methyl, ethyl and propyl. For example, R15 may be propyl. Suitably, each of R16 and R17 may be the same one of methyl, ethyl or propyl, such as ethyl.
In some embodiments, R9 is R13 R14, where R13 is a single bond and R14 is a saturated heterocyclic ring comprising one N heteroatom. Said saturated heterocyclic ring may for example be a 5-7-membered ring. Optionally, said saturated heterocyclic ring may be substituted once by phenylalkyl such as phenylmethyl. Said saturated heterocyclic ring may additionally or alternatively be fused to a benzene ring.
In other embodiments, R9 is R13 R14, and R13 is C1-3 alkyl such as methyl, whilst R14 is a ring moiety such as phenyl.
In another aspect of the invention, R8 and R9 together with the N atom to which they are attached form a 5-7-membered saturated heterocyclic ring. Said heterocyclic ring may for example have six ring members. Optionally, said heterocyclic ring may comprise one additional heteroatom which is N or S. Advantageously, said heterocyclic ring may be fused or linked to an aryl group such as a benzene ring. In especially preferred embodiments, said heterocyclic ring comprises one additional heteroatom which is N, which one additional N atom is linked to a phenyl substituent. Said heterocyclic ring may optionally be substituted once by oxo or hydroxy.
In preferred embodiments of the invention, R1 is H, R2 is cyclohexyl, R3 is methyl, R5 is phenyl, R6 is H, R7 is H, a is 1 and R4 is selected from the following substituents:
In further preferred embodiments of the invention, R1 is H, R2 is unsubstituted cyclohexyl, R3 is unsubstituted methyl, R5 is unsubstituted phenyl, R6 is H, R7 is 6-F, a is 1 and R4 is selected from the following substituents:
Particularly preferred compounds of formula (I) which are of special interest as agents useful in the treatment and/or prophylaxis of conditions which are characterised by overstimulation of the Tachykinin receptors, in particular NK3 and NK2, are those listed in Table 4 below.
The compounds of formula (I) may have at least one asymmetric centre—for example the carbon atom labelled with an asterisk (*) in the compound of formula (1)—and therefore may exist in more than one stereoisomeric form. The invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates. In particular, the invention includes compounds wherein the asterisked carbon atom in formula (I) has the stereochemistry shown in formula (Ia):
wherein R1, R2, R3, R5, R6, and R7 are as defined in relation to formula (I), and X represents the moiety
The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
Suitable salts are pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula (I) when they are present, for example salts of carboxy groups or phenolic hydroxy groups.
Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-□-phenethylamine, dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
Suitable solvates are pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable solvates include hydrates.
The term ‘alkyl’ (unless specified to the contrary) when used alone or when forming part of other groups (such as the ‘alkoxy’ group) includes straight—or branched-chain alkyl groups containing 1 to 12, preferably 1-6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
The term ‘cycloalkyl’ (unless specified to the contrary) when used alone or when forming part of other groups (such as the ‘cycloalkylalkyl’ group) includes cyclic saturated or unsaturated carbon rings including 3-12, preferably 3-8 carbon ring members. Examples include cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl.
The term ‘alkenyl’ (unless specified to the contrary) when used alone or when forming part of other groups includes straight—or branched—unsaturated carbon chains including at least one double C═C bond and containing 2-12, preferably 2-6 carbon atoms.
The term ‘carbocyclic’ refers to cycloalkyl and aryl rings.
The term ‘aryl’ includes phenyl and naphthyl, preferably phenyl which unless specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
The term ‘aromatic heterocyclic group’ includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.
Composite terms such as ‘alkylcarboxy’, ‘cycloalkylalkyl’ and so forth refer to components of a compound which include two interlinked groups, with the group named latterly in the term being the linking group, so that ‘alkylcarboxy’ means (alkyl)-COO— whilst ‘cycloalkylalkyl’ means (cycloalkyl)-(alkyl)-.
Unless specified to the contrary, suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
It will be understood that, unless otherwise specified, groups and substituents forming part of a compound in accordance with the invention are unsubstituted.
When used herein the term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.
When used herein the term “acyl” includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl-carbonyl group.
