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WO2006011035A1 - Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs - Google Patents

Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs Download PDF

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WO2006011035A1
WO2006011035A1 PCT/IB2005/002146 IB2005002146W WO2006011035A1 WO 2006011035 A1 WO2006011035 A1 WO 2006011035A1 IB 2005002146 W IB2005002146 W IB 2005002146W WO 2006011035 A1 WO2006011035 A1 WO 2006011035A1
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substituted
unsubstituted
methyl
oxoethylamino
mmol
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PCT/IB2005/002146
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English (en)
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Abraham Thomas
Gopalan Balasubramanian
Prasada Rao V. S. Lingam
Daisy Manish Shah
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Glenmark Pharmaceuticals Ltd.
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Publication of WO2006011035A1 publication Critical patent/WO2006011035A1/fr

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    • 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
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • 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
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    • 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
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel organic compounds, their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • the present invention more particularly relates to novel dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I), or analogs, tautomers, enantiomers, diastereomers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.
  • DPP-IV dipeptidyl peptidase IV
  • novel compounds are of general formula (I)
  • Y is -S (O) m -, -CH 2 -, -CHF-, or -CF 2 -;
  • X and Z are independently -C(O)-,-NR 3 -, -O- or -S (O) m -; each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [ — ] in the carbocyclic ring represents an optional double bond;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substitute
  • Each occurrence of R 3 is independently hydrogen, hydroxy, acetyl, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • Each occurrence of R 4 and R 5 may be the same or different and are independently hydrogen, nitro, hydroxy, cyano, formyl, acetyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
  • the present invention also relates to a process for the preparation of the novel organic compounds of formula (I) as defined above.
  • the present invention also relates to compounds which are inhibitors of dipeptidyl peptidase IV (DPP-IV), and to a method for treating diabetes, especially Type II diabetes, as well as impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, anorexia nervosa, osteoporosis, hyperglycemia, syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases, various immunomodulatory diseases, and chronic inflammatory bowel disease (Such as Crohn's disease and ulcerative colitis) with one or more compounds of formula (I).
  • DPP-IV dipeptidyl peptidase IV
  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type II diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type I diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • Type II diabetes which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat.
  • sulfonylureas e.g. tolbutamide and glipizide
  • meglitinide which stimulate the pancreatic ⁇ -cells to secrete more insulin, and/or by injection of insulin when sulphonylureas or meglitinide becomes ineffective, can results in insulin concentrations high enough to stimulate the very insulin-resistance tissues.
  • sulfonylureas or meglitinide sulfonylureas or meglitinide
  • the biguanides increase insulin sensitivity resulting in some correction of hyperglycemia.
  • the two biguanides, phenformin and metformin can induce lactic acidosis and nausea/diarrhea.
  • Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type II diabetes.
  • the glitazones i.e. 5-benzylthiazolidine-2,4-diones
  • glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype.
  • PPAR-gama agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones.
  • Newer PPAR agonists that are being tested for treatment of Type II diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e. , they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have occurred with some of the PPAR agonists, such as troglitazone.
  • New biochemical approaches that have been recently introduced or are still under development include treatment with alpha-glucosidase inhibitors (e.g. acrabose) and protein tyrosine phosphatase- IB (PTP-IB) inhibitors.
  • alpha-glucosidase inhibitors e.g. acrabose
  • PTP-IB protein tyrosine phosphatase- IB
  • DP-IV dipeptidyl peptidase-IV
  • DPP-IV dipeptidyl peptidase-IV
  • DP-IV in vivo readily inactivates glucagon like peptide -1 (GLP-I) and gastric inhibitory peptide (GIP).
  • GLP-I and GIP are incretins and are produced when food is consumed. The increntins stimulate production of insulin. Inhibition of DP-IV leads to decreased inactivation of the incretins, and this in turn results in increased effectiveness of the incretins in stimulating production of insulin by pancreas. DP-IV inhibition therefore results in an increased level of serum insulin.
  • DP-IV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is dangerous side effect associated with the use of insulin secretagogues.
