Patent Application
20080125424
The present invention relates to urea derivatives useful in the physiological modulation of the activity of inorganic ions, particularly through their effect on inorganic ion receptors and especially on membrane calcium receptors capable of binding extra cellular calcium; to processes for the preparation thereof; to their use as medicaments; to pharmaceutical compositions containing them; and to the their uses.
Extra cellular calcium concentration is precisely regulated in the organism and one of the key elements of this regulation is the calcium receptor known as the Ca sensing receptor or CaSR. A receptor of this type at the surface of specific cells can detect the presence of calcium. Specific cells of the organism respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca++): changes in the concentration of these extracellular Ca++ ions can modify the functional responses of these cells. These cells include parathyroid cells which secrete the parathyroid hormone known as PTH. Parathyroid cells thus have at their surface the calcium receptor (CaSR), which detects changes in extracellular calcium concentration, and initiates the functional response of this cell, which is a modulation of the secretion of the parathyroid hormone (PTH). PTH, by acting in particular on the bone cells or on the renal cells, increases the calcium level in the blood. This increase then acts as a negative control on PTH secretion. The reciprocal relationship between calcium concentration and PTH level is an essential mechanism for calcium homeostasis maintenance.
The cloning of the calcium receptor by Brown in 1993 consequently demonstrated two possible signalling pathways for this G protein coupled receptor: one pathway by activation of the Gi protein (sensitive to the pertussis toxin) which stimulates phospholipase C and inhibits adenylate cyclase; the other pathway by activating the Gq protein responsible for mobilising intracellular calcium. These two signalling pathways, either independently of one another or together, can be activated so as to trigger the associated biological effect.
On its extracellular portion, the calcium receptor is a low affinity receptor which is stimulated by millimolar concentrations of agonists, in particular the calcium ion Ca2+. In addition, this receptor can also be activated by some divalent metals (magnesium) or trivalent metals (gadolinium, lanthanum, etc.) or else by polycationic compounds such as neomycin or spermin.
Novel compounds acting on the transmembrane portion of the receptor have been identified by Edward F. Nemeth et al (company NPS, U.S. Pat. No. 6,211,244, EP-787 122, WO 06031003) and allow the calcium receptor to be modulated allosterically. The action of first generation and second generation compounds on the pharmacological regulation of parathyroid hormone (PTH) secretion is described, for example, by E. F. Nemeth in Current Pharmaceutical Design, 2002, 8, 2077-2087. In particular, the compound AMG073 (cinacalcet, Sensipar®, Mimpara®) acts as an agonist of the calcium receptor and is sold for the treatment of secondary hyperparathyroidism (Idrugs, 2003, 6, 587-592 J. Iqbal, M. Zaidi, A. E. Schneider).
The current invention encompasses compounds of Formula I or pharmaceutically acceptable salts thereof
wherein all substituents are as defined in Detailed Description.
In one aspect, R1 and R2 can be the same or different, and each represents a monocyclic aryl group, a monocyclic heteroaryl group, or Z, R1 and R2 together form said fused ring structure, wherein each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group ‘c’. In a further aspect, R1 and R2 each represent a phenyl, pyridinyl, or thienyl radical, or R1 and R2 represent a fused ring structure as defined in claim 1, wherein each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted. In another aspect, each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group c′, consisting of: fluorine and chlorine atoms, hydroxyl, linear and branched alkyl, alkylthio, hydroxyalkyl, and fluoroalkyl groups; linear and branched alkoxyl groups; trifluoromethyl; trifluoromethoxyl; —CN; alkylcarbonyl groups; alkylsulphonyl groups, and any alkyl component has from 1 to 4 carbon atoms, and wherein, when there is more than one substituent, then each said substituent is the same or different. In one aspect, each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group consisting of: fluorine and chlorine atoms, hydroxyl groups, linear or branched alkoxy groups containing from 1 to 5 carbon atoms, linear or branched alkyl groups containing from 1 to 5 carbon atoms, trifluoromethyl and trifluoromethoxy groups, and —CN groups, and wherein, when there is more than one substituent, then each said substituent is the same or different. For example, each of R1 and R2 can be an optionally substituted phenyl, pyridinyl, or thienyl group. In one aspect, each R1 and R2 can be substituted with a substituent selected from: hydrogen; chlorine atoms; hydroxyl groups; carboxyl groups; linear and branched alkyl and hydroxyalkyl groups; linear and branched alkoxyl groups; alkoxycarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; alkylthio groups; alkylsulphonyl groups; and sulphonamide groups. In another aspect, R1 and R2, or Z, R1 and R2 together forming the fused ring structure, are unsubstituted. In one aspect, R1 and R2 can be each phenyl.
The invention provides compounds of Formula I, wherein R3 represents a group selected from: -AlkCOOR, -AlkNR7R8, -AlkCONR7R8, -AlkCOR9, -AlkSO2NR10R10′, -AlkOR10, and -AlkS(O)nR10.
The invention provides compounds of Formula I, wherein R6 is a monocyclic aryl or a 5 or 6 membered heteroaryl ring. In one aspect, R6 represents two linked rings, optionally substituted, and wherein said rings are linked by Alk, Alk-S or Alk-O. In a further aspect, R6 can be an aryl or heteroaryl group selected from the group consisting of: fluorenyl, phenyl, naphthyl, monocyclic heteroaryls, and bicyclic heteroaryls, optionally substituted. In one aspect, R6 is selected from the group consisting of: phenyl, naphthyl, benzothiazolyl, fluorenyl, benzazolyl, benzoxazolyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, indolyl, pyrrolyl, quinolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiazyl, benzimidazolyl, indazolyl, tetraquinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, indolyl, carbazolyl, indolinyl, alpha- or beta-carbolinyl, and benzothienyl groups. For example, R6 can be substituted by at least one substituent selected from substituents a′: fluorine atoms; chlorine atoms; hydroxyl groups; carboxyl groups; aldehyde groups; linear and branched alkyl, hydroxyalkyl, and fluoroalkyl groups; linear and branched alkoxyl groups; linear and branched thioalkyl groups; alkoxycarbonyl groups; benzylcarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, dialkylamino, acylamino, and diacylamino groups; alkoxycarbonylamino, alkylcarbonylamino groups; alkylaminocarbonyloxy groups; alkyl groups substituted with an amino, alkylamino, dialkylamino, acylamino, or diacylamino group; CONH2; alkylamido groups; alkylthio; alkylsulphoxide; sulphonyl, and alkylsulphonyl groups; sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups; trifluoromethylsulphoxide; trifluoromethylsulphonyl groups; trifluoromethylsulphonamide, and di(trifluoromethylsulphonyl)amino groups; alkylcarbonylalkyl; phenyl, phenoxy, phenylthio, and benzyl groups; and saturated monocyclic heterocyclyl groups, said aryl and heterocyclyl groups being optionally substituted by one or more substituents, which may be the same or different, selected from the group b. In one aspect, R6 can be substituted by at least one substituent selected from substituents a″: chlorine atoms; hydroxyl groups; carboxyl groups; linear and branched alkyl, hydroxyalkyl; linear and branched alkoxyl groups; alkoxycarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, and dialkylamino groups; alkoxycarbonylamino, alkylcarbonylamino groups; alkylaminocarbonyloxy groups; alkyl groups substituted with an amino, alkylamino, or dialkylamino group; CONH2; alkylcarbonylalkyl; alkylthio; sulphonyl and alkylsulphonyl groups; sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups; trifluoromethylsulphoxide; trifluoromethylsulphonyl groups; trifluoromethylsulphonamide, and di(trifluoromethylsulphonyl)amino groups; and phenyl, phenoxyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups optionally substituted by one or more substituents, which may be the same or different, selected from the group b,
and wherein any pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups are not further substituted. In one aspect, substituents b can be selected from substituents b′ consisting of: chlorine atoms; hydroxyl groups; linear and branched alkyl, hydroxyalkyl, and alkoxyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, and dialkylamino groups; sulphonyl, alkylsulphonyl groups; and sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups.
The invention provides compounds of Formula I, wherein R3 represents a group -AlkCONR7R8, wherein R7 and R8, together with the nitrogen atom to which they are linked, form a five-, six- or seven-membered heterocyclic group. For example, the heterocyclic group can be pyrrolidinyl, pyrrolinyl, morpholinyl, piperidinyl, piperazinyl, or homopiperazinyl. In one aspect, the heterocyclic group comprises an unsubstituted nitrogen atom therein. In another aspect, the heterocyclic group is substituted by at least one substituent ‘b’. For example, the heterocyclic group is piperazinyl and the substituent is attached to the available nitrogen atom. In one aspect, the substituent is selected from alkyl, and substituted carbonyl. The substituted carbonyl can be, for example, butoxycarbonyl, aminocarbonyl or alkylcarbonyl. In another aspect, the heterocyclic group can be substituted by an alkyl group.
The invention provides compounds of Formula I, wherein R3 represents a group -AlkCONR7R8 or -AlkNR7R8, and one of R7 and R8 represents a hydrogen atom or a methyl group, and the other represents an optionally substituted cycle. For example, the cycle can be a six-membered cycle. In another aspect, the cycle can be a five-membered cycle. For example, the cycle can be cyclohexyl, phenyl, piperidinyl, piperazinyl, cyclopentyl or pyrrolidinyl. In one aspect, R3 represents a group -AlkCONR7R8 or -AlkNR7R8, and one of R7 and R8 represents a hydrogen atom and the other represents a hydrogen atom or an optionally substituted alkyl group. For example, one of R7 and R8 represents an alkyl group substituted by one or two substituents selected from: alkoxy, carboxyl, amino, alkylamino, dialkylamino, and aromatic groups. The aromatic group can be, for example, a phenyl or pyridinyl group. In one aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a sulphonyl optionally substituted by an alkyl, amino, alkylamino or dialkylamino group. In another aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a sulphonyl substituted by an aryl group optionally substituted by a substituent selected from substituents b. In a further aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a carbonyl group substituted by an optionally substituted alkyl group or heterocyclic group optionally substituted with a substituent selected from substituents b. In yet another aspect, R3 can be -AlkCOOR and R is H. In one aspect, R3 is -AlkCOOR and R is an alkyl group. R can be ethyl or tert-butyl. In another aspect, R3 represents -AlkCOR9 and R9 is a saturated heterocycle. The heterocycle, for example, can comprise an unsubstituted nitrogen atom therein. In another aspect, R9 can be a pyrrolidinyl or piperidinyl group. In one aspect, R3 represents -AlkCOR9 and R9 is an alkyl group substituted by phenyl group. In another aspect, R3 represents -AlkOR10 or -AlkS(O)nR10 in which n is 0, and R10 is hydrogen. In a further aspect, R3 represents -AlkOR10 or -AlkS(O)nR10, and R10 is carbamoyl. In one aspect, R3 represents -AlkOR10 or -AlkS(O)nR10, and R10 is a C1-4 alkyl group. In another aspect, R3 represents -AlkS(O)nR10, and n is 0. In another aspect, R3 represents -AlkSO2NR10R10′ and R10 and R10′ are independently hydrogen or a C1-4 alkyl group. Alk can represent, for example, a propylene group. In another example, Alk is C1-4-alkylene.
The invention provides compounds of Formula I, wherein Z is >CH—, or Z is >C═CH—, or Z is >N—. In one aspect, p is 2 when Z is >C— or >N—, or p is 1 when Z is >C═CH—.
The invention provides compounds of Formula I, wherein q is 0.
The invention further provides compounds of Formula I, wherein R5 is a methyl group or hydrogen.
The invention provides compounds of Formula I, wherein Q is >C═O and Z is >N—.
The invention provides compounds of Formula I, wherein Q is >C═S. In one aspect, Q is a sulphonyl group.
In one aspect, the invention provides compounds of Formula I, wherein any alkyl, alkenyl or alkynyl component has no more than 4 carbon atoms.
The invention encompasses the following compounds:
The invention provides pharmaceutically acceptable compositions comprising compounds of Formula I, and a pharmaceutically acceptable carrier.
The invention further provides the use of the compounds of Formula I as calcimimetics in therapy. For example, the invention provides methods of treating parathyroid cancer comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof. In one aspect, the invention provides methods of treating hyperplasia or parathyroid adenoma comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof. In another aspect, the invention provides methods of treating abnormal calcium homeostasis comprising administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof. In one aspect, the abnormal calcium homeostasis is hypercalcemia. In a further aspect, the invention provides methods of treating intestinal malabsorption comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In one aspect, the invention provides methods of treating biliary lithiasis and renal lithiasis comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In one aspect, the invention provides methods of treating hyperparathyroidism comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In one aspect, hyperparathyroidism can be primary hyperparathyroidism. In another aspect, hyperparathyroidism can be secondary hyperparathyroidism. In one aspect, the invention provides methods of treating vascular calcification comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In another aspect, the invention provides methods of treating diarrhea comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In a further aspect, the invention provides methods of treating polycystic kidney disease or a podocyte-related disorder comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof. In another aspect, the invention provides methods of treating hypertension comprising administering a therapeutically effective amount of a compound or salt of Formula I to a subject in need thereof.
“Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a subject that may be or has been exposed to the disease or conditions that may cause the disease, or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or any of its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or any of its clinical symptoms.
The phrase “therapeutically effective amount” is the amount of the compound of the invention that will achieve the goal of prevention of the disorder or improvement in disorder severity and the frequency of incidence. The improvement in disorder severity includes the reversal of the disease, as well as slowing down the progression of the disease.
As used herein, “calcium sensing receptor” or “CaSR” refers to the G-protein-coupled receptor responding to changes in extracellular calcium and/or magnesium levels. Activation of the CaSR produces rapid, transient increases in cytosolic calcium concentration by mobilizing calcium from thapsigargin-sensitive intracellular stores and by increasing calcium influx though voltage-insensitive calcium channels in the cell membrane (Brown et al., Nature 366: 575-580, 1993; Yamaguchi et al., Adv Pharmacol 47: 209-253, 2000).
As used herein, the term “calcimimetic compound” or “calcimimetic” refers to a compound that binds to calcium sensing receptors and induces a conformational change that reduces the threshold for calcium sensing receptor activation by the endogenous ligand Ca2+. These calcimimetic compounds can also be considered allosteric modulators of the calcium receptors.
In one aspect, a calcimimetic can have one or more of the following activities: it evokes a transient increase in internal calcium, having a duration of less than 30 seconds (for example, by mobilizing internal calcium); it evokes a rapid increase in [Ca2+]i occurring within thirty seconds; it evokes a sustained increase (greater than thirty seconds) in [Ca2+]i (for example, by causing an influx of external calcium); evokes an increase in inositol-1,4,5-triphosphate or diacylglycerol levels, usually within less than 60 seconds; and inhibits dopamine- or isoproterenol-stimulated cyclic AMP formation. In one aspect, the transient increase in [Ca2+]i can be abolished by pretreatment of the cell for ten minutes with 10 mM sodium fluoride or with an inhibitor of phospholipase C, or the transient increase is diminished by brief pretreatment (not more than ten minutes) of the cell with an activator of protein kinase C, for example, phorbol myristate acetate (PMA), mezerein or (−) indolactam V.
While the compounds of the invention are believed to exert their effects by interacting with the calcium sensing receptor (CaSR), the mechanism of action by which the compounds act is not a limiting embodiment of the invention. For example, compounds of the invention may interact with calcium sensing receptors other than CaSR.
Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
In certain aspects, the compound of the invention is chosen from compounds of Formula I or a pharmaceutically acceptable salt thereof:
wherein:
Z is >CH—, >C═CH— or >N—,
R1 and R2 are the same or different, and each represents an aryl group, a heteroaryl group, or Z, R1 and R2 form a fused ring structure of formula:
in which A represents a single bond, a methylene group, a dimethylene group, oxygen,
nitrogen or sulphur, said sulphur optionally being in the sulphoxide or sulphone forms, wherein each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group c
and wherein, when there is more than one substituent, then each said substituent is the same or different,
R3 represents hydrogen, a group selected from: -AlkCOOR, -AlkNR7R8, -AlkCONR7R8, -AlkCOR9, -AlkSO2NR10R10′, -AlkOR10, and -AlkS(O)nR10, wherein
n is 0, 1 or 2,
R9 is a linear or branched C1-6 alkyl group and is optionally substituted by at least one of a phenyl group, a halogen atom, a hydroxyl group, or a C1-6 alkoxy group; an alkylaminoalkyl or dialkylaminoalkyl group wherein each alkyl group contains from 1 to 6 carbon atoms; a saturated or unsaturated cycle containing 0, 1, 2, or 3 heteroatoms and having 5, 6, or 7 ring atoms, said cycle being optionally substituted by at least one substituent selected from the group ‘b’ defined below,
R10 and R10′ are independently a hydrogen atom, a linear or branched C1-6 alkyl group optionally substituted by at least one of a phenyl group, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, or a C1-6 alkoxy group; an alkylaminoalkyl or dialkylaminoalkyl group wherein each alkyl group contains from 1 to 6 carbon atoms; an aminocarbonyl group; a saturated or unsaturated cycle, optionally spaced from the S or O to which the cycle is linked by an Alk group as defined, and containing 0, 1, 2, or 3 heteroatoms and having 5, 6, or 7 ring atoms, or 3-7 ring atoms when the cycle is a carbocycle, said cycle being optionally substituted by at least one substituent selected from the group ‘b’ defined below,
R7 and R8, which may be the same or different, each represents: a hydrogen atom; an alkylsulphonyl group; alkylamino- or dialkylamino-sulphonyl; a linear or branched alkyl group containing from 1 to 6 carbon atoms and optionally substituted by at least one of a phenyl group, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, or an alkoxy group containing from 1 to 6 carbon atoms; an alkylaminoalkyl or dialkylaminoalkyl group wherein each alkyl group contains from 1 to 6 carbon atoms; an amino group; an aminocarbonyl group; an alkylamino group; a saturated or unsaturated cycle, optionally spaced from the N to which the cycle is linked by an —SO2— group, —C(O)— group, —C(O)O— group, —C(O)NH— group or an Alk group as defined, and containing 0, 1, 2, or 3 heteroatoms and having 5, 6, or 7 ring atoms, or 3-7 ring atoms when the cycle is a carbocycle, said cycle being optionally substituted by at least one substituent selected from the group ‘b’ defined below,
or R7 and R8, in the group -AlkCONR7R8, together with the nitrogen atom to which they are linked, form a saturated or unsaturated heterocycle containing 0, 1 or 2 additional heteroatoms and having 5, 6, or 7 ring atoms, said heterocycle being optionally substituted by at least one substituent selected from the group ‘b’ defined below,
and wherein, when there is more than one substituent, said substituent is the same or different,
Q represents >C═O or >C═S,
R5 represents a hydrogen atom or an alkyl, alkoxy, hydroxyalkyl, alkylthio, or thioalkyl group wherein any alkyl part contains from 1 to 4 carbon atoms,
p is 1, 2 or 3,
q is 0, 1 or 2,
R6 represents an aryl or heteroaryl ring, two linked rings each being selected from aryl or heteroaryl rings, or a fused double or triple ring system comprising at least two rings each being selected from aryl or heteroaryl rings, and wherein said ring or rings forming R6 are optionally substituted by at least one substituent selected from the group a,
wherein the group a consists of: halogen atoms; hydroxyl; carboxyl; aldehyde groups; aryl groups; linear and branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, and haloalkynyl groups; linear and branched alkoxyl groups; linear and branched thioalkyl groups; heteroaryl groups; saturated or unsaturated heterocycyl groups; aralkoxy groups; aryloxy groups; alkoxycarbonyl; aralkoxycarbonyl; aryloxycarbonyl; heteroaralkoxy groups; heteroaryloxy groups; heteroaralkoxycarbonyl; heteroaryloxycarbonyl; hydroxycarbonylalkyl; alkoxycarbonylalkyl; aralkoxycarbonylalkyl; aryloxycarbonylalkyl; heteroaralkoxycarbonylalkyl; heteroaryloxycarbonylalkyl; perfluoroalkyl; perfluoroalkoxy; —CN; —NO2; acyl; amino, alkylamino, aralkylamino, arylamino, dialkylamino, diaralkylamino, diarylamino, heteroaralkylamino, heteroarylamino, diheteroaralkylamino, diheteroarylamino, alkylsulphonylamino, haloalkylsulphonylamino, acylamino, and diacylamino groups; alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, heteroaralkoxycarbonylamino, heteroaryloxycarbonylamino, alkylcarbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, alkylaminocarbonyloxy, aralkylaminocarbonyloxy, and arylaminocarbonyloxy groups; alkyl groups substituted with an amino, alkylamino, aminoalkylamino, alkylaminoalkylamino, aralkylamino, arylamino, aryloxy, arylthio, heteroaralkylamino, heteroarylamino, heteroaryloxy, heteroarylthio, heterocycyloxy, heterocycylthio, dialkylamino, diaralkylamino, diarylamino, diheteroaralkylamino, diheteroarylamino, acylamino, trifluoromethylcarbonylamino, fluoroalkylcarbonylamino, diacylamino group; a carbamoyl group optionally substituted by an alkyl, alkylsulphonamide, sulphonamide, alkylsulphonyl, sulphonyl, aminoalkyl, or alkylaminoalkyl group; a sulphonamide group optionally substituted by an alkyl, acyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, or carbamoyl further substituted by a carboxylic acid, aminoalkyl, or alkylaminoalkyl group; alkyl-, aralkyl-, aryl-, heteroaralkyl-, and heteroaryl-amido groups; alkylthio, arylthio, aralkylthio, heteroarylthio and heteroaralkylthio and the oxidised sulphoxide and sulphone forms thereof; sulphonyl, alkylsulphonyl, haloalkylsulphonyl, arylsulphonyl, aralkylsulphonyl, and heteroaralkylsulphonyl groups; alkylsulphonamide, haloalkylsulphonamide, di(alkylsulphonyl)amino, aralkylsulphonamide, di(aralkylsulphonyl)amino, arylsulphonamide, di(arylsulphonyl)amino, heteroaralkylsulphonamide, di(heteroaralkylsulphonyl)amino, heteroarylsulphonamide, and di(heteroarylsulphonyl)amino; and saturated and unsaturated heterocyclyl groups, said aryl, heteroaryl and heterocyclyl groups being mono- or bi-cyclic and being optionally substituted by one or more substituents, which may be the same or different, selected from the group b,
wherein the group b consists of: keto when substituting a saturated or partially unsaturated heterocycle, halogen atoms; hydroxyl; carboxyl; aldehyde groups; linear and branched alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, and haloalkynyl groups; linear and branched alkoxyl groups; linear and branched thioalkyl groups; alkoxycarbonyl; hydroxycarbonylalkyl; alkoxycarbonylalkyl; perfluoroalkyl; perfluoroalkoxy; —CN; acyl; amino, alkylamino, dialkylamino, acylamino, and diacylamino groups; alkyl groups substituted with an amino, alkylamino, dialkylamino, acylamino, or diacylamino group; CONH2; alkylamido groups; alkylthio and the oxidised sulphoxide and sulphone forms thereof; sulphonyl, alkylsulphonyl groups; and sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups
wherein two groups a, where present, optionally form a fused carbocycle or heterocycle with the ring on which they are located, and are optionally substituted with a keto or a substituent selected from group b, as defined,
In one aspect, R1 and R2 can be the same or different, and each represents a monocyclic aryl group, a monocyclic heteroaryl group, or Z, R1 and R2 together form said fused ring structure, wherein each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group ‘c’. In a further aspect, R1 and R2 each represent a phenyl, pyridinyl, or thienyl radical, or R1 and R2 represent a fused ring structure as defined in claim 1, wherein each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted. In another aspect, each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group c′, consisting of: fluorine and chlorine atoms, hydroxyl, linear and branched alkyl, alkylthio, hydroxyalkyl, and fluoroalkyl groups; linear and branched alkoxyl groups; trifluoromethyl; trifluoromethoxyl; —CN; alkylcarbonyl groups; alkylsulphonyl groups, and any alkyl component has from 1 to 4 carbon atoms, and wherein, when there is more than one substituent, then each said substituent is the same or different. In one aspect, each of R1 and R2, or said fused ring structure formed thereby, is optionally substituted by at least one substituent selected from the group consisting of: fluorine and chlorine atoms, hydroxyl groups, linear or branched alkoxy groups containing from 1 to 5 carbon atoms, linear or branched alkyl groups containing from 1 to 5 carbon atoms, trifluoromethyl and trifluoromethoxy groups, and —CN groups, and wherein, when there is more than one substituent, then each said substituent is the same or different. For example, each of R1 and R2 can be an optionally substituted phenyl, pyridinyl, or thienyl group. In one aspect, each R1 and R2 can be substituted with a substituent selected from: hydrogen; chlorine atoms; hydroxyl groups; carboxyl groups; linear and branched alkyl and hydroxyalkyl groups; linear and branched alkoxyl groups; alkoxycarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; alkylthio groups; alkylsulphonyl groups; and sulphonamide groups. In another aspect, R1 and R2, or Z, R1 and R2 together forming the fused ring structure, are unsubstituted. In one aspect, R1 and R2 can be each phenyl.