The invention also provides in one aspect a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (II) or an active derivative thereof:
wherein R′6, R′7, R′5 and X′ are R6, R7, R5 and X respectively as hereinbefore defined in relation to formula (I) or (Ia), or a group convertible to R6, R7, R5 and X respectively; with a compound of formula (III):
wherein R′1, R′2, and R′3 are R1, R2, and R3 as defined for formula (I) or a group or atom convertible to R1, R2, and R3 respectively; to form a compound of formula (Ib):
wherein R′1, R′2, R′3, X′, R′5, R′6 and R′7 are as defined above, and thereafter carrying out one or more of the following optional steps:
Suitable groups convertible into other groups include protected forms of said groups.
Suitably R′1, R′2, R′3, X′, R′5, R′6 and R′7 each represents R1, R2, R3, X, R5, R6 and R7 respectively or a protected form thereof.
It is favoured if the compound of formula (II) is present as an active derivative.
A suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (I) has been replaced by a different group or atom, for example by an acyl halide, preferably a chloride, or an acylazide or a carboxylic acid anhydride.
Other suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimido ester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,N′-carbonyldiimidazole.
The reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the compound of formula (II) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (Ib) and thereafter the compound of formula (I) or a salt thereof and/or a solvate thereof is prepared.
For example, the reaction between an active derivative of the compound of formula (II) and the compound of formula (III) may be carried out:
A preferred reaction is set out in Scheme 1 shown below:
wherein R′1, R′2, R′3, X′, R′5, R′6 and R′7 are as defined above.
In the case in which the corresponding alkyl (such as methyl or ethyl) ester of compound (II) is utilised, an hydrolysis to compound (II) is required before conversion to compound (Ib) in Scheme 1. Such hydrolysis can be carried out under acidic conditions, such 10-36% hydrochloric acid at a temperature in the range between 30 and 100° C.
It will be appreciated that a compound of formula (Ib) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I) by interconversion of suitable substituents. Thus, certain compounds of formula (I) and (Ib) are useful intermediates in forming other compounds of the present invention.
Accordingly, in a further aspect the invention provides a process for preparing a compound of formula (I), or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (Ib) wherein at least one of R′1, R′2, R′3, X′, R′5, R′6 and R′7 is not R1, R2, R3, X, R5, R6 or R7 respectively, thereby to provide a compound of formula (I); and thereafter, as required, carrying out one or more of the following optional steps:
Suitably, in the compound of formula (Ib) the variables R′1, R′2, R′3, X′, R′5, R′6 and R′7 are R1, R2, R3, X, R5, R6 and R7 respectively or they are protected forms thereof.
The above mentioned conversions, protections and deprotections are carried out using the appropriate conventional reagents and conditions and are further discussed below.
A chiral compound of formula (III) wherein R2 is a C5 or C7 cycloalkyl group, R3 is methyl and R1 is H are described in J. Org. Chem. (1996), 61 (12), 4130-4135. A chiral compound of formula (III) wherein R2 is phenyl, R3 is isopropyl and R1 is H is a known compound described in for example Tetrahedron Lett. (1994), 35(22), 3745-6.
The compounds of formula (III) are known commercially available compounds or they can be prepared from known compounds by known methods, or methods analogous to those used to prepare known compounds, for example the methods described in Liebigs Ann. der Chemie, (1936), 523, 199.
In some embodiments of the invention, a compound of formula (II) or the corresponding alkyl (such as methyl or ethyl) ester is prepared by reacting a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester:
wherein R′6, R′7, R′5 and a are as defined above and L1 represents a halogen atom such as a bromine atom, with a compound of formula (V):
H—R′4 (V)
wherein R′4 is R4 as defined in relation to formula (I) or a protected form thereof.
Suitably, R′4 is R4.
Suitably, reaction between the compounds of formulae (IV) or the corresponding alkyl (such as methyl or ethyl) ester and (V) is carried out under conventional amination conditions, for example when L1 is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K2CO3.
The compounds of formula (V) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
In cases where a is 1, a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester may be prepared by appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester:
wherein R′6, R′7 and R′5 are as defined above in relation to formula (II).
Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when L1 is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
The halogenation of the compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester is suitably carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CCl4, or 1,2-dichloroethane or CH3CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60° C. to 100° C., for example 80° C.; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
A compound of formula (VI) is conveniently prepared by reacting a compound of formula (VII):
wherein R′6 and R′7 are as defined in relation to formula (II), with a compound of formula (XIII):
R5′—CO—CH2-Me (XIII)
wherein R′5 is as defined in relation to formula (II).