  • DP-IV inhibitors may also have other therapeutic utilities, as discussed herein. DP-IV inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DP-IV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions.
  • NDP-DPP-728 which has the formula A
  • Probiodrug " P32/98 which has the formula B
  • Novartis "NVP-LAF-237” which has the formula C .
  • DPP-IV inhibitors Although a number of DPP-IV inhibitors have been described in the literature, all have limitations relating to potency, stability or toxicity, accordingly, it is clear that a great need exists for new DPP-IV inhibitors which are useful in treating conditions mediated by DPP-IV inhibition.
  • the present invention relates to novel organic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, their N- oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them.
  • the present invention more particularly relates to novel dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I), their analogs, their tautomers, their enantiomers, their diastereomers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their N- oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.
  • DPP-IV dipeptidyl peptidase IV
  • the present invention encompasses compounds of general formula (I)
  • Y is -S (O) 111 -, -CH 2 -, -CHF-, or -CF 2 -;
  • X and Z are independently -C(O)-,-NR 3 ., -O- or -S (O) m -; Each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [ — ] in the carbocyclic ring represents an optional double bond ;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl ;
  • R is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid, including, but not limited to SO 3 H, CONOH, B(OH) 2 , PO 3 R 4 R 5 ,SO 2 N R 4 R
  • R 3 is independently hydrogen, hydroxy, acetyl,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy;
  • R 4 and R 5 may be same or different and are independently hydrogen, nitro, hydroxy, cyano, formyl, acetyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, or a substitute
  • the cyclopentane and cyclopentene ring bearing 1,3-substituents in the compounds of formula I can fall into a cis or trans geometry leading to a mixture of compounds. Such substitution patterns with two chiral centres can lead up to 4 enantiomers. Therefore, the compounds of interest of the present invention may be prepared as single enantiomers or as a mixture of enanatiomers. Mixtures as well as single enantiomers of the above mentioned isomers are encompassed within the scope of this invention.
  • the optically active compounds useful for the present invention may be obtained by resolution, asymmetric synthesis, or other methods known in the art.
  • X is -NR 3 .
  • Z is -S(O) m " and m is 2.
  • a is 0 and b is 1.
  • Y is CH 2
  • Y is CHF
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring. In a further preferred embodiment, R 1 is methyl.
  • R 1 is butyl
  • R 1 is phenyl
  • R 1 is 4-methyl phenyl.
  • R 1 is 4-trifluoromethyl phenyl. In a further preferred embodiment, R 1 is 4-fluoro phenyl.
  • R 1 is 2-fluoro phenyl.
  • R 1 is 2, 4-dichloro phenyl
  • R 1 is 3, 4-dichloro phenyl. hi a further preferred embodiment, R 1 is 4-methyl sulfanyl phenyl. In a further preferred embodiment, R 1 is 4-methyl sulfonyl phenyl.
  • R 1 is 4-methoxy phenyl.
  • R 1 is 3,4-di (difluoromethoxy) phenyl.
  • R 1 is pyridine-3-yl.
  • R 1 is adamantane-1-yl. In a further preferred embodiment, R 1 is 1- benzyloxycarbonyl -pyrorolidin-2- yi.
  • R 1 1- benzyloxycarbonyl -4-fluoro- pyrorolidin-2-yl.
  • R 1 lH-pyrrole-2-yl In a further preferred embodiment, R 1 1- benzyloxycarbonyl -2,3-dihydro-l//- indole-2-yl.
  • R 1 lH-indole-3-yl In a further preferred embodiment, R 1 lH-indole-3-yl.
  • R 1 is a moiety of the formula:
  • R 2 is nitrile (-CN)
  • R 3 is hydrogen
  • aryl refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group, e.g., -CH 2 C 6 H 5 , -C 2 H 5 C 6 H 5 and the like.
  • heterocyclic ring refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidiny
  • heteroaryl refers to an aromatic heterocyclic ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical as defined above directly bonded to alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
  • alkyl' refers to a straight or branched hydrocarbon chain radical containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl), and the like.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2 -methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having in the range of 2 up to about 12 carbon atoms (with radicals having in the range of 2 up to about 10 carbon atoms presently being preferred), e.g., ethynyl, propynyl, butnyl and the like.
