WO2008029217A2 - Dipeptidyl peptidase iv inhibitors - Google Patents

Dipeptidyl peptidase iv inhibitors Download PDF

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Publication number
WO2008029217A2
WO2008029217A2 PCT/IB2007/002403 IB2007002403W WO2008029217A2 WO 2008029217 A2 WO2008029217 A2 WO 2008029217A2 IB 2007002403 W IB2007002403 W IB 2007002403W WO 2008029217 A2 WO2008029217 A2 WO 2008029217A2
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Prior art keywords
amino
phenyl
trifluoroacetic acid
acid salt
oxy
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PCT/IB2007/002403
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French (fr)
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WO2008029217A3 (en
Inventor
Surendrakumar Satyanarayan Pandey
Uma Ramachandran
Gajendra Singh
Chithra Santhanagopalan
Venkatachalapathi Sanjay Kadnur
Sivanesan Dharmalingam
Naresh Chidurula
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Orchid Research Laboratories Limited
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Publication of WO2008029217A2 publication Critical patent/WO2008029217A2/en
Publication of WO2008029217A3 publication Critical patent/WO2008029217A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • the present invention more particularly provides novel compounds of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
  • the compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
  • the compounds of the present invention are useful for the treatment of disorders associated with insulin resistance such as polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
  • the present invention relates to a method for delaying the onset of type II diabetes and alleviating the physiological consequences of type II diabetes.
  • Diabetes is a disease in which the body does not produce or properly use insulin. Around 150 million people have diabetes mellitus worldwide and this number will be double by the year 2025. Much of this increase will occur in developing countries and will be due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years. Diabetes is the leading cause of blindness, lower limb amputations, and renal failure in the United States. The healthcare cost of diabetes is high, with the total estimated cost in the United States exceeding $100 billion. Estimated number of diabetes cases in India in 2002 was 31.7 million. A report by American Diabetes Association, April 2004 stated that by 2030, 79.4 million people are going to be affected by diabetes. As of today, approximately 5% of world population is suffering from type II diabetes.
  • the other targets are the same targets.
  • PDPlB Protein Tyrosine Phosphatase IB
  • Glycogen Synthase Kinase-3 Glycogen Synthase Kinase-3 (GSK-3) Adiponectin
  • GLP-I Insulin Receptor Mimetic Glucagon-like Peptide 1
  • DPPIV Dipeptidylpeptidase IV Inhibitors
  • DPP-IV was discovered in the 1960's as an aminopeptidase. It was identified as characteristic antigen marker CD26 of T cell activation and it was demonstrated that the protein is a component of the T cell receptor complex. Different binding partners were found within this context, for example adenosine deaminase (ADA), tyrosine phosphatase CD45. These compounds act, at least in part, by blocking the inactivation of endogenous incretins such as GLP-I and GIP, resulting in an increased sensitivity to insulin and reduced post-prandial hyperglycaemia. To date, however, these compounds have only been examined as a method for controlling the management of blood glucose levels on an acute basis. The implications of long-term treatment with these compounds have not been considered.
  • the present invention relates to a series of novel compounds that are inhibitors of the enzyme dipeptidyl peptidase IV, to pharmaceutical compositions comprising these inhibitors and their use in the treatment of human diseases.
  • WO 96/38415 discloses, novel 2-amino-3-phenylpropionic acid derivatives represented by general formula (I) or salts,
  • A represents a nitrogenous heterocycle
  • W represents oxygen or carbonyl
  • Rl represents hydroxy, an ester residue or a substituted imide group
  • R2 and R3 represents each hydrogen, alkyl, aralkyl, alkanoyl, benzoyl etc.
  • R4 is hydrogen permuted by benzene ring, a nitro group, an alkoxy group, a halogen atom, or a hydroxyl group.
  • X is , Y is selected from the group consisting of C 1 -S alkylene,
  • Co-8 alkylene ⁇ NR 3 -CO-Co -8 alkylene, C 0- S alkylene-O-Co-s alkylene, Co -8 alkylene- NR 3 ⁇ Co- 8 alkylene and A is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, C 1-4 alkoxy C 0-6 alkylene, C 1-4 alkoxycarbonyl C 0-6 alkyl, Ci -6 alkylamino C 0-8 alkyl, Ci -6 dialkylamino C 0-8 alkyl, amino C 0-8 alkyl and arylCo -8 alkyl;
  • R 5 is selected from the group consisting of hydrogen, Cj -4 alkoxy Co -6 alkylene, Ci -4 alkoxycarbonyl C 0-6 alkylene;
  • R 6 and R 7 are each independently selected from the group consisting of: hydrogen, C 0-6 alkylamino Co-6 alkyl, Co -6 dialkylamino C 0-6 alkyl.
  • R 1 is a hydrogen atom or an amino-protecting group
  • R 2 is a hydrogen atom or an aryl, aralkyl or alkyl group
  • R is (1) a halogen atom, (2) an aroylamino group, (3) a phenyl group substituted with lower alkyl, phenyl, phenoxy, pyridyl, pyrimidinyl or quinolyl.
  • a naphthyl or tetrahydronaphthyl group optionally substituted with hydroxy, lower alkoxy or (5) an unsaturated mono-cyclic heterocyclic group containing N, O and/or S substituted with lower alkyl, phenyl, naphthyl or tetrahydroquinolyl, in which each substituent on the mono-cyclic heterocyclic group may be further substituted with halogen atom, hydroxy or phenyl, X is a halogen atom, an alkyl group or an alkoxygroup, Y is O or NH, I is 0 or 1, m is 0, 1 or 2 and n is an integer of 0-5.
  • WO 99/29640 comprises the aromatic acids have formula (II),
  • Ar 2 is monocyclic or polycyclic heteroaryl group, which is unsubstituted or substituted with one or more substituents.
  • X 2 is selected from alkylene, sulfonyl, sulfinyl, thio, amino oxy.
  • Ar 3 is 1,4 arylene or heteroarylene and is unsubstituted or substituted with one or more substituents.
  • X 3 is selected from alkylene, alkenylene, carbonylalkynylene and -CH 2 CH(NHR 6 )-, where R 6 is hydrogen, q is 0 or 1 and Y 2 is a carboxylic, sulfonic, boronic or phosphonic acid group.
  • the main objective of the present invention is therefore, to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts that are also useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease.
  • Another objective of the present invention is to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts having enhanced activities, without toxic effects or with reduced toxic effects.
  • Yet another objective of the present invention is to provide a process for the preparation of novel heterocyclic derivatives of the formula (I) and their pharmaceutically acceptable salts.
  • the present invention relates to novel compounds of the general formula (I),
  • R represents hydrogen, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C 4 )alkyl, alkoxy, aryl, aralkyl, heterocyclyl groups, which may be may be mono or fused systems, -NR 10 R 11
  • X represents nitrogen or CH
  • Y represents sulphur, CH 2 , CH-R',
  • R3, R 4 , R 5 , R 6 , R 7 and R 8 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy groups; Rio and Rn may be same or different and
  • the present invention relates to novel compounds of the general formula (I),
  • R represents hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C 4 )alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, phenylethyl, phenylpropyl and the like; heterocyclyl groups which may be mono or fused systems such as morpholine, piperazine, piperidine, pyrrolidine, thiazolidine
  • R' represents hydrogen, hydroxy and halogen;
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R9, R 10 and R 11 are optionally substituted with one or more substituents selected from nitro, hydroxy, cyano, formyl, azido, alkyl, alkoxy, acyl, halogens, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulf ⁇ nyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, aryl and carboxylic acid or its derivatives.
  • analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms.
  • a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium.
  • the enol-keto tautomerism is an example.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
  • salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, trifluoroacetates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Pharmaceutically acceptable salts forming part of this invention include base addition salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts.
  • base addition salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts.
  • Salts may include acid addition salts which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, trifluoroacetates, p-toluenesulphonates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • the reaction is carried out at a temperature in the range of room temperature to reflux temperature, mostly 0 0 C to 100 0 C.
  • the single S isomer of the compound of formula (2a) is prepared by condensation of the compound of formula (Ia) (wherein Ri is OH) with halo nitrobenzene followed by alkylation using conventional methods.
  • Hydrogenation of the compound of the formula (3a), (wherein R 3 is NO 2 ) is carried out using a catalyst such as Raney nickel, Pd/C in the presence of solvents such as methanol, ethanol, ethylacetate, n-butylacetate or a mixture thereof.
  • the reaction may be carried out at temperature in the range of 0 0 C to 100 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (4a).
  • the compound of formula (4a) is reacted with a compound of formula (5a) in the presence of solvents such as toluene, methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof or even without solvent.
  • solvents such as toluene, methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof or even without solvent.
  • the reaction may be carried out at temperature in the range of 50 °C to 150 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (6a).
  • the compound of formula (6a) is hydrolyzed by means of base such as alkali hydroxide, alkaline earth metal hydroxide, or by using alkali carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and the like, in the presence of solvents such as water, methanol, ethanol, ethylacetate, n- butylacetate, tetrahydrofuran, 1,4-dioxane or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 0 0 C to 100 0 C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (7a).
  • Coupling of the compound of formula (7a) with compound of formula (8a) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to about 48 hours at an ambient temperature to provide the compound of formula (9a).
  • the compound of formula (9a) is treated with a dehydrating agent such as
  • deprotection of compound of formula (6a) may be carried out using Pd/C, HCl or trifluoroacetic acid in the presence of solvents such as acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof at 0 0 C to 30 0 C.
  • solvents such as acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof at 0 0 C to 30 0 C.
  • the deprotection may also be carried out by passing HCl gas in the presence of solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof give the compound of formula (1 Ia).
  • solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof give the compound of formula (1 Ia).
  • solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl
  • coupling of the compound of formula (7a) with compound of formula (13a) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, or BOP reagent and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to 48 hours at an ambient temperature to provide the compound of formula (14a).
  • any reactive group in the substrate molecule may be protected according to the conventional chemical practice.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • the protecting groups P used particularly in the present invention are conventional protecting groups such as t-butoxy carbonyl (t-Boc), trityl, trifluoroacetyl, benzyloxy, benzyloxy carbonyl (Cbz) and the like and deprotection can be done by conventional methods.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • Organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, jP-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, jP-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicy
  • compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like.
  • Prodrugs of the compounds of formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
  • solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of and/or prophylaxis of type II diabetes.
  • These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the compositions may be prepared by processes known in the art.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • compositions of the invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
  • polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the term "therapeutically effective amount” or “effective amount” refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other . therapies to a mammal in need of such treatment.