The invention provides compounds of Formula I, wherein R3 represents a group selected from: -AlkCOOR, -AlkNR7R8, -AlkCONR7R8, -AlkCOR9, -AlkSO2NR10R10′, -AlkOR10, and -AlkS(O)nR10.
The invention provides compounds of Formula I, wherein R6 is a monocyclic aryl or a 5 or 6 membered heteroaryl ring. In one aspect, R6 represents two linked rings, optionally substituted, and wherein said rings are linked by Alk, Alk-S or Alk-O. In a further aspect, R6 can be an aryl or heteroaryl group selected from the group consisting of: fluorenyl, phenyl, naphthyl, monocyclic heteroaryls, and bicyclic heteroaryls, optionally substituted. In one aspect, R6 is selected from the group consisting of: phenyl, naphthyl, benzothiazolyl, fluorenyl, benzazolyl, benzoxazolyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, indolyl, pyrrolyl, quinolyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothiazyl, benzimidazolyl, indazolyl, tetraquinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, indolyl, carbazolyl, indolinyl, alpha- or beta-carbolinyl, and benzothienyl groups. For example, R6 can be substituted by at least one substituent selected from substituents a′: fluorine atoms; chlorine atoms; hydroxyl groups; carboxyl groups; aldehyde groups; linear and branched alkyl, hydroxyalkyl, and fluoroalkyl groups; linear and branched alkoxyl groups; linear and branched thioalkyl groups; alkoxycarbonyl groups; benzylcarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, dialkylamino, acylamino, and diacylamino groups; alkoxycarbonylamino, alkylcarbonylamino groups; alkylaminocarbonyloxy groups; alkyl groups substituted with an amino, alkylamino, dialkylamino, acylamino, or diacylamino group; CONH2; alkylamido groups; alkylthio; alkylsulphoxide; sulphonyl, and alkylsulphonyl groups; sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups; trifluoromethylsulphoxide; trifluoromethylsulphonyl groups; trifluoromethylsulphonamide, and di(trifluoromethylsulphonyl)amino groups; alkylcarbonylalkyl; phenyl, phenoxy, phenylthio, and benzyl groups; and saturated monocyclic heterocyclyl groups, said aryl and heterocyclyl groups being optionally substituted by one or more substituents, which may be the same or different, selected from the group b. In one aspect, R6 can be substituted by at least one substituent selected from substituents a″: chlorine atoms; hydroxyl groups; carboxyl groups; linear and branched alkyl, hydroxyalkyl; linear and branched alkoxyl groups; alkoxycarbonyl groups; hydroxycarbonylalkyl groups; alkoxycarbonylalkyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, and dialkylamino groups; alkoxycarbonylamino, alkylcarbonylamino groups; alkylaminocarbonyloxy groups; alkyl groups substituted with an amino, alkylamino, or dialkylamino group; CONH2; alkylcarbonylalkyl; alkylthio; sulphonyl and alkylsulphonyl groups; sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups; trifluoromethylsulphoxide; trifluoromethylsulphonyl groups; trifluoromethylsulphonamide, and di(trifluoromethylsulphonyl)amino groups; and phenyl, phenoxyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups optionally substituted by one or more substituents, which may be the same or different, selected from the group b,
and wherein any pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl groups are not further substituted. In one aspect, substituents b can be selected from substituents b′ consisting of: chlorine atoms; hydroxyl groups; linear and branched alkyl, hydroxyalkyl, and alkoxyl groups; trifluoromethyl groups; trifluoromethoxy groups; —CN groups; amino, alkylamino, and dialkylamino groups; sulphonyl, alkylsulphonyl groups; and sulphonamide, alkylsulphonamide, and di(alkylsulphonyl)amino groups.
The invention provides compounds of Formula I, wherein R3 represents a group -AlkCONR7R8, wherein R7 and R8, together with the nitrogen atom to which they are linked, form a five-, six- or seven-membered heterocyclic group. For example, the heterocyclic group can be pyrrolidinyl, pyrrolinyl, morpholinyl, piperidinyl, piperazinyl, or homopiperazinyl. In one aspect, the heterocyclic group comprises an unsubstituted nitrogen atom therein. In another aspect, the heterocyclic group is substituted by at least one substituent ‘b’. For example, the heterocyclic group is piperazinyl and the substituent is attached to the available nitrogen atom. In one aspect, the substituent is selected from alkyl, and substituted carbonyl. The substituted carbonyl can be, for example, butoxycarbonyl, aminocarbonyl or alkylcarbonyl. In another aspect, the heterocyclic group can be substituted by an alkyl group.
The invention provides compounds of Formula I, wherein R3 represents a group -AlkCONR7R8 or -AlkNR7R8, and one of R7 and R8 represents a hydrogen atom or a methyl group, and the other represents an optionally substituted cycle. For example, the cycle can be a six-membered cycle. In another aspect, the cycle can be a five-membered cycle. For example, the cycle can be cyclohexyl, phenyl, piperidinyl, piperazinyl, cyclopentyl or pyrrolidinyl. In one aspect, R3 represents a group -AlkCONR7R8 or -AlkNR7R8, and one of R7 and R8 represents a hydrogen atom and the other represents a hydrogen atom or an optionally substituted alkyl group. For example, one of R7 and R8 represents an alkyl group substituted by one or two substituents selected from: alkoxy, carboxyl, amino, alkylamino, dialkylamino, and aromatic groups. The aromatic group can be, for example, a phenyl or pyridinyl group. In one aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a sulphonyl optionally substituted by an alkyl, amino, alkylamino or dialkylamino group. In another aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a sulphonyl substituted by an aryl group optionally substituted by a substituent selected from substituents b. In a further aspect, R3 represents a group -AlkCONR7R8 and one of R7 and R8 is a carbonyl group substituted by an optionally substituted alkyl group or heterocyclic group optionally substituted with a substituent selected from substituents b. In yet another aspect, R3 can be -AlkCOOR and R is H. In one aspect, R3 is -AlkCOOR and R is an alkyl group. R can be ethyl or tert-butyl. In another aspect, R3 represents -AlkCOR9 and R9 is a saturated heterocycle. The heterocycle, for example, can comprise an unsubstituted nitrogen atom therein. In another aspect, R9 can be a pyrrolidinyl or piperidinyl group. In one aspect, R3 represents -AlkCOR9 and R9 is an alkyl group substituted by phenyl group. In another aspect, R3 represents -AlkOR10 or -AlkS(O)nR10 in which n is 0, and R10 is hydrogen. In a further aspect, R3 represents -AlkOR10 or -AlkS(O)nR10, and R10 is carbamoyl. In one aspect, R3 represents -AlkOR10 or -AlkS(O)nR10, and R10 is a C1-4 alkyl group. In another aspect, R3 represents -AlkS(O)nR10, and n is 0. In another aspect, R3 represents -AlkSO2NR10R10′ and R10 and R10′ are independently hydrogen or a C1-4 alkyl group. Alk can represent, for example, a propylene group. In another example, Alk is C1-4-alkylene.
The invention provides compounds of Formula I, wherein Z is >CH—, or Z is >C═CH—, or Z is >N—. In one aspect, p is 2 when Z is >C— or >N—, or p is 1 when Z is >C═CH—.
The invention provides compounds of Formula I, wherein q is 0.
The invention further provides compounds of Formula I, wherein R5 is a methyl group or hydrogen.
The invention provides compounds of Formula I, wherein Q is >C═O and Z is >N—.
The invention provides compounds of Formula I, wherein Q is >C═S. In one aspect, Q is a sulphonyl group.
In one aspect, the invention provides compounds of Formula I, wherein any alkyl, alkenyl or alkynyl component has no more than 4 carbon atoms.
The invention encompasses the following compounds:
Addition salts with inorganic or organic acids of the compounds of Formula I can optionally be salts formed between a molecule of Formula I and one, two or three acid molecules. These salts may be, for example, salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic or ascorbic acids, alkylmonosulphonic acids such as, for example, methanesulphonic acid, ethanesulphonic acid, propanesulphonic acid, alkyldisulphonic acids such as, for example, methanedisulphonic acid, alpha-, beta-ethane disulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryl disulphonic acids.
Stereoisomerism can be defined broadly as isomerism of compounds having the same general formulae, but of which the different groups are disposed differently in space such as, in particular, in monosubstituted cyclohexanes of which the substituent can be in the axial or equatorial position, and the various possible rotational configurations of ethane derivatives. However, there is another type of stereoisomerism due to the different spatial arrangements of substituents fixed either on double bonds or on rings, which is often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in its broadest sense in the present application and therefore relates to all of the above-mentioned compounds.
There is further provided the use of a compound as defined in any of the accompanying claims in the manufacture of a medicament for the treatment or the prevention of diseases or disorders linked to abnormal physiological behaviour of inorganic ion receptors and in particular of the calcium receptor. Preferably, the calcium receptor is expressed in the parathyroid, the thyroid, the bone cells, the renal cells, the lung, the brain, the pituitary gland, the hypothalamus, the gastrointestinal cells, the pancreas cells, the skin cells, the cells of the central or peripheral nervous system and/or the smooth muscle cells.
The present invention relates in particular to the compounds of Formula I and especially to those compounds exemplified in the accompanying Examples.
The above-described compounds can, if desired, be subjected to salification reactions, for example using an inorganic or organic acid or an inorganic or organic base, by conventional methods known to the person skilled in the art.
The optically active forms of the above-described compounds may be prepared by resolving the racemic forms by conventional methods known to the person skilled in the art.
Illustrations of reactions of the type defined above are given in the preparation of the examples described hereinafter. The above reactions are further illustrated in the accompanying, non-limiting Examples.
Compounds and compositions of the present application which act on calcium receptors may thus be used, in particular, for the treatment or prevention of diseases or disorders linked with abnormal physiological behaviour of inorganic ion receptors and, in particular, of calcium receptors such as membrane calcium receptors capable of binding extracellular calcium. While the compounds of the invention are believed to exert their effects by interacting with the calcium sensing receptor (CaSR), the mechanism of action by which the compounds act is not a limiting embodiment of the invention. For example, compounds of the invention may interact with calcium sensing receptors other than CaSR.
Thus, the compounds and compositions of the present invention are of particular use in regulating the serum levels of PTH and extracellular Ca++. For example, they can therefore be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful, in particular, for the treatment of diseases such as hyperparathyroidism. Similarly, abnormalities in calcium homeostasis can be treated with these compounds, in particular hypercalcaemia. Still in the region of the parathyroid, the compounds of formula (I) as defined can treat hyperplasia and parathyroid adenoma.
Another class of products of Formula I as defined above has properties which enable them to reduce bone resorption which depends directly on the fluctuation of circulating PTH levels: these products could be useful, in particular, for the treatment of diseases such as osteoporosis, osteopaenia Paget's disease and the reconstruction of fractures. They can also be used in the treatment and prophylaxis of polyarthritis and osteoarthritis.
It will be appreciated that reference to treatment herein includes reference to all applicable forms of treatment and prophylaxis.
With regard to digestion, the compounds and compositions of the present invention may also be used for the treatment of motor disorders (such as diarrhea or constipation), functional digestive disorders, ulcerous diseases, sarcoidosis, familial adenomatous polyposis, polyps of the intestine and colon, cancer of the colon and intestinal malabsorption.
The presence of the calcium receptor in various cells of the nervous system (in particular the pituitary gland and hypothalamus) indicates that the products of the present invention can thus be used for the treatment or prevention of diseases or disorders such as, in particular: inappropriate antidiuretic hormone secretion (ADH syndrome), convulsions, stroke, cranial traumatism, diseases of the spinal marrow, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease and Huntington's chorea), dementia, migraine, cerebral hypoxia, abnormalities in growth hormone secretion, psychiatric diseases (such as depression, anxiety, obsessive behaviour disorder, schizophrenia, post-traumatic stress, and neuroleptic malignant syndrome).
The compounds and compositions of Formula I of the present invention may also possess therapeutic properties in regard of the following: thrombopaenia, platelet hypo- or hyper-coagulability, arterial hypertension, cardiac insufficiency, prevention or attenuation of renal toxicity of aminosides, renal lithiasis, pancreas insufficiency, diabetes, psoriasis, breast adenoma and cancer, cirrhosis, biliary lithiasis, and obesity.
The present invention further provides medicaments comprising compounds of Formula I, in any and all possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as the pharmaceutically acceptable addition salts thereof with inorganic and organic acids or inorganic or organic bases.
The invention further relates to the use of the compounds of Formula I as defined above and/or their pharmaceutically acceptable salts:
for the manufacture of medicaments for the treatment or prevention of diseases or disorders linked to abnormal physiological behaviour of inorganic ion receptors and in particular of the calcium receptor, characterised in that the calcium receptor is expressed in at least one of the parathyroid, the thyroid, the bone cells, the renal cells, the lung, the brain, the pituitary gland, the hypothalamus, the gastrointestinal cells, the pancreas cells, the skin cells, the cells of the central or peripheral nervous system and the smooth muscle cells,
for the manufacture of medicaments for the prevention or treatment of cancers, in particular of the parathyroid and/or the digestive tract,
for the manufacture of medicaments for the prevention or treatment of neurodegenerative diseases,
for the manufacture of medicaments for the prevention or treatment of bone and articular metabolism diseases, in particular osteoporosis, osteopaenia and Paget's disease, rheumatoid arthritis and/or osteoarthritis,
for the manufacture of medicaments for the prevention or treatment of abnormal calcium homeostasis,
for the manufacture of medicaments for the prevention or treatment of hyperplasia and/or parathyroid adenoma,
for the manufacture of medicaments for the prevention or treatment of intestinal malabsorption,
for the manufacture of medicaments for the prevention or treatment of biliary lithiasis and/or renal lithiasis,
for the manufacture of medicaments for the prevention or treatment of hyperparathyroidism, characterised in that secondary hyperparathyroidism is observed in the event of renal insufficiency,
for the manufacture of medicaments for the prevention or treatment of ionised serum calcium level reduction during the treatment of hypercalcaemia,
for the manufacture of medicaments for the prevention or treatment of cardiovascular diseases.
In one aspect, the invention provides a method of inhibiting, decreasing or preventing vascular calcification in an individual. The method comprises administering to the individual a therapeutically effective amount of the calcimimetic compound of the invention. In one aspect, administration of the compound of the invention retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits. In another aspect of the invention, administration of the compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.
In one aspect, the compounds of the invention may be used to prevent or treat atherosclerotic calcification and medial calcification and other conditions characterized by vascular calcification. In one aspect, vascular calcification may be associated with chronic renal insufficiency or end-stage renal disease. In another aspect, vascular calcification may be associated with pre- or post-dialysis or uremia. In a further aspect, vascular calcification may be associated with diabetes mellitus I or II. In yet another aspect, vascular calcification may be associated with a cardiovascular disorder.
In one aspect, administration of an effective amount of the compounds of the invention can reduce serum PTH without causing aortic calcification. In another aspect, administration of the compounds of the invention can reduce serum creatinine level or can prevent increase of serum creatinine level. In another aspect, administration of the compounds of the invention can attenuates parathyroid (PT) hyperplasia.
The compounds of the invention may be administered alone or in combination with other drugs for treating vascular calcification, such as vitamin D sterols and/or RENAGEL®. Vitamin D sterols can include calcitriol, alfacalcidol, doxercalciferol, maxacalcitol or paricalcitol. In one aspect, the compounds of the invention can be administered before or after administration of vitamin D sterols. In another aspect, the compounds of the invention can be co-administered with vitamin D sterols. The methods of the invention can be practised to attenuate the mineralising effect of calcitriol on vascular tissue. In one aspect, the methods of the invention can be used to reverse the effect of calcitriol of increasing the serum levels of calcium, phosphorus and Ca×P product thereby preventing or inhibiting vascular calcification. In another aspect, the compounds of the invention of the invention can be used to stabilise or decrease serum creatinine levels. In one aspect, in addition to creatinine level increase due to a disease, a further increase in creatinine level can be due to treatment with vitamin D sterols such as calcitriol. In addition, the compounds of the invention may be administered in conjunction with surgical and non-surgical treatments. In one aspect, the methods of the invention can be practised in injunction with dialysis.
In one aspect, the compounds of the invention can be used for treating abnormal intestinal motility disorders such as diarrhea. The methods of the invention comprise administering to the individual a therapeutically effective amount of the compounds of Formula I.
As used herein, the term “diarrhea” refers to a condition of three or more unformed stools in a 24-hour period of volume more than 200 g per day. In one aspect, diarrhea can be osmotic, i.e., resulting if the osmotic pressure of intestinal contents is higher than that of the serum. This condition may result from malabsorption of fat (e.g., in celiac disease) or of lactose (e.g., in intestinal lactase deficiency), or it can happen due to the use of certain laxatives (e.g., lactulose, magnesium hydroxide) or artificial sweeteners (e.g., sorbitol, mannitol). In another aspect, diarrhea can be secretory, i.e., occurring when there is a net secretion of water into the lumen. This may occur with bacterial toxins (such as those produced, e.g., by E. coli and Vibrio cholerae), or with hormones, such as vasoactive intestinal polypeptide, which is produced by rare islet cell tumors (pancreatic cholera). Both osmotic and secretory diarrheas result from abnormalities in the small intestine such that the flow of water through the ileocecal area overcomes the absorptive capacity of the colon.
In a further aspect, diarrhea can be exudative diarrhea, i.e., resulting from direct damage to the small or large intestinal mucosa. This type of diarrhea can be caused by infectious or inflammatory disorders of the gut. In one aspect, exudative diarrhea can be associated with chemotherapy, radiation treatment, inflammation or toxic traumatic injury. In another aspect, exudative diarrhea can be associated with a gastrointestinal or abdominal surgery.
In another aspect, diarrhea can be due to acceleration of intestinal transit (rapid transit diarrhea). Such condition may occur because the rapid flow-through impairs the ability of the gut to absorb water.
In one aspect, the invention provides the compounds and compositions for treating abnormal gastric fluid secretion/absorption disorders in conjunction with treating underlying causes of, for example, diarrhea or with other treatment methods. In one aspect, calcimimetics can be administered to a subject before, after or concurrently with oral rehydration therapy. For example, oral rehydration therapy may contain the following ingredients: sodium, potassium, chloride, bicarbonate, citrate and glucose. In another aspect, the compounds of the invention can be administered to a subject before, after or concurrently with an antimotility agent, such as loperamide (Imodium), diphenoxylate, or bismuth subsalicylate (Pepto-Bismol). In another aspect, calcimimetics can be administered with antibiotics (e.g., trimethoprim-sulfamethoxazole (Bactrim DS), ciprofloxacin (Cipro), norfloxacin (Noroxin), ofloxacin (Floxin), doxycycline (Vibramycin), erythromycin). In one aspect, the compounds of the invention can be administered together with calcium or polyamines such as spermine, spermidine, putrescine, and ornithine metabolites or amino acids such of α-tryptophan, L-phenylalanine. In another aspect, the compounds of the invention can be administered together with sodium and glucose. In addition, the compounds of the invention may be administered in conjunction with surgical and non-surgical treatments.
The invention further provides methods for modulating intestinal fluid secretion and absorption. In one aspect, the purpose can be to increase fluid absorption and/or decrease fluid secretion in a subject and thus the methods of the invention can comprise administering an effective amount of a pharmaceutical composition comprising a compound of the invention.
The invention provides methods of modulation the absorption or secretion of a drug, poison or nutrient in the intestinal tract of a subject, comprising administering an effective amount of a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier to the subject. In one aspect, the invention provides methods of treatment of a malassimilation or a malabsorption of a subject, comprising administering an effective amount of a pharmaceutical composition comprising a compound of Formula I together with a pharmaceutically acceptable carrier to the subject.
As used herein, the term “malassimilation” encompasses impaired processes of food digestions and absorption occurring in one of two ways (1) through intraluminal disorders (maldigestion of food) and (2) through intramural disorders (malabsorption of food).
Methods of the invention comprising administering a pharmaceutical composition of the invention can also be practised to treat malnutrition in a subject. For example, a subject can be malnourished if the subject is grossly underweight (weight for height is below 80% of the standard), grossly overweight (weight for height above 120% of the standard), if the subject unintentionally lost 10% or more of body weight, has a gastrointestinal tract surgery, experienced nutrient losses (e.g., from diarrhea, dialysis, vomiting), has increased metabolic needs (e.g., due to pregnancy, lactation, increased physical activity, fever, injury), is an alcoholic or chronic drug user (antibiotics, antidepressants, diuretics), has medical conditions which interfere with nutrient intake, absorption, metabolism, or utilisation, has poor dentition (particularly in the elderly subjects), or has mouth sores due to herpes, HIV or chemotherapy. In another aspect, the subject can be malnourished due to dietary risk factors (e.g., loss of appetite, inadequate food or nutrient intake, lack of variety of foods, fad, weight-loss diets, inadequate fibre, excessive fat, sodium, sugar, excess alcohol, eats too few fruits, vegetables) or due to social risk factors (e.g., chronic ill health, poverty, inadequate money to buy food, low socioeconomic status, immobility or inability to purchase, store, or cook food, social isolation, eats alone most of the time, substance abuser, conditions which limit subject's ability to eat). Further, the methods of the invention can be practised when a subject has limited access to nutrients such as during survival following environmental disasters, survival at sea, marooning and deep-sea living or space travel.