  • alkoxy denotes an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH 3 , -OC 2 H 5 and the like.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms directly attached to alkyl group which are then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl, and the like.
  • cycloalkenyl refers to cyclic ring-containing radicals containing in the range of 3 up to about 8 carbon atoms with at least one carbon- carbon double bond, such as cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifiuoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexyl amine, metformin, benzylamine, trialkylamine, thiamine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, and the like; quaternary ammonium salts of the compounds of
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates such as trifluroacetate , tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing a compound of the invention of the present invention may be prepared by conventional techniques, e.g. as described in
  • compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of the invention which inhibits the enzymatic activity of DPP-IV or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-IV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: 1 Core: Active compound (as free compound or salt thereof) 250 mg
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of a condition that may be regulated or normalized via inhibition of DPP- IV.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of metabolic disorders.
  • a further aspect of the present invention is the use of a compound of formula (I)
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of Type II diabetes.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of impaired glucose tolerance (IGT).
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of impaired fasting glucose (IFG).
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the prevention of hyperglycemia.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for delaying the progression of impaired glucose tolerance (IGT) to Type II diabetes.
  • a further aspect of the present invention is the use of a compound of formula (I)
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for increasing the number and/or the size of beta cells in a subject.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of beta cell degeneration, in particular apoptosis of beta cells.
  • a further aspect of the present invention is the use of a compound of formula (I)
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of obesity.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for appetite regulation or induction of satiety.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of dyslipidemia.
  • a further aspect of the present invention is the use of a compound of formula (I) as a pharmaceutical composition in a therapeutically effective amount for the treatment of functional dyspepsia, in particular irritable bowel syndrome.
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g., Type II diabetes, IGT, IFG, obesity, appetite regulation or as a blood glucose lowering agent, and especially Type II diabetes.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used.
  • a most preferable dosage is about 0.5 mg to about 250 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • the invention also encompasses prodrugs of a compound of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of a compound of the invention, which are readily convertible in vivo into a compound of the invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the invention also encompasses active metabolites of a compound of the invention.
  • Y is -S (O) 1n -, -CH 2 -, -CHF-, or -CF 2 -;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl ;
  • R 2 is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid, including, but not limited to SO 3 H, CONOH, B(OH) 2 , PO 3 R 4 R 5 ,SO 2 N R 4
  • R 3 is independently hydrogen, hydroxy, acetyl,substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
  • R and R 5 may be same or different and are independently hydrogen, nitro, hydroxy, cyano, formyl, acetyl, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstit
  • L is a leaving group and PG is protecting group
  • the compounds of general formula (I) can be prepared using a variety of methods known in the literature and known to those skilled in the art. One such approach is given in the general synthetic scheme.
  • Intermediate of general formula (1) can be coupled with mono-protected bifunctional intermediate of the general (2) and the coupled product can be deprotected to yield intermediate of general formula (3).
  • Compounds of the general formula (I) can also be obtained by coupling of intermediates (3) and (4) using the suitable base such as triethylamine, K 2 CO 3 and the like.
  • the coupling sequence of the fragments (l)-(4) can also be altered and the compounds of general formula I can be obtained by a variety of other methods known to persons skilled in the art.
  • the compounds of the invention are isolated and purified via known techniques, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecepitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.
  • the chlorinated solvent which may be employed include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, chloroform, and carbontetrachloride.
  • the aromatic solvents which may be employed include, but are not limited to, benzene and toluene.
  • the alchoholic solvents which may be employed include, but are not limited to, methanol, ethanol, n-propanol, iso propanol, and tert-butanol.
  • the compounds prepared in the above described processes are obtained in pure form by using known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethan
  • polymorphs of a compound of general formula (I) may be prepared by crystallization of compound of formula (I) under different conditions, for example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides novel organic compounds of general formula (I), their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides and their pharmaceutically acceptable solvates.