  • animal as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • treatment means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms.
  • Step VII Preparation of (2S)-l- ⁇ (2S)-2-[(*-butoxycarbonyl) amino]-3-[4-(4-(pyridin-2- ylamino) phenoxy) phenyl] propanoyl ⁇ pyrrolidine-2-carbonitrile
  • the DPP IV assay was done using human plasma as a source of DPP IV.
  • the compounds were incubated at a concentration of 1 and 10 ⁇ M in assay buffer containing DPP IV enzyme.
  • the compounds were incubated for 1 hour and then the substrate H-gly-pro AMC was added and further incubated for 20 minutes and then the reaction was stopped on addition of 25% glacial acetic acid.
  • the plates were read in a spectrofluorimeter to get RFU on setting excitation wavelength of 360nm and emission wavelength of 460 nm. Percentage inhibition is calculated as compared to vehicle control. Compounds showing greater than 50% inhibition at 1 ⁇ M were taken for Dose response studies for DPP IV inhibition to calculate IC50 value.
  • Table-I show significant DPP IV inhibition. Table-I

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Abstract

Abstract The present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, their hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel compounds of the general formula (I). The compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Description

DIPEPTIDYL PEPTD3ASE IV INHIBITORS
Field of the invention
The present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel compounds of the general formula (I).
Figure imgf000002_0001
The present invention also provides a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof.
The compounds of the present invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity.
Furthermore, the compounds of the present invention are useful for the treatment of disorders associated with insulin resistance such as polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
The present invention relates to a method for delaying the onset of type II diabetes and alleviating the physiological consequences of type II diabetes. Diabetes is a disease in which the body does not produce or properly use insulin. Around 150 million people have diabetes mellitus worldwide and this number will be double by the year 2025. Much of this increase will occur in developing countries and will be due to population growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years. Diabetes is the leading cause of blindness, lower limb amputations, and renal failure in the United States. The healthcare cost of diabetes is high, with the total estimated cost in the United States exceeding $100 billion. Estimated number of diabetes cases in India in 2002 was 31.7 million. A report by American Diabetes Association, April 2004 stated that by 2030, 79.4 million people are going to be affected by diabetes. As of today, approximately 5% of world population is suffering from type II diabetes.
Emerging therapeutic targets for diabetes
The worldwide epidemic of type II diabetes has been stimulating the search for new concepts and targets for the treatment of this incurable disease. Most current therapies were developed in the absence of defined molecular targets. Increasing knowledge on the biochemical and cellular alterations occurring in NIDDM has led to the development of novel and potentially more effective therapeutic approaches to treat the disease. The role of peroxisome proliferator activated receptor in the regulation of lipid metabolism, insulin and triglycerides led to the rational design of several PPAR agonists. However, many promising molecules, especially the dual acting PPAR γ/α, are yet to be approved due to safety issues.
The other targets are
Protein Tyrosine Phosphatase IB (PTPlB) Glycogen Synthase Kinase-3 (GSK-3) Adiponectin
Insulin Receptor Mimetic Glucagon-like Peptide 1 (GLP-I) Dipeptidylpeptidase IV Inhibitors (DPPIV)
Background of the Invention
A number of drugs are available for the treatment of type II diabetes, but new ones, particularly those acting by novel mechanisms, are still needed. DPP-IV was discovered in the 1960's as an aminopeptidase. It was identified as characteristic antigen marker CD26 of T cell activation and it was demonstrated that the protein is a component of the T cell receptor complex. Different binding partners were found within this context, for example adenosine deaminase (ADA), tyrosine phosphatase CD45. These compounds act, at least in part, by blocking the inactivation of endogenous incretins such as GLP-I and GIP, resulting in an increased sensitivity to insulin and reduced post-prandial hyperglycaemia. To date, however, these compounds have only been examined as a method for controlling the management of blood glucose levels on an acute basis. The implications of long-term treatment with these compounds have not been considered.
The present invention relates to a series of novel compounds that are inhibitors of the enzyme dipeptidyl peptidase IV, to pharmaceutical compositions comprising these inhibitors and their use in the treatment of human diseases.
Few prior art reference which disclose the closest compounds are given here:
(I). WO 96/38415 discloses, novel 2-amino-3-phenylpropionic acid derivatives represented by general formula (I) or salts,
Figure imgf000004_0001
C ) wherein, A represents a nitrogenous heterocycle; W represents oxygen or carbonyl; Rl represents hydroxy, an ester residue or a substituted imide group; and R2 and R3 represents each hydrogen, alkyl, aralkyl, alkanoyl, benzoyl etc. R4 is hydrogen permuted by benzene ring, a nitro group, an alkoxy group, a halogen atom, or a hydroxyl group.
(II). US 5,741,796 discloses compounds of the general structure (I),
Figure imgf000005_0001
(I)
wherein, X is
Figure imgf000005_0002
, Y is selected from the group consisting of C1-S alkylene,
Co-8 alkylene~NR3 -CO-Co-8 alkylene, C0-S alkylene-O-Co-s alkylene, Co-8alkylene- NR3~Co-8alkylene and A is selected from the group consisting of
-(CH2)m-- B is
Figure imgf000005_0003
. R1, R2, R3 and R4 are each independently selected from the group consisting of hydrogen, C1-4 alkoxy C0-6 alkylene, C1-4 alkoxycarbonyl C0-6 alkyl, Ci-6 alkylamino C0-8 alkyl, Ci-6 dialkylamino C0-8 alkyl, amino C0-8 alkyl and arylCo-8alkyl; R5 is selected from the group consisting of hydrogen, Cj-4 alkoxy Co-6 alkylene, Ci-4 alkoxycarbonyl C0-6 alkylene; R6 and R7 are each independently selected from the group consisting of: hydrogen, C0-6 alkylamino Co-6 alkyl, Co-6 dialkylamino C0-6 alkyl.
(III). US 2005/0119256 Al discloses the amino acid derivatives represented by the formula (I),
Figure imgf000005_0004
wherein, R1 is a hydrogen atom or an amino-protecting group; R2 is a hydrogen atom or an aryl, aralkyl or alkyl group, R is (1) a halogen atom, (2) an aroylamino group, (3) a phenyl group substituted with lower alkyl, phenyl, phenoxy, pyridyl, pyrimidinyl or quinolyl. (4) a naphthyl or tetrahydronaphthyl group optionally substituted with hydroxy, lower alkoxy or (5) an unsaturated mono-cyclic heterocyclic group containing N, O and/or S substituted with lower alkyl, phenyl, naphthyl or tetrahydroquinolyl, in which each substituent on the mono-cyclic heterocyclic group may be further substituted with halogen atom, hydroxy or phenyl, X is a halogen atom, an alkyl group or an alkoxygroup, Y is O or NH, I is 0 or 1, m is 0, 1 or 2 and n is an integer of 0-5.
(IV). WO 99/29640 comprises the aromatic acids have formula (II),
Ar^-ArMX^-Y2
(H) wherein, Ar2 is monocyclic or polycyclic heteroaryl group, which is unsubstituted or substituted with one or more substituents. X2 is selected from alkylene, sulfonyl, sulfinyl, thio, amino oxy. Ar3 is 1,4 arylene or heteroarylene and is unsubstituted or substituted with one or more substituents. X3 is selected from alkylene, alkenylene, carbonylalkynylene and -CH2CH(NHR6)-, where R6 is hydrogen, q is 0 or 1 and Y2 is a carboxylic, sulfonic, boronic or phosphonic acid group.
Objective of the invention
With an objective to develop novel compounds for lowering blood glucose, free fatty acids, cholesterol and triglyceride levels in the type II diabetes and to treat autoimmune diseases such as multiple sclerosis and rheumatoid arthritis we focused our research to develop new compounds effective in the treatment of the above mentioned diseases and efforts in this direction have led to compounds having the general formula (I). The main objective of the present invention is therefore, to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts that are also useful for the treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease. Another objective of the present invention is to provide novel heterocyclic derivatives and their pharmaceutically acceptable salts having enhanced activities, without toxic effects or with reduced toxic effects. Yet another objective of the present invention is to provide a process for the preparation of novel heterocyclic derivatives of the formula (I) and their pharmaceutically acceptable salts.
Summary of the invention
The present invention relates to novel compounds of the general formula (I),
Figure imgf000007_0001
their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, prodrugs and metabolites thereof; wherein R represents hydrogen, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C4)alkyl, alkoxy, aryl, aralkyl, heterocyclyl groups, which may be may be mono or fused systems, -NR10R11
Figure imgf000007_0002
and ; X represents nitrogen or CH; Y represents sulphur, CH2, CH-R',
<R1.
R , C=O; R' represents hydrogen, hydroxy, halogens; R" represents hydrogen, halogen, haloalkyl groups, cyano, -(C=O)NH2; R1 and R2 may be same or different and independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl, cycloalkyl, -CH2-(C=O)-R, COR9, where R9 represents substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aryloxy , alkoxy, aralkoxy, or a counter ion ; R3, R4, R5, R6, R7 and R8 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy groups; Rio and Rn may be same or different and independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, or may be combined together (cyclize) to form a five or six membered heterocyclic ring which may be further substituted with one or more subsituents like hydroxy, halogen, oxo, alkyl and haloalkyl groups. m and n are integers in the range of 0 to 2, with the proviso that when m is 0, then n is 1. p is an integer in the range of 0 to 1.
Detailed description of the invention
The present invention relates to novel compounds of the general formula (I),
Figure imgf000008_0001
their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, prodrugs and metabolites thereof; wherein R represents hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted groups selected from linear or branched (Ci-C4)alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, phenylethyl, phenylpropyl and the like; heterocyclyl groups which may be mono or fused systems such as morpholine, piperazine, piperidine, pyrrolidine, thiazolidine, pyrrolidyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, 5,6-dihydro [1,2,4] triazolo [4,3-α]
Figure imgf000009_0001
pyrazin-7 (8H)-yl), and the like; -NR10R11 , ; X represents nitrogen or CH;
<R1.
Y represents sulphur, CH2, CH-R', R , C=O; R' represents hydrogen, hydroxy and halogen; R" represents hydrogen, halogen, haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; cyano, -(C=O)NH2; R1 and R2 may be same or different and independently represents hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, -CH2-(C=O)-R, COR9; where R9 represents substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aryloxy, alkoxy, aralkoxy, or a counter ion ; R3, R4, R5, RO, R7 and R8 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl, alkoxy groups; R10 and R11 may be same or different and independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, or may be combined together (cyclize) to form a five or six membered heterocyclic ring such as pyridyl, pyrrolidiyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl, quinolinyl and the like which may be further substituted with one or more subsituents like hydroxy, halogen, oxo, alkyl and haloalkyl groups. m and n are integers in the range of 0 to 2, with the proviso that when m is 0, then n is 1. p is an integer in the range of 0 to 1.