The reaction between the compounds of formula (VII) and (XIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)). For example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide. It will be appreciated that the Pfitzinger reaction can be also carried out in presence of an acid, such as acetic acid or hydrochloric acid, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, as described in .J. Med. Chem. 38, 906 (1995).
The compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
Alternatively a compound of formula (VI) may be conveniently prepared by reacting a compound of formula (XIV)
wherein R′6 and R′7 are as defined in relation to formula (II), with a compound of formula (XV):
R5′—CHO (XV)
wherein R′5 is as defined in relation to formula (II) in presence of oxobutyric acid.
The reaction between the compounds of formula (XIV) and (XV) is conveniently carried out using Doebner reaction conditions (see for example Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); J. Chem. Soc. B, 1969, 805), for example in an alcoholic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent.
The compounds of formula (XV) and (XV) are known compounds or they are prepared according to methods used to prepare known compounds for example as described in Vogel's Textbook of Practical Organic Chemistry.
In some alternative embodiments of the invention, a compound of formula (II) wherein X′ represents
is prepared by reacting a compound of formula (VII) as defined above with a compound of formula (VIII):
R5′—CO—CH2—(CH2)a-T5 (VIII)
wherein R′5 is as defined in relation to formula (II), and T5 is a group
—R′4—Y
where Y is a protecting group such as a benzyl group, particularly a protecting group which is stable in basic conditions such as a terbutoxycarbonyl group; and a is as defined in relation to formula (II); and thereafter as required removing any protecting group, for example by dehydrogenation, and/or converting any group T5 to R4.
The reaction between the compounds of formula (VII) and (VIII) is conveniently carried out using Pfitzinger reaction conditions (see for example J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888), J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example in an alkanolic solvent such as ethanol, at any temperature providing a suitable rate of formation of the required product, but generally at an elevated temperature, such as the reflux temperature of the solvent, and preferably in the presence of a base such as potassium hydroxide or potassium tert-butoxide.
Protected forms of R4 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice.
Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the R4 under consideration.
Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting T5 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
A compound of formula (VIII) is prepared from a compound of formula (IX):
R5′—CO—CH2—(CH2)—OH (IX)
wherein R′5 is as defined in relation to formula (II) and a is as defined in relation to formula (VIII), by first halogenating, preferably brominating, or mesylating the compound of formula (IX) and thereafter reacting the halogenation or mesylation product so formed with a compound capable of forming a group T5 so as to provide the required compound of formula (VII).
When T5 is a group R4, a compound capable of forming a group T5 is a compound of the above defined formula (V).
The halogenation of the compound of formula (IX) is suitably carried out using a conventional halogenation reagent. Mesylation is conveniently carried out using mesyl chloride in an inert solvent such as methylene dichloride, at a temperature below room temperature, such as 0° C., preferably in the presence of triethylamine.
The reaction conditions between the compound of formula (IX) and the compound capable of forming a group T5 will be those conventional conditions dictated by the specific nature of the reactants, for example when the T5 required is a group R4 and the required compound capable of forming a group T5 is a compound of the above defined formula (V), then the reaction between the halogenation or mesylation product of the compound of formula (IX) and the compound of formula (V) is carried out under analogous conditions to those described for the reaction between the compounds of formulae (IV) and (V).
Other compounds capable of forming a group T5 will depend upon the particular nature of T5, but will be those appropriate compounds dictated by conventional chemical practice with reference to standard texts such as Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; and Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
A compound of formula (IX) may be prepared by reacting a compound of formula (X):
wherein a is as defined in relation to formula (VIII), with a lithium salt of formula (XI):
R′5 Li (XI)
wherein R′5 is as defined in relation to formula (II).
The reaction between the compounds of formulae (X) and (XI) can be carried out in an aprotic solvent, such as diethyl-ether at any temperature providing a suitable rate of formation of the required product, usually at a low temperature such as in the range of −10° C. to −30° C., for example −20° C.
The compounds of formula (VII) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).
The compounds of formula (X) and (XI) are known compounds or they are prepared according to methods used to prepare known compounds for example those disclosed by Krow G. R. in Organic Reactions, Vol 43, page 251, John Wiley & Sons Inc. 1994 (for the compounds of formula (X)) and Organometallics in Synthesis, Schlosser M.(Ed), John Wiley & Sons Inc. 1994 (for the compounds of formula (XI)).