The products of Formula I and their pharmaceutically acceptable salts may be administered to animals, preferably to mammals and, in particular, to humans, as therapeutic or prophylactic medicaments.
They may be administered as they are or in a mixture with one or more compounds of Formula I or else in the form of a pharmaceutical composition containing as the active compound an effective dose of at least one product of formula (I) and/or their pharmaceutically acceptable salts and common pharmaceutically inert excipients and/or additives.
These pharmaceutical compositions can be administered buccally, enterally or parenterally or topically to the skin and mucous membranes or by intravenous or intramuscular injection.
The medicaments may therefore be administered orally, for example in the form of pills, tablets, coated tablets, gel-coated tablets, granules, hard and soft capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
The medicaments may however be effectively administered rectally, for example in the form of suppositories, or as pessaries, or parenterally, for example in the form of injectable solutions or infusions, microcapsules or implants, percutaneously, for example in the form of an ointment, solutions, pigments or colorants, transdermally (patches) or by other methods, for example in the form of an aerosol or nasal spray.
The medicaments according to the present invention may therefore be formulated as pharmaceutical compositions containing one or more products of formula (I) as defined above.
Pharmaceutical compositions of this type can therefore constitute the form in which the products of Formula I as defined above are used in the therapeutic application thereof.
The pharmaceutical compositions according to the invention are prepared by conventional methods, pharmaceutically inert organic or inorganic excipients being added to the compounds of Formula I and/or their pharmaceutically acceptable salts.
These compositions may therefore be solid or liquid and may have any pharmaceutical forms commonly employed in human medicine, for example, simple tablets or dragees, pills, tablets, hard capsules, droplets, granules, injectable preparations, ointments, creams or gels; they are prepared by conventional methods.
Excipients such as lactose, cornstarch or derivatives thereof, talc, stearic acid or the salts thereof, for example, may be used for producing pills, tablets, coated tablets and hard gelatin capsules.
Suitable vehicles for soft gelatin capsules or suppositories include, for example, fats, semi-solid or liquid polyol waxes and natural or modified oils, etc. Appropriate vehicles for the preparation of solutions, for example injectable solutions, emulsions or syrups include, for example, water, alcohols, glycerol, polyols, sucrose, invert sugars, glucose, vegetable oils, etc. Suitable vehicles for microcapsules or implants include, for example, glyoxylic and lactic acid copolymers. The pharmaceutical preparations normally contain from 0.5% to 90% by weight of products of Formula I and/or the physiologically acceptable salts thereof.
The active principle may be incorporated in excipients which are normally used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives.
In addition to the active principles and excipients, the pharmaceutical compositions may contain additives such as, for example, diluents, disintegrating agents, binders, lubricants, wetting agents, stabilisers, emulsifiers, preservatives, sweeteners, colorants, flavourings or aromatising agents, thickeners, buffers and also solvents or solubilisers or retarding agents and also salts to modify osmotic pressure, coating agents or antioxidants.
They can also contain two or more products of Formula I and/or their pharmaceutically acceptable salts as defined above. Moreover, in addition to at least one or more products of Formula I and/or their pharmaceutically acceptable salts, they can contain at least one or more other active principle which can be used therapeutically or prophylactically.
Pharmaceutical compositions of this type contain as active compound an effective dose of at least one product of Formula I and/or its pharmaceutically acceptable salts as well as one or more pharmaceutically acceptable excipients and/or vehicles and optionally one or more conventional additives.
The present invention thus extends to pharmaceutical compositions containing at least one of the medicaments as defined above as the active ingredient.
When using the products of Formula I, the doses can vary within wide limits and will be determined by the skilled physician, taking into account such factors as the age, weight and sex of the patient. Other factors to be taken into consideration include the compound employed, the nature and severity of the disease to be treated, whether the condition is serious or chronic, and whether a prophylactic treatment is being employed.
The pharmaceutical compositions normally contain from 0.2 to 500 mg, preferably from 1 to 200 g of compound of Formula I and/or their pharmaceutically acceptable salts.
In the case of oral administration, the daily dose varies generally from 0.05 to 10 mg/kg and preferably from 0.1 to 8 mg/kg, in particular from 0.1 to 6 mg/kg. For an adult, for example, a daily dose varying from 5 to 500 mg could be considered.
In the case of intravenous administration, the daily dose varies approximately from 0.05 to 6 mg/kg and preferably from 0.1 to 5 mg/kg.
The daily dose may be divided into a plurality of portions, for example 2, 3 or 4 portions, in particular if a large amount of active ingredient is to be administered. It may possibly be necessary to administer the various doses in an increasing or decreasing manner, depending on the behaviour in an individual case. These doses may be applied multiple times per day, once a day, once every other day, or any other regimen deemed appropriate by the skilled physician. Apart from the use of the products of formula (I) as defined above as medicaments, their use as a vehicle or support for active compounds for transporting these active compounds specifically toward a site of action can also be envisaged (Drug targeting, see Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al, Springer Verlag). The active compounds which may be transported are, in particular, those used for the treatment or prevention of the above-mentioned diseases.
The pharmaceutical compositions according to the present invention thus containing compounds of Formula I and/or their pharmaceutically acceptable salts can thus be used, in particular, for the treatment or prevention of diseases necessitating the administration of products which are agonists or antagonists of inorganic ion receptors such as, in particular, calcium receptors.
The present invention accordingly relates, in particular, to the use of the products of Formula I as defined above and/or their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment or prevention of diseases or disorders linked to abnormal physiological behaviour of inorganic ion receptors and in particular of calcium receptors.
The pharmaceutical compositions according to the present invention can thus be used as medicaments for the above-mentioned therapeutic applications.
The present invention further relates to processes for the preparation of compounds of Formula I, as defined above, and the salts and/or isomers thereof.
The experimental section hereinafter provides examples of the preparation of compounds of Formula I. These Examples illustrate the invention without limiting it.
All reagents were obtained commercially unless otherwise noted.
Unless run in aqueous media, all reactions were performed using oven-dried glassware under an atmosphere of dry nitrogen.
Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula.
Organic solutions were concentrated under reduced pressure (ca. 15-30 mm Hg) by rotary evaporation.
Anhydrous solvents were purchased from VWR or Aldrich and used as received.
Chromatographic purification of products was accomplished using forced-flow chromatography on EMD Chemicals Inc. silica gel 60 (40-63 μm) or the Teledyne Isco Combiflash Companion equipped with Teledyne Isco Redi-Sep normal phase disposable flash columns (silica 35-70 μm).
Thin layer chromatography was performed on Analtech, Inc. thin layer chromatography plates bearing silica gel HLF (250 microns, catalog #47521). Visualization of the developed chromatogram was accomplished by fluorescence quenching and by staining with ethanolic anisaldehyde, aqueous potassium permanganate, or aqueous ceric ammonium molybdate (CAM) solution.
Reverse phase HPLC was performed with an Agilent 1200 Series HPLC using a Phenomenex Gemini 10μ C18 110A preparative column (250×30 mm) with UV detection of product (λ=214 nm and 254 nm). The products were eluted using a solvent gradient (solvent A=0.1% TFA/H2O; solvent B=0.1% TFA/CH3CN).
NMR spectra were acquired on Bruker 400 and 500 NMR instruments operating at 400 and 500 MHz, respectively, for 1H NMR, and were referenced internally according to residual proton solvent signals. Data for 1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet, t, triplet; q, quartet; sept, septet; m, multiplet), coupling constant (Hz), integration. Mass spectra were obtained on an Agilent 1100 Series HPLC equipped with a Shiseido Co., Ltd. Capcell Pak 3μ analytical column and Agilent 6140 Quadrupole LC/MS detector. Samples were eluted in positive mode using a solvent gradient (solvent A=0.1% HCO2H/H2O; solvent B=0.1% HCO2H/CH3CN) and negative mode using a solvent gradient (solvent A=5 mM NH4O2CH in 95:5 H2O/CH3CN; solvent B=100% CH3CN).
Preparation of Thioureas of Formula (II), Ureas of Formula (III):
As mentioned hereinafter, this may be achieved in several ways:
In the accompanying schemes, the substituent labels R1 and R1′ correspond to substituents R1 and R2 of Formula I, R2 corresponds to R6, and R3 corresponds to R9.
Preparation of Amines of Formula (IV):
This may be achieved by the method of synthesis described below:
Method A:
Method A: ‘Synthesis of Substituted 3,3-propylamines’
The synthesis of 2-(9H-fluoren-9-yl)-ethylamine in which R1, R′1=fluorenyl is described by way of example.
528 mg of NaH (in a 55-65% suspension in oil)(13.2 mmol, 2.2 eq) in suspension in 20 mL of DME were introduced into a 100 mL Woulff bottle equipped with a straight condenser. 1.94 mL of diethyl cyanomethylphosphonate (12 mmol, 2 eq) in solution in 5 mL of DME were then added dropwise. After the release of gas, the reaction medium was heated under reflux for 15 min, then 1.08 g of fluoren-9-one (6 mmol, 1 eq) in solution in 5 mL of DME were added dropwise.
After refluxing for 2 hours, the reaction was stopped by addition of 40 mL of an aqueous ammonium chloride solution.
The medium was taken up with ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The organic phases were collected, dried over MgSO4, filtered and concentrated. The fluoren-9-ylidene-acetonitrile was purified by chromatography over silica gel (CH2Cl2/heptane elution gradient: 80/20) and obtained in a yield of 50%.
610 mg (3 mmol, 1 eq) of fluoren-9-ylidene-acetonitrile in solution in 40 mL of methanol and 10 mL of ethyl acetate, then 225 mg of palladium hydroxide over coal are introduced into a 250 mL flask under a nitrogen atmosphere. The reaction medium was purged then placed under a hydrogen atmosphere (skin flask) and stirred for 6 hours while stirring. The catalyst was removed by filtration over Clarcel. The solvent was evaporated and the expected product was obtained in a yield of 73%.
6.3 mL (6.3 mmol, 2.7 eq) of a 1 M solution of LiAlH4 in THF were dissolved in 20 mL of THF in a 250 mL flask under argon. The reaction medium was cooled to −78° C. and 478 mg (2.3 mmol, 1 eq) of (9H-fluoren-9-yl)-acetonitrile in solution in 20 mL of THF were added dropwise. The temperature was allowed to rise progressively to ambient temperature. Stirring was continued for 5 hours, then the medium was hydrolysed at 0° C. by addition of 30 mL of a sodium and potassium tartrate solution.
The THF was evaporated and the aqueous phase was extracted with ethyl acetate. After drying over Mg2SO4 and evaporation of the solvent, the crude product was subjected to chromatography over silica gel (elution gradient: CH2Cl2—CH2Cl2/MeOH: 9/1 to CH2Cl2/MeOH/NH4OH: 9/1/0.5). The 2-(9H-fluoren-9-yl)-ethylamine was obtained in a yield of 12%.
Amines of Formula (IV) Obtained by Method A:
This may be achieved by the method of synthesis described below:
The amine (0.5 mmol, 1 eq) of formula (IV) in solution in 6 mL of dichloromethane then the isocyanate (0.5 mmol, 1 eq) of formula (VI) were introduced into a 100 mL flask under N2.
After 2 hours of stirring, the reaction mixture was taken up by 60 mL of dichloromethane and washed with 20 mL of water then 20 mL of brine. The organic phase was then dried over MgSO4 and concentrated in a rotary evaporator.
The product was recrystallised in diethyl ether or subjected to chromatography over silica gel with an eluant: CH2Cl2/AcOEt—90/10. The expected ureas were obtained in an average yield of 79%.
1H NMR (400 MHz, CDCl3) δ 7.30 to 7.14 (m, 10H, aromatic H), 7.11 (d, 2H, aromatic H), 6.86 (d, 2H, aromatic H), 6.00 (sl, 1H, NH-Ph-OMe), 4.53 (tl, 1H, CO—NH—CH2), 3.93 (t, 1H, CH), 3.80 (s, 3H, OCH3), 3.20 (ql, 2H, CH2N), 2.27 (ql, 2H, CH2)
MS (EI): 360+ [M]+
1H NMR (400 MHz, CDCl3) δ 7.31 to 7.04 (m, 14H, aromatic H), 6.20 (sl, 1H, NH), 3.94 (t, 1H, CH), 3.21 (m, 2H, CH2N), 2.32 (s, 3H, CH3), 2.27 (m, 2H, CH2)
MS (Electrospray): 345+ [M+H]+
1H NMR (300 MHz, CDCl3) δ 7.43 to 7.12 (m, 14H, aromatic H), 4.40 (sl, 2H, NH—CH2-Ph), 3.94 (tl, 1H, CH), 3.14 (tl, 2H, CH2CH2N), 2.26 (ql, 2H, CH2)
MS (Electrospray): 379+ and 381+ [M+H]+, 757+ [2M+H]+
1H NMR (300 MHz, CDCl3) δ 7.81 (dd, 1H, aromatic H), 7.73 (ddd, 1H, aromatic H), 7.61 (ddd, 1H, aromatic H), 7.36 (t, 1H, aromatic H), (7.31 to 7.13 (m, 10H, aromatic H), 6.38 (sl, 1H, NH), 3.97 (t, 1H, CH), 3.89 (s, 3H, OCH3), 3.25 (m, 2H, CH2N), 2.31 (m, 2H, CH2)
MS (EI (70 eV)): 388+ [M]+
1H NMR (300 MHz, CDCl3) δ 7.34 to 7.17 (m, 10H, aromatic H), 6.88 (d, 2H, aromatic H), 6.73 (d, 2H, aromatic H), 5.94 (s, 1H, CO—NH-Ph), 4.54 (tl, 1H, CH2—NH), 4.21 (t, 1H, CH), 3.85 (dd, 2H, CH2N), 3.77 (s, 3H, OCH3)
MS (EI): 346+ [M]+
H NMR (300 MHz, CDCl3) δ 7.34 to 7.18 (m, 10H, aromatic H), 7.10 (t, 1H, aromatic H), 6.81 (dd, 1H, aromatic H), 6.60 (dd, 1H, aromatic H), 6.56 (dd, 1H, aromatic H), 6.14 (sl, 1H, CO—NH-Ph), 4.73 (tl, 1H, CH2—NH), 4.23 (t, 1H, CH), 3.89 (dd, 2H, CH2N), 3.73 (s, 3H, OCH3)
MS (EI): 346+ [M]+
H NMR (300 MHz, CDCl3) δ 7.37 to 7.12 (m, 14H, aromatic H), 4.38 (sl, 2H, NH—CH2-Ph), 4.17 (tl, 1H, CH), 3.83 (d, 2H, CH2CH)
MS (Electrospray): 365+ [M+H]+, 387+ [M+Na]+
H NMR (300 MHz, CDCl3) δ 7.78 (sl, 1H, aromatic H), 7.70 (dd, 1H, aromatic H), 7.49 (dd, 1H, aromatic H), 7.37 to 7.16 (m, 11H, aromatic H), 6.40 (sl, 1H, NH), 4.23 (tl, 1H, CH), 3.90 (d, 2H, CH2—CH), 3.88 (s, 3H, OCH3)
MS (Electrospray): 375+ [M+H]+, 397+ [M+Na]+, 749+ [2M+H]+
The synthesis of ureas of formula (III) after intermediate formation of 3,3′-diphenylpropyl isocyanate of formula (VII) in which R1=phenyl and R′1=phenyl is described by way of example.
2.11 g of 3,3′-diphenylpropylamine (10 mmol, 1 eq) in solution in 60 mL of toluene, 100 mg of activated carbon and 905 μL of diphosgene (7.5 mmol, 0.75 eq) were introduced into a 250 ml, flask under N2. The reaction mixture was heated under reflux for 5 hours. After confirmation of the formation of the isocyanate by IR (νN═C═O=2280 cm−1), the crude reaction product was filtered over Clarcel and concentrated to dryness. The medium was then taken up by dichloromethane and subjected to simultaneous synthesis. 0.5 mmol (1 eq) of amine of formula (V) was introduced into test tubes, then 0.75 mmol (1.5 eq) of 3,3′-diphenylpropyl isocyanate of formula (VII) in solution in 8 mL of CH2Cl2. The reaction medium was stirred for 1 night. After washing with water, the organic phases were dried over magnesium sulphate and evaporated. The products were recrystallised in diethyl ether or subjected to chromatography over silica gel with an eluant: CH2Cl2/AcOEt—90/10. The average yield over two stages was 48%.
This may be achieved by one of the two methods of synthesis described below:
Same method as method B, replacing the isocyanate of formula (VI) with an isothiocyanate of formula (VIII). After extraction, the products obtained were recrystallised in methanol or diethyl ether and the expected thioureas were obtained in an average yield of 94%.
The synthesis of [3-(3,3-diphenyl-propyl)-thioureido]-benzoic acid ethyl ester is described by way of example.
422 mg (2 mmol, 1 eq) of 3,3′-diphenylpropylamine in solution in 20 mL of dimethylformamide, then 1.2 mL of CS2 (20 mmol, 10 eq) and 836 μL (6 mmol, 3 eq) of triethylamine were introduced into a 100 mL flask under a nitrogen atmosphere. 884 mg (2 mmol, 1 eq) of BOP were then added to the reaction medium, which was left with stirring for 3 hours at ambient temperature. The mixture was concentrated to dryness to remove the excess CS2, then taken up with 50 mL of water. The aqueous phase was extracted with 150 mL of ethyl acetate, and the organic phase was dried over MgSO4 then concentrated to dryness. The intermediate 3,3′-diphenylpropyl isothiocyanate obtained was dissolved in 15 mL of dimethylformamide under a nitrogen atmosphere. 2.2 mmol (1.1 eq) of 3-aminobenzoic acid ethyl ester of formula (V) were added and the mixture was left with stirring for 3 hours. The reaction medium was taken up with 50 mL of water, and the aqueous phase was extracted with 150 mL of ethyl acetate. The organic phase was washed with 40 mL of HCl (1 M) then 40 mL of water, dried over MgSO4 and concentrated in a rotary evaporator. The product was recrystallised in diethyl ether. The 3-[3-(3,3-diphenyl-propyl)-thioureido]-benzoic acid ethyl ester was obtained in a yield of 40% in two stages.
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H, aromatic H), 7.65 (m, 2H, aromatic H), 7.44 (m, 1H, aromatic H), 7.33 to 7.13 (m, 10H, aromatic H), 4.30 (q, 2H, CH2), 4.02 (t, 1H, CH), 3.29 (q, 2H, CH2), 2.32 (q, 2H, CH2), 1.37 (t, 3H, CH3)
MS: 419+[M+H]+, 441+[M+Na]+, 859+ [2M+Na]+
0.1 mmol of ester (1 eq) in solution in 2 mL of methanol then 1 mmol of 1 M sodium hydroxide solution (10 eq) were introduced into a 10 mL flask equipped with a straight condenser. The reaction mixture was heated under reflux for 1 hour. It was subsequently concentrated to dryness and taken up with water then 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, then the organic phase was dried over MgSO4 and concentrated. The expected acids were obtained in an average yield of 80%.
Method E: Synthesis of a Primary Alcohol Analogue, Synthesis of a Urea of Formula (III) by Reduction of Ester
150 mg (0.375 mmol, 1 eq) of 3-[3-(3,3-diphenyl-propyl)-ureido]-benzoic acid ethyl ester in solution in 3 mL of THF then 70.9 mg (1.875 mmol, 5 eq) of NaBH4 were introduced into a 20 mL Woulff bottle under N2. The mixture was brought to reflux and 0.6 mL of methanol was added dropwise. After 18 hours of reflux, the crude product was concentrated to dryness then taken up with 50 mL of ethyl acetate. After washing with a brine solution, the organic phase was dried over MgSO4 and concentrated.
The product was obtained by purification over a silica column (CH2Cl2/MeOH elution: 9/1) with a yield of 21% (m=29 mg).
The synthesis of 1-(2-bromo-5-methoxy-phenyl)-3-(3,3-diphenyl-propyl)-urea starting from 1-(3,3-diphenyl-propyl)-3-(3-methoxy-phenyl)-urea was described by way of example.
750 mg (2.08 mmol, 1 eq) of 1-(3,3-diphenyl-propyl)-3-(3-methoxy-phenyl)-urea in solution in 20 mL of acetonitrile (insoluble reagent) were introduced under a nitrogen atmosphere. Then, 389 mg (2.11 mmol, 1.05 eq) of N-bromosuccinimide were added in one batch, and the reaction medium dissolves. The mixture was stirred for 6 hours at ambient temperature. The medium precipitates after one and a half hours of reaction. The acetonitrile was concentrated. The white solid was taken up in diethyl ether and filtered. The solid obtained was purified over a silica column after solid deposition (cyclohexane/ethyl acetate elution: 4/1 to 1/1, m=600 mg, R=66%).
H NMR (300 MHz, CDCl3) δ 7.37 (d, 1H, aromatic H), 7.31 to 7.13 (m, 10H, aromatic H), 7.22 (masked s, 1H, aromatic H), 6.50 (dd, 1H aromatic H), 6.20 (sl, 1H, CO—NH-Ph), 4.59 (sl, 1H, NH), 3.96 (t, 1H, CH), 3.86 (s, 3H, OCH3), 3.24 (tl, 2H, CH2—N), 2.30 (q, 2H, CH2—CH)
MS (Electrospray): 439+ [M+H]+, 480+ [M+CH3CN]+, 877+ [2M+H]+
MS (Electrospray): 398+ [M+H]+
Rf: 0.27 (Heptane/AcOEt: 1/1)
MS (Electrospray): 388+ [M+H]+
Rf: 0.27 (Heptane/AcOEt: 1/1)
Preparation of the Secondary Amines of Formula (II) can be Accomplished by the method of synthesis described below:
Alkylation of the Primary Amine of Formula (IV)
Method A
The alkyl halide (1 mmol, 1 eq) of formula (V) was dissolved in 40 mL of acetonitrile in a 100 mL flask equipped with a straight condenser, then 1 eq of K2CO3 was added to the medium. The primary amine of formula (IV) in excess (5 mmol, 5 eq) was subsequently added and the medium was heated under reflux for 12 hours. After evaporation of acetonitrile, the residue was taken up with ethyl acetate. The organic phase was washed with an ammonium chloride solution, then with brine, dried over MgSO4 and concentrated. The oil obtained was subjected to chromatography over silica gel (elution gradient: CH2Cl2 to CH2Cl2/MeOH: 9/1 then CH2Cl2/MeOH/NH3: 9/1/0.1) and the amine of formula (II) was obtained in an average yield of 65%.