The groups R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are optionally substituted with one or more substituents selected from nitro, hydroxy, cyano, formyl, azido, alkyl, alkoxy, acyl, halogens, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfϊnyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, aryl and carboxylic acid or its derivatives.
The term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
The term stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
The term tautomers include readily interconvertible isomeric forms of a compound in equilibrium. The enol-keto tautomerism is an example.
The term polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
The term pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound. The term derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like. Pharmaceutically acceptable salts of the present invention include alkali metal like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, trifluoroacetates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
A term once described, the same meaning applies for it, throughout the patent Particularly useful compounds according to the invention include:
I. (2S)-l-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt; 2. (2S)-l-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl}pyrrolidine-2-carbonitrile di p-toluenesuphonic acid salt;
3. (2S)-l-{(2S)-2-amino-3-[4-(4[5-(trifluoromethyl) pyridin-2-yl]amino) phenoxy)phenyl]propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
4. (2S)-l-{(2S)-2-amino-3- [4-(4-(3-nitropyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
5. 3-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} 1,3-thiazolidine di trifluoroacetic acid salt;
6. (2S)-l-{(2S)-2-amino-3- [4-(4-(3-cyanopyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt; 7. (4R)-3-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} -1,3-thiazolidine carbonitrile di trifluoroacetic acid salt;
8. (2S)-l-{(2S)-2-cyclohexylamino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
9. (2S)-l-[(2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl]pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
10. (2S)-l-[(2S)-2-amino-3- {4-[(3-nitropyridin-2-yl) oxy] phenyl} propanoyl] pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
II. 2-(4-{(2S)-2-amino-3-[(2S)-2-cyanopyrrolidin-l-yl]-3-oxopropyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt; 12. (2S)-l-{(2S)-2-amino-3-[4-(pyridin-2-ylmethoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
13. (4R)-3-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl] -l,3-thiazolidine-4-carbonitrile di trifluoroacetic acid salt;
14. (4R)-3-[(2S)-2-amino-3- {4-[(3-nitropyridin-2-yl) oxy] phenyl} propanoyl]-l,3- thiazolidine-4-carbonitrile di trifluoroacetic acid salt;
15. 2-(4-{(2S)-2-amino-3-[(4R)-4-cyano-l, 3-thiazolidin-3-yl]-3-oxopropyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt; 16. 2-(4-{(2S)-2-amino-3-[(2S)-2-cyanopyrrolidin-l-yl]-3-oxopropyl}phenoxy) -6-methylnicotinonitrile di trifluoroacetic acid salt;
17. 2-{4-[(2S)-2-amino-3-oxo-3- (l,3-thiazolidin-3-yl) propyl] phenoxy} nicotinonitrile di hydrochloride salt; 18. (2S)-l-[(2S)-2-amino-3- (4-{[5-(trifluoromethyl) ρyridin-2-yl] oxy} phenyl) propanoyl] pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
19. (2S)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl}-l-oxo-l-[(2S)-2- (trifluoromethyl)pyrrolidin-l-yl]propan-2-amine di trifluoroacetic acid salt;
20. (2S)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} -1-oxo-l -[(2S)-2- (trifluoromethyl)pyrrolidin-l-yl]propan-2-amine di trifluoroacetic acid salt;
21. 2-(4- { (2S)-2-amino-3 -[(3 S)-3 -fluoropyrrolidin- 1 -yl] -3 -oxopropyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt;
22. (2S)-l-[(3S)-3-fluoropyrrolidin-l-yl]-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl}-l- oxopropan-2-amine di hydrochloride salt; 23. (2S)-l-[(2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl] pyrrolidine-2-carboxamide di trifluoroacetic acid salt;
24. (2S)-I -[(3 S)-3-fluoropyrrolidin- 1 -yl]-l -oxo-3-[4-(pyridin-2-yl methoxy) phenyl] propan-2-amine di trifluoroacetic acid salt;
25. (2S)-l-((2S)-2-adamantylamino-3-{4-[(5-nitropyridin-2-yl)oxy] phenyl} propanoyl) pyrrolidine-2-carbonitrile;
26. (2S,4S)-l-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl)oxy]phenyl}propanoyl] -4-fluoropyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
27. 2-{4-[(2S)-2-amino-3-oxo-3- (3-oxopyrrolidin-l-yl) propyl] phenoxy} nicotinonitrile di hydrochloride salt; 28. 2-{4-[(2S)-2-amino-3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo [4,3- - α]pyrazin-7(8H)-yl)propyl]phenoxy}nicotinonitrile di trifluoroacetic acid salt;
29. 2-{4-[(2S)-2-amino-3-(3,3-difluoropyrrolidin-l-yl)-3-oxopropyl]phenoxy} nicotinonitrile di hydrochloride salt;
30. Methyl (2S) 2-{[2-((2S)-2-cyanopyrrolidin-l-yl)-2-oxoethyl] amino} 3{4[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoate;
31. (2S) l-({[(lS)-2-((3R) 3-hydroxy-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)-2-oxoethyl] amino} acetyl)-ρyrrolidine-2-carbonitrile; 32. (2S) l-({[(lS)-2-((3S) 3-fluoro-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)- 2-oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile;
33. (2S) l-({[(lS)-2-(3,3-difluoro-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)- 2-oxoethyl]amino}acetyl)-pyrrolidine-2-carbonitrile; 34. (2S) l-({[(lS)-2-((2S)-2-trifluoromethyl-pyrrolidine)-l-(-4-(3-nitropyridin -2-yloxy) benzyl)-2-oxoethyl] amino} acetyl)-pyrrolidine-2τcarbonitrile;
35. (2S)-2-amino-N, N-dimethyl-3- (4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanamide dihydrochloride salt;
36. (2S)-2-amino-N, N-dimethyl-3- {4-[4[5-(trifluoromethyl)pyridin-2-yl]amino) phenoxy]phenyl}propanamide dihydrochloride salt ;
37. (2S)- 2-amino-N, N-dimethyl-3- {4-[4-(3-nitropyridin-2-ylamino) phenoxy] phenyl}propanamide dihydrochloride salt;
38. (2S)-2-amino-N, N-dimethyl-3- (4-{4-[(3-cyanopyridin-2-yl) amino] phenoxy} phenyl)-propanamide di hydrochloride salt; 39. (2S)-2-amino-N, N-dimethyl-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di hydrochloride salt;
40. (2S)-2-amino-N-(4-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
41. (2S)-2-amino-N-(3-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
42. (2S)-2-amino-N-(2-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
43. (2S)-2-amino-N- (3,4-difluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; 44. (2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
45. (2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
46. (2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
47. (2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; 48. (2S)-2-amino-N- (3,4-difluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt;
49. (2S)-2-amino-N- (3,5-difluorophenyl)~3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt; 50. (2S)-2-amino-N- (2-chloro-3, 6-difluorobenzyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoro hydrochloride salt;
51. (2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt;
52. (2S)-2-amino-3- {4-[(3-nitropyridin-2-yl) oxy] phenyl} -N- [4-(trifluoromethyl) phenyl] propanamide di tifluoroacetic acid salt;
53. (2S)-2-amino-N- (4-cyanophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
54. (2S)-2-amino-N- (2-fluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; 55. (2S)-2-amino-N- (3-fluoro-4-methylphenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
56. (2S)-2-amino-N- (4-bromo-3-fluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt;
57. (2S)-2-amino-N- (2-chloro-3, 6-difluorobenzyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
58. (2S)-2-amino-3- [4-(pyridin-2-ylmethoxy) phenyl]-N- [4-(trifluoromethyl) phenyl] propanamide di trifluoroacetic acid salt;
59. (2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl}-N- [4-(trifluoromethyl) phenyl] propanamide di trifluoroacetic acid salt; 60. (2S)-2-amino-N-(3-fluoro-4-methylphenyl)-3-(4-{[5-(trifluoromethyl) pyridin-2-yl] oxy}phenyl)propanamide di trifluoroacetic acid salt;
61. (2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(5-(trifluoromethyl)pyridin- 2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
62. (2S)-2-amino-N-[4-(trifluoromethyl)phenyl]-3-(4-{[5-(trifluoromethyl) pyridin-2-yl]oxy} phenyl) propanamide di trifluoroacetic acid salt;
63. (2S)-2-amino-3- [4-(pyridin-2-ylmethoxy) phenyl]-N- (3,4,5-trifluorophenyl) propanamide di trifluoroacetic acid salt; 64. (2S)-2-amino~N- (3-chloro-4-fluorophenyl)-3-(4-{[5-(trifluoroniethyl) pyridin-2-yl] oxy} phenyl) propanamide trifluoroacetic acid salt;
65. (2S)-2-amino-3- (4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl)-N- (3,4,5-trifluorophenyl) propanamide trifluoroacetic acid salt and 66. (2S)-2-amino-3- (4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl)-N- (2,4,5-trifluorophenyl) propanamide trifluoroacetic acid salt.
Pharmaceutically acceptable salts forming part of this invention include base addition salts such as alkali metal salts like Li, Na, and K salts, alkaline earth metal salts like Ca and Mg salts, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts. Salts may include acid addition salts which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, trifluoroacetates, p-toluenesulphonates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
According to another feature of the present invention, there is provided a process for the preparation of compounds of the formula (I), wherein all other symbols are as defined earlier, as shown in the scheme-I
Scheme: a) Reacting the compound of formula (Ia) with a compound of formula (2a, wherein Xi is an halogen) to give compound of formula (3a). Reducing the compound of formula (3 a) (wherein R5 is a nitro group) to give the compound of formula (4a).
Figure imgf000015_0001
3a
4a b) Reacting the compound of formula (4a) with a compound of formula (5a) to give the compound of formula (6a), which on hydrolysis gives the compound of formula (7a).
Figure imgf000016_0001
4a 6a 7a
c) Peptide coupling of compound of formula (7a) with a compound of formula (8a) to give compound of formula (9a).
Figure imgf000016_0002
7a
9a
d) Dehydration of the compound of formula (9a) to give the compound of formula (10a) and further deprotection to give compound of formula (I)
Figure imgf000017_0001
9a 10a (I)
e) Deprotecting the compound of formula (6a) to give the compound of formula (Ha) and further reacting with compound of formula (12a) to give the compound of formula
(I)
Figure imgf000017_0002
6a 11a (1)
f) Reacting the compound of formula (7a) with the compound of formula (13a) to give the compound of formula (14a) and further deprotection to give the compound of formula (I).