In another aspect, the present invention provides a process for the preparation of a compound of formula (I), or a salt thereof and/or a solvate thereof, wherein a is 1, which process comprises reacting a compound of formula (XVI):
wherein each of R′1, R′2, R′3, R′5, R′6, and R′7 is respectively R1, R2, R3, R5, R6, or R7 as defined above or a group convertible to R1, R2, R3, R5, R6, or R7 respectively as defined above providing R′2 is not aromatic in character, and L1 represents a halogen atom such as a bromine atom, with a compound of formula (XVII):
H—R′4 (XVII)
wherein R′4 is R4 as defined in relation to formula (I) or a protected form thereof or a group convertible thereto; and thereafter carrying out one or more of the following optional steps:
Protected forms of R4 will vary according to the particular nature of the group being protected but will be chosen in accordance with normal chemical practice.
Groups convertible to R4 include groups dictated by conventional chemical practice to be required and to be appropriate, depending upon the specific nature of the R4 under consideration.
Suitable deprotection methods for deprotecting protected forms of R4 and conversion methods for converting R′4 to R4 will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
Suitable groups convertible into other groups include protected forms of said groups.
Advantageously, a compound of formula (XVII) will be a compound of formula (V) as defined above.
Suitably R′1, R′2, R′3, R′4, R′5, R′6 and R′7 each represents R1, R2, R3, R4, R5, R6 and R7 respectively or a protected form thereof.
Suitable deprotection methods for deprotecting protected forms of R1, R2, R3, R4, R5, R6 and R7 and conversion methods for converting R′1, R′2, R′3, R′4, R′5, R′6 and R′7 to R1, R2, R3, R4, R5, R6 and R7 respectively will be those used conventionally in the art depending upon the particular groups under consideration with reference to standard texts such as Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.
Suitably, reaction between the compounds of formulae (XVI) and (XVI) is carried out under conventional amination conditions, for example when L1 is a bromine atom then the reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide or acetonitrile at any temperature providing a suitable rate of formation of the required product, usually at ambient temperature; preferably the reaction is carried out in the presence of triethylamine (TEA), sodium hydride or K2CO3.
The compounds of formula (XVII) are known, commercially available compounds or they can be prepared using methods analogous to those used to prepare known compounds; for example the methods described in the Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992 ; J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med. Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis (second edition), Wiley Interscience, (1991) or other methods mentioned herein.
A compound of formula (XVI) is prepared by appropriate halogenation of a compound of formula XVII):
wherein R′1, R′2, R′3, R′5, R′6, and R′7 are as defined above in relation to formula (XVI).
Suitable halogenation reagents are conventional reagents depending upon the nature of the halogen atom required, for example when L1 is bromine a preferred halogenation reagent is N-bromosuccinimide (NBS).
The halogenation of the compound of formula (XVIII) is carried out under conventional conditions, for example bromination is carried out by treatment with NBS in an inert solvent, such as carbon tetrachloride CCl4, or 1,2-dichloroethane or CH3CN, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature such as a temperature in the range of 60° C. to 100° C., for example 80° C.; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.
Suitably, the compound of formula (XVIII) may be prepared by reacting a compound of formula (VI) as defined above or an active derivative thereof with a compound of formula (III) as defined above wherein R′2 is not aromatic in character.
It is favoured if the compound of formula (VI) is present in the reaction mix as an active derivative, as hereinbefore described.
The reaction between the compound of formula (VI) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the compound of formula (VI) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (XVIII).
For example, the reaction between an active derivative of the compound of formula (VI) and the compound of formula (III) may be carried out:
A preferred reaction is set out in Scheme 2 shown below:
In the case in which the corresponding alkyl (such as methyl or ethyl) ester of compounds (VI) is utilised, a hydrolysis is required before conversion to compound (XVIII) in Scheme 2. Such hydrolysis can be carried out under acidic conditions, such 10-36% hydrochloric acid at a temperature in the range between 30 and 100° C.
As hereinbefore mentioned, the compounds of formula (I) may exist in more than one stereoisomeric form—and the process of the invention may produce racemates as well as enantiomerically pure forms. Accordingly, a pure enantiomer of a compound of formula (I) can be obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (IIIa) or (IIIc):
wherein R′1, R′2 and R′3 are as defined above, to obtain a compound of formula (I′a) or (I′c):
wherein R′1, R′2, R′3, X′, R′5, R′6, and R′7 are as defined above.