  • the present invention also provides pharmaceutical compositions, containing compounds of general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.
  • some of the compounds of general formula (I) can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in the compounds of general formula (I) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.
  • the invention may also contain E & Z geometrical isomers wherever possible in the compounds of general formula (I) which includes the single isomer or mixture of both the isomers
  • Step 1 ( ⁇ )-2-N-BOC-Azabicyclo[2.2.1]hept-5-ene-3-one: A solution of di-tert-butyl dicarbonate (144.0 g, 660.5 mmol) in THF (100 ml) was added (20 min) to a stirred solution of ( ⁇ )-2-Azabicyclo[2.2.1]hept-5-ene-3-one (60.0 g, 549.8 mmol), triethylamine (83.5 g, 824.6 mmol) and 4-dimethylaminopyridine (6.7 g, 54.8 mmol) in THF (500 ml) at room temperature. The reaction mixture was stirred for another 4 h at room temperature.
  • Step 2 c/s-( ⁇ )-4-N-BOC-Aminocyclopent-2-ene-l-carboxylic acid: To a stirred solution of Step 1 intermediate (30.0 g, 143.3 mmol) in THF (100 ml) was added IN sodium hydroxide (300 ml) and the mixture was stirred at 40 °C for 20 h. The reaction mixture was cooled to 0 °C and acidified to pH 3.5 with IN hydrochloric acid. The mixture was extracted with dichloromethane (3 x 200 ml) and the combined extracts were washed with water (2 x 300 ml), brine (300 ml) and dried (Na 2 SO 4 ).
  • Step 3 cis-( ⁇ )-3 -N-BOC- Aminocyclopentane-1-carboxylic acid: To a solution of Step 2 intermediate (15.0 g, 66.0 mmol) in methanol (100 ml) was added 5 % Pd/C (1.0 g) and the mixture was maintained under hydrogen pressure (40 psi) for 2 h at room temperature.
  • Step 1 cis-( ⁇ )-3 -N-BOC- Aminocyclopentylmethanol: Ethyl chloroformate (4.73 g, 43.58 mmol) was added to a stirred solution of Intermediate 1 (10.0 g, 43.66 mmol) and triethylamine (4.42 g, 43.76 mmol) in dry THF (100 ml) at 0 0 C over 5 min under a nitrogen atmosphere. The reaction mixture was stirred for another 30 min at the same temperature. It was then filtered to remove the precipitated triethylamine hydrochloride.
  • the filtrate containing the mixed anhydride was slowly added to a stirred suspension Of NaBH 4 (4.95 g, 130.84 mmol) in 20 % aqueous THF (100 ml) maintained at 10 0 C.
  • the mixture was stirred for another 30 min at the same temperature and then acidified with IN HCl to pH 4.
  • the mixture was extracted with EtOAc (3 x 200 ml) and the organic layer was washed with 2 NNaOH (2 x 250 ml), water (2 x 250 ml) and brine (300 ml).
  • Step 2 cis-( ⁇ )-(l»S7?,3i?S)-3-N-BOC-Aminocyclopentylmethyl methanesulfonate: Methanesulfonyl chloride (15.23 g, 0.13 mol) was added to a stirred and cooled (10 0 C) solution of Step 1 intermediate (26.0 g, 0.12 mol) and triethylamine (15.0 g, 0.15 mol) in dry dichloromethane (150 ml) under a nitrogen atmosphere. The mixture was stirred at the same temperature for 15 min and then diluted with water (150 ml). The organic and aqueous layers were separated.
  • Step 3 cw-( ⁇ )-3-N-BOC-Aminocyclopentylmethyl azide: Sodium azide (3.1 g, 47.6 mmol) was added to a stirred solution of Step 1 intermediate (7.0 g, 23.8 mmol) in DMF (100 ml) and the mixture was stirred at 60 0 C for 6 h under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with EtOAc (500 ml) and water (500 ml). The layers were separated and the organic layer was washed with water (3 x 300 ml), brine (300 ml) and dried (Na 2 SO 4 ).