Figure imgf000018_0001
7a
14a (I)
The reactions described in the processes outlined above are performed by using the methods described herein:
Condensation of the amino acid derivative of the compound of formula (Ia), (wherein P represents a protecting group) with compound of formula (2a), (wherein X represents an halogen) carried out in the presence of solvents selected from toluene, DMF, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethyl acetate, o- dichlorobenzene or a mixture thereof, in the presence of a base such as triethylamine, diethylamine, pyridine, DMAP, alkali hydroxides, alkaline earth metal hydroxide, alkali carbonates such as sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and the like, gave the compound of the formula (3 a). The reaction is carried out at a temperature in the range of room temperature to reflux temperature, mostly 0 0C to 100 0C. Alternatively the single S isomer of the compound of formula (2a) is prepared by condensation of the compound of formula (Ia) (wherein Ri is OH) with halo nitrobenzene followed by alkylation using conventional methods.
Hydrogenation of the compound of the formula (3a), (wherein R3 is NO2) is carried out using a catalyst such as Raney nickel, Pd/C in the presence of solvents such as methanol, ethanol, ethylacetate, n-butylacetate or a mixture thereof. The reaction may be carried out at temperature in the range of 0 0C to 100 0C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (4a). The compound of formula (4a) is reacted with a compound of formula (5a) in the presence of solvents such as toluene, methanol, ethanol, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, ethylacetate, o-dichlorobenzene or a mixture thereof or even without solvent. The reaction may be carried out at temperature in the range of 50 °C to 150 0C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (6a).
The compound of formula (6a) is hydrolyzed by means of base such as alkali hydroxide, alkaline earth metal hydroxide, or by using alkali carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and the like, in the presence of solvents such as water, methanol, ethanol, ethylacetate, n- butylacetate, tetrahydrofuran, 1,4-dioxane or a mixture thereof. The reaction may be carried out at a temperature in the range of 0 0C to 100 0C and the duration of the reaction may range from 2 to 24 hours, to produce a compound of the formula (7a).
Coupling of the compound of formula (7a) with compound of formula (8a) (prepared according to procedure described in WO2005/058849) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to about 48 hours at an ambient temperature to provide the compound of formula (9a). The compound of formula (9a) is treated with a dehydrating agent such as
POCypyridine, trifluoroacetic anhydride/diisopropylethylamine or cyanuric chloride in the presence of a solvent such as dimethyl formamide, tetrahydofuran, methylene chloride or MTBE at -30 0C to 30 0C to afford the compound of formula (10a) followed by deprotection using common methods known in art to give the preferred compound of formula (I). It is also understood that the compound of formula (7a) and/or (9a) as described above may be further modified prior to the formation of the preferred compound of formula (I).
In another embodiment, deprotection of compound of formula (6a) may be carried out using Pd/C, HCl or trifluoroacetic acid in the presence of solvents such as acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof at 0 0C to 30 0C. Alternatively the deprotection may also be carried out by passing HCl gas in the presence of solvents selected from acetonitrile, dichloromethane, methanol, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, trifluoroacetic acid, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide and the like or mixtures thereof give the compound of formula (1 Ia). The compound of formula (Ha) is treated with compound of formula (12a),
(prepared according to the process described in the Journal of Medicinal Chemistry 2003, 46, 2774) in the presence of solvents such as dimethylformamide, tetrahydrofuran, methylene chloride, dimethylacetamide at -10 0C to 70 °C to afford the compound of formula (I). In another embodiment, coupling of the compound of formula (7a) with compound of formula (13a) is carried out under standard peptide coupling conditions, for example, using EDC, HOBt, or BOP reagent and a base, generally diisopropylethylamine, in a solvent such as DMF, tetrahydrofuran or methylene chloride for about 3 to 48 hours at an ambient temperature to provide the compound of formula (14a). Subsequent deprotection of (14a) using common methods known in art gave the preferred compound of formula (I). It is also understood that the compound of formula (7a) and/or (14a) as described above may be further modified prior to the formation of the preferred compound of formula (I).
It is appreciated that in any of the above-mentioned reactions, any reactive group in the substrate molecule may be protected according to the conventional chemical practice. Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. More specifically the protecting groups P used particularly in the present invention are conventional protecting groups such as t-butoxy carbonyl (t-Boc), trityl, trifluoroacetyl, benzyloxy, benzyloxy carbonyl (Cbz) and the like and deprotection can be done by conventional methods.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used. Organic bases such as diethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts. Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, jP-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like. Prodrugs of the compounds of formula (I) are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
Various polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
Pharmaceutically acceptable solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The compositions may be prepared by processes known in the art. The amount of the active ingredient in the composition may be less than 70% by weight. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The pharmaceutical compositions of the invention are effective in lowering blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and are useful in the treatment and/or prophylaxis of type II diabetes. These compounds are effective in the treatment of obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Surprisingly, these compounds increase the leptin level and have no liver toxicity. Furthermore, they are useful for the treatment of disorders associated with insulin resistance such as polycystic ovary syndrome as well as hyperlipidemia, coronary artery disease and peripheral vascular disease; they are also useful in treating an individual at a risk of developing type II diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises administration to the individual thereof, repeated doses of an inhibitor of dipeptidyl peptidase IV.
Generally, the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease. Generally, a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results. The daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose. Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition. The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other . therapies to a mammal in need of such treatment. More specifically, it is that amount that is sufficient to lower the blood glucose, serum insulin, free fatty acids, cholesterol, triglyceride levels and to treat type II diabetes, obesity, inflammation, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
The term "animal" as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term "treatment" or "treating" means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, make various changes and modifications of the invention to adapt it to various usages and conditions.
The present invention is provided by the examples given below, which are provided by the way of illustration only, and should not be construed to limit the scope of the invention. Variation and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims.
Example 1
Synthesis of (2S)-l-{(2S)-2-amino-3-[4-(4-(pyridin-2-ylamino)phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt
Figure imgf000025_0001
Step I
Preparation of (2S)-2-[(tf-butoxycarbonyl) amino]-3-[4-(4-nitrophenoxy) phenyl] propanoic acid
Figure imgf000025_0002
To a solution of N-f-butoxy carbonyl-L-tyrosine (1Og, 35.5mmol) and potassium carbonate (29.4g, 213.5mmol) in dimethylformamide (5OmI) was charged 4- fluoronitrobenzene (6.02g, 43.6mmol). The reaction mixture was heated to 80 0C for 15 hours. After completion of the reaction, the reaction mixture was quenched with saturated cold ammonium chloride solution (300ml), extracted with ethyl acetate and the organic layer was separated. The aqueous layer was acidified using 2N HCl to pH 2 and was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the product (14.13g, 98.5%), 1HNMR (CDCl3, 400 MHz) δ ppm: 1.39(s, 9H), 2.92(m, IH)), 3.0(d, IH), 4.35(m, IH), 7.06(m, 4H), 7.32(m, 2H), 8.22(m, 2H); m/zM+1 403.2
Step II
Preparation of (2S)-2-[(/-butoxycarbonyl)amino]-3-[4-(4-nitrophenoxy) phenyl] propanoic acid methyl ester
Figure imgf000026_0001
To a solution of 2-[(t-butoxycarbonyl) amino]-3-[4-(4-nitrophenoxy) phenyl] propanoic acid and sodium bicarbonate (4.38g, 52.25mmol) in dry DMF (40ml), was added iodomethane (14.83g, 104.4mmol) under an inert atmosphere and the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was quenched with 0.5M KOH solution and was extracted with ethyl acetate. The organic layer was washed with brine and evaporated under reduced pressure to yield the desired product (7.Og, 97.2%), 1HNMR (CDCl3, 400 MHz) δ ppm:
1.42(s, 9H), 3.15(m, IH)), 3.18(m, IH), 3.74(s, 3H), 4.6(m, IH), 5.06(m, IH), 7.0(m,
4H), 7.19(m, 2H), 8.19(m, 2H); m/zM+1 417.2
Step HI Preparation of methyl-(2S) 2-[(*-butoxycarbonyl) amino]-3-[4-(4-amino phenoxy) phenyl] propanoate
Figure imgf000027_0001
10% Pd/C (0.6g) was added to a solution of methyl 2-amino-3-[4-(4- nitrophenoxy) phenyl] propanoate (6.19g, 14.6mmol) in dichloromethane (300ml) and the reaction mixture was hydrogenated at 30psi for 11 hours. After completion of reaction the catalyst was filtered off, and the total material was concentrated to give methyl 2-amino-3- [4-(4-aminophenoxy) phenyl] propanoate (5.48g, 84.4%); 1HNMR (CDCl3, 400 MHz) δ ppm: 1.41(s, 9H), 3.02(m, 2H), 3.60 (bs, 2H), 3.7(s, 3H), 4.5(m, IH), 5.0 l(d, IH), 6.66(m, 2H), 6.84(m, 4H), 7.0(m, 2H); m/zM+1 387.2
Step IV
Preparation of methyl (2S)-2-[(f-butoxycarbonyl) amino]-3-{4-[4-(pyridin-2- ylamino) phenoxy] phenyl} propanoate
Figure imgf000027_0002
Methyl 2-[(t-butoxycarbonyl) amino]-3-[4-(4-aminophenoxy) phenyl] propanoate (0.6g, 1.55mmαl) and 2-chloropyridine (1.2ml, 10.57mmol) were stirred under a nitrogen atmosphere at 130 0C for 20 hours. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution (25ml) and was extracted with ethylacetate (3x25 ml). The solvent was evaporated to give the crude product, which was purified by column chromatography to yield the desired product (0.6g, 54.5%) 1HNMR. (DMSOd6, 400 MHz) δ ppm: 1.42(s, 9H), 3.0(m, 2H), 3.7(s,
3H), 4.5(d, IH), 4.99(d, IH) 6.45(s, IH), 6.7(m, 2H), 6.92(d, 2H), 6.99(d, 2H), 7.07(d,
2H), 7.31(d, 2H), 7.49(t, IH), 8.1(d, IH); m/zM+1 464.2 Step V
Preparation of (2S)-2-[(*-butoxycarbonyl) aniino]--3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoic acid
Figure imgf000028_0001
To a solution of methyl (2S)-2-[(t-butoxycarbonyl) amino]-3-{4-[4-(pyridin-2- ylamino)phenoxy]phenyl}propanoate (2.Og, 4.3mmol) in tetrahydrofuran (20ml) was added a suspension of lithium hydroxide (0.181g, 4.3mmol) in water (2ml) and the reaction mixture was stirred at ambient temperature for 2-3 hours. After completion of reaction the solvent was removed under reduced pressure and the residue was dissolved in ethylacetate and washed with 5% HCl. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated to afford the title compound (1.89g, 97.9%), m/zM+1 449.9
Step VI
Preparation of (2S)-l-{(2S)-2-[(*-butoxycarbonyl) amino]-3-[4-(4-(pyridin-2- ylamino) phenoxy) phenyl] propanoyl} pyrroIidine-2- carboxamide
Figure imgf000028_0002
To a solution of (2S)-2-[(t-butoxycarbonyl) amino]-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoic acid (1.Og, 2.2mmol) in dimethylformamide (15ml) was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.512g, 2.6mmol) and HOBt (0.36g, 2.6mmol). The reaction mixture was stirred for 30 minutes at room temperature. To the above reaction mixture was added pyrrolidine-2- carboxamide (0.304g, 2.6mmol) and di-isopropyl ethylamine (0.48ml, 2.6mmol) and it was stirred further for 15 hours at room temperature. Subsequently the reaction mixture was poured on to 5% aqueous HCl and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was subjected to column chromatography (0.23Og, 19%).