Compounds of formula (I′a) or (I′c) may subsequently be converted to compounds of formula (Ia) or (Ic) by the methods of conversion mentioned before:
wherein R1, R2, R3, X, R5, R6, and R7 are as defined above.
Suitably, in the above mentioned compounds of formulae (Ia), (Ic), (I′a), (I′c), (IIIa) and (IIIc) R1 represents hydrogen.
An alternative method for separating optical isomers is to use conventional, fractional separation methods in particular fractional crystallization methods. Thus, a pure enantiomer of a compound of formula (I) is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula (I) with an optically active strong acid resolving agent, such as camphosulphonic acid, tartaric acid, O,O′-di-p-toluoyltartaric acid or mandelic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone. The salt formation process should be conducted at a temperature between 20° C. and 80° C., preferably at 50° C.
A suitable conversion of one compound of formula (I) into a further compound of formula (I) involves converting one group X into another group X by for example:
As indicated above, where necessary, the conversion of any group R′1, R′2, R′3, X′, R′5, R′6, and R′7 into R1, R2, R3, X, R5, R6, and R7 which as stated above usually protected forms of R1, R2, R3, X, R5, R6, or R7 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.
It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected and deprotected according to conventional chemical practice, for example as described by Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994.
Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. Thus, for example suitable hydroxy protecting groups include benzyl or trialkylsilyl groups.
The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
As indicated above, the compounds of formula (I) have useful pharmaceutical properties.
Accordingly the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
In particular, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prophylaxis of the Primary and Secondary Conditions.
The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Conditions.
As mentioned above the Primary conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), gastro-exophageous reflex disease (GERD); urinary incontinence and disorders of the bladder function; renal disorders; increased blood pressure, proteinuria, coagulopathy and peripheral and cerebral oedema following pre-eclampsia in pregnancies.
As mentioned above, the Secondary conditions include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntingdon's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilatation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine.
Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions.
Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatine containing the compound, if desired with a carrier or other excipients.
Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.
A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.
The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
The activity of the compounds of the present invention, as NK3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK3 ligands, [125I]-[Me-Phe7]-NKB or [3H]-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
The binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the [125I]-[Me-Phe7]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.1-1000 nM. The NK3-antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK3 receptors-mediated Ca++ mobilisation (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean KB value of 3-8 separate experiments, where KB is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca++ mobilisation induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.
The activity of the compounds of the present invention, as NK-2 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK-2 ligands, [125I]-NKA or [3H]-NKA, to human NK-2 receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).
The binding assays utilised allow the determination of the concentration of the individual compound required to reduce by 50% the [125I]-NKA and [3H]-NKA specific binding to NK2 receptor in equilibrium conditions (IC50).
Binding assays provide for each compound tested a mean IC50 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC50 values in the range 0.5-1000 nM, such as 1-1000 nM. The NK-2-antagonist activity of the compounds of the present invention is determined by their ability to inhibit human NK-2 receptor-mediated Ca++ mobilisation (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC50 values) the Ca++ mobilisation induced by the agonist NKA. In this assay, the compounds of the present invention behave as antagonists.
The therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.
As stated above, the compounds of formula (I) are also considered to be useful as diagnostic tools. Accordingly; the invention includes a compound of formula (I) for use as diagnostic tools for assessing the degree to which neurokinin-3 and neurokinin-2 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms. Such use comprises the use of a compound of formula (I) as an antagonist of said activity, for example including but not restricted to Tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula (I), will disclose the degree of NK-3 and NK-2 receptor involvement in the mediation of agonist effects in that tissue.
The following Descriptions illustrate the preparation of the intermediates, whereas the following Examples illustrate the preparation of the compounds of the invention.
Isatine (40 g, 0.272 mol) is suspended in EtOH (11) and KOH (62.8 g, 1.1 mol). Suspension is stirred for 30 min. Propiophenone (36.2 cc, 0.272 mol) was added and the reaction was refluxed for 4 h. The reaction was left overnight at room temperature and then EtOH was evaporated under vacuum. The solid was dissolved in water (400 ml) and washed with Et2O. The aqueous phase was acidified with citric acid (saturated solution) and a solid was obtained. The solid was filtered by suction, washed with water and dried in oven to obtain the title compound, mp>280° C.