Preparation of the Ureas of Formula (I):
Method B: Synthesis of the Ureas of Formula (I) Starting from Isocyanates
The amine (0.5 mmol, 1 eq) of formula (II) in solution in 6 mL of dichloromethane then the isocyanate (0.5 mmol, 1 eq) of formula (III) were introduced into a 100 mL flask under N2. After 2 hours of stirring, the reaction mixture was taken up with 60 mL of dichloromethane and washed with 20 mL of water then 20 mL of brine. The organic phase was subsequently dried over MgSO4 and concentrated in a rotary evaporator. The product was recrystallised in diethyl ether or subjected to chromatography over silica gel with an eluant: CH2Cl2/AcOEt—90/10. The expected ureas were obtained in an average yield of 79%.
Ureas of Formula (I) Obtained by Method B:
Obtained from Preparatory Example 61.
Obtained from Preparatory Example 62.
Method D: Synthesis of Carboxylic Acid Analogs, Synthesis of Ureas of Formula (I) by Saponification
0.1 mmol of ester (1 eq) in solution in 2 mL of methanol then 1 mmol of 1 M sodium hydroxide solution (10 eq) were introduced into a 10 mL flask equipped with a straight condenser. The reaction mixture was heated under reflux for 1 hour. It was subsequently concentrated to dryness and taken up with water then 1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, then the organic phase was dried over MgSO4 and concentrated. The expected acids were obtained in an average yield of 80%.
Ureas of Formula (I) Obtained by Method D:
Obtained from Example 64.
Obtained from Example 63.
Thiazole Preparation
Thiazoles not commercially available were prepared according to the procedures described in WO 07/060,026. In some cases the 5-chloro thiazole derivative was prepared. Chlorination was achieved by 1 of 2 procedures: either the 5-chloro group was introduced onto the thiazole before urea formation, or else following urea formation. Chlorination of urea products was described individually.
Chlorination Pre-Urea:
300 mg (1.06 mmol, 1 eq) of the 4-dimethylsulfonamide aminothiazole were dissolved into 4 mL of dry THF (low solubility in THF), and 3 mL of dry DMF then 170 mg (1.27 mmol, 1.2 eq) of NCS were added to the solution mixture. The mixture becomes red within 5 minutes, and was stirred overnight at RT. After evaporation of the solvents, the crude was purified by flash chromatography (DCM/AcOEt, gradient from 100/0 to 3/1) to give 282 mg (91% yield) of the desired chloride compound.
Step 1: Tert-butyl 3-bromopropionate 1 (0.5 mL, 3.0 mmol) was dissolved in 100 mL of dry acetonitrile. To this solution was added potassium carbonate (0.415 g, 3.0 mmol) and 3,3-diphenylpropylamine 2. The reaction mixture was refluxed overnight. The mixture was then allowed to cool to room temperature and was concentrated in vacuo. The crude residue obtained was dissolved in ethyl acetate (45 mL) and washed with saturated aqueous ammonium chloride solution and then with brine. The organics were dried over magnesium sulfate, filtered and concentrated to obtain the crude product as a clear oil. This product was purified by column chromatography on silica using 89:9:1/DCM:MeOH:ammonium hydroxide as eluent. Fractions containing product were combined and concentrated in vacuo to obtain 3 as a white solid (0.54 g, 52.6% yield).
Step 2: To a solution of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide (0.158 g, 0.59 mmol) in 1.5 mL of DCM was added 0.2 mL of DMF. Then added DMAP (0.11 g, 0.88 mmol) and CDI (0.14 g, 0.88 mmol). The reaction mixture was stirred at room temperature for 48 h. Tert-butyl 4-(3,3-diphenylpropylamino)butanoate 3, was then added to the reaction mixture and it was stirred at room temperature for 12 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. This crude product was purified by column chromatography on silica (gradient eluent from 50% ethyl acetate in hexane to 80% ethyl acetate in hexane). Fractions containing product were combined and concentrated to yield the product 4 (0.25 g, 67% yield) as a tan solid.
Step 3: Tert-butyl 4-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)butanoate 4 (0.097 g, 0.15 mmol) was dissolved in 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo and purified by RP-HPLC. Fractions containing product were combined and lyophilized to obtain the product 5 as a white solid (0.085 g, 98% yield). LC-MS ESI (neg.) m/e: 591.6 (M−H). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (1H, s), 9.81 (1H, s), 7.78-7.92 (2H, m), 7.32-7.38 (5H, m), 7.26-7.32 (4H, m), 7.20-7.26 (2H, m), 7.13-7.20 (2H, m), 4.48 (1H, s), 4.01 (1H, t, J=7.8 Hz), 3.27-3.37 (2H, m), 3.19-3.28 (2H, m), 3.01 (3H, s), 2.26-2.37 (2H, m), 2.20 (2H, t, J=7.4 Hz), 1.58-1.73 (2H, m)
Step 4: To a solution of 4-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)butanoic acid 5 (0.29 g, 0.493 mmol) in dry DMF (10 mL) was added R-3-amino-1-N-Boc-piperidine (0.197 g, 0.986 mmol), DIEA (0.34 mL, 1.97 mmol), DMAP (0.006 g, 0.049 mmol) and PyBrOP (0.276 g, 0.592 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (50 mL) and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This oil was further purified by column chromatography on silica using ethyl acetate as eluent to give the pure product 6 (0.39 g, 55% yield).
Step 5: (R)-tert-butyl 3-(4-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)-thiazol-2-yl)ureido)butanamido)piperidine-1-carboxylate 6 (0.246 g, 0.318 mmol) was dissolved in 10 mL of DCM. To this solution was added trifluoroacetic acid (2.0 mL) and the reaction was stirred at room temperature for 6 h. The reaction mixture was made basic with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to yield a residue that was purified by column chromatography on silica using 89:9:1/DCM:MeOH:ammonium hydroxide as eluent to yield the product 7 as white solid (0.15 g, 70.5% yield).
LC-MS ESI (pos.) m/e: 675 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40-1.50 (m, 1H) 1.54-1.70 (m, 3H) 1.70-1.80 (m, 2H) 2.11-2.19 (m, 2H) 2.22-2.33 (m, J=6.65 Hz, 2H) 2.64 (dd, J=12.32, 5.67 Hz, 1H) 2.69-2.77 (m, 2H) 2.89 (s, 3H) 2.94 (dd, J=11.93, 3.33 Hz, 1H) 3.13-3.24 (m, 2H) 3.26-3.34 (m, 2H) 3.79-3.88 (m, 1H) 4.00 (br. s., 1H) 6.35 (br. s., 1H) 6.90 (s, 1H) 7.07-7.14 (m, 4H) 7.15-7.24 (m, 12H) 7.67 (d, J=8.22 Hz, 2H)
Step 6: To a solution of 5 (prepared as described in Example 67) (0.1 g, 0.168 mmol) in dry acetonitrile (1.5 mL) was added BOC-anhydride (0.048 g, 0.22 mmol), pyridine (0.01 mL) and ammonium bicarbonate (0.017 g, 0.22 mmol). The reaction mixture was stirred at room temperature overnight and was then purified by RP-HPLC. Fractions containing product were combined and lyophilized to obtain the product 8 as a white solid (0.070 g, 75% yield).
LC-MS ESI (pos.) m/e: 592 (M+H)
1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.86-1.91 (m, 2H) 2.38-2.43 (m, 4H) 3.07 (s, 3H) 3.35-3.42 (m, 4H) 4.0-4.1 (m, 1H) 5.87 (br s, 1H) 6.81 (br s, 1H) 6.93 (s, 1H) 7.16-7.23 (m, 2H) 7.28-7.32 (m, 9H) 7.69-7.72 (m, 2H)
Step 7: To a solution of 3,3-diphenyl propylamine 1 (5.3 g, 25 mmol) in 25 mL of ethanol at room temperature was added ethyl methacrylate 9 (3.1 mL, 25 mmol) and the reaction was stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica using 89:9:1/DCM:MeOH:ammonium hydroxide as an eluent to yield the product 10 as a colorless oil (5.85 g, 72% yield).
Step 8: The urea coupling between ethyl 3-(3,3-diphenylpropylamino)-2-methylpropanoate 10 and 2-aminophenylthiazole was carried out as described in Example 67, Step 2 and the product was obtained as a tan solid (50.0 mg, 0.095 mmol, 65% yield).
Step 9: To a solution of ethyl 3-(1-(3,3-diphenylpropyl)-3-(4-phenylthiazol-2-yl)ureido)-2-methylpropanoate 11 (50.0 mg, 0.095 mmol) in 2.0 mL of methanol was added 1 mL of aqueous sodium hydroxide solution (1N). The reaction mixture was heated to reflux overnight, cooled to room temperature, concentrated in vacuo and purified by RP-HPLC. Fractions containing the product were combined and lyophilized to yield the product 12 as a white solid (29.5 mg, 62% yield).
LC-MS ESI (neg.) m/e: 498 (M−H)
1H NMR (400 MHz, DMSO-d6) δ ppm 7.84-7.92 (2H, m, J=8.4, 1.4 Hz), 7.46 (1H, s), 7.38-7.44 (2H, m, J=7.6, 7.6 Hz), 7.31-7.37 (4H, m, J=7.4, 7.4 Hz), 7.24-7.31 (5H, m), 7.11-7.20 (2H, m, J=7.2, 7.2 Hz), 4.01 (1H, t, J=7.8 Hz), 3.44 (2H, d, J=6.3 Hz), 3.15-3.28 (1H, m), 2.55-2.72 (2H, m), 2.22-2.38 (2H, m), 1.00 (3H, d, J=7.0 Hz)
The procedure described in Example 67 was used with the exception of substituting tert-butyl 4-aminopiperidine-1-carboxylate for R-3-amino-1-N-Boc-piperidine in step 4 to prepare 1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(4-oxo-4-(piperidin-4-ylamino)butyl)urea 13 as a white solid.
LC-MS ESI (pos.) m/e: 675 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.42 (m, 2H) 1.78-1.88 (m, 2H) 1.97 (d, J=12.13 Hz, 2H) 2.15-2.25 (m, 2H) 2.39 (q, J=7.69 Hz, 2H) 2.64-2.76 (m, 2H) 2.97 (s, 5H) 3.04-3.12 (m, 2H) 3.25-3.34 (m, J=5.48 Hz, 2H) 3.39 (t, J=7.24 Hz, 2H) 3.95 (t, J=7.43 Hz, 2H) 6.98 (s, 2H) 7.16 (d, J=8.61 Hz, 2H) 7.18-7.24 (m, 2H) 7.24-7.34 (m, 8H) 7.74 (d, J=8.22 Hz, 2H)
The procedure described in Example 67 was used with the exception of substituting 2-aminobenzothiazole for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 to give 14 as a white solid.
LC-MS ESI (pos.) m/e: 556 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50-1.61 (m, 1H) 1.67-1.77 (m, 3H) 1.77-1.86 (m, 2H) 2.24 (q, J=5.48 Hz, 2H) 2.43 (q, J=7.43 Hz, 2H) 2.78 (none, 5H) 2.88-2.97 (m, J=11.74 Hz, 2H) 3.01 (dd, J=11.93, 2.93 Hz, 1H) 3.24-3.44 (m, 4H) 3.45-3.55 (m, 1H) 3.98 (t, J=7.83 Hz, 1H) 4.22 (br. s., 1H) 6.90 (br. s., 1H) 7.15-7.24 (m, 3H) 7.25-7.38 (m, 9H) 7.55 (d, J=7.82 Hz, 1H) 7.70 (d, J=8.61 Hz, 1H)
The procedure described in Example 67 was used with the exception of substituting 5-chloro-4-(4-(methylsulfonyl)phenyl)thiazol-2-amine for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in step 2 to prepare 15 as a white solid.
LC-MS ESI (neg.) m/e: 611.2 (M−H); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18 (1H, s), 8.11-8.18 (2H, m), 7.99-8.06 (2H, m), 7.32-7.38 (4H, m), 7.28 (4H, t, J=7.6 Hz), 7.13-7.21 (2H, m), 4.00 (1H, t, J=7.6 Hz), 3.42-3.76 (1H, m), 3.28-3.38 (2H, m), 3.26 (3H, s), 3.23 (2H, d, J=7.8 Hz), 2.23-2.38 (2H, m), 2.20 (2H, t, J=7.2 Hz), 1.58-1.74 (2H, m)
The procedure described in Example 67 was used with the exception of substituting N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in step 2 to prepare 15 as a white solid.
LC-MS ESI (neg.) m/e: 626 (M−H)
1H NMR (400 MHz, DMSO-d6) 8 ppm 11.05 (1H, s), 9.96 (1H, s), 7.84 (2H, dt, J=9.2, 2.3, 2.2 Hz), 7.32-7.37 (4H, m), 7.25-7.31 (10H, m), 7.16 (2H, tt), 4.00 (1H, t), 3.27 (4H, dt, J=26.8, 7.4, 7.2 Hz), 3.04 (3H, s), 2.30 (2H, q), 2.19 (2H, t, J=7.4 Hz), 1.56-1.71 (2H, m)
The procedure described in Example 67 was used with the exception of substituting 2-aminobenzothiazole for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and (S)-tert-butyl 3-aminopiperidine-1-carboxylate for (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4 to obtain 17 as a white solid.
LC-MS ESI (pos.) m/e: 556 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.45-1.54 (m, J=10.56 Hz, 1H) 1.58-1.78 (m, 5H) 2.12-2.21 (m, 2H) 2.34 (q, J=7.96 Hz, 2H) 2.65-2.82 (m, 2H) 2.90-2.99 (m, 2H) 3.15-3.34 (m, 4H) 3.34-3.45 (m, 1H) 3.89 (t, J=7.43 Hz, 1H) 4.14 (br. s., 1H) 6.96 (br. s., 1H) 7.07-7.16 (m, 3H) 7.16-7.30 (m, 9H) 7.48 (d, J=8.22 Hz, 1H) 7.62 (d, J=8.22 Hz, 1H)
The procedure described in Example 67 was used with the exception of substituting 2-aminobenzothiazole for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and tert-butyl 4-aminopiperidine-1-carboxylate for (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4 to obtain 18 as a white solid.
LC-MS ESI (pos.) m/e: 556 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.74-1.92 (m, 5H) 1.98-2.12 (m, J=17.61 Hz, 2H) 2.18-2.28 (m, 2H) 2.33-2.48 (m, 4H) 2.92-3.06 (m, 2H) 3.26-3.48 (m, 9H) 3.86-4.01 (m, 2H) 4.04-4.12 (m, 1H) 7.14-7.36 (m, 13H) 7.64 (br. s., 2H) 7.74 (d, J=7.83 Hz, 1H)
The procedure described in Example 67 was used with the exception of substituting 2-amino phenyl thiazole for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 to obtain 19 as a white solid.
LC-MS ESI (pos.) m/e: 582 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.61 (m, 1H) 1.70-1.81 (m, 3H) 1.82-1.90 (m, 2H) 2.23-2.28 (m, 2H) 2.39-2.46 (m, 2H) 2.75-2.84 (m, 2H) 2.88-2.95 (m, 1H) 3.01 (dd, J=12.10, 2.81 Hz, 1H) 3.27-3.34 (m, 2H) 3.34-3.47 (m, 2H) 3.96 (t, J=7.83 Hz, 1H) 4.15 (br. s., 1H) 6.75 (br. s., 1H) 7.05 (s, 2H) 7.22 (t, J=6.36 Hz, 2H) 7.26-7.35 (m, 9H) 7.41 (t, J=7.70 Hz, 2H) 7.86 (dd, J=8.31, 1.22 Hz, 2H)
The procedure described in Example 68 was used to prepare 20 from 3-(1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)ureido)propanoic acid.
LC-MS ESI (pos.) m/e: 578 (M+H)
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.21-2.25 (m, 2H), 2.42-2.44 (m, 2H), 3.32-3.35 (m, 4H), 4.12-4.25 (m, 1H), 6.65 (s, 1H), 7.2-7.24 (m, 2H), 7.3-7.33 (m, 9H), 7.71-7.73 (m, 2H)
The procedure described in Example 67 was used with the exception of substituting 2-amino phenylthiazolee for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and (S)-tert-butyl 3-aminopiperidine-1-carboxylate for (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4 to obtain 21 as a white solid.
LC-MS ESI (pos.) m/e: 582 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.59 (m, 1H) 1.64-1.79 (m, 3H) 1.79-1.88 (m, 2H) 2.23 (dd, J=7.24, 5.28 Hz, 2H) 2.34-2.45 (m, 2H) 2.70-2.81 (m, 2H) 2.81-2.91 (m, 1H) 3.00 (dd, J=12.13, 3.13 Hz, 1H) 3.23-3.32 (m, 2H) 3.32-3.47 (m, 2H) 3.93 (t, J=7.63 Hz, 1H) 4.11 (br. s., 1H) 6.61 (d, J=6.65 Hz, 1H) 7.05 (s, 1H) 7.20 (t, J=7.04 Hz, 2H) 7.24-7.36 (m, 9H) 7.40 (t, J=7.63 Hz, 2H) 7.86 (d, J=7.04 Hz, 2H)
The procedure described in Example 67 was used with the exception of substituting 4-(4-(methylsulfonyl)phenyl)thiazol-2-amine for N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2.
LC-MS ESI (neg.) m/e: 576 (M−H)
1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (1H, s), 8.10-8.19 (2H, m), 7.90-8.00 (2H, m), 7.75 (1H, s), 7.32-7.38 (4H, m), 7.26-7.32 (4H, m), 7.17 (2H, tt, J=7.2, 1.4 Hz), 4.01 (1H, t, J=7.6 Hz), 3.30 (2H, t), 3.24-3.29 (2H, m, J=7.0 Hz), 3.23 (3H, s), 2.31 (2H, q, J=7.4 Hz), 2.21 (2H, t, J=7.2 Hz), 1.55-1.72 (2H, m)
The procedure described in Example 68 was used to prepare 23 from 4-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)butanoic acid.
LC-MS ESI (pos.) m/e: 473.5 (M+H)
1H NMR (500 MHz, MeOH) δ ppm 7.72 (1H, d, J=7.8 Hz), 7.49 (1H, d, J=8.1 Hz), 7.36-7.42 (1H, m), 7.32-7.36 (4H, m), 7.27-7.32 (4H, m), 7.23-7.27 (2H, m), 7.16-7.20 (2H, m), 4.02 (1H, t, J=7.8 Hz), 3.25-3.32 (2H, m), 2.44 (2H, q, J=7.8 Hz), 2.38 (2H, t, J=8.1 Hz), 1.96-2.10 (2H, m), 1.72-1.84 (2H, m)
The procedure described in Example 68 was used to prepare 24 from 4-(3-(5-chloro-4-phenylthiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)butanoic acid.
LC-MS ESI (pos.) m/e: 534.0 (M+H)
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.71 (2H, d, J=6.7 Hz), 7.45-7.55 (3H, m), 7.28-7.34 (8H, m), 7.16-7.23 (2H, m, J=6.7, 6.7 Hz), 6.15 (1H, s), 3.92-4.24 (1H, m), 3.23-3.49 (4H, m), 2.35-2.49 (2H, m, J=7.9, 7.9, 7.9 Hz), 2.19-2.34 (2H, m), 1.80-1.98 (2H, m)
The procedure described in Example 67 was used to prepare 25 using 1-Boc-piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4 and 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2.
LC-MS ESI (pos.) m/e: 542 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.78-1.88 (m, 2H) 2.23-2.28 (m, 2H) 2.30-2.38 (m, 2H) 2.78-2.87 (m, 4H) 3.15-3.39 (m, 6H) 3.39-3.43 (m, 2H) 3.70 (s, 2H) 3.87-3.93 (m, 1H) 7.03-7.30 (m, 12H) 7.66 (d, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 26 using 5-chloro-4-phenylthiazol-2-amine instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2.