Step VII Preparation of (2S)-l-{(2S)-2-[(*-butoxycarbonyl) amino]-3-[4-(4-(pyridin-2- ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile
Figure imgf000029_0001
To a solution of (2S)-l-{(2S)-2-[(/-butoxycarbonyl)amino]-3-[4-(4-(pyridin-2- ylamino)phenoxy)phenyl]propanoyl}pyrrolidine-2-carboxamide (0.22g, 0.4mmol) in dry tetrahydrofuran at 0 0C was added trifluoroacetic anhydride (0.27ml) and diisopropylethyl amine (0.55ml) and the reaction mixture was stirred for 1 hour at 0 0C. After completion of reaction, the reaction mixture was diluted with ethylacetate and washed with water, dried over sodium sulphate and concentrated to give the crude product which was purified by flash column chromatography on neutral alumina with methylene chloride /methanol: 9.7/0.3 as the eluent to give the title compound (0.152g, 71.3%)
Step VIII
Preparation of (2S)-l-{(2S)-2-amino-3-[4-(4-(pyridin-2-ylamino)phenoxy) phenyl]propanoyl}pyrrolidine-2-carbonitrile di trifluoroacetic acid salt
Figure imgf000030_0001
To cooled trifluoroacetic acid (0.46ml) was added (2S)-l-{(2S)-2-[(f- butoxycarbonyl)amino]-3-[4-(4-(pyridin-2-ylamino)phenoxy)phenyl]ρropanoyl} pyrrolidine-2-carbonitrile (0.08g, O.lmmol) and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was removed under vacuum; methylene chloride was added to the above and the whole was again concentrated under vacuum to give the title compound (0.04g); 1HNMR. (DMSOd6, 400 MHz): δ 1.89(m, IH), 2.07(m, IH), 2.15(m, IH)5 2.2 (m, IH), 2.8 (m, IH), 3.01(dd, IH), 3.08 (dd, IH), 3.48 (dd, IH), 4.32 (t, IH), 4.80 (m, IH), 6.79 (t, IH), 6.88(dd, IH), 6.93(d, 2H), 6.98 (d, 2H), 7.23(d, 2H), 7.64(d, 2H), 8.08(d, IH), 8.28(bs, 2H), 9.39(bs, IH); m/zM+1 428.1
The following compounds were prepared according to the procedure given in example 1
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000032_0002
Example 8
Synthesis of (2S)-l-{(2S)-2-cyclohexylamino-3-[4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propaπoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt
Figure imgf000032_0001
To a solution of (2S)-l-{(2S)-2-amino-3-[4-(4-(pyridin-2-ylamino) phenoxy)phenyl]propanoyl}pyrrolidine-2-carbonitrile di trifluoroacetic acid salt (0.06Og, 0.14mmol) in methanol was added cylcohexanone (0.145ml, 0.14mmol) and the reaction mixture was stirred at room temperature for 15 minutes. Subsequently sodium triacetoxyborohydride (0.030g, 0.14mmol) was added to the above and the reaction mixture was stirred overnight. The solvent was evaporated and the crude material was purified by column chromatography to yield the title compound (0.017g); 1HNMR. (DMSOd6, 400 MHz): δ 1.17 (m, 6H), 1.52 (m, 2H), 1.65(m, 4H), 2.1 l(m, 4H), 2.78(m, 2H), 3.0(m, IH), 3.32 (m, IH), 4.77 (t, IH), 6.72 (m, IH), 6.78 (dd, IH), 6.86 (dd, 2H), 6.93(dd, 2H), 7.21(dd, 2H), 7.55(t, IH), 7.68 (dd, 2H), 8.12 (d, IH), 9.02 (bs, IH); m/zM+1 446.1 Example 9
Synthesis of (2S)-l-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl]pyrrolidine-2-carbonitrile di trifluoroacetic acid salt
Figure imgf000033_0001
Step I
Preparation of methyl (2S)-2-[(*-butoxycarbonyI) amino]-3-{4-[(5-nitro pyridin-2- yl) oxy] phenyl} propanoate
Figure imgf000033_0002
To a solution of methyl (2S)-2-[(/-butoxycarbonyl) amino]-3-(4-hydroxyphenyl) propanoate (0.5g, l.όmmol) in dimethylformamide (20ml) was added potassium carbonate (0.46g, 3.3mmol) followed by 2-bromo-5-nitropyridine (0.43g, l.όmmol) and the reaction mixture was stirred for 3-4 hours at 80-85 0C. After completion of reaction, the reaction mixture was poured onto water and extracted with ethylacetate. The organic layer was dried over sodium sulphate and concentrated to give the title compound (0. 65g, 92%).
Step II
Preparation of (2S)-2-[(f-butoxycarbonyl) amino]-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoic acid
Figure imgf000034_0001
To a solution of methyl (2S)-2-[(Y-butoxycarbonyl) amino]-3-{4-[(5- nitropyridin-2-yl)oxy]phenyl}propanoate (0.62g, 1.4mmol) in tetrahydrofuran (20ml) was added a suspension of lithium hydroxide (0.044g, 2.0mmol) in water (2ml) and the reaction mixture was stirred at an ambient temperature for 2-3 hours. After completion of reaction the solvent was removed under reduced pressure and the residue was dissolved in ethylacetate and washed with 5% HCl. The organic layer was washed with water and dried over anhydrous sodium sulphate and concentrated to afford the title compound (0.57g, 96%)
Step III
Preparation of (2S)-1-{(2S)- 2-[(*-butoxycarbonyl) amino]-3-[4-(5-nitro pyridin-2- yloxy) phenyl] propanoyl} pyrrolidine-2-carboxamide
Figure imgf000034_0002
To a solution of (2S)-2-[(t-butoxycarbonyl)amino]-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoic acid (0.54g, 1.3mmol) in dimethylformamide (20ml), was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.3Og, l.όmmol), diisopropylethyl amine (0.296ml, l.όmmol) and HOBt (0.36g, 2.6mmol) and the reaction mixture was stirred for 30 minutes at room temperature. To the above reaction mixture was added pyrrolidine-2-carboxamide (0.183g, 1.6mmol) and it was stirred for 15 hours at room temperature. Subsequently the reaction mixture was poured on to 5% aqueous HCl and was extracted with ethylacetate; the organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was subjected to column chromatography to afford the title compound (0.6 Ig, 92%); m/zM+1 500.2
Step IV
Preparation of (2S)-l-{(2S)-2-[(f-butoxycarbonyl) amino]-3-[4-(5-nitro pyridin -2- yloxy) phenyl] propanoyl}pyrroIidine-2-carbonitrile
Figure imgf000035_0001
To a solution of (2S)-l-{(2S)-2-[(r-butoxycarbonyl)amino]-3-[4-(5-nitro pyridin-2-yloxy)phenyl]propanoyl}pyrrolidine-2-carboxamide (0.447g, 0.8mmol) in dry tetrahydrofuran at 0 0C was added trifluoroacetic anhydride (0.22ml, l.βmmol) and diisopropylethyl amine (0.28ml, l.όmmol). The reaction mixture was stirred for 1 hour at 0 0C. After completion of reaction, the reaction mixture was diluted with ethylacetate and washed with water, dried over sodium sulphate and concentrated to give crude product. Purification by flash column chromatography on neutral alumina with methylene chloride /methanol: 9.8/0.2 as the eluent gave the title compound (0.175g;
41%); m/zM+1 482.1
Step V Preparation of (2S)-l-{(2S)-2-amino-3-[4-(5-nitropyridin-2-yloxy) phenyl] propanoyl} pyrroIidine-2-carbonitrile
Figure imgf000035_0002
To cooled trifluoro acetic acid (0.22ml, 1.9mmol) was added (2S)-1-{(2S)- 2- [(t-butoxycarbonyl)amino]-3-[4-(5-nitropyridin-2-yloxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile (0.05g, O.lmmol) and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was removed under vacuum; methylene chloride was added to the above and the whole was again concentrated under vacuum to give the title compound (0.048g, 76%); 1HNMR. (DMSOd6, 400 MHz): δ 1.85(m, 2H), 2.11(m, 2H), 2.76(m, IH), 3.06 (m, IH), 3.14 (m, IH), 3.45 (m, IH)3 4.37 (t, IH), 4.81(t, 2H), 7.19(d, 2H), 7.28(d, IH), 7.34(d, 2H), 8.31(bs, 2H), 8.64(d, IH), 8.97(s, IH); m/zM+1 382.1
The following compounds were prepared according to the procedure given in the example 9
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
8
Figure imgf000039_0001
Figure imgf000040_0001
Example 25
Synthesis of l-(2-adamantyIamino-3-{4-[(5-nitropyridin-2-yI) oxy] phenyl} propanoyl) pyrrolidine-2-carbonitrile
Figure imgf000040_0002