4-Carboxy-3-methyl-2-phenylquinoline (40 g, 0.152 mol) prepared as in Description 1, was suspended in CH2Cl2 (600 ml) and oxalyl chloride (6.6 ml, 0.311 mol) was added dropwise at 0° C. under magnetic stirring. After 15 min 2 drops of DMF were added. The reaction was vigorous with gas evolution. The mixture was stirred at room temperature until the solid was completely dissolved (about 2 h). The solution was evaporated. The crude material was re-dissolved in CH2Cl2 (150 ml) and slowly dropped into a suspension of K2CO3 (47 g) and (S)-1-cyclohexylethyl amine (29 ml, 0.196 mol) in CH2Cl2 (250 ml) maintaining the temperature between 10-15° C. The dark solution was left 1 h at room temperature and 1 h refluxing. The organic phase was then washed with water, NaOH 1N, brine, dried over Na2SO4 and then evaporated under vacuum. The crude residue was triturated with EtOAc. After filtration the title compound was obtained, mp=177-180° C.
MW=372.51
[a]D=+21.77 (c=0.4 in MeOH).
3-Methyl-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (9.8 g, 26 mmol; compound prepared as in Description 2) and N-bromosuccinmmide (9.8 g, 55 mmol) were suspended in CCl4 (100 ml) and warmed to incipient reflux. Dibenzoyl peroxide (about 300 mg) was carefully added dropwise and the solution was then refluxed for 2 h. The solvent was removed under vacuum and the residue was re-dissolved in CH2Cl2 (200 ml) and filtered. DCM was then evaporated and the residue was dissolved in EtOAc and washed with a saturated solution of NaHCO3, brine, dried over Na2SO4, filtered and evaporated to give the title compound. The title compound may be used in the next step without further purification, mp: 182-184° C.
MW 451.41
[a]D -5.76 (c=0.5% in CH2Cl2)
A solution of 5,6-difluoroisatine (4.68 g; 25.6 mmol) (prepared as in JACS 1958, 23, 1858) and phenylethylketone (3.40 ml; 25.6 mmol) in glacial acetic acid (150 ml) was stirred for 5 minutes at 105° C. HCl 37% was added (38 ml) and the reaction mixture was stirred at 105° C. for 24 h. The reaction was then cooled at room temperature and diluted with water (400 ml). Filtration and subsequent drying of the precipitate afforded the title compound as a solid.
A solution of 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (10 g, 22 mmol, prepared as in Description 3), piperazin-2-one (CAS [5625-67-2]) (3 g, 30 mmol) and ethyldiisopropylamine (11 ml, 66 mmol) in dry THF (200 ml) was stirred for 24 h at room temperature. The solvent was evaporated to dryness in vacuum and the residue was re-dissolved in EtOAc. This mixture was washed with a dilute NaOH solution, with water and dried over Na2SO4. After evaporating to dryness, the residue was triturated with Et2O to afford the desired compound, which may be used without further purification.
Method A: To a solution of the piperazinone derivative (1 mmol, compound prepared as in Description 5) in anhydrous DMF (10 ml), 60% NaH (2 mmol, 29 mg) was added at 0° C. The dark solution obtained was stirred for 10 minutes at 0° C. and then for additional 20 minutes at room temperature. The solution was re-cooled at 0° C. and the electrophilic species (1 mmol) were added.
The reaction was stirred overnight then poured into a saturated solution of NaCl and extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and evaporated under vacuum to give after purification by flash chromatography the desired compound.
Method B: A mixture of the piperazinone derivative (0.47 g, 1 mmol, compound prepared as in Description 5), alkylating reagent (1.2 mmol) and KOH (0.23g, 4 mmol) in anhydrous DMSO (10 ml), was stirred for 36 hours at room temperature. The reaction was diluted with a saturated solution of NaCl and the product was extracted with DCM. The organic phases were dried over Na2SO4, filtered and evaporated under vacuum; the residue was purificated by flash chromatography to afford the desired compound.
The compound was prepared according to Descriptions 2 and 3 starting from the compound in Description 4.
The compound was prepared according to Description 1, starting from 5-fluoroisatine CAS[443-69-6] and phenylethylketone, Description 2 and 3.
The compound was prepared according to Description 5 starting from the compound of Description 8 and piperazinone (CAS[5625-67-2]).