LC-MS ESI (neg.) m/e: 533.0 (M−H)
1H NMR (500 MHz, DMSO-d6) δ ppm 7.87 (2H, d, J=7.3 Hz), 7.47 (2H, t, J=7.6 Hz), 7.36-7.42 (1H, m, J=7.3, 7.3 Hz), 7.31-7.36 (4H, m), 7.28 (4H, t, J=7.9 Hz), 7.16 (2H, t, J=7.0 Hz), 4.00 (1H, t, J=7.6 Hz), 3.27 (4H, dt, J=32.8, 7.5, 7.3 Hz), 2.30 (2H, q, J=7.9 Hz), 2.19 (2H, t, J=7.0 Hz), 1.58-1.70 (2H, m)
The procedure described in Example 67 was used to prepare 27 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and 1-(piperazin-1-yl)ethanone instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 610 (M+H); Elemental analysis: Theoretical C, 68.94; H, 6.45; N, 11.49. Found C, 66.66; H, 6.28; N, 10.96. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.88-1.97 (m, J=5.14 Hz, 2H) 2.08-2.15 (m, 3H) 2.31-2.37 (m, 2H) 2.41 (dd, 2H) 3.28-3.39 (m, 4H) 3.39-3.43 (m, 1H) 3.46 (s, 3H) 3.59-3.66 (m, 2H) 3.71-3.82 (m, 2H) 3.97 (t, J=7.70 Hz, 1H) 7.06 (s, 1H) 7.17-7.24 (m, 2H) 7.25-7.35 (m, 8H) 7.40 (t, J=7.58 Hz, 2H) 7.88 (d, J=7.34 Hz, 2H)
The procedure described in Example 67 was used to prepare 28 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and ethanamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 501 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.18 (t, J=7.34 Hz, 3H) 1.83-1.91 (m, 2H) 2.23-2.29 (m, 2H) 2.40-2.47 (m, 2H) 3.31-3.45 (m, 8H) 3.99 (t, J=8.19 Hz, 1H) 4.11-4.18 (m, 2H) 7.21 (t, J=6.60 Hz, 4H) 7.24-7.35 (m, 7H) 7.39-7.45 (m, 1H) 7.77 (d, J=8.07 Hz, 2H)
The procedure described in Example 67 was used to prepare 29 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and benzylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 563 (M+H);
1H NMR (400 MHz, DMSO-d6) δ ppm 10.94-11.19 (1H, m), 8.33 (1H, s), 7.86 (1H, s), 7.62 (1H, s), 7.32-7.38 (5H, m), 7.25-7.31 (5H, m), 7.19-7.25 (4H, m), 7.16 (2H, t, J=7.2 Hz), 4.25 (2H, d, J=5.9 Hz), 3.93-4.05 (1H, m), 3.16-3.30 (3H, m), 2.24-2.38 (2H, m), 2.03-2.21 (2H, m), 1.70 (2H, s), 1.18-1.34 (1H, m)
The procedure described in Example 67 was used to prepare 30 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and N,N-dimethylpiperazine-1-carboxamide instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 613 (M+H); Elemental analysis: Theoretical C, 66.64; H, 6.58; N, 13.71. Found C, 65.16; H, 6.63; N, 13.33. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.90-2.00 (m, 3H) 2.41-2.50 (m, 4H) 2.81-2.89 (m, 3H) 2.88 (s, 6H) 3.20-3.31 (m, 4H) 3.37-3.48 (m, 4H) 3.49-3.56 (m, 2H) 3.68-3.77 (m, 2H) 7.17-7.23 (m, 3H) 7.23-7.34 (m, 9H) 7.76 (d, J=8.80 Hz, 1H) 7.80 (d, J=7.58 Hz, 1H)
The procedure described in Example 67 was used to prepare 31 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and 1-Boc piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4. LC-MS ESI (pos.) m/e: 568 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.78-1.87 (m, 2H) 2.19-2.26 (m, 2H) 2.29-2.37 (m, 2H) 2.74-2.85 (m, 4H) 3.18-3.30 (m, 4H) 3.33-3.39 (m, 2H) 3.64-3.72 (m, 2H) 3.89 (t, J=7.58 Hz, 1H) 6.96 (s, 1H) 7.11 (t, J=6.72 Hz, 2H) 7.14-7.26 (m, 9H) 7.29 (t, J=7.83 Hz, 2H) 7.80 (d, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 32 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and dimethylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 501 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.90-1.99 (m, 2H) 2.37-2.50 (m, 4H) 3.08 (s, 3H) 3.33-3.47 (m, 4H) 4.04 (br. s., 1H) 7.16-7.23 (m, 4H) 7.24-7.33 (m, 7H) 7.43 (t, J=7.83 Hz, 1H) 7.78 (dd, J=7.34, 2.20 Hz, 2H)
The procedure described in Example 67 was used to prepare 33 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and (S)-1-Boc-2-methylpiperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 582 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.11 (dd, J=10.64, 5.50 Hz, 3H) 1.86-1.95 (m, 2H) 2.22-2.46 (m, 5H) 2.71-2.84 (m, 3H) 3.00-3.14 (m, 2H) 3.25-3.42 (m, 4H) 3.57-3.68 (m, 1H) 3.97 (t, J=7.58 Hz, 1H) 4.61-4.76 (m, 1H) 7.06 (s, 1H) 7.16-7.23 (m, 2H) 7.23-7.34 (m, 9H) 7.35-7.42 (m, 2H) 7.91 (t, J=7.70 Hz, 2H)
The procedure described in Example 67 was used to prepare 34 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2 and (S)-1-Boc-3-methylpiperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 582 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.73-0.90 (m, 2H) 1.13-1.42 (m, 4H) 1.71-1.89 (m, 2H) 2.13-2.48 (m, 4H) 2.73-2.89 (m, 1H) 2.97-3.14 (m, 2H) 3.20-3.44 (m, 4H) 3.83-3.99 (m, 1H) 6.88 (s, 1H) 7.06-7.34 (m, 11H) 7.35-7.50 (m, 2H) 7.60-7.72 (m, 2H) 7.88 (br. s., 1H)
The procedure described in Example 67 was used to prepare 35 using 4-(2-amino-5-chlorothiazol-4-yl)benzonitrile instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2. LC-MS ESI (pos.) m/e: 559.2 (M)
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74 (4H, q, J=8.3 Hz), 7.29-7.33 (3H, m), 7.22-7.26 (3H, m), 7.17-7.23 (2H, m), 4.00 (1H, s), 3.28-3.48 (4H, m, J=15.6 Hz), 2.38 (4H, t, J=6.7 Hz), 1.78-1.92 (2H, m)
The procedure described in Example 67 was used to prepare 36 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, (S)-tert-butyl 3-aminopiperidine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4 and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 582 (M+H); Elemental analysis: Theoretical C, 70.19; H, 6.76; N, 12.04. Found C, 68.82; H, 6.68; N, 11.60. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.33 (d, J=6.36 Hz, 3H) 1.86-1.98 (m, J=5.14 Hz, 2H) 2.19-2.37 (m, 2H) 2.42 (q, J=7.74 Hz, 2H) 2.68 (td, J=12.29, 3.55 Hz, 1H) 2.80-3.11 (m, 3H) 3.24-3.42 (m, 4H) 3.98 (t, J=7.58 Hz, 1H) 7.06 (s, 1H) 7.18-7.23 (m, 2H) 7.25-7.35 (m, 9H) 7.39 (t, J=7.70 Hz, 2H) 7.91 (d, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 37 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and morpholine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 543 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.91-1.99 (m, 2H) 2.32-2.39 (m, 2H) 2.40-2.48 (m, 2H) 3.28-3.34 (m, 2H) 3.36-3.43 (m, 2H) 3.43-3.49 (m, 2H) 3.65-3.73 (m, 4H) 3.73-3.80 (m, 2H) 4.00 (t, J=7.70 Hz, 1H) 7.17-7.34 (m, 11H) 7.36-7.41 (m, 1H) 7.77 (d, J=7.83 Hz, 2H)
The procedure described in Example 67 was used to prepare 38 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and 1-Boc piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 642 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.50 (d, J=1.47 Hz, 9H) 1.88-1.97 (m, 2H) 2.32-2.39 (m, 2H) 2.40-2.47 (m, 2H) 3.25-3.34 (m, 2H) 3.35-3.48 (m, 8H) 3.69 (br. s., 2H) 4.00 (t, J=8.19 Hz, 1H) 7.15-7.39 (m, 12H) 7.76 (d, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 39 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and 1-Boc piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4. LC-MS ESI (pos.) m/e: 668 (M+H); 1H NMR (500 MHz, DMSO-d6) δ ppm 1.41 (s, 9H) 1.64-1.73 (m, 2H) 2.27-2.38 (m, 4H) 2.53-2.67 (m, 2H) 3.16-3.25 (m, 4H) 3.31 (s, 2H) 3.37 (s, 2H) 3.41-3.46 (m, 2H) 3.99-4.03 (m, 1H) 7.18 (t, J=6.72 Hz, 2H) 7.30 (t, J=7.70 Hz, 6H) 7.34-7.38 (m, 4H) 7.38-7.47 (m, 3H) 7.90 (d, J=8.07 Hz, 2H)
The procedure described in Example 67 was used to prepare 40 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and cyclohexylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 555 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.85-0.95 (m, 4H) 1.25-1.36 (m, 4H) 1.36-1.48 (m, 4H) 1.61-1.69 (m, 1H) 1.74 (d, J=14.92 Hz, 2H) 1.82-1.90 (m, 2H) 1.93-2.00 (m, J=11.74 Hz, 2H) 2.21-2.27 (m, 2H) 2.39-2.49 (m, 2H) 3.31-3.45 (m, 4H) 3.87-4.03 (m, 1H) 7.16-7.35 (m, 11H) 7.39-7.45 (m, 1H) 7.70-7.79 (m, 2H)
The procedure described in Example 67 was used to prepare 41 using N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 614.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (1H, s), 9.96 (1H, s), 7.84 (2H, d, J=8.6 Hz), 7.31-7.38 (4H, m), 7.25-7.31 (6H, m), 7.13-7.20 (2H, m, J=7.2, 7.2 Hz), 4.43 (1H, s), 4.00 (1H, t, J=7.6 Hz), 3.42-3.58 (2H, m), 3.20-3.33 (2H, m), 2.96-3.10 (3H, m), 2.44 (2H, t, J=7.2 Hz), 2.23-2.36 (2H, m)
The procedure described in Example 67 was used to prepare 42 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and (R)-tert-butyl 2-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 582 (M+H); Elemental analysis: Theoretical C, 70.19; H, 6.76; N, 12.04. Found C, 68.05; H, 6.72; N, 11.46. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.94-1.05 (m, 3H) 1.74-1.85 (m, 2H) 2.12-2.38 (m, 5H) 2.62-2.77 (m, 3H) 2.97 (d, J=11.74 Hz, 1H) 3.02-3.10 (m, 1H) 3.14-3.30 (m, 4H) 3.48-3.61 (m, 1H) 3.86 (t, J=7.83 Hz, 1H) 4.52-4.64 (m, 1H) 6.94 (s, 1H) 7.09 (t, J=6.36 Hz, 2H) 7.13-7.23 (m, 9H) 7.23-7.30 (m, 2H) 7.78 (t, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 42 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and (R)-tert-butyl 3-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 582 (M+H); Elemental analysis: Theoretical C, 70.19; H, 6.76; N, 12.04. Found C, 68.82; H, 6.68; N, 11.60. 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.33 (d, J=6.36 Hz, 3H) 1.86-1.98 (m, J=5.14 Hz, 2H) 2.19-2.37 (m, 2H) 2.42 (q, J=7.74 Hz, 2H) 2.68 (td, J=12.29, 3.55 Hz, 1H) 2.80-3.11 (m, 3H) 3.24-3.42 (m, 4H) 3.98 (t, J=7.58 Hz, 1H) 7.06 (s, 1H) 7.18-7.23 (m, 2H) 7.25-7.35 (m, 9H) 7.39 (t, J=7.70 Hz, 2H) 7.91 (d, J=7.58 Hz, 2H)
The procedure described in Example 67 was used to prepare 42 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2.
LC-MS ESI (pos.) m/e: 530 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.50 (s, 9H) 1.81-1.90 (m, 2H) 2.29 (t, J=6.72 Hz, 2H) 2.41-2.49 (m, 2H) 3.31-3.42 (m, 4H) 4.00 (t, J=7.83 Hz, 1H) 7.18-7.24 (m, 2H) 7.26-7.35 (m, 9H) 7.39-7.44 (m, 1H) 7.70 (d, J=8.56 Hz, 1H) 7.78 (d, J=8.80 Hz, 1H)
The procedure described in Example 67 was used to prepare 45 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 568 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.46 (m, 1H) 1.47-1.65 (m, 3H) 2.27-2.41 (m, 4H) 2.56-2.67 (m, 2H) 2.69-2.78 (m, 1H) 2.82 (dd, J=11.93, 2.93 Hz, 1H) 3.17 (dd, J=9.00, 5.48 Hz, 2H) 3.52 (t, J=5.87 Hz, 2H) 3.87 (t, J=7.83 Hz, 1H) 3.92-4.00 (m, 1H) 6.57 (d, J=6.65 Hz, 1H) 6.94 (s, 1H) 7.08-7.16 (m, 2H) 7.16-7.27 (m, 9H) 7.31 (t, J=7.63 Hz, 2H) 7.76 (d, J=7.43 Hz, 2H)
The procedure described in Example 67 was used to prepare 46 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, morpholine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 529 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (1H, s), 7.86 (1H, s), 7.63 (1H, s), 7.31-7.41 (5H, m), 7.28 (4H, t, J=7.6 Hz), 7.17 (3H, t, J=7.2 Hz), 3.88-4.07 (1H, m), 3.47-3.72 (5H, m), 3.35-3.45 (4H, m), 3.15-3.28 (3H, m), 2.54-2.66 (2H, m), 2.25-2.43 (2H, m)
The procedure described in Example 67 was used to prepare 47 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2.
LC-MS ESI (pos.) m/e: 474 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.73 (m, 2H) 2.19 (t, J=7.43 Hz, 2H) 2.31 (q, J=7.56 Hz, 2H) 3.20-3.30 (m, 2H) 3.30-3.40 (m, 2H) 3.99 (t, J=8.02 Hz, 1H) 7.12-7.23 (m, 3H) 7.28 (t, J=7.63 Hz, 4H) 7.32-7.39 (m, 5H) 7.51 (br. s., 1H) 7.80 (d, J=9.78 Hz, 1H)
The procedure described in Example 67 was used to prepare 48 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and piperidine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 541 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.43-1.56 (m, 2H) 1.58-1.73 (m, 6H) 1.90-2.00 (m, 2H) 2.38-2.48 (m, 4H) 3.29-3.37 (m, 2H) 3.42 (dd, J=10.88, 5.99 Hz, 4H) 3.72-3.78 (m, 2H) 3.98-4.05 (m, 1H) 7.18-7.24 (m, 2H) 7.27-7.35 (m, 9H) 7.42-7.48 (m, 1H) 7.76-7.85 (m, 2H)
The procedure described in Example 67 was used to prepare 49 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, 1-Boc piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 528 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.30-2.47 (m, 4H) 2.69-2.80 (m, 4H) 3.15-3.22 (m, 2H) 3.28-3.34 (m, 2H) 3.52-3.61 (m, 4H) 3.86-3.93 (m, 1H) 7.08-7.14 (m, 3H) 7.14-7.25 (m, 8H) 7.27 (t, J=7.70 Hz, 1H) 7.65 (d, J=7.34 Hz, 2H)
The procedure described in Example 67 was used to prepare 50 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, dimethylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 487 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.47 (d, J=7.34 Hz, 1H) 1.49-1.56 (m, 1H) 2.43-2.50 (m, 4H) 2.54-2.59 (m, 2H) 2.96-3.01 (m, 6H) 3.25-3.37 (m, 2H) 3.63-3.71 (m, 2H) 7.19-7.23 (m, 2H) 7.25-7.37 (m, 9H) 7.48 (t, J=8.19 Hz, 1H) 7.76-7.81 (m, 2H)
The procedure described in Example 67 was used to prepare 51 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and 1-methyl piperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 556 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.17 (t, J=6.97 Hz, 2H) 1.36 (s, 1H) 1.78-1.87 (m, 2H) 2.21-2.29 (m, 6H) 2.30-2.37 (m, 4H) 2.42 (dd, J=13.20, 5.38 Hz, 4H) 3.16-3.25 (m, 2H) 3.26-3.33 (m, 2H) 3.37-3.49 (m, 3H) 3.60-3.68 (m, 1H) 3.74-3.82 (m, 2H) 3.90 (t, J=7.83 Hz, 1H) 7.04-7.24 (m, 11H) 7.27 (t, J=7.70 Hz, 1H) 7.66 (d, J=7.83 Hz, 2H)
The procedure described in Example 68 was used to prepare 52 from 3-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)propanoic acid. LC-MS ESI (pos.) m/e: 459 (M+H). 1H NMR (500 MHz, MeOH) δ ppm 7.74 (1H, d, J=7.7 Hz), 7.51 (1H, d, J=8.0 Hz), 7.35-7.40 (1H, m), 7.30-7.34 (4H, m), 7.25-7.32 (4H, m), 7.21-7.26 (2H, m), 7.1-7.20 (2H, m), 4.02 (1H, t, J=7.8 Hz), 3.25-3.32 (2H, m), 2.38 (2H, m), 1.96-2.10 (2H, m), 1.72-1.84 (2H, m)
The procedure described in Example 68 was used to prepare 52 from 3-(3-(5-chloro-4-phenylthiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)propanoic acid.
LC-MS ESI (pos.) m/e: 519 (M+H). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.89 (1H, d, J=7.3 Hz), 7.67-7.73 (2H, m), 7.47-7.57 (3H, m), 7.28-7.34 (7H, m), 7.17-7.23 (2H, m), 3.99 (1H, t, J=7.6 Hz), 3.55-3.69 (2H, m), 3.46-3.54 (1H, m), 3.38-3.46 (2H, m), 2.71 (1H, t, J=6.7 Hz), 2.50-2.59 (2H, m), 2.35-2.48 (2H, m)
The procedure described in Example 67 was used to prepare 54 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2. LC-MS ESI (pos.) m/e: 500 (M+H); 1H NMR (500 MHz, DMSO-d6) δ ppm 1.60-1.73 (m, 2H) 2.22 (t, J=7.21 Hz, 2H) 2.28-2.36 (m, 2H) 3.26 (dd, J=16.14, 9.05 Hz, 4H) 3.98-4.07 (m, 1H) 7.18 (t, J=7.83 Hz, 2H) 7.30 (t, J=7.58 Hz, 5H) 7.33-7.38 (m, 4H) 7.41 (t, J=7.58 Hz, 2H) 7.45 (s, 1H) 7.90 (d, J=8.31 Hz, 2H)
The procedure described in Example 67 was used to prepare 55 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, cyclohexylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 541 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.84-0.94 (m, 2H) 1.02-1.19 (m, 4H) 1.56-1.72 (m, 4H) 1.82-1.90 (m, 2H) 2.38-2.48 (m, 4H) 3.26-3.32 (m, 2H) 3.59-3.65 (m, 2H) 3.82 (br. s., 1H) 3.98 (t, J=7.70 Hz, 1H) 5.57 (br. s., 1H) 7.17-7.35 (m, 11H) 7.39 (t, J=7.34 Hz, 1H) 7.76 (d, J=7.83 Hz, 2H)
The procedure described in Example 67 was used to prepare 56 using tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (neg.) m/e: 577.0 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.02 (2H, d, J=7.8 Hz), 7.97 (2H, dd, J=7.8, 1.6 Hz), 7.72-7.81 (2H, m), 7.51-7.62 (2H, m), 7.38-7.47 (3H, m), 7.34 (2H, t, J=7.4 Hz), 7.13-7.21 (2H, m), 4.47-4.70 (2H, m), 4.25 (1H, t, J=5.5 Hz), 3.98-4.17 (2H, m), 3.34-3.59 (4H, m), 2.83-3.05 (2H, m)
The procedure described in Example 67 was used to prepare 57 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 460 (M+H); 1H NMR (500 MHz, DMSO-d6) δ ppm 2.28-2.36 (m, 2H) 2.41-2.48 (m, 4H) 3.50-3.61 (m, 2H) 4.01 (t, J=7.58 Hz, 1H) 7.13-7.22 (m, 3H) 7.29 (t, J=7.70 Hz, 4H) 7.31-7.38 (m, 5H) 7.50 (br. s., 1H) 7.80 (d, J=7.58 Hz, 1H)
The procedure described in Example 67 was used to prepare 58 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, (S)-tert-butyl 2-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 542 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.02 (m, 3H) 2.15-2.26 (m, 1H) 2.30-2.47 (m, 4H) 2.53-2.69 (m, 3H) 2.85-3.04 (m, 2H) 3.10-3.25 (m, 2H) 3.40-3.64 (m, 3H) 3.88 (t, J=7.63 Hz, 1H) 4.41-4.55 (m, 1H) 7.06-7.16 (m, 3H) 7.16-7.23 (m, 8H) 7.27 (t, J=7.63 Hz, 1H) 7.65 (d, J=7.82 Hz, 2H)
The procedure described in Example 67 was used to prepare 59 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, ethyl-3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 502 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.09-1.16 (m, 4H) 1.69-1.77 (m, 2H) 2.21 (t, J=6.72 Hz, 2H) 2.23-2.32 (m, 2H) 3.15-3.26 (m, 4H) 3.83 (t, J=7.83 Hz, 1H) 4.05-4.12 (m, 2H) 7.05 (t, J=6.97 Hz, 2H) 7.08-7.19 (m, 9H) 7.25 (t, J=7.58 Hz, 1H) 7.58 (dd, J=32.28, 7.83 Hz, 2H)
The procedure described in Example 67 was used to prepare 60 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, benzylamine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 549 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.38-2.46 (m, 2H) 2.46-2.51 (m, 2H) 3.23-3.32 (m, 2H) 3.61-3.68 (m, 2H) 3.97 (t, J=7.58 Hz, 1H) 4.44 (d, J=5.62 Hz, 2H) 6.12 (br. s., 1H) 7.15-7.34 (m, 11H) 7.39 (t, J=7.70 Hz, 1H) 7.66-7.78 (m, 2H)
The procedure described in Example 67 was used to prepare 61 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and 1-isopropylpiperazine instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4.