To a solution of (2S)-l-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl)oxy] phenyl}propanoyl]pyrrolidine-2-carbonitrile di trifluoroacetic acid salt (0.20Og, 0.52mmol, prepared as in example- 13) in ethanol, was added titanium isopropoxide (0.155g, 0.52mmol), triethylamine (0.15ml,1.04mmol) and adamantanone (0.08Og, 0.52mmol) and the reaction mixture was stirred overnight at room temperature .After 12 hours, sodium borohydride (0.03Og, 0.78mmol) was added to the above reaction mixture which was stirred further for another 24 hours. Subsequently the solvent was evaporated and the crude material was purified by column chromatography to afford the title compound (0.015g). 1HNMR. [DMSOd6, 400 MHz] δ ppm: 1.71(m, 16H), 2.06(m, 4H), 2.82(m, 2H), 3.39(m, IH), 4.5(m, IH)5 4.78 (m, IH), 7.09(dd, 2H), 7.21(dd, 2H), 7.35(dd, 2H), 8.98(s, IH); m/zM+I 516.0. Example 26
Synthesis of (25',4»S)-l-[(25)-2-amino-3-{4-[(5-nitropyridin-2-yl)oxy] phenyl} propanoyl]-4-fluoropyrrolidine-2-carbonitriledi trifluoroacetic acid salt
Figure imgf000041_0001
Step I
Preparation of (2S,4R)-l-{(25)-2-(l'-butoxycarbonyl) amino-3-[4-(5-nitro pyridin-
2-yI oxy)phenyI]propanoyI}-4-hydroxypyrrolidine-2-carboxamide
Figure imgf000041_0002
To a solution of (2S)-2-[(f-butoxycarbonyl)amino]-3-{4-[(5-nitropyridin-2- yl)oxy]phenyl} propanoic acid (0.4g, 0.99mmol) in dimethylformamide (8ml), was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.228g, 1.19mmol), diisopropylethyl amine (0.2ml, 1.19mmol) and HOBt (0.26g, mmol) and the reaction mixture was stirred for 30 minutes at room temperature. To the above reaction mixture was added 4-hydroxypyrrolidine-2-carboxamide (0.29g, 1.19mmol) and it was stirred further for another 15 hours at room temperature. Subsequently the reaction mixture was poured onto 5% aqueous HCl and extracted with ethylacetate; the organic layer was washed with water, dried over sodium sulphate and concentrated to give the crude product which was subjected to column chromatography to afford the title compound (0. 4Ig); m/zM+I 516.0
Step II
Preparation of (2S,4R)-l-[(2S)-2-(r-butoxycarbonyl)amino-3-{4-[(5-nitro pyridin-
2-yl)oxy]phenyl}propanoyI]-4-hydroxypyrrolidine-2-carbonitriIe
Figure imgf000042_0001
To a cooled solution of (2S,4R)-l-{(2S)-2-(t-butoxycarbonyl) amino-3-[4-(5- nitropyridinpyridin-2-yloxy)phenyl]propanoyl } -4-hydroxypyrrolidine-2-carboxamide (0.398g, 0.77mmol), was added trifluoroacetic anhydride (0.21ml, 1.5mmol) and diisopropyl ethlylenediamine (0.26ml, 1.5mmol) and the reaction mixture was stirred for 3 hours. After completion, the mixture was washed with water (10ml), 10% KHSO4 and finally with brine solution (10ml). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. The crude material obtained was purified by column chromatography to afford the required product (0. 23g); m/zM"' 422.0 Step III
Preparation of (2S,4S)-l-[(2S)-2-(f-butoxycarbonyl)ainino-3-{4-[(5-nitro pyridin-2- yl)oxy]phenyl}propanoyI]-4-fluoropyrrolidine-2-carbonitrile
Figure imgf000042_0002
(2S,4R)-l-[(2S)-2-(t-butoxycarbonyl)amino-3-{4-[(5-nitropyridin-2-yl) oxy]phenyl}propanoyl]-4-hydroxypyrrolidine-2-carbonitrile (0.41g, 0.28mmol) was dissolved in dichloromethane (15ml) and was cooled to -78 0C. To the above cooled solution was added diethylaminosulphur trifluoride (DAST, 0.05ml, 0.42mmol) and the reaction mixture was stirred at the same temperature for 30 minutes. Subsequently the ice bath was removed and the reaction was stirred further for another 2 hours. After completion; the reaction mixture was diluted carefully with saturated sodium bicarbonate solution (10ml); the organic layer was separated, dried over anhydrous sodium sulphate and the solvent was evaporated to afford the crude material which was purified by column chromatography to yield the required product (0.030g); m/zM+1 500.0
Step IV
Preparation of (2S, 4S)-l-[(2S)-2-amino-3-{4-[(5-nitropyridiπ-2-yl)oxy] phenyI}propanoyI]-4-fIuoropyrroIidine-2-carbonitriIe di trifluoroacetic acid salt
Figure imgf000043_0001
To cooled trifluoroacetic acid (0.15ml), was added (2S, 4S)-l-[(2_S)-2-(/- butoxycarbonyl)amino-3-{4-[(5-nitropyridin-2-yl)oxy]phenyl}propanoyl]-4-fluoro pyrrolidine-2-carbonitrile (0.03g, O.Oόmmol) and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was removed under vacuum; methylene chloride was added to the above and the whole was again concentrated under vacuum to give the title compound (0.016g); IHNMR. (DMSOd6, 400 MHz): δ 2.42 (m, IH), 3.16 (m, 4H), 3.74 (dd, IH), 4.31 (t, IH), 5.09(d, IH), 5.44 (dd, IH), 7.18(m, 3H), 7.35 (d, 2H), 8.32 (bs, 2H), 8.59 (d, IH), 9 .00 (s, IH); m/zM+1 400.1 Example 27
Synthesis of 2-{4-[(2S)-2-amino-3-oxo-3-(3-oxopyrrolidin-l-yl) propyl] phenoxy} nicotinonitrile di hydrochloride salt
Figure imgf000044_0001
Step I
Preparation of 2-(4-{(2S)-2-(M)utoxycarbonyl) amino-3-[(3R)-3- hydroxy pyrrolidin-l-yl]-3-oxopropyl} phenoxy) nicotinonitrile H
Figure imgf000044_0002
To a solution of (2S)-2-[(t-butoxycarbonyl)amino]-3-{4-[(3-cyano pyridin-2- yl)oxy]phenyl}propanoic acid (0.4g, l.Ommol) in dimethylformamide (20ml) was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.239g, 1.2mmol), diisopropylethyl amine (0.2ml, 1.2mmol) and HOBt (0.28g, 0.2mmol). The reaction mixture was stirred for 30 minutes at room temperature. To the above reaction mixture was then added pyrrolidin-3-ol (0.108g, 1.2mmol) and it was stirred further for 15 hours at room temperature. Subsequently the reaction mixture was poured on to 5% aqueous HCl and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was subjected to column chromatography to afford the expected product (0.5g). Step II
Preparation of 2-{4-[(2S)-2-(f-butoxycarbonyl) amino-3-oxo-3-(3-oxo pyrrolidin- l-yl) propyl] phenoxy} nicotinonitrile
Figure imgf000045_0001
To a suspended solution of pyridinium chlorochromate (0.357g, l.όmmol) in dichloromethane was added 2-{4-[(2S)-2-(£-butoxycarbonyl)amino-3-(3- hydroxypyrrolidin-l-yI)-3-oxopropyl] phenoxy} nicotinonitrile (0.5g, l.lmmol) and the reaction mixture was stirred for 24 hours. Subsequently the reaction mixture was concentrated to afford the crude product, which was subjected to column chromatography furnishing the title compound (0.15Og, 30.6%).
Step HI
Preparation of 2-{4-[(2S)-2-amino-3-oxo-3-(3-oxopyrrolidin-l-yl)propyI] phenoxy} nicotinonitrile di hydrochloride salt
Figure imgf000045_0002
To an ice cooled solution of 2-{4-[(2S)~2-(/-butoxycarbonyl)amino-3-oxo-3-(3- oxopyrrolidin-l-yl)propyl]phenoxy} nicotinonitrile (0.050g, O.l lmmol) in dichloromethane (25 ml) was bubbled dry HCl gas for about 30 minutes. After completion of the reaction, the excess of HCl gas was removed by nitrogen gas bubbling and the solvent was removed under reduced pressure to give the product (0.02Og); 1HNMR. (DMSOd6, 400 MHz): δ 3.03 (m, 3H), 3.74 (dd, IH), 3.84 (m, 2H), 4.09 (dd, IH), 4.31(m, IH), 4.54 (m, IH), 7.23(d, 2H), 7.32 (m, 3H), 8.30 (m, IH), 8 .42 (m, IH); m/zM+1 351.1.
Example 28
Synthesis of 2-{4-[(2S)-2-amino-3-oxo-3-[3-(trifluoromethyI)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H)-yl) propyl] phenoxy} nicotinonitrile di trifluoroacetic acid salt
Figure imgf000046_0001
Stepl
Preparation of 2-{4-[(2S)-2-(*-butoxycarbonyl) amino-3-oxo-3- [3-(trifluoro methyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (SH)-yϊ) propyl] phenoxy} nicotinonitrile
Figure imgf000046_0002
To an ice cold solution of (2S)-2-[(M>utoxycarbonyl) amino]-3-{4-[(3- cyanopyridin-2-yl) oxy] phenyl} propanoic acid (0.3g, 0.74mmol) in DMF (10ml) was added di-isopropyl ethylamine (0.16ml, 0.89mmol), BOP (0.39g, 0.89mmol), HOBt (0.02Og, 0.14mmol) followed by 3-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4] triazolo
[4,3-α] pyrazine hydrochloride salt (0.18g, O.δlmmol, prepared according to the process described in Organic letters 2005, 7, 1039-1042) and the reaction mixture was stirred for 5 hours. After completion, the reaction mixture was poured into water (50ml) and extracted twice with ethyl acetate (50ml). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to give the crude product which was purified by column chromatography to afford the title compound (0. 350g (84.5%).