The compound was prepared according to Description 1, starting from 1-thiophen-2-yl-propan-1-one CAS [13679-75-9] and isatine, Description 2 and 3.
The compound was prepared according to Description 5 starting from the compound of Description 10 and piperazinone (CAS [5625-67-2]).
The compound was prepared according to Description 1, starting from 1-thiophen-3-yl-propan-1-one CAS [51179-52-3] and isatine, Description 2 and 3.
To a suspension of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 1.5 mmol, CAS [76003-29-7]) in DMF/DMSO 2/1 (10 ml), 60% NaH (60 mg, 1.5 mmol) was added at 0° C. After stirring for 30 minutes a solution of 3-bromomethyl-6-fluoro-2-phenyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (0.6 g, 1.3 mmol, prepared according to Description 8) in DMF (3ml) was slowly added. The reaction was stirred for 3 hours at room temperature then poured into a saturated solution of NaCl. The precipitate was filtered and purified by flash chromatography to afford the title compound.
To a solution of piperazine (30 g, 350 mmol) in water (370 ml) and tBuOH (420 ml), a solution of 4N NaOH (70 ml) was added. The mixture was cooled to 0° C. and then BOC2O (38 g, 170 mmol) was added portionwise. After stirring at room temperature for 45 minutes, tBuOH was evaporated under vacuum, the precipitate (diBOCpiperazine) was filtered and water was extracted with CH2Cl2. After drying over Na2SO4 the solvent was removed under vacuum to afford the title compound.
MW=186.25
4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 4.5 mmol, prepared according to Description 5 using piperazine-1-carboxylic acid tert-butyl ester (Description 14) as nucleophile) was dissolved in CH2Cl2 (60 ml) and TFA (3 ml) was added. The red solution was stirred at room temperature overnight; then the solvent and the excess of TFA were removed under vacuum. The residue was dissolved in H2O and washed 2 times with Et2O. The water extract was made alkaline by addition of 2N NaOH solution and the product was extracted with EtOAc. The solvent was evaporated to dryness and the residue was purified by flash chromatography (eluent CH2Cl2: MeOH 93:7) to afford the title compound.
A solution of 2-phenyl-3-piperazin-1-ylmethyl-quinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (0.3 g, 0.65 mmol, prepared according to Description 15), isocyanate (0.65 mmol) in CH3CN (20 ml) was stirred for 1 hour at room temperature. The solvent was evaporated under vacuum; the residue was re-dissolved in EtOAc and washed with a saturated solution of NaCl. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography to afford the urea derivative.
Examples from 1 to 15, 17 and 22, in Table 1, were prepared according to the following general procedure:
A solution of 3-bromomethyl-2-phenylquinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (1 mmol, 0.45 g; compound prepared as in Description 3), 1.5 mmol of amine and ethyldiisopropylamine (3 mmol, 0.5 ml) in dry THF (15 ml) was stirred for 24 h at room temperature. The solvent was evaporated to dryness in vacuum and the residue was re-dissolved in EtOAc. This mixture was washed with a dilute NaOH solution, with water and dried over Na2SO4. After evaporating to dryness, the residue was purified by flash chromatography to afford the desired compound.
The compound was prepared following the Description 6 (method A) starting from the compound of Description 9 and 1-(2-chloroethyl)piperidine.
The compound was prepared following the Description 6, method A, starting from the compound of Description 5 and 1-3-(chloropropyl)piperidine (CAS[5472-49-1)).
The compound was prepared according to Description 13 using 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (CAS[54906-42-2]) and compound of Description 3.
The compound was prepared according to Description 5 starting from the compound in Description 8 and dimethylamine.
The compound was prepared according to Description 13 starting from the compound of Description 8 and 3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (CAS[54906-42-2]).
The compound was prepared following Description 6, method B, starting from the compound prepared in Description 5 and 3-dimethylaminopropylchloride.
The compound was prepared following Description 6, method A, starting from the compound of Description 5 and methyl iodide.
The compound was prepared following the above Description 6, method A, starting from the compound in Description 5 and ethyl bromide.
A mixture of 3-bromomethyl-2-phenyl-quinoline-4carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide (0.5g, 1.1 mmol) (prepared as in Description 3), 2-imidazolidone (0.1 g, 1.2 mmol, and K2CO3 (0.3 g, 2.2 mmol) in CH3CN (20 ml) was stirred overnight at room temperature. The carbonate was filtered and the solvent evaporated under vacuum. The solid was re-dissolved in EtOAc, washed with 0.5 N NaOH and a saturated solution of NaCl. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified on column chromatography (CH2Cl2/MeOH 95/5) to give the title compound.