LC-MS ESI (pos.) m/e: 584 (M+H); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.16-1.30 (m, 4H) 1.44 (d, J=6.36 Hz, 3H) 1.49 (d, J=5.38 Hz, 3H) 1.51-1.55 (m, 2H) 1.81-1.88 (m, 2H) 2.36-2.47 (m, 3H) 3.11-3.19 (m, 4H) 3.27-3.41 (m, 2H) 3.66-3.74 (m, 1H) 3.96-4.02 (m, 1H) 7.14-7.40 (m, 12H) 7.75 (d, J=7.82 Hz, 2H)
The procedure described in Example 67 was used to prepare 62 using 4-(4-(methylsulfonyl)phenyl)thiazol-2-amine instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 564.1 (M+H)
1H NMR (400 MHz, DMSO-d6) δ ppm 8.12-8.18 (2H, m), 7.91-8.00 (2H, m), 7.76 (1H, s), 7.32-7.40 (4H, m), 7.28 (4H, t, J=7.8 Hz), 7.11-7.20 (2H, m), 4.01 (1H, t, J=7.6 Hz), 3.47-3.60 (2H, m), 3.27 (3H, t), 3.23 (3H, s), 2.46 (2H, t, J=7.0 Hz), 2.31 (2H, q)
The procedure described in Example 67 was used to prepare 63 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, (R)-tert-butyl 3-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 542 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (dd, 4H) 2.24-2.43 (m, 4H) 2.72-2.83 (m, 5H) 2.86 (s, 3H) 2.91-3.01 (m, 1H) 3.05-3.42 (m, 4H) 3.44-3.66 (m, 2H) 3.88 (t, J=7.63 Hz, 1H) 7.04-7.14 (m, 3H) 7.14-7.23 (m, 7H) 7.25 (t, J=7.63 Hz, 1H) 7.63 (d, J=7.43 Hz, 2H) 7.92 (s, 1H)
The procedure described in Example 67 was used to prepare 64 using 2-amino, 5-chloro phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (neg.) m/e: 518 (M−H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.13 (1H, s), 7.87 (2H, d, J=6.7 Hz), 7.47 (2H, t, J=7.6 Hz), 7.36-7.41 (1H, m, J=7.3, 7.3 Hz), 7.32-7.36 (4H, m), 7.28 (4H, t, J=7.6 Hz), 7.10-7.20 (2H, m), 4.33-5.90 (2H, m), 4.00 (1H, t, J=7.6 Hz), 3.41-3.60 (2H, m), 3.18-3.35 (2H, m), 2.45 (2H, t, J=7.0 Hz), 2.23-2.37 (2H, m)
The procedure described in Example 69 was used to prepare 65 using 2-amino benzothiazole instead of 2-amino phenyl thiazole in Step 8. LC-MS ESI (neg.) m/e: 472.1 (M−H). 1H NMR (400 MHz, DMSO-d6) 8 ppm 7.84-7.93 (2H, m), 7.44-7.48 (1H, m), 7.38-7.44 (2H, m, J=7.6, 7.6 Hz), 7.31-7.37 (4H, m, J=7.4, 7.4 Hz), 7.24-7.31 (4H, m), 7.11-7.20 (2H, m, J=6.8, 6.8 Hz), 4.01 (1H, t, J=7.8 Hz), 3.38-3.51 (2H, m, J=6.3 Hz), 3.16-3.28 (1H, m), 2.56-2.69 (2H, m), 2.16-2.38 (2H, m, J=13.5, 13.5 Hz), 1.00 (3H, d, J=7.0 Hz)
The procedure described in Example 67 was used to prepare 66 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, (S)-tert-butyl 3-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 542 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.13-1.30 (m, 4H) 2.22-2.47 (m, 4H) 2.75-2.84 (m, 5H) 2.88 (s, 3H) 2.92-3.03 (m, J=11.74 Hz, 1H) 3.09-3.44 (m, 4H) 3.47-3.69 (m, 2H) 3.90 (t, J=7.83 Hz, 1H) 7.07-7.17 (m, 3H) 7.17-7.25 (m, 7H) 7.28 (t, J=7.63 Hz, 1H) 7.66 (d, J=7.82 Hz, 2H) 7.94 (s, 1H)
The procedure described in Example 67 was used to prepare 67 using 4-(2-aminothiazol-4-yl)benzenesulfonamide instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, only one equivalent of CDI and no DMAP in Step 2. LC-MS ESI (pos.) m/e: 579 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59-11.00 (1H, m), 8.07 (2H, dt, J=8.6, 2.0 Hz), 7.86 (2H, dt, J=8.7, 1.9 Hz), 7.65 (1H, s), 7.32-7.40 (6H, m), 7.25-7.32 (4H, m), 7.17 (2H, tt, J=7.2, 1.4 Hz), 4.01 (1H, t, J=7.6 Hz), 3.67-3.95 (2H, m), 3.28 (4H, dt, J=30.0, 7.5 Hz), 2.31 (2H, q), 2.21 (2H, t, J=7.4 Hz), 1.59-1.75 (2H, m)
The procedure described in Example 67 was used to prepare 68 using 2-amino benzothiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, (R)-tert-butyl 2-methylpiperazine-1-carboxylate instead of (R)-tert-butyl 3-aminopiperidine-1-carboxylate in Step 4, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1. LC-MS ESI (pos.) m/e: 542 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 0.77-0.90 (m, 4H) 0.97 (d, J=6.26 Hz, 3H) 1.15-1.41 (m, 6H) 1.55-1.68 (m, 1H) 2.14-2.27 (m, 1H) 2.29-2.49 (m, 4H) 2.53-2.72 (m, 3H) 2.84-3.07 (m, 1H) 3.10-3.27 (m, 2H) 3.40-3.65 (m, 3H) 3.88 (t, J=7.83 Hz, 1H) 4.07-4.22 (m, 1H) 4.40-4.55 (m, J=12.13 Hz, 1H) 7.16-7.23 (m, 7H) 7.26 (t, J=7.63 Hz, 1H) 7.44 (dd, J=5.48, 3.52 Hz, 1H) 7.55-7.76 (m, 2H)
The procedure described in Example 67 was used to prepare 69 using 2-amino phenyl thiazole instead of N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide in Step 2, and tert-butyl 3-bromopropanoate instead of tert-butyl 4-bromobutanoate in Step 1.
LC-MS ESI (pos.) m/e: 486 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (1H, s), 10.86 (1H, s), 7.88 (2H, t, J=7.0 Hz), 7.45 (1H, s), 7.40 (2H, t, J=7.6 Hz), 7.33-7.37 (4H, m), 7.25-7.32 (5H, m), 7.17 (2H, t, J=7.2 Hz), 4.01 (1H, t, J=7.6 Hz), 3.53 (2H, t, J=6.8 Hz), 3.20-3.29 (2H, m), 2.46 (2H, t, J=7.0 Hz), 2.31 (2H, q, J=7.7 Hz)
Step 1: To a solution of 3,3-diphenylpropanal 1 (1.05 g, 5 mmol) and tert-butyl 4-aminobutylcarbamate 2 (1.18 g, 6.25 mmol) in CH2Cl2 (32 ml) was added sodium triacetoxyborohydride (2.65 g, 12.5 mmol). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was poured into 30 mL of aqueous saturated NaHCO3, allowed to stir for 1 h, and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica using 0->10% MeOH/CH2Cl2+0->1% NH4OH as eluent.) to yield 3 as a faint yellow oil (1.12 g, 58% yield).
LCMS (ES) calcd for C24H34N2O2 382.2 found 383.2 (MH+).
Step 2: To a solution of benzo[d]thiazol-2-amine 4 (378 mg, 2.52 mmol) in CH2Cl2 (10 ml) was added di(1H-imidazol-1-yl)methanone (162 mg, 1 mmol). The reaction mixture was stirred overnight at 35° C. Tert-butyl 4-(3,3-diphenylpropylamino)butylcarbamate 3 (1.12 g, 2.94 mmol) was added and the reaction mixture was heated to 35° C. overnight. The reaction mixture was poured into 20 mL of aqueous saturated NaHCO3 and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica using EtOAc/Hexanes as eluent to give 5 as a white solid (500 mg, 35.5% yield).
LCMS (ES) calcd for C32H38N4O3S 558.3 found 559.3 (MH+).
Step 3: To a solution of tert-butyl 4-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)butylcarbamate (500 mg, 895 μmol) in CH2Cl2 (5 ml) was added an equivalent volume of TFA (5 mL). The reaction mixture was stirred for 4 h at of 25° C. Volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 60 mL of a 1:1 mixture of aqueous saturated NaHCO3 and Dichloromethane. The organic phase was separated and the aqueous phase was extracted further with Dichloromethane (2×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The amine 6 was concentrated to an off-white foam that was used without further purification.
Step 4: To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid 7 (115 mg, 0.435 mmol) in 9:1 CH2Cl2/DMF (10 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (94.5 mg, 0.493 mmol). The reaction mixture was stirred for 30 min at room temperature. Then 1-(4-aminobutyl)-3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)urea (133 mg, 0.290 mmol) 6 was added and the reaction mixture was heated to 39° C. overnight. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica using EtOAc/Hexanes as eluent to give 8 as a clear oil (119 mg, 58% yield).
LCMS (ES) calcd for C41H43N5O4S 703.3 found 704.3 (MH+).
Step 5: To a solution of benzyl 4-((4-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)butyl)carbamoyl)piperidine-1-carboxylate 8 (119 mg, 169 μmol) in dioxane (1.5 ml) was added 0.5 mL of HBr 33% by wt. in AcOH. The reaction mixture was stirred for 40 min at 25° C. Volatiles were removed by concentration under reduced pressure. The residue was re-concentrated twice from heptane (2×10 mL). Finally, the leftover residue was purified by injection as a solution in DMF on a reverse phase HPLC column using 5->95% CH3CN/0.1% aqueous TFA as eluent to give 9 as a white solid (69.7 mg, 60% yield). Significant broadening due to rotamers was observed in NMR spectra.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.71 (m, 4H) 1.91-2.15 (m, 4H) 2.30-2.60 (m, 3H) 2.88-3.13 (m, 2H) 3.17-3.57 (m, 8H) 7.15-7.23 (m, 2H) 7.26-7.34 (m, 8H) 7.45 (t, J=7.63 Hz, 1H) 7.56 (t, J=7.63 Hz, 1H) 7.79 (dd, J=7.83, 4.30 Hz, 2H) 8.88 (br. s., 1H) 9.53 (br. s., 1H);
LCMS (ES) calcd for C33H39N5O2S 569.3 found 570.3 (MH+).
The procedure described in Example 127 with the exception of substituting 1-(benzyloxycarbonyl)piperidine-2-carboxylic acid for 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid 7 in Step 4 was used to prepare 3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(4-(piperidine-2-carboxamido)butyl)urea 10 as a white solid. Significant broadening due to rotamers was observed in NMR spectra.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.66 (m, 5H) 1.68-1.97 (m, 4H) 2.03-2.15 (m, 1H) 2.32-2.48 (m, 2H) 3.02-3.16 (m, 1H) 3.20-3.57 (m, 7H) 3.93-4.08 (m, 2H) 7.13-7.23 (m, 2H) 7.25-7.35 (m, 7H) 7.42 (t, J=7.63 Hz, 1H) 7.49-7.58 (m, 1H) 7.60-7.69 (m, 1H) 7.69-7.76 (m, 1H) 7.79 (d, J=7.82 Hz, 1H);
LCMS (ES) calcd for C33H39N5O2S 569.3 found 570.3 (MH+).
The procedure described in Example 127 with the exceptions of substituting tert-butyl 2-aminoethylcarbamate for tert-butyl 4-aminobutylcarbamate 2 in Step 1 and of substituting 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid for 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid 7 in Step 4 was used to prepare 3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(piperidine-3-carboxamido)ethyl)urea 11 as a white solid. Significant broadening due to rotamers was observed in NMR spectra.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.53 (m, 1H) 1.53-1.77 (m, 2H) 1.86-2.00 (m, 1H) 2.40 (q, J=7.82 Hz, 2H) 2.46-2.57 (m, 1H) 2.65-2.75 (m, 1H) 2.87 (dd, J=12.13, 3.13 Hz, 2H) 3.02 (dd, J=11.35, 3.52 Hz, 1H) 3.33-3.52 (m, 6H) 3.95 (t, J=7.83 Hz, 1H) 4.97 (br. s., 2H) 7.16-7.39 (m, 10H) 7.69 (d, J=8.22 Hz, 2H) 7.72 (d, J=7.82 Hz, 2H) 8.55 (br. s., 1H);
LCMS (ES) calcd for C31H35N5O2S 541.3 found 542.3 (MH+).
The procedure described in Example 127 with the exceptions of substituting tert-butyl 2-aminoethylcarbamate for tert-butyl 4-aminobutylcarbamate 2 in Step 1, of substituting N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide for benzo[d]thiazol-2-amine 4 in Step 2, and of substituting 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid for 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid 7 in Step 4 was used to prepare 1-(3,3-diphenylpropyl)-3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(2-(piperidine-3-carboxamido)ethyl)urea 12 as a white solid. 1H NMR (500 MHz, MeOH) δ ppm 1.75-1.85 (m, 2H) 1.85-1.93 (m, 2H) 2.38-2.49 (m, 3H) 2.93 (td, J=12.36, 3.36 Hz, 2H) 2.99-3.03 (m, 3H) 3.34-3.43 (m, 6H) 3.50 (t, J=5.80 Hz, 2H) 4.05 (t, J=7.63 Hz, 1H) 7.19 (t, J=7.32 Hz, 2H) 7.23 (s, 1H) 7.28-7.33 (m, 6H) 7.33-7.38 (m, 4H) 7.87 (d, J=8.54 Hz, 2H);
LCMS (ES) calcd for C34H40N6O4S2 660.3 found 661.2 (MH+).
The procedure described in Example 127 with the exceptions of substituting tert-butyl 2-aminoethylcarbamate for tert-butyl 4-aminobutylcarbamate 2 in Step 1, of substituting N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide for benzo[d]thiazol-2-amine 4 in Step 2, and of substituting 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid for 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid 7 in Step 4 was used to prepare 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(piperidine-3-carboxamido)ethyl)urea 13 as a white solid.
1H NMR (400 MHz, MeOH) δ ppm 1.73-1.93 (m, 4H) 2.35-2.48 (m, 3H) 2.95 (td, J=12.13, 3.52 Hz, 2H) 3.02 (s, 3H) 3.34-3.41 (m, 6H) 3.47 (t, J=5.87 Hz, 2H) 4.03 (t, J=7.83 Hz, 1H) 7.14-7.21 (m, 2H) 7.26-7.37 (m, 10H) 7.91-7.97 (m, 2H); LCMS (ES) calcd for C34H39ClN6O4S2 694.2 found 695.2 (MH+).
Step 1. Procedure A. A microwave compatible vial was charged with 3-bromo-1,1-diphenylpropane (5.02 g, 18.2 mmol), 2-aminoethanol (2.19 ml, 36.5 mmol), potassium carbonate (3.78 g, 27.4 mmol), and 8 mL of AcCN. The vial was sealed and purged with N2 for 5 min. The reaction was subjected to microwave irradiation for 30 min at 130° C. The solution was diluted with EtOAc and was washed with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude material was purified by ISCO column chromatography using a 10% to 90% gradient of 10% MeOH—CH2Cl2/CH2Cl2 eluent. The desired fractions were combined and concentrated to give 2-(3,3-diphenylpropylamino)ethanol (3.20 g, 68.7% yield) as a colorless oil.
Mass spectrum: calculated for C17H21NO 255.4. found 256.3 (M++1).
Step 2. A solution of 2-(3,3-diphenylpropylamino)ethanol (3.20 g, 13 mmol) and pyridine (1.2 ml, 15 mmol) in CH2Cl2 was chilled to 0° C. in an ice bath. To this solution was added Cbz-Cl (2.0 ml, 14 mmol) slowly via syringe. The reaction mixture was allowed to warm to room temperature and was stirred under N2 for 4 h. The solution was diluted with CH2Cl2 and then washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by ISCO column chromatography using a 5% to 70% gradient of EtOAc/hexane as eluent. The desired fractions were combined and concentrated to give benzyl 3,3-diphenylpropyl(2-hydroxyethyl)carbamate (3.41 g, 70% yield) as a colorless, viscous oil. Mass spectrum: calculated for C25H27NO3 389.5. found 390.4 (M++1).
Step 3. A solution of benzyl 3,3-diphenylpropyl(2-hydroxyethyl)carbamate (150 mg, 385 μmol) in THF was chilled to 0° C. in an ice bath. To this solution was added 2,2,2-trichloroacetyl isocyanate (73 mg, 385 μmol) and the mixture was stirred at 0° C. for 3 h. The reaction was warmed to room temperature and stirred overnight under a N2 atmosphere. The solvent was removed in vacuo and the crude material was dissolved with MeOH. Pd/C (41 mg, 385 mmol) was added to solution and the reaction flask was evacuated and purged with H2 (0.78 mg, 385 μmol) three times. The reaction was stirred for 4 h under H2 atmosphere using a balloon. The balloon was removed and the solution was purged with N2 for 10 min. A solution of 10% aqueous Na2CO3 was added to the mixture and the reaction was stirred overnight. The mixture was filtered to remove the solid material and the filtrate was concentrated. The crude material was diluted with EtOAc and was extracted with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by ISCO column chromatography using a 5% to 90% gradient of EtOAc/hexane as eluent. The desired fractions were combined and concentrated to give 2-(3,3-diphenylpropyl-amino)ethyl carbamate (71 mg, 62% yield) as a colorless oil. Mass spectrum: calculated for C18H22N2O2 298.4. found 299.3 (M++1).
Step 4. Procedure B. A solution of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide (134 mg, 442 μmol), DMAP (63 mg, 516 μmol), and CDI (84 mg, 516 μmol) in 3 ml, of dry DMF was heated to 55° C. under a N2 atmosphere. After 18 h, a solution of 2-(3,3-diphenylpropylamino)ethyl carbamate (110 mg, 369 μmol) in 2 mL of DMF was added to the reaction mixture. The reaction temperature was increased to 85° C. and the mixture was stirred for 8 h. The mixture was cooled to room temperature and then water was added to the reaction to precipitate the product. The precipitate was filtered and washed with water. The crude solid was dissolved in MeOH/CH2Cl2, and was absorbed onto silica gel. The material was purified by ISCO column chromatography using a 10% to 90% gradient of 110% MeOH—CH2Cl2/CH2Cl2 eluent. The desired fractions were combined and concentrated to give the product as a colorless oil. The product was converted to the HCl salt by adding 1 N HCl in ether to give 2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethyl carbamate hydrochloride (55 mg, 24% yield) as a white solid.
Mass spectrum: calculated for C29H30ClN5O5S2 628.2. found 629.2 (M++1) 1H NMR (400 MHz, CDCl3) δ ppm 2.37-2.43 (q, 2H) 2.91 (s, 3H) 3.34-3.38 (m, 2H) 3.52-3.56 (m, 2H) 3.98-4.02 (t, 1H) 4.15-4.20 (m, 2H) 6.98-7.01 (m, 2H) 7.17-7.20 (m, 2H) 7.26-7.31 (m, 8H) 7.57-7.59 (d, 2H).
Step 1. The compound 2 shown above was prepared using Procedure B of Example 132. The reaction conditions yielded 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-hydroxyethyl)urea hydrochloride (144 mg, 74.8% yield) as a white solid. Mass spectrum: calculated for C28H29ClN4O4S2 585.1. found 589.2 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 2.40-2.46 (q, 2H) 3.02 (s, 3H) 3.37-3.48 (m, 4H) 3.69-3.73 (m, 2H) 4.01-4.04 (t, 1H) 7.15-7.19 (m, 2H) 7.26-7.36 (m, 10H) 7.87-7.89 (d, 2H).
Step 1. The alcohol shown above was prepared using Procedure A of Example 132. The reaction conditions yielded 3-(3,3-diphenylpropylamino)propan-1-ol (1.13 g, 58.4% yield) as a colorless oil. Mass spectrum: calculated for C18H23NO 269.4. found 270.2 (M++1).
Step 2. The compound 3 shown above was prepared using Procedure B of Example 132. The reaction conditions yielded 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(3-hydroxypropyl)urea hydrochloride (120 mg, 73.0% yield) as a white solid.
Mass spectrum: calculated for C29H31ClN4O4S2 599.2. found 600.3 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 1.72-1.75 (m, 2H) 2.39-2.44 (q, 2H) 3.01 (s, 3H) 3.32-3.36 (m, 2H) 3.40-3.44 (m, 2H) 3.57-3.59 (m, 2H) 3.99-4.03 (t, 1H) 7.15-7.19 (m, 2H) 7.26-7.36 (m, 10H) 7.86-7.90 (d, 2H).
Step 1. The alcohol shown above was prepared using Procedure A of Example 132. The reaction conditions yielded tert-butyl 2-(3,3-diphenylpropylamino)ethylcarbamate (820 mg, 42.4% yield) as a colorless oil.
Mass spectrum: calculated for C22H30N2O2 354.5. found 355.4 (M++1).
Step 2. The compound 4 shown above was prepared using Procedure B of Example 132 followed by stirring of the Boc protected intermediate with 2 mL of 4 N HCl in dioxane and 10 mL of dichloromethane for 8 h at room temperature. Concentration of the reaction mixture yielded tert-butyl 2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethylcarbamate hydrochloride (120 mg, 73.0% yield) as a white solid. Mass spectrum: calculated for C28H30ClN5O3S2 584.2. found 585.2 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 2.43-2.48 (m, 2H) 3.02 (s, 3H) 3.06-3.08 (m, 2H) 3.43-3.45 (m, 2H) 3.60-3.62 (m, 2H) 4.06-4.10 (t, 1H) 7.17-7.20 (m, 2H) 7.26-7.37 (m, 10H) 7.91-7.93 (d, 2H).
Step 1. The sulfonamide shown above was prepared using Procedure A of Example 132. The reaction conditions yielded 2-(3,3-diphenylpropylamino)ethanesulfonamide (101 mg, 43.6% yield) as a light yellow oil.
Mass spectrum: calculated for C17H22N2O2S 318.4. found 319.3 (M++1).
Step 2. The compound 5 shown above was prepared using Procedure B of Example 132. The reaction conditions yielded 2-[{[(5-chloro-4-{4-[(methylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)amino]carbonyl}(3,3-diphenylpropyl)amino]ethanesulfonamide hydrochloride (72 mg, 34% yield) as a yellow solid. Mass spectrum: calculated for C28H30ClN5O5S3 648.2. found 649.2 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 2.42-2.47 (m, 2H) 3.02 (s, 3H) 3.30-3.35 (m, 2H) 3.41-3.45 (m, 2H) 3.76-3.80 (m, 2H) 4.04-4.06 (t, 1H) 7.15-7.19 (m, 2H) 7.27-7.35 (m, 10H) 7.89-7.92 (m, 2H).
Step 1. The thioether shown above was prepared using Procedure A of Example 132. The reaction conditions yielded N-(2-(methylthio)ethyl)-3,3-diphenylpropan-1-amine (180 mg, 86.8% yield) as a colorless oil. Mass spectrum: calculated for C18H23NS 285.4. found 286.3 (M++1).
Step 2. The compound shown above was prepared using Procedure B of Example 132. The reaction conditions yielded 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(methylthio)ethyl)urea hydrochloride (85 mg, 42% yield) as a white solid. Mass spectrum: calculated for C29H31ClN4O3S3 615.2. found 616.2 (M++1).
Step 3. Procedure C. A solution of 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(methylthio)ethyl)urea (60 mg, 98 μmol) in MeOH was chilled to 0° C. in an ice bath. To this solution was added a solution of oxone (90 mg, 146 μmol) in water. The mixture was slowly warmed to room temperature and stirred for 18 h. The solution was diluted with water and CH2Cl2. The aqueous layer was extracted with 3×CH2Cl2. The combined organic solution was washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified by ISCO column chromatography using 5% to 80% of 110% MeOH—CH2Cl2/CH2Cl2 eluent. The desired fractions were combined, concentrated, and converted to the HCl salt to give 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(methylsulfonyl)ethyl)urea hydrochloride (55 mg, 87% yield) as a white solid.
Mass spectrum: calculated for C29H31ClN4O5S3 647.2. found 648.3 (M++1). 1H NMR (400 MHz, CDCl3) δ ppm 2.33-2.37 (m, 2H) 2.97 (s, 3H) 3.05 (s, 3H) 3.30-3.36 (m, 4H) 3.68-3.71 (m, 2H) 4.00-4.04 (t, 1H) 7.15-7.17 (m, 2H) 7.26-7.30 (m, 6H) 7.34-7.38 (m, 4H) 7.84-7.86 (m, 2H) 9.95 (s, 1H) 11.25 (s, 1H).
Step 1. The thioether shown above was prepared using Procedure A of Example 132. The reaction conditions yielded N-(3-(methylthio)propyl)-3,3-diphenylpropan-1-amine (210 mg, 77.2% yield) as a colorless oil.
Mass spectrum: calculated for C19H25NS 299.5. found 300.3 (M++1).
Step 2. The compound shown above was prepared using Procedure B of Example 132. The reaction conditions yielded 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(3-(methylthio)propyl)urea hydrochloride (97 mg, 47% yield) as a white solid.
Mass spectrum: calculated for C30H33ClN4O3S3 629.3. found 630.2 (M++1).
Step 3. The compound 7 shown above was prepared using Procedure C. The reaction conditions yielded 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(3-(methylsulfonyl)propyl)urea hydrochloride (35 mg, 36% yield) as a white solid.