Step II
Preparation of 2-{4-[(2S)-2-amino-3-oxo-3- [3-(trifluoromethyI)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H)-yl)propyl]phenoxy}nicotinonitrile di trifluoroacetic acid salt
Figure imgf000047_0001
To cooled trifluoroacetic acid (0.4ml) was added 2-{4-[(2S)-2-(f- butoxycarbonyl)amino-3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7 (8H)-yl)propyl]phenoxy}nicotinonitrile (0.288g, 0.51mmol), and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoroacetic acid was removed under vacuum; methylene chloride was added to the above and the whole was again concentrated under vacuum to give the title compound (0.05Ig); 1HNMR. (DMSO-d6, 400 MHz): δ 3.08 (m, 2H), 3.78 (m, 2H), 4.03 (m, 2H), 4.53 (dd, IH), 4.78(m, IH), 5.04 (dd, IH), 7.13(d, IH), 7.20 (d, IH), 7.33 (m, 3H), 8.28 (bs, 2H), 8 .30 (dd, IH). m/zM+1 458.1
Example 29
Synthesis of 2-{4-[(2S)-2-amino-3-(3,3-difluoropyrrolidin-l-yl)-3-oxopropyl]
Figure imgf000048_0001
phenoxy} nicotinonitrile di hydrochloride salt
Step I
Preparation of 2-{4-[(2S)-2-(f-butoxycarbonyl) amino-3-(3,3-difluoro pyrrolidin-1- yl)-3-oxopropyl] phenoxy} nicotinonitrile
Figure imgf000048_0002
2-{4-[(2S)-2-(t-butoxycarbonyl) amino-3-oxo-3-(3-oxo pyrrolidin-1-yl) propyl] phenoxy} nicotinonitrile (0.15g, 0.33mmol, as prepared in example-29, step II) was dissolved in dichloromethane and the reaction mixture was then cooled to -78 0C. To the above cooled solution was added DAST (0.269g, l.όmmol) and the reaction mixture was stirred at the same temperature for 30 minutes. Removed the ice cooled bath and continued the reaction for 2 hours. After completion, the reaction mixture was diluted carefully with saturated sodium bicarbonate solution (10ml); the organic layer was separated, dried over anhydrous sodium sulphate and the solvent was evaporated to afford the crude material which was purified by column chromatography to yield the required product (0.05Og); m/zM+1 473.2
Step II Preparation of 2-{4-[(2S)-2-amino-3-(3,3-difluoropyrroIidin-l-yI)-3-oxo propyl] phenoxy} nicotinonitrile di hydrochloride salt
Figure imgf000049_0001
To an ice cooled solution of 2-{4-[(2S)-2-(t-butoxycarbonyl)amino-3-(3,3- difluoropyrrolidin-l-yl)-3-oxopropyl]phenoxy}nicotinonitriIe (0.043g, 0.09 mmol) in dichloromethane (50 ml) was bubbled dry HCl gas for about 30 minutes. After completion of the reaction, the excess of HCl gas was removed by nitrogen gas bubbling and the solvent was removed under reduced pressure to give the desired product (0.02Og); IHNMR. (DMSOd6, 400 MHz): δ 2.3 (m, 2H), 2.93 (m, IH), 3.01 (m, IH), 3.12 (m, IH), 3.66(m, 2H), 4.0 (m, IH), 4.31 (dd, IH)5 7.22(d, 2H), 7.32 (d, 3H), 8.31 (d, IH), 8 .39 (dd, IH); m/zM+1 373.1
Example 30
Synthesis of methyl (2S) 2-{[2-((2S)-2-cyanopyrrolidin-l-yl)-2-oxoethyl] amino}-3-
{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoate
Figure imgf000049_0002
Step I
Preparation of methyl (2S)-2-anιino-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoate dihydrochloride
Figure imgf000050_0001
To a solution of methyl (2S)-2-[(/-butoxycarbonyl) amino]-3-{4-[4-(pyridin-2- ylamino) phenoxy] phenyl} propanoate (0.29g, 0.43mmol, as prepared in step IV of example-1) in dichloromethane (25 ml) was bubbled dry HCl gas for about 2 hours. After completion of the reaction, the excess of HCl gas was removed by nitrogen gas bubbling and the solvent was removed under reduced pressure to give the product as an off white solid (0.10Og, 66%), 1HNMR. [DMSOd6, 400 MHz] δ ppm: 3.1(dd, 2H), 3.7(s, 3H), 4.2(m, IH), 6.9(t, IH), 7.0(d, 2H), 7.07(dd, 3H), 7.2(d, 2H), 7.5(d, 2H), 8.0(d, IH), 8.1(d, IH), 8.5(bs, 2H), 10.31(bs, IH); m/zM+1 363.9
Step II Preparation of methyl (2S) 2-{[2-((2S)-2-cyanopyrrolidin-l-yl)-2-oxoethyl] amino}- 3-{4-[4-(pyridin-2-yIamino) phenoxy] phenyl} propanoate
Figure imgf000050_0002
To a solution of methyl (2S)-2-amino-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl}propanoate dihydrochloride (0.65g,1.7mmol) in methylene chloride was added potassium carbonate (0.737g, 5.3mmol) followed by (2,S)-l-(chloroacetyl)pyrrolidine- 2-carbonitrile at 0 0C and the reaction mixture was stirred for 2 hours after which it was allowed to attain room temperature gradually and was stirred further for 48 hours at room temperature. Subsequently the reaction mixture was filtered, the filtrate was concentrated and chromatographed over neutral alumina column using methylene chloride/methanol: 9.9/0.1 as the eluent to yield the product (0.025g, 2.7%), 1HNMR. [DMSOd6, 400 MHz] δ ppm: 1.96 (m, 2H), 2.09 (d, 2H)5 2.87 (m, 2H), 3.30 (d, 2H), 3.47 (m, IH), 3.53 (dd, 2H), 3.59 (s, 3H), 4.710, IH), 6.71(t, IH), 6.79(dd, IH), 6.84(dd, 2H), 6.95(dd, 2H), 7.14 (dd, 2H), 7.540, 2H), 7.68(dd, 2H), 8.1 l(d, IH), 9.01(bs, IH); m/zM+1 500.2.
Example 31
Synthesis of (2S) l-({[(lS)-2-((3R) 3-hydroxy-pyrrolidine)-l-(-4-(3-nitro pyridin-2- yloxy) benzyl)-2-oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile
OH
Figure imgf000051_0001
To a solution of (3R)-l-[(2S)-2-amino-3-{4-[(3-nitropyridin-2~ yl)oxy]phenyl}propanoyl]pyrrolidin-3-ol dihydrochloride (0.213g, 5mmol, prepared as in example 24) in methylene chloride was added potassium carbonate (0.236g, 1.7mmol), catalytic amount of potassium iodide and (25)-l-(chloroacetyl)pyrrolidine- 2-carbonitrile (0.049g, 2.8mmol) at 0 0C and the reaction mixture was stirred for 2 hours after which it was allowed to attain room temperature gradually and was stirred further for another 48 hours at room temperature. Subsequently the reaction mixture was filtered, the filtrate was concentrated and chromatographed over neutral alumina column using methylene chloride/methanol: 9.9/0.1 as the eluent to yield 0.06Og of the product. 1HNMR. (DMSOd6, 400 MHz) δ ppm: 1.25(dd, 2H), 1.70(d, 2H), 1.950, 2H), 2.10 (t, 2H)5 2.79 (m, 2H), 3.4 (m, 7H), 4.20 (dd, IH), 4.70(t, IH), 7.10(d, 2H), 7.28(m, 2H), 7.36(t, IH), 8.38 (d, IH), 8 .56(dd, IH). m/zM+1 509.2
The following compounds were prepared according to the procedure given in example 31
Figure imgf000052_0001
Example 35
Synthesis of (2S)-2-amino-ΛyV-dimethyl-3-{4-[4-(pyridin-2-ylaniino) phenoxy] phenyl} propanamide
Figure imgf000053_0001
Step I
Preparation of (2S)-2-[(f-butoxycarbonyl) amino]-iV, iV-dimethyl-3- {4-[4-(pyridin-
2-ylamino) phenoxy] phenyl} propanamide
Figure imgf000053_0002
To a solution of (2S)-2-[(Y-butoxycarbonyl) amino]-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoic acid (0.5g, ll.lmmol, as prepared in step-IV, example I) in dry methylene chloride (30ml) was added triethylamine (0.135g, 13mmol) followed by BOP reagent (0.54g, 12.1mmol) and the reaction mixture was stirred for 15 minutes. To the above dimethylamine (0.45g, 56mmol) in tetrahydofuran (5 ml) was added and the reaction mixture was stirred for 15 hours. Subsequently the solvent was removed under vacuum, the residue was dissolved in ethylacetate, washed with IN NaOH aqueous solution followed by water, dried over anhydrous sodium sulphate and concentrated to give the title compound (0. 4Og, 75.4%) Step II
Preparation of (2S)-2-amino-i\yV-dimethyl-3-{4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanamide
Figure imgf000054_0001
To a solution of (2S)-2-[(/-butoxycarbonyl) amino]-N,N-dimethyl-3-{4-[4-
(pyridin-2-ylamino) phenoxy] phenyl} propanamide (0.4g, 8.9mmol) in dichloromethane (25 ml) was bubbled dry HCl gas for 2 hours. After completion of the reaction, the excess of HCl gas was removed by nitrogen gas bubbling and the solvent was removed under reduced pressure to give the product as an off white solid (0.02g); 1HNMR. (DMSOd6, 400 MHz): δ 2.73(s, 3H), 2.82 (s, *H), 2.99 (m, 2H), 4.54 (m, IH), 6.90 (s, IH), 7.02 (m, 5H), 7.23(d, 2H), 7.54(d, 2H), 7.83(bs, IH), 8.04(d, IH), 8.23(s, 2H); m/zM+1 377.1
The following compounds were prepared according to the procedure given in example 35
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
(s,
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Protocols for biological testing
DPP IV Assay
The DPP IV assay was done using human plasma as a source of DPP IV. The compounds were incubated at a concentration of 1 and 10 μM in assay buffer containing DPP IV enzyme. The compounds were incubated for 1 hour and then the substrate H-gly-pro AMC was added and further incubated for 20 minutes and then the reaction was stopped on addition of 25% glacial acetic acid. The plates were read in a spectrofluorimeter to get RFU on setting excitation wavelength of 360nm and emission wavelength of 460 nm. Percentage inhibition is calculated as compared to vehicle control. Compounds showing greater than 50% inhibition at 1 μM were taken for Dose response studies for DPP IV inhibition to calculate IC50 value. The examples shown in Table-I show significant DPP IV inhibition. Table-I
DPP IV inhibition of compounds
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001

Claims

We Claim:
1. Novel compounds of the general formula (I),
Figure imgf000066_0001
their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, prodrugs and metabolites thereof, wherein R represents hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted groups selected from linear or branched
Figure imgf000066_0002
groups comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and f-butyl; alkoxy groups comprising methoxy, ethoxy, n-propoxy and isopropoxy; aryl groups comprising phenyl and naphthyl; aralkyl groups comprising benzyl, phenylethyl and phenylpropyl; heterocyclyl groups, which are mono or fused systems comprising morpholine, piperazine, piperidine, pyrrolidine, thiazolidine, pyrrolidyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl and 5,6-dihydro [1,2,4] triazolo [4,3-α] pyrazin-7
Figure imgf000066_0003
X represents nitrogen or CH; Y represents sulphur, CH2, CH-R', <l R , C=O; R' represents hydrogen, hydroxy and halogen; R" represents hydrogen, halogen, haloalkyl groups comprising chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl and dichloroethyl; cyano, -(C=O)NH2;
R1 and R2 are same or different and independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, heteroaryl, cycloalkyl groups comprising cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl; -CH2-(C=O)-R, COR9; where R9 represents substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aryloxy, alkoxy, aralkoxy, or a counter ion;
R3, R4, R5, Re, R7 and R8 may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, formyl, amino, alkyl, haloalkyl and alkoxy groups; Rio and Rn are same or different and independently represent hydrogen, substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, or are combined together (cyclize) to form a five or six membered heterocyclic ring comprising pyridyl, pyrrolidiyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyranyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrrolyl, benzoxadiazolyl, benzothiadiazolyl, benzodioxolyl and quinolinyl which are optionally further substituted with one or more subsituents selected from hydroxy, halogen, oxo, alkyl and haloalkyl groups; m and n are integers in the range of 0 to 2, with the proviso that when m is 0, then n is 1; p is an integer in the range of 0 to 1;
The groups R, R1, R2, R3, R4, R5, Re, R7, Rs, R9, Rio and Rn are optionally substituted with one or more substituents selected from nitro, hydroxy, cyano, formyl, azido, alkyl, alkoxy, acyl, halogens, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfmyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, aryl and carboxylic acid or its derivatives.