The compound was prepared following Description 6 (method B) starting from the compound of Description 5 and 1-(2-chloroethyl)pyrrolidine.
The compound was prepared following Description 6 (method B) starting from the compound of Description 5 and 2-diethylaminoethyl chloride.
The compound was prepared following Description 6 (method B) starting from the compound in Description 5 and dimethylamino ethyl chloride.
To a solution of (2-{4-[4-((S)-1-cyclohexyl-ethylcarbamoyl)-2-phenyl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-ethyl)-carbamic acid tert-butyl ester (30 mg, 0.05 mmol, prepared according to Description 6 (method B) starting from the compound in Description 5 and 2-(BOC-amino)ethylbromide) in CH2Cl2 (4 ml), TFA (0.2 ml) was added drop-wise at room temperature. Stirring was continued for 1 hour. The solvent was evaporated under vacuum and the residue was basified with a saturated solution of K2CO3 and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound.
The compound was prepared following Description 6 (method B) starting from the compound in Description 5 and 4-(2-chloroethyl)morpholine.
The compound was prepared following Description 16 starting from compound in Description 15 and ethylisocyanate.
The compound was prepared following Description 16 starting from the compound of Description 15 and isopropylisocyanate.
The compound was prepared according to Description 5 starting from the compound of Description 12 and piperazinone (CAS [5625-67-2]).
The compound was prepared following Description 6, method A, starting from the compound of Description 9 and 3-dimethylaminopropylchloride.
1H NMR and/or mass spectroscopy data for Examples 1-60
1H NMR (Solvent) ppm and/or MS
1H NMR(DMSO-d6 -333K) δ: 8.34(d br, 1H); 8.01(d, 1H);
1H NMR(DMSO-d6) δ: 8.75(d br, 1H); 8.04(d, 1H);
1H NMR(DMSO-d6) δ: 8.75(d br, 1H); 8.04(d, 1H);
1H NMR(DMSO-d6) δ: 8.33(d br, 1H); 8.10(dd, 1H);
1H NMR(DMSO-d6) δ: 8.30(d br, 1H); 8.03(d, 1H);
1H NMR(DMSO-d6) δ: 8.28(d br, 1H); 8.02(d, 1H);
1H NMR(DMSO-d6) δ: 8.40(d br, 1H); 8.04(d, 1H);
1H NMR(CDCl3) δ: 8.63(d br, 1H); 8.10(dd, 1H); 7.80
1H NMR(CDCl3) δ: 8.03(dd, 1H); 8.01(d br, 1H); 7.58
1H NMR(DMSO-d6) δ: 8.22(d br, 1H); 8.18(s br, 1H);
1H NMR(DMSO-d6) δ: 8.53(s br, 1H); 8.02(d, 1H);
1H NMR(DMSO-d6) δ: 8.16(d, 1H); 7.96(d, 1H); 7.75
1H NMR(DMSO-d6) δ: 8.14(d, 1H); 8.01(d, 1H); 7.75
1H NMR(DMSO-d6-343 K) δ: 8.45(d br, 1H); 8.01
1H NMR(DMSO-d6) δ: 8.28(d br, 1H); 8.02(d, 1H);
1H NMR(DMSO-d6) δ: 8.03(d, 1H); 7.88(d, 1H); 7.77
1H NMR(DMSO-d6) δ: 8.26(d br, 1H); 8.02(d, 1H);
1H NMR(DMSO-d6) δ: 8.23(d br, 1H); 8.01(d, 1H);
1H NMR(DMSO-d6) δ: 8.26(d br, 1H); 8.02(d, 1H);
1H NMR(DMSO-d6) δ: 8.29(d br, 1H); 8.01(d, 1H);
1H NMR(DMSO-d6) δ: 8.54(s br, 1H); 8.11(dd, 1H);
| Number | Date | Country | Kind |
|---|---|---|---|
| 0109123.0 | Apr 2001 | GB | national |
| 0205649.7 | Mar 2002 | GB | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10474542 | Mar 2004 | US |
| Child | 11100256 | Apr 2005 | US |