Mass spectrum: calculated for C30H33ClN4O5S3 661.3. found 662.3 (M++1). 1H NMR (400 MHz, CDCl3) 8 ppm 1.97-2.00 (m, 2H) 2.38-2.43 (m, 2H) 2.94 (s, 3H) 3.00 (s, 3H) 3.08-3.12 (m, 2H) 3.33-3.37 (m, 2H) 3.41-3.50 (m, 2H) 3.99-4.03 (t, 1H) 7.14-7.17 (m, 2H) 7.26-7.33 (m, 10H) 7.89-7.92 (m, 2H).
Step 1. A solution of 1-(2-aminoethyl)-3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)urea hydrochloride (35 mg, 56 μmol) and pyridine (11 μl, 141 μmol) in dry CH2Cl2 was chilled to 0° C. in an ice bath. Methanesulfonyl chloride (4.6 μl, 59 μmol) was then added to the mixture via syringe. The reaction mixture was warmed slowly to room temperature and stirred for 3 h. The reaction was quenched with 1 N NaOH, and then the solution was diluted with CH2Cl2 and water. The water layer was extracted with CH2Cl2×2, and the combined organic extracts were washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude material was purified by ISCO column chromatography using a 5% to 90% gradient of 10% MeOH—CH2Cl2/CH2Cl2 eluent. The desired fractions were combined, concentrated, and converted to the HCl salt to give 3-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-1-(3,3-diphenylpropyl)-1-(2-(methylsulfonamido)-ethyl)urea hydrochloride (15 mg, 40% yield) as a colorless oil.
Mass spectrum: calculated for C29H32ClN5O5S3 662.4. found 663.3 (M++1). 1H NMR (400 MHz, MeOH) δ ppm 2.41-2.46 (m, 2H) 2.90 (s, 3H) 3.02 (s, 3H) 3.19-3.22 (m, 2H) 3.40-3.47 (m, 4H) 4.00-4.04 (t, 1H) 7.14-7.18 (m, 2H) 7.26-7.35 (m, 10H) 7.90-7.92 (d, 2H).
Step 1: To a solution of 3-bromo-1,1-diphenylpropane 1 (4.50 g, 16.4 mmol) in 100 mL of acetonitrile was added potassium carbonate (0.987 ml, 16.4 mmol), followed by 2-ethanolamine (9.81 ml, 164 mmol). The reaction mixture was heated to 80° C. while stirring under nitrogen for 18 hours. The reaction was then removed from heat, allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was further purified by column chromatography on silica using a gradient eluent: 0% to 15% of methanol in dichloromethane (with 0.1% ammonia) to give 2 as a white amorphous solid (3.4 g, 81.4% yield).
Step 2: 2-(3,3-diphenylpropylamino)ethanol 2 (3.4 g, 13 mmol) was dissolved in 100 mL of dichloromethane, stirring at 0° C. under an atmosphere of N2. Benzyl chloroformate (2.3 mL, 16 mmol) was slowly injected into the round bottom flask using a 5 cc syringe. The reaction was allowed to warm up to room temperature and was stirred at room temperature for 40 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with 1M HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield 3 as a colorless oil (2.16 g, 42% yield).
Step 3: Benzyl 3,3-diphenylpropyl(2-hydroxyethyl)carbamate 3 (2.157 g, 5.54 mmol) was dissolved in 50 mL of dichloromethane. Dess-Martin Periodinane (17.3 ml, 8.31 mmol) was added to the reaction in one portion. The reaction was stirred under N2 at room temperature for 18 h. The reaction was diluted with aqueous sodium thiosulfate solution and extracted. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude product which was further purified by column chromatography on silica using a gradient eluent: 0% to 100% of ethyl acetate in hexane. Fractions containing product were combined and concentrated in vacuo to give 4 as a clear oil (1.75 g, 82% yield).
Step 4: To a solution of benzyl 3,3-diphenylpropyl(2-oxoethyl)carbamate 4 (0.300 g, 0.774 mmol) in 20 ml of dichloromethane was added (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.140 g, 0.929 mmol) followed by sodium triacetoxyborohydride (0.246 g, 1.16 mmol). The reaction was stirred for 20 h and then diluted with dichloromethane (25 mL), washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to yield 5 as a colorless oil (0.34 g, 90%).
Step 5: (R)-tert-butyl 3-(2-(benzyloxycarbonyl)ethylamino)piperidine-1-carboxylate 5 (0.340 g, 0.700 mmol) was dissolved in 20 ml of Methanol and flushed with N2. Then added palladium, 10 wt. % (dry basis) on activated carbon (0.0745 ml, 0.700 mmol). The flask was evacuated and flushed with H2 3× and then left under a H2 balloon and was allowed to stir for 1 hour. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo to yield 6 as an off-white film (0.194 g, 79% yield).
Step 6: To a solution of 1,1′-carbonyldiimidazole (0.141 g, 0.868 mmol) in 10 ml of DCM, was added N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide (0.176 g, 0.579 mmol) in 5 ml DCM and 2 ml of DMF. The reaction was stirred under N2 at room temperature for 20 h. (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate 6 (0.304 g, 0.695 mmol) was dissolved in 5 ml DCM and this solution was added to the reaction mixture and the reaction was stirred for 6 hrs. The reaction mixture was diluted with DCM (25 mL) and washed with water 2× followed by brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield 7 as a white solid (0.34 g, 77% yield).
Step 7: To a solution of (R)-tert-butyl 3-(2-(3-(5-chloro-4-(4-(methylsulfonamido)phenyl)-thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)ethylamino)piperidine-1-carboxylate 7 (0.444 g, 0.579 mmol) in 5 ml of dichloromethane, was added trifluoroacetic acid (0.0430 ml, 0.579 mmol) and the reaction mixture was stirred under N2 at room temperature for 16 hrs. The reaction mixture was then purified by RP-HPLC to yield the product 8 as a white solid (0.36 g, 95% yield). LC-MS ESI (pos.) m/e: 667.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.26 (1H, s), 9.99 (1H, s), 9.21 (1H, s), 8.95 (2H, s), 7.84 (2H, d, J=8.6 Hz), 7.32-7.38 (4H, m), 7.25-7.32 (6H, m), 7.13-7.21 (2H, m), 4.06 (1H, t), 3.46-3.60 (3H, m), 3.36-3.44 (1H, m), 3.23-3.36 (3H, m), 3.08-3.18 (2H, m), 3.05 (3H, s), 2.74-2.94 (2H, m), 2.33 (2H, q), 2.11 (1H, d, J=10.2 Hz), 1.91 (1H, d, J=14.1 Hz), 1.43-1.68 (2H, m).
The procedure described in Example 140 was used to prepare 9, using (S)-tert-butyl 3-aminopiperidine-1-carboxylate instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4. LC-MS ESI (pos.) m/e: 667.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 9.02 (1H, s), 8.65-8.88 (2H, m), 7.84 (2H, d, J=8.6 Hz), 7.33-7.38 (4H, m), 7.26-7.32 (6H, m), 7.18 (2H, t, J=7.0 Hz), 4.01-4.12 (1H, m), 3.27-3.39 (4H, m), 3.20-3.27 (2H, m), 3.08-3.18 (2H, m), 3.05 (3H, s), 2.72-2.92 (3H, m), 2.27-2.41 (3H, m), 2.04-2.16 (1H, m), 1.83-1.99 (1H, m), 1.42-1.66 (2H, m).
The procedure described in Example 140 was used to prepare 10, using (S)-5-aminopiperidin-2-one instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4 and 5-chloro-4-phenylthiazol-2-amine instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 589 (M+H); 1H NMR (400 MHz, MeOH) δ ppm 2.23-2.52 (m, 6H) 2.79-2.88 (m, 2H) 2.89-3.00 (m, 1H) 3.11-3.21 (m, 1H) 3.29-3.39 (m, 8H) 3.45 (dd, J=12.13, 3.52 Hz, 1H) 3.99 (t, J=7.83 Hz, 1H) 7.13-7.19 (m, 2H) 7.24-7.37 (m, 9H) 7.39-7.47 (m, 2H) 7.85-7.94 (m, 2H).
The procedure described in Example 140 was used to prepare 11, using tert-butyl 4-aminopiperidine-1-carboxylate instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4 and 2-amino benzothiazole instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 514 (M+H); 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.39 (dd, J=9.59, 4.89 Hz, 1H) 1.52-1.73 (m, 3H) 2.19-2.36 (m, 2H) 2.59 (dd, J=12.91, 7.04 Hz, 1H) 2.73-2.96 (m, 8H) 3.06 (dd, J=12.91, 2.74 Hz, 1H) 3.11-3.34 (m, 5H) 3.88 (t, J=7.63 Hz, 1H) 7.00-7.07 (m, 1H) 7.07-7.14 (m, 2H) 7.15-7.25 (m, 8H) 7.51-7.60 (m, 2H) 7.92 (s, 1H).
The procedure described in Example 140 was used to prepare 12, using (R)-5-aminopiperidin-2-one instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4 and 2-amino benzothiazole instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 528 (M+H); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.77-1.89 (m, 2H) 2.21-2.48 (m, 5H) 2.60 (dd, J=12.13, 7.83 Hz, 1H) 2.90-2.97 (m, 1H) 2.97-3.06 (m, 1H) 3.15-3.39 (m, 4H) 3.48-3.60 (m, 2H) 3.91 (t, J=7.83 Hz, 1H) 7.02-7.08 (m, 2H) 7.08-7.15 (m, 2H) 7.17-7.26 (m, 8H) 7.39-7.47 (m, 1H) 7.60-7.68 (m, 1H).
The procedure described in Example 140 was used to prepare 13, using 2-amino benzothiazole instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 514 (M+H); 1H NMR (400 MHz, METHANOL-d4) 8 ppm 1.61-1.74 (m, 1H) 1.74-1.90 (m, 1H) 2.03-2.14 (m, 1H) 2.28 (d, J=14.09 Hz, 1H) 2.44 (q, J=7.69 Hz, 2H) 2.96 (td, J=12.72, 3.13 Hz, 1H) 3.08 (t, J=11.74 Hz, 1H) 3.28 (t, J=5.67 Hz, 2H) 3.40 (d, J=12.52 Hz, 1H) 3.46-3.80 (m, 6H) 4.01 (t, J=7.63 Hz, 1H) 7.11-7.19 (m, 2H) 7.19-7.34 (m, 9H) 7.34-7.41 (m, 2H) 7.64 (d, J=7.82 Hz, 1H).
The procedure described in Example 140 was used to prepare 14, using (R)-5-aminopiperidin-2-one instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4 and 2-amino benzothiazole instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 528 (M+H); 1H NMR (500 MHz, MeOH) δ ppm 1.96-2.08 (m, 1H) 2.22-2.32 (m, 1H) 2.39-2.54 (m, 4H) 3.28 (q, J=5.90 Hz, 2H) 3.36-3.43 (m, 1H) 3.54 (s, 2H) 3.61-3.77 (m, 4H) 4.03 (t, J=7.63 Hz, 1H) 7.18 (t, J=7.02 Hz, 2H) 7.21-7.26 (m, 1H) 7.27-7.36 (m, 8H) 7.36-7.43 (m, 2H) 7.66 (d, J=7.93 Hz, 1H).
The procedure described in Example 140 was used to prepare 15, using (R)-5-aminopiperidin-2-one instead of (R)-tert-butyl 3-(2-(3,3-diphenylpropylamino)ethylamino)piperidine-1-carboxylate in Step 4 and 5-chloro-4-phenylthiazol-2-amine instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide in Step 6. LC-MS ESI (pos.) m/e: 589 (M+H);
1H NMR (400 MHz, MeOH) δ ppm 2.24-2.50 (m, 4H) 2.82-2.89 (m, 2H) 2.92-3.00 (m, 1H) 3.18 (dd, J=11.35, 9.00 Hz, 1H) 3.32-3.41 (m, 4H) 3.46 (dd, J=11.74, 3.91 Hz, 1H) 4.00 (t, J=7.63 Hz, 1H) 7.12-7.20 (m, 2H) 7.23-7.38 (m, 9H) 7.38-7.46 (m, 2H) 7.85-7.91 (m, 2H).
15 g of 3,3-diphenyl-propylamine (71.1 mmol, 1 eq) and 13.7 g of N-Boc-Glycine (78.2 mmol, 1.1 eq) were diluted in 100 mL of dry DCM. 10.6 g of HOBt (78.2 mmol, 1.1 eq) and 15 g of EDC.HCl (78.2 mmol, 1.1 eq) were added to the solution. The reaction mixture was stirred for 16 h at room temperature, under argon, before addition of water. The aqueous phase was extracted several times with DCM, the organics were washed with brine, dried over MgSO4, filtered then concentrated. The crude product was purified by flash chromatography over silica gel (DCM/MeOH: 98/2 to 96/4) to give 23.6 g of the desired amide intermediate [(3,3-diphenyl-propylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (90% yield).
12 g of this amide intermediate (32.5 mmol, 1 eq) were solubilized in 100 mL of dry THF, under argon. After cooling the solution to 0° C., 71.6 mL of LiAlH4 (1 M in THF, 71.6 mmol, 2.2 eq) were added dropwise to the solution. The reaction mixture was stirred for 16 h at room temperature, then cooled to 0° C. before slow addition of water. After stirring for 1 h at room temperature, the mixture was filtered to get rid of aluminium salts and the solid was washed several times with EtOAc. The aqueous phase was extracted several times with EtOAc, then the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified with flash chromatography over silica gel (DCM/MeOH: 98/2 to 90/10) to give 8.6 g of the desired secondary amine [2-(3,3-diphenylpropylamino)-ethyl]-carbamic acid tert-butyl ester (70% yield). 1H NMR (400 MHz, DMSO): δ 7.28 (m, 8H, aromatic H), 7.15 (m, 2H, aromatic H), 6.68 (t, 1H, NH), 4.02 (t, 1H, CH), 2.93 (q, 2H, CH2), 2.45 (t, 2H, CH2), 2.38 (t, 2H, CH2), 2.11 (q, 2H, CH2), 1.36 (s, 9H, 3×CH3). MS (ES+): 355.2+(M+H)+
648.6 mg (4 mmol, 1.5 eq) of carbonyl diimidazole were dissolved in 6 mL of CH2Cl2 then 2.66 g of 2-amino-benzothiazole (2.66 mmol, 1 eq) were added to the solution. A white precipitate appeared. The suspension was stirred for 15 hours at room temperature. 1.13 g of [2-(3,3-diphenyl-propylamino)-ethyl]-carbamic acid tert-butyl ester (3.19 mmol, 1.2 eq) in CH2Cl2 were then added. The solution, which has become clear again, was stirred for 5 hours at room temperature. A sodium bicarbonate solution was added and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was subjected to chromatography over silica gel (Hept/EtOAc: 80/20 to 70/30) to obtain 929 mg of the desired urea (65% yield).
1H NMR (400 MHz, DMSO): δ 7.88 (m, 1H, aromatic H), 7.62 (m, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.28 (m, 4H, aromatic H), 7.22 (m, 1H, aromatic H), 7.18 (m, 3H, aromatic H), 6.81 (t, 1H, NH), 4.01 (m, 1H, CH), 3.35 (m, 2H, CH2), 3.28 (m, 2H, CH2), 3.02 (m, 2H, CH2), 2.32 (m, 2H, CH2), 1.30 (s, 9H, 3×CH3). MS (ES+): 355.2+, 531.3+ (M+H)+
Method A, route a, was used to prepare the above product of formula:
595 mg of the product of example 148 (1.12 mmol, 1 eq) were diluted in 12 mL of EtOH, then 3 mL of HCl conc. (20% vol) were added to the solution. The reaction mixture was heated to reflux and stirred for 1 h 30. The mixture was evaporated to dryness then the insoluble matter was triturated with diethyl ether, filtered and washed again several times with Et2O. A 1 N sodium hydroxide solution was added to the suspension in solution in DCM. The aqueous phase was extracted 3 times with DCM then the organic phases were washed with 1N NaOH solution, water, brine, then dried over MgSO4, filtered and concentrated to give 375 mg of the desired intermediate 1-(2-amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenyl-propyl)-urea (78% yield for 2 steps). There was no need to purify this primary amine intermediate for the next steps.
100 mg of 1-(2-amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenyl-propyl)-urea (0.232 mmol, 1 eq) and 63 mg of 4-formyl-piperidine-1-carboxylic acid benzyl ester (0.255 mmol, 1.1 eq) were diluted in 3 mL of dry DCM and a catalytic amount of AcOH, under argon. 73.4 mg of NaBH(OAc)3 (0.348 mmol, 1.5 eq) were then added to the solution. The reaction mixture was stirred for 16 h at RT before addition of a 1 N NaOH solution. The aqueous phase was extracted with EtOAc, and then the organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography over SiO2 (DCM/MeOH: 99/1 to 98/2). 84 mg of the desired compound were obtained (64% yield).
1H NMR (400 MHz, CD3COCD3): δ 7.82 (m, 1H, aromatic H), 7.60 (m, 1H, aromatic H), 7.38 (m, 8H, aromatic H), 7.30 (m, 6H, aromatic H), 7.18 (m, 3H, aromatic H), 5.10 (s, 2H, CH2), 4.18 (m, 2H, CH2), 4.07 (t, 1H, CH), 3.50 (m, 2H, CH2), 3.38 (m, 2H, CH2), 2.96 (m, 2H, CH2), 2.80 (m, 2H, CH2), 2.61 (m, 2H, CH2), 2.43 (m, 2H, CH2), 2.05 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.15 (m, 2H, CH2). MS (ES+): 486.2+, 662.2+ (M+H)+
Method A, route a, followed by HCl salification was used to prepare the above product of formula:
87.7 mg (0.161 mmol, 1 eq) of urea, 3-benzothiazol-2-yl-1-[2-(3-dimethylamino-2,2-dimethyl-propylamino)-ethyl]-1-(3,3-diphenyl-propyl), in a basic state were dissolved in a minimum amount of DCM (until complete dissolution). 322 μL (0.645 mmol, 4 eq) of 2 N HCl in diethyl ether were added. The mixture was stirred for 20 sec then concentrated to dryness. The residue was taken up in the minimum of dichloromethane, and then diethyl ether was added to precipitate the product. The insoluble matter was filtered then washed with diethyl ether (m=100 mg, 95% yield).
1H NMR (400 MHz, DMSO): δ 8.90 (brs, 1H, NH), 7.80 (d, 1H, aromatic H), 7.49 (m, 1H, aromatic H), 7.38 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 4.06 (t, 1H, CH), 3.72 (m, 2H, CH2), 3.38 (m, 2H, CH2), 3.30 (m, 2H, CH2), 3.12 (m, 4H, 2×CH2), 2.82 (s, 6H, N(CH3)2), 2.38 (m, 2H, CH2), 1.20 (s, 6H, 2×CH3).
MS (ES+): 368.2+, 544.2+ (M+H-3HCl)+
Method A, route a, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.51 (m, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 4.09 (q, 2H, CH2), 4.00 (t, 1H, CH), 3.30 (m, 6H, 3×CH2), 2.70 (m, 2H, CH2), 2.32 (m, 2H, CH2), 1.18 (t, 3H, CH3). MS (ES+): 341.1+, 517.0+ (M+H)+
Method A, route a, was used to prepare the above product of formula:
MS (ES+): 381.1+, 547.0+ (M+H)+
Method A, route a, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (m, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 4.70 (m, 1H, CH), 3.99 (t, 1H, CH), 3.38 (m, 2H, CH2), 3.30 (s, 6H, 2×OCH3), 3.25 (m, 2H, CH2), 2.72 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.30 (m, 2H, CH2). MS (ES+): 519.0+ (M+H)+
Method A, route a, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 8.10 (s, 1H, aromatic H), 7.82 (d, 1H, aromatic H), 7.78 (m, 1H, aromatic H), 7.51 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 6.72 (d, 1H, aromatic H), 3.99 (t, 1H, CH), 3.80 (s, 3H, OCH3), 3.75 (m, 2H, CH2), 3.39 (m, 2H, CH2), 3.25 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.30 (m, 2H, CH2). MS (ES+): 376.1+, 552.06+ (M+H)+
Method A, route b, was used to prepare the above product of formula:
595 mg of the product of Example 148 (1.12 mmol, 1 eq) were diluted in 12 mL of EtOH, then 3 mL, of HCl conc. (20% vol) were added to the solution. The reaction mixture was heated to reflux and stirred for 1 h 30. The mixture was evaporated to dryness then the insoluble matter was triturated with diethyl ether, filtered and washed again several times with Et2O. A 1 N sodium hydroxide solution was added to the suspension in solution in DCM. The aqueous phase was extracted 3 times with DCM then the organic phases were washed with 1 N NaOH solution, with water, brine, then dried over MgSO4, filtered and concentrated to give 375 mg of the desired intermediate 1-(2-amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenylpropyl)-urea (78% yield for 2 steps). There was no need to purify this primary amine intermediate for the next steps.
100 mg of 1-(2-amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenyl-propyl)-urea (0.232 mmol, 1.5 eq) and 18 mg of tetrahydro-thiopyran-4-one (0.155 mmol, 1 eq) were diluted in 2 mL of dry DCM, under argon. 19.5 mg of NaBH3CN (0.310 mmol, 2 eq) were then added to the solution. The reaction mixture was stirred for 16 h at room temperature before addition of a 1 N NaOH solution. The aqueous phase was extracted with EtOAc, then the organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product was subjected to flash chromatography over SiO2 (DCM/MeOH: 99/1 to 95/5). 40 mg of the desired urea were obtained (49% yield).
1H NMR (400 MHz, DMSO): 6.7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 5.98 (m, 1H, NH), 3.99 (t, 1H, CH), 3.48 (m, 1H, CH), 3.30 (m, 5H, CH+2×CH2), 2.75 (m, 1H, CH), 2.65 (m, 2H, CH2), 2.52 (m, 2H, CH2), 2.31 (m, 2H, CH2), 2.18 (m, 2H, CH2), 1.50 (m, 2H, CH2). MS (ES+): 355.1+, 531.1+ (M+H)+
Method A, route b, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.82 (m, 2H, CH2), 3.38 (m, 3H, CH+CH2), 3.28 (m, 3H, CH+CH2), 2.80 (m, 2H, CH2), 2.70 (m, 1H, CH), 2.31 (m, 2H, CH2), 1.82 (m, 2H, CH2), 1.38 (m, 2H, CH2). MS (ES+): 339.1+, 515.1+ (M+H)+
Method A, route b, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 5.98 (m, 1H, NH), 3.99 (t, 1H, CH), 3.72 (m, 2H, CH2), 3.32 (m, 5H, CH+2×CH2), 2.80-2.65 (m, 3H, CH+CH2), 2.32 (m, 2H, CH2), 2.02 (m, 1H, CH), 1.71 (m, 1H, CH), 1.10 (m, 3H, CH3). MS (ES+): 339.1+, 515.1+ (M+H)+
Method A, route b, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.35 (m, 2H, CH2), 3.25 (m, 2H, CH2), 3.02 (s, 2H, CH2), 2.77 (m, 4H, 2×CH2), 2.70 (m, 1H, CH), 2.40 (m, 1H, CH), 2.32 (m, 2H, CH2), 2.15 (m, 2H, CH2), 1.85 (m, 2H, CH2), 1.68 (m, 1H, CH), 1.38 (s, 9H, 3×CH3). MS (ES+): 452.1+, 628.1+ (M+H)+
Method A, route b, was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.84 (m, 2H, CH2), 3.36 (m, 4H, 2×CH2), 3.25 (m, 2H, CH2), 2.77 (m, 2H, CH2), 2.60 (m, 1H, CH), 2.32 (m, 2H, CH2), 2.15 (m, 2H, CH2), 1.83 (m, 2H, CH2), 1.35 (s, 9H, 3×CH3). MS (ES+): 614.2+ (M+H)+
Method B
100 mg of the product of Example 159 (0.163 mmol, 1 eq) were diluted in 4 mL of EtOH, then 1 mL of HCl conc. (20% vol) was added to the solution. The reaction mixture was heated to reflux and stirred for 1 h. The mixture was evaporated to dryness then the insoluble matter was diluted in a 1 N sodium hydroxide solution and extracted with EtOAc. The organic phases were washed with 1 N NaOH solution, with water, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography over silica gel (DCM/MeOH/NH4OH: 90/10/0.1 to 90/10/0.4) allowed to give 54 mg of the desired free piperidine (65% yield).