  • Step 4 cw-( ⁇ )-3-N-BOC-Aminocyclopentylmethylamine: To a solution of azide, from Step 2 (5.0 g, 20.8 mmol) in methanol (100 ml) was added 5 % Pd/C (300 mg) and the mixture was maintained under hydrogen pressure (40 psi) for 3 h at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 4.45 g of the amine as a semisolid, which was used as such for the coupling reaction.
  • Step 1 (15',4i?)-(+)-2-N-BOC-Azabicyclo[2.2.1]he ⁇ t-5-ene-3-one: This intermediate was synthesized from (15',4i?)-(+)-2-Azabicyclo[2.2.1]hept-5-ene-3-one (10.0 g, 91.74 mmol) and di-tert-buty ⁇ dicarbonate (26.0 g, 119.26 mmol) using triethylamine (13.92 g, 137.5 mmol) and 4-dimethylaminopyridine (1.1 g, 9.17 mmol) in THF (50 ml) as described in Intermediate 1, Step 1 to give 19.3 g of the compound as a white solid; IR and 1 H NMR spectra of the product were identical with that of the racemic product from Intermediate 1, Step 1.
  • Step 2 (li?,45)-(+)-2-N-BOC-Azabicyclo[2,2,l]he ⁇ tan-3-one:
  • the Step 1 intermediate (9.0 g, 43.26 mmol) from Method B was hydrogenated using 5 % Pd/C (1.0 g) to give 9.0 g of the product as a white solid;
  • 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.42 (d, J 10.2 Hz, IH), 1.52 (s, 9H), 1.73-1.96 (m, 5H), 2.86 (brs, IH), 4.53 (brs, IH).
  • Step 3 (15',3i?)-(+)-3-iV-BOC-Aminocyclopentane-l-carboxylic acid: To a stirred solution of Step 2 intermediate (8.5 g, 40.26 mmol) in THF (40 ml) was added ⁇ N sodium hydroxide (80 ml) and the mixture was stirred at 50 °C for 24 h. The reaction mixture was cooled to 0 °C and acidified to pH 3.5 with 1 N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 100 ml) and the combined organic extracts were washed with water (2 x 100 ml), brine (100 ml) and dried (Na 2 SO 4 ). The solvent was evaporated under reduced pressure to give 8.0 g of the product as a white solid, which was identical in all respects with the product isolated by Method A.
  • Step 3 (15',3 ⁇ )-(+)-3-N-BOC-Aminocyclopentylmethyl azide: Sodium azide (3.1 g, 47.6 mmol) was added to a stirred solution of Step 2 intermediate (7.0 g, 23.8 mmol) in DMF (100 ml) and the mixture was stirred at 60 0 C for 6 h under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with EtOAc (500 ml) and water (500 ml). The layers were separated and the organic layer was washed with water, brine and dried (Na 2 SO 4 ).
  • Step 4 ( ⁇ S,3R)-(+)-3 -N-BOC- Aminocyclopentylmethylamine: To a solution of Step 3 intermediate (6.0 g, 25.0 mmol) in methanol (150 ml) was added 5 % Pd/C (300 mg) and the mixture was maintained under hydrogen pressure at 50 psi to give 5.35 g of the amine as a semisolid, which was used as such for the coupling reaction.
  • This intermediate was prepared by the optical resolution of Intermediate 1 using (R)- (+)-phenylethylamine in isopropyl alcohol.
  • Step 1 (li?,45)-(-)-2-N-BOC-Azabicyclo[2,2,l]hept-5-ene-3-one: This intermediate was synthesized from (l ⁇ ,45)-(-)-2-Azabicyclo[2,2,l]he ⁇ t-5-ene-3-one (10.0 g, 91.74 mmol) and di-tert-butyl dicarbonate (23.9 g, 119.26 mmol) in the presence of triethylamine (13.9 g, 137.3 mmol) and 4-dimethylaminopyridine (1.1 g, 9.0 mmol) in THF (50 ml) as described in Intermediate 1, Step 1 to give 19.1 g of the compound as a white solid; IR and 1 H NMR spectra of the product were identical with that of the racemic product from Intermediate 1 , Step