2. A compound of formula (I), as claimed in claim 1, which is selected from a group consisting of:
(2S)-l-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt; (2S)-l-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl}pyrrolidine-2-carbonitrile dip-toluenesuphonic acid salt;
(2S)-l-{(2S)-2-amino-3-[4-(4[5-(trifluoromethyl) pyridin-2-yl]amino) phenoxy)phenyl]propanoyl}pyrrolidine-2-carbonitrile di trifluoroacetic acid salt; (2S)-l-{(2S)-2-amino-3- [4-(4-(3-nitropyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
3-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} 1,3-thiazolidine di trifluoroacetic acid salt;
(2S)-l-{(2S)-2-amino-3- [4-(4-(3-cyanopyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
(4R)-3-{(2S)-2-amino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} -1,3-thiazolidine carbonitrile di trifluoroacetic acid salt;
(2S)-l-{(2S)-2-cyclohexylamino-3- [4-(4-(pyridin-2-ylamino) phenoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt; (2S)-l-[(2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl]pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
(2S)-l-[(2S)-2-amino-3- {4-[(3-nitropyridin-2-yl) oxy] phenyl} propanoyl] pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
2-(4- { (2S)-2-amino-3 -[(2S)-2-cyanopyrrolidin- 1 -yl]-3 -oxopropyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt;
(2S)-l-{(2S)-2-amino-3-[4-(pyridin-2-ylmethoxy) phenyl] propanoyl} pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
(4R)-3-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl]
-l,3-thiazolidine-4-carbonitrile di trifluoroacetic acid salt; (4R)-3-[(2S)-2-amino-3- {4-[(3-nitropyridin-2-yl) oxy] phenyl} propanoyl]-l,3- thiazolidine-4-carbonitrile di trifluoroacetic acid salt;
2-(4- { (2 S)-2-amino-3 -[(4R)-4-cyano- 1 , 3 -thiazolidin-3 -yl] -3 -oxopropyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt;
2-(4- { (2S)-2-amino-3-[(2S)-2-cyanopyrrolidin- 1 -yl]-3 -oxopropyl} phenoxy) -6-methylnicotinonitrile di trifluoroacetic acid salt;
2-{4-[(2S)-2-amino-3-oxo-3- (l,3-thiazolidin-3-yl) propyl] phenoxy} nicotinonitrile di hydrochloride salt; (2S)-l-[(2S)-2-amino-3- (4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl) propanoyl] pyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
(2S)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl}-l-oxo-l-[(2S)-2-
(trifluoromethyl)pyrrolidin-l-yl]propan-2-amine di trifluoroacetic acid salt; (2S)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} -1-oxo-l -[(2S)-2-
(trifluoromethyl)pyrrolidin-l-yl]propan-2-amine di trifluoroacetic acid salt;
2-(4-{(2S)-2-amino-3-[(3S)-3-fluoropyrrolidin-l-yl]-3-oxoproρyl} phenoxy) nicotinonitrile di trifluoroacetic acid salt;
(2S)-l-[(3S)-3-fluoropyrrolidin-l-yl]-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl}-l- oxopropan-2-amine di hydrochloride salt;
(2S)-l-[(2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanoyl] pyrrolidine-
2-carboxamide di trifluoroacetic acid salt;
(2S)-l-[(3S)-3-fluoropyrrolidin-l-yl]-l-oxo-3-[4-(pyridin-2-yl methoxy) phenyl] ρropan-2-amine di trifluoroacetic acid salt; (2S)-l-((2S)-2-adamantylamino-3-{4-[(5-nitropyridin-2-yl)oxy] phenyl} propanoyl) pyrrolidine-2-carbonitrile;
(2S,4S)-l-[(2S)-2-amino-3-{4-[(5-nitropyridin-2-yl)oxy]phenyl}propanoyl]
-4-fluoropyrrolidine-2-carbonitrile di trifluoroacetic acid salt;
2-{4-[(2S)-2-amino-3-oxo-3- (3-oxopyrrolidin-l-yl) propyl] phenoxy} nicotinonitrile di hydrochloride salt;
2-{4-[(2S)-2-amino-3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo [4,3- α]pyrazin-7(8H)-yl)propyl]phenoxy}nicotinonitrile di trifluoroacetic acid salt;
2-{4-[(2S)-2-amino-3-(3,3-difluoropyrrolidin-l-yl)-3-oxopropyl]phenoxy} nicotinonitrile di hydrochloride salt; Methyl (2S) 2-{[2-((2S)-2-cyanopyrrolidin-l-yl)-2-oxoethyl] amino}
3{4[4-(pyridin-2-ylamino) phenoxy] phenyl} propanoate;
(2S) l-({[(lS)-2-((3R) 3-hydroxy-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)-
2-oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile;
(2S) l-({[(lS)-2-((3S) 3-fluoro-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)-2- oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile;
(2S) l-({[(lS)-2-(3,3-difluoro-pyrrolidine)-l-(-4-(3-nitropyridin-2-yloxy) benzyl)-2- oxoethyl]amino}acetyl)-pyrrolidine-2-carbonitrile; (2S) l-({[(lS)-2-((2S)-2-trifluoromethyl-pyrrolidine)-l-(-4-(3-nitropyridin -2-yloxy) benzyl)-2-oxoethyl] amino} acetyl)-pyrrolidine-2-carbonitrile; (2S)-2-amino-N, N-dimethyl-3- {4-[4-(pyridin-2-ylamino) phenoxy] phenyl} propanamide dihydrochloride salt; (2S)-2-amino-N, N-dimethyl-3-{4-[4[5-(trifluoromethyl)pyridin-2-yl]amino) phenoxy]phenyl}propanamide dihydrochloride salt;
(2S)- 2-amino-N, N-dimethyl-3- {4-[4-(3-nitropyridin-2-ylamino) phenoxy] phenyl}propanamide dihydrochloride salt;
(2S)-2-amino-N, N-dimethyl-3- (4-{4-[(3-cyanopyridin-2-yl) amino] phenoxy} phenyl)-propanamide di hydrochloride salt;
(2S)-2-amino-N, N-dimethyl-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di hydrochloride salt;
(2S)-2-amino-N-(4-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; (2S)-2-amino-N-(3-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N-(2-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,4-difluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; (2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,4-difluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,5-difluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt; (2S)-2-amino-N- (2-chIoro-3, 6-difluorobenzyl)-3-{4-[(5-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoro hydrochloride salt;
(2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt; (2S)-2-amino-3- |4-[(3-nitropyridin-2-yl) oxy] phenyl}-N- [4-(trifluoromethyl) phenyl] propanamide di tifluoroacetic acid salt;
(2S)-2-amino-N- (4-cyanophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (2-fluorophenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)~2-amino-N- (3-fluoro-4-methylphenyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)~2-amino-N- (4-bromo-3-fluorophenyl)-3-[4-(pyridin-2-ylmethoxy) phenyl] propanamide di trifluoroacetic acid salt; (2S)-2-amino-N- (2-chloro-3, 6-difluorobenzyl)-3-{4-[(3-nitropyridin-2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt;
(2S)-2-amino-3- [4-(pyridin-2-ylmethoxy) phenyl]-N- [4-(trifluoromethyl) phenyl] propanamide di trifluoroacetic acid salt;
(2S)-2-amino-3- {4-[(5-nitropyridin-2-yl) oxy] phenyl}-N- [4-(trifluoromethyl) phenyl] propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N-(3-fluoro-4-methylphenyl)-3-(4-{[5-(trifluoromethyl) pyridin-2-yl] oxy}phenyl)propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3,5-difluorophenyl)-3-{4-[(5-(trifluoromethyl)pyridin-
2-yl) oxy] phenyl} propanamide di trifluoroacetic acid salt; (2S)-2-amino-N-[4-(trifluoromethyl)phenyl]-3-(4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl) propanamide di trifluoroacetic acid salt;
(2S)-2-amino-3- [4-(pyridin-2-ylmethoxy) phenyl]-N- (3,4,5-trifluorophenyl) propanamide di trifluoroacetic acid salt;
(2S)-2-amino-N- (3-chloro-4-fluorophenyl)-3-(4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl) propanamide trifluoroacetic acid salt;
(2S)-2-amino-3- (4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl)-N-
(3,4,5-trifluorophenyl) propanamide trifluoroacetic acid salt and (2S)-2-amino-3- (4-{[5-(trifluoromethyl) pyridin-2-yl] oxy} phenyl)-N- (2,4,5-trifluorophenyl) propanamide trifluoroacetic acid salt.
3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate.
4. A pharmaceutical composition as claimed in claim 3, wherein the amount of the compound of claim 1 in the composition is less than 70% by weight.
5. A pharmaceutical composition as claimed in claim 2, in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension
6. A method for the treatment of diseases which are associated with DPP-IV, selected from the group consisting of type II diabetes (non-insulin dependent diabetes mellitus), impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and obesity, which method comprises administering to a patient suffering there from a therapeutically effective amount of a compound according to claim 1
7. The method of claim 6, wherein the compound is administered in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
8. A method of treating insulin resistant non-impaired glucose tolerance in order to prevent or delay the onset of non-insulin dependent diabetes mellitus comprising administering to a patient suffering there from a therapeutically effective amount of a compound according to claim 1.
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WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
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WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
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WO2014064215A1 (en) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2014064215A1 (en) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) TPL2 KINASE INHIBITORS FOR PREVENTING OR TREATING DIABETES AND FOR PROMOTING β-CELL SURVIVAL
WO2016151018A1 (en) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Method and pharmaceutical composition for use in the treatment of diabetes

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