1H NMR (400 MHz, DMSO): δ 7.80 (d, 1H, aromatic H), 7.50 (d, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.35 (m, 2H, CH2), 3.25 (m, 2H, CH2), 2.93 (m, 2H, CH2), 2.78 (m, 2H, CH2), 2.43 (m, 3H, CH+CH2), 2.30 (m, 2H, CH2), 1.85 (m, 2H, CH2), 1.22 (m, 2H, CH2). MS (ES+): 338.1+, 514.1+ (M+H)+
Method C: Saponification
54 mg of the product of Example 151 (0.104 mmol, 1 eq) were diluted in 3 mL of MeOH, then 209 μL of 1 N NaOH solution (0.209 mmol, 2 eq) were added to the solution. The reaction mixture was heated to reflux and stirred for 16 h. The mixture was evaporated then 2 N HCl solution was added until the pH was 5-6, then extracted with EtOAc and with DCM. The organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography over silica gel (DCM/MeOH/NH4OH: 90/10/0.2 to 90/10/0.4) followed by trituration with diethyl ether allowed to obtain 17 mg of the desired amino-acid (51% yield).
1H NMR (400 MHz, DMSO): δ 7.80 (d, 1H, aromatic H), 7.49 (d, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.52 (m, 2H, CH2), 3.25 (m, 4H, 2×CH2), 2.95 (m, 2H, CH2), 2.32 (m, 2H, CH2). MS (ES+): 313.0+, 489.0+ (M+H)+
Method C of Example 161 was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.49 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.39 (m, 2H, CH2), 3.26 (m, 2H, CH2), 3.20 (s, 2H, CH2), 3.12 (m, 2H, CH2), 2.78 (m, 2H, CH2), 2.62 (m, 3H, CH+CH2), 2.32 (m, 2H, CH2), 1.93 (m, 2H, CH2), 1.55 (m, 2H, CH2). MS (ES+): 396.2+, 572.1+ (M+H)+
Method D
25 g (0.118 mol, 1 eq) of 3,3-diphenyl-propylamine and 20.7 mL (0.147 mol, 1.25 eq) of triethylamine were diluted in 250 mL of THF at 0° C., under argon. 9.85 mL (0.124 mol, 1.05 eq) of chloroacetyl chloride were added dropwise. White fumes formed then gradually dissipated. The mixture was stirred for 2 h at 0° C., the solution became red and a white precipitate formed. The precipitate was filtered then washed several times with EtOAc. The organic phase was extracted with dilute HCl solution, with water then with brine, dried over MgSO4, filtered and concentrated. The product was obtained as a yellow solid (m=32 g, yield=91%).
1H NMR (400 MHz, CDCl3): δ 2.24 (q, 2H, CH2), 3.21 (q, 2H, CH2), 3.82-3.92 (m, 3H, CH+CH2), 6.37-6.50 (m, 1H, NH), 7.06-7.25 (m, 10H, aromatic H). MS (ES+): 288.09+ (M+H)+, 329.11+(M+H+CH3CN)+
To a solution of 2-chloro-N-(3,3-diphenyl-propyl)-acetamide (1 eq) in THF in a microwave sealed tube was added 2 eq of cyclohexyl-methyl-amine, 1 eq of NaI and 2 eq of K2CO3. The mixture was irradiated with microwaves for 20 minutes at 110° C. The mixture was then filtered, washed with EtOAc, concentrated and purified by flash chromatography over silica gel to obtain the corresponding 2-(cyclohexyl-methyl-amino)-N-(3,3-diphenylpropyl)-acetamide.
The crude product was dissolved in 10 mL of THF then at 0° C., 2.5 eq of LiAlH4 1M in THF were added dropwise. The reaction mixture was stirred at room temperature for 20 h under argon. The mixture was then hydrolysed slowly at 0° C. with a small amount of water, then Na2SO4 was added to dry the solution. After filtration, washing with EtOAc, then evaporation of the organic phase, the obtained crude product was used directly for the next step without any purification.
1.5 eq of carbonyl diimidazole were dissolved in a minimum amount (c=0.5-1 M) of CH2Cl2 then 1 eq of 2-aminobenzothiazole were added to the solution. A white precipitate appeared. The suspension was stirred for 15 hours at room temperature. 1.2 eq of N-cyclohexyl-N′-(3,3-diphenyl-propyl)-N-methyl-ethane-1,2-diamine in CH2Cl2 were then added. The solution, which has become clear again, was stirred for 3 hours at room temperature. A sodium bicarbonate solution was added and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was subjected to chromatography over silica gel (EtOAc/MeOH: 95/5) to obtain the desired urea.
1H NMR (400 MHz, DMSO): δ 7.82 (d, 1H, aromatic H), 7.52 (d, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.30 (m, 5H, aromatic H), 7.16 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.39 (m, 2H, CH2), 3.24 (m, 2H, CH2), 2.62 (m, 2H, CH2), 2.32 (m, 5H, NCH3+CH2), 1.78 (m, 2H, CH2), 1.69 (m, 2H, CH2), 1.52 (m, 2H, CH2), 1.15 (m, 4H, 2×CH2), 1.02 (m, 1H, CH). MS (ES+): 351.2+, 527.15+ (M+H)+
Method D of Example 162 was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.88 (d, 2H, aromatic H), 7.38 (m, 6H, aromatic H), 7.30 (m, 6H, aromatic H), 7.18 (m, 2H, aromatic H), 3.99 (t, 1H, CH), 3.38 (m, 2H, CH2), 3.22 (m, 2H, CH2), 2.65 (m, 2H, CH2), 2.32 (m, 5H, NCH3+CH2), 1.90 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.52 (m, 2H, CH2), 1.20 (m, 4H, 2×CH2), 1.02 (m, 1H, CH). MS (ES+): 351.2+, 553.2+ (M+H)+
Method E: Amide Formation
100 mg of 1-(2-amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenyl-propyl)-urea (0.232 mmol, 1 eq) and 58.5 mg of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.255 mmol, 1.1 eq) were dissolved in 5 mL of dry DCM. 34.5 mg of HOBt (0.255 mmol, 1.1 eq) and 49 mg of EDC.HCl (0.255 mmol, 1.1 eq) were added to the solution. The reaction mixture was stirred for 16 h at room temperature, under argon, before addition of water. The aqueous phase was extracted several times with DCM, the organics were washed with brine, dried over MgSO4, filtered then concentrated. The crude product was purified with flash chromatography over silica gel (DCM/MeOH) to give 121 mg of the desired amide (81% yield).
1H NMR (400 MHz, DMSO): δ 7.85 (m, 2H, NH+aromatic H), 7.53 (m, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.82 (m, 2H, CH2), 3.39 (m, 2H, CH2), 3.24 (m, 2H, CH2), 3.18 (m, 2H, CH2), 2.60 (m, 2H, CH2), 2.30 (m, 2H, CH2), 2.12 (m, 1H, CH), 1.48 (m, 2H, CH2), 1.37 (s, 9H, 3×CH3), 1.23 (m, 2H, CH2). MS (ES+): 466.2+, 642.2+ (M+H)+
Method B of Example 160 was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.89 (m, 1H, NH), 7.78 (d, 1H, aromatic H), 7.49 (d, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (t, 1H, CH), 3.39 (m, 2H, CH2), 3.26 (m, 2H, CH2), 3.18 (m, 2H, CH2), 3.12 (m, 2H, CH2), 2.42 (m, 2H, CH2), 2.30 (m, 2H, CH2), 2.09 (m, 1H, CH), 1.49 (m, 2H, CH2), 1.38 (m, 2H, CH2). MS (ES+): 366.2+, 542.2+ (M+H)+
Method F: Sulfonamide Formation
1 eq of 1-(2-Amino-ethyl)-3-benzothiazol-2-yl-1-(3,3-diphenyl-propyl)-urea was diluted in 10 mL of dry DCM. 1.5 eq of triethylamine followed by 1.2 eq of sulfonylchloride derivative were then added to the solution. The reaction mixture was stirred for 5 h at room temperature, under argon, before addition of water. The aqueous phase was extracted several times with DCM, the organics were washed with brine, dried over MgSO4, filtered then concentrated. The crude product was purified by flash chromatography over silica gel to give the desired sulfonamide derivative.
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.89 (m, 1H, aromatic H), 7.62 (m, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 2H, aromatic H), 7.08 (m, 1H, aromatic H), 4.01 (m, 1H, CH), 3.40 (m, 4H, 2×CH2), 3.09 (m, 2H, CH2), 2.86 (s, 3H, CH3), 2.35 (m, 2H, CH2).
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.89 (m, 1H, aromatic H), 7.63 (m, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.30 (m, 4H, aromatic H), 7.18 (m, 2H, aromatic H), 7.08 (m, 1H, aromatic H), 4.01 (m, 1H, CH), 3.40 (m, 4H, 2×CH2), 3.05 (m, 2H, CH2), 2.92 (m, 2H, CH2), 2.35 (m, 2H, CH2), 1.62 (m, 2H, CH2), 0.92 (t, 3H, CH3). MS (ES+): 361.1+, 537.1+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 8.00 (d, 2H, aromatic H), 7.89 (d, 2H, aromatic H), 7.79 (m, 1H, aromatic H), 7.49 (m, 1H, aromatic H), 7.30 (m, 9H, aromatic H), 7.18 (m, 3H, aromatic H), 3.98 (m, 1H, CH), 3.36 (m, 2H, CH2), 3.21 (m, 2H, CH2), 2.91 (m, 2H, CH2), 2.26 (m, 2H, CH2). MS (ES+): 420.1+, 596.0+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.88 (m, 1H, aromatic H), 7.74 (d, 2H, aromatic H), 7.68 (d, 2H, aromatic H), 7.55 (m, 1H, aromatic H), 7.30 (m, 9H, aromatic H), 7.18 (m, 3H, aromatic H), 3.98 (m, 1H, CH), 3.28 (m, 4H, 2×CH2), 2.82 (m, 2H, CH2), 2.28 (m, 2H, CH2), 2.08 (s, 3H, CH3). MS (ES+): 452.1+, 628.1+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 8.30 (d, 1H, aromatic H), 8.05 (m, 3H, aromatic H), 7.85 (m, 1H, aromatic H), 7.63 (m, 1H, aromatic H), 7.30 (m, 1H, aromatic H), 7.20 (m, 8H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (m, 1H, CH), 3.89 (m, 3H, CH3), 3.62 (m, 2H, CH2), 3.31 (m, 2H, CH2), 3.25 (m, 2H, CH2), 2.26 (m, 2H, CH2). MS (ES+): 453.1+, 629.1+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.78 (m, 1H, aromatic H), 7.69 (d, 2H, aromatic H), 7.51 (m, 2H, aromatic H), 7.30 (m, 8H, aromatic H), 7.18 (m, 2H, aromatic H), 7.05 (d, 2H, aromatic H), 3.98 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.31 (m, 2H, CH2), 3.23 (m, 2H, CH2), 2.81 (m, 2H, CH2), 2.28 (m, 2H, CH2). MS (ES+): 425.1+, 601.1+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.95 (m, 5H, aromatic H), 7.62 (d, 1H, aromatic H), 7.30 (m, 9H, aromatic H), 7.18 (m, 3H, aromatic H), 3.98 (m, 1H, CH), 3.42 (m, 2H, CH2), 3.25 (m, 2H, CH2), 2.90 (m, 2H, CH2), 2.28 (m, 2H, CH2). MS (ES+): 463.1+, 639.05+ (M+H)+
Method F was used to prepare the above product of formula:
1H NMR (400 MHz, DMSO): δ 7.89 (m, 1H, aromatic H), 7.62 (m, 1H, aromatic H), 7.35 (m, 4H, aromatic H), 7.29 (m, 4H, aromatic H), 7.18 (m, 4H, aromatic H), 3.98 (m, 1H, CH), 3.31 (m, 4H, 2×CH2), 3.02 (m, 2H, CH2), 2.60 (m, 6H, N(CH3)2), 2.32 (m, 2H, CH2). MS (ES+): 362.1+, 538.1+ (M+H)+
Method G
10 g of 3,3-diphenylpropylamine (47.4 mmol, 1 eq) were diluted in 200 mL of CH3CN at room temperature, under argon. 9.8 g of K2CO3 (71.08 mmol, 1.5 eq) then 7.9 g of acetic acid 2-bromo-ethyl ester (47.4 mmol, 1 eq) were added slowly. The mixture was heated to reflux and stirred for 4 h. The insoluble was filtered and washed several times with EtOAc. The filtrate was then concentrated and purified by flash chromatography over silica gel (DCM/MeOH: 95/5) to give 6 g of the desired secondary amine, acetic acid 2-(3,3-diphenyl-propylamino)-ethyl ester, which was submitted to the next step.
6 g of acetic acid 2-(3,3-diphenyl-propylamino)-ethyl ester were (20 mmol, 1 eq) solubilized in 100 mL of EtOH, then 20 mL of 2 N NaOH solution (40.4 mmol, 2 eq) were added to the solution. The mixture was stirred for 2 h at room temperature before adding 1 N HCl solution until pH=7, and evaporating EtOH. The aqueous phase was extracted with EtOAc, then the organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated. The crude product, 2-(3,3-diphenyl-propylamino)-ethanol, was submitted to the next step without any purification.
396 mg of carbonyl diimidazole (2.44 mmol, 1.5 eq) were dissolved in 4 mL of DCM then 245 mg (1.63 mmol, 1 eq) of 2-aminobenzothiazole were added to the solution. A white precipitate appeared. The suspension was stirred for 15 hours at room temperature. 500 mg (1.96 mmol, 1.2 eq) of 2-(3,3-diphenyl-propylamino)-ethanol in DCM were then added. The solution, which has become clear again, was stirred for 5 hours at room temperature. A sodium bicarbonate solution was added and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was subjected to chromatography over silica gel (EtOAc/MeOH: 95/5) to obtain 500 mg of the desired urea (71% yield).
1H NMR (400 MHz, DMSO): δ 7.82 (m, 1H, aromatic H), 7.55 (m, 1H, aromatic H), 7.35 (m, 5H, aromatic H), 7.29 (m, 4H, aromatic H), 7.18 (m, 3H, aromatic H), 3.99 (m, 1H, CH), 3.52 (m, 2H, CH2), 3.41 (m, 2H, CH2), 3.30 (m, 2H, CH2), 2.32 (m, 2H, CH2). MS (ES+): 256.1+, 432.1+ (M+H)+.
To a mixture of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide 2 (0.103 g, 0.34 mmol), DMAP (0.056 g, 0.46 mmol), and CDI (0.085 g, 0.52 mmol) was added DMF (0.5 mL). The reaction mixture was heated to 40° C. for 20 h and 3,3-diphenylpropan-1-amine 1 (0.072 g, 0.34 mmol) was added. The reaction mixture was heated to 40° C. for 2 d. Direct purification by flash column chromatography on silica gel (eluted with 30% to 70% EtOAc in hexanes) gave 1-(5-chloro-4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)-3-(3,3-diphenylpropyl)urea 3 (0.047 g, 25% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.23 (q, J=6.8 Hz, 2H), 3.04 (q, J=6.6 Hz, 2H), 3.04 (s, 3H), 3.99 (t, J=7.6 Hz, 1H), 6.58 (s br, 1H), 7.17 (t, J=5.5 Hz, 2H), 7.27-7.34 (m, 10H), 7.84 (d, J=8.8 Hz, 2H), 9.95 (s br, 1H), 10.81 (s br, 1H). Mass spectrum: calculated for C26H25ClN4O3S2 540.1. found 541.2 (M++1)
The activities of the compounds of the present invention on calcium receptors were measured in accordance with the method described hereinbelow.
Human Ca2+ receptor cDNA was subcloned into the mammalian expression vector PECE as described in Ellis, L et al. (1986) Cell vol. 45, 721-732. The luciferase reporter was subcloned into the mammalian expression vector pGL3basic (Promega). Resistance to neomycin (pSV2-neo) and resistance to puromycin (pSG5-puro) were used as selection markers. All these plasmids were simultaneously transfected into CHO cells by calcium phosphate precipitation. Transfected cells were grown in F12 medium containing 7.5% foetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin (as 1% Pen-Strep, BioWithaker), neomycin (750 μg/ml) and puromycin (5 μg/ml). Neomycin and puromycin resistant colonies were subcloned and assayed for activation against a range of calcium concentration. Clone 8-5-5 was used to assess the effects of compounds on [Ca2+]i. This stably transfected cell line was termed ET8-5-5.
For measurements of [Ca2+]i, the cells were recovered from tissue culture flasks by brief treatment with Trypsin-EDTA (Invitrogen; containing 0.53 mM EDTA.4Na in HBSS) and then seeded in culture-treated 96-well plates (Greiner) at 50 k cells per well in the growth media (same as above, except neomycin 400 μg/ml). Cells were grown in 37° C. TC incubator for 24 h. The culture medium was then removed and replaced with F12 medium, 1% Pen-Strep for an overnight foetal bovine serum starvation in 37° C. TC incubator. Then the starvation medium was removed and replaced with a test buffer (20 mM HEPES pH 7.4, 125 mM NaCl, 5 mM KCl, 1 mM MgCl2, 5.5 mM Glucose, 2 g/l lysosyme and 0.3 mM CaCl2) supplemented with a range of test compound concentrations crossed against a super-added range of CaCl2 concentrations. The cells were incubated with the test compounds for 5 h in 37° C. TC incubator. Then the test buffer was discarded, and cells were added with the substrate for Luciferase from SteadyLite Kit (Perkin-Elmer). The luminescence was recorded.
The compounds of Examples 1 to 176 were tested according to this procedure described above and all were found to have an EC50 of 10 μM or less. Examples of those activities were shown in Table 1.
The activities of the compounds of the present invention on calcium receptors were measured. In one embodiment, the measurement was performed in accordance with the method described in Example 4 of Nemeth et al., PCT/US95/13704 (International Publication No. WO96/12697) herein incorporated by reference.
A 4.0-kb NotI-HindIII fragment of the human parathyroid cell Ca2+ receptor (hPCaR) cDNA was subcloned into the mammalian expression vector pCEP4 (Invitrogen) containing the hygromycin-resistant gene as a selectable marker. This plasmid was transfected into HEK 293 cells by calcium phosphate precipitation. Transfected cells were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and hygromycin (200 μg/mL). Hygromycin-resistant colonies were subcloned and assayed for hPCaR mRNA by solution hybridization using a 32P-labeled RNA probe complementary to the (4.0 kb) hPCaR sequence (Garrett, et al., J. Biol. Chem. 270, 12919-12925 (1995)). Clone 7 was used to assess the effects of compounds on [Ca2+]i. This stably transfected cell line was termed HEK 293 4.0-7. For measurements of [Ca2+]i, the cells were recovered from tissue culture flasks by brief treatment with Versene (Invitrogen; Containing 0.2 g/L EDTA.4Na in phosphate-buffered saline) and then seeded in collagen coated 384-well plates (BD Biosciences) at 20K cells per well in the growth media (same as above). Cells were grown in 37c TC incubator overnight. Then, the media was discarded and cells were loaded with 1× dye from Ca2+ Assay Kit I (BD Biosciences) in parathyroid cell buffer (126 mM NaCl, 4 mM KCl, 1 mM MgSO4, 0.7 mM K2HPO4/KH2PO4, 20 mM HEPES.NaOH (pH 7.45)) containing 0.5% BSA and 1 mM CaCl2. Cells were loaded at room temperature for 90 minutes. Each test compound was added to the cells and the fluorescence was recorded by using excitation and emission wavelengths of 485 and 530 nm, respectively.
The compounds of Examples 67 to 175 were tested according to this procedure described and were shown in Table 2
Male Sprague-Dawley rats weighing 250-400 g were given free access to food and water. Unanesthetized rats were gavaged with an 18-gauge balled needle at a volume between 0.5 and 1 ml. Compounds were formulated in 20% captisol in water at pH 7.0 or 2% hydroxypropyl methylcellulose (HPMC)/1% Tween 80/5% Captisol in water pH 2.0. Calcimimetics were administered at various doses covering the following range 0.03-30 mg/kg in 20% captisol. Vehicle-treated rats received one of the above two vehicles at the maximum volume (0.5-1 ml) used for the calcimimetics. Each rat was bled at time 0 (pre-calcimimetic or vehicle administration) and at various times (1, 2, 4, 8 and 24 h) after oral gavage of calcimimetic or vehicle.
For measurements of blood-ionized Ca2+ levels, blood (50 μl) was collected from the orbital sinus of anesthetized rats (3% isoflurane in O2) with heparinized capillary tubes. Blood samples were analyzed within seconds of collection using a Rapidlab 348 Blood Gas Analyzer (Bayer HealthCare LLC Diagnostic Division; Tarrytown, N.Y.).
For measurements of serum PTH, phosphorus, a nonheparinized capillary tube was inserted into the orbital sinus and blood (0.5 ml) was collected into SST (clot activator) brand blood tubes. Blood samples were allowed to clot for 15-30 min and centrifuged (3000 rpm; Sorvall RT 600B) at 4° C. Serum was removed and stored below 0° C. until assayed. Serum PTH levels were quantified according to the vendor's instructions using rat PTH immunoradiometric assay kits (Immutopics, San Clemente, Calif.) or rat bioactive intact PTH elisa kit (Immutopics, San Clemente, Calif.). Serum phosphorus levels were determined using a blood chemistry analyzer (AU 400; Olympus, Melville, N.Y.).
All publications, patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0613674.1 | Jul 2006 | GB | national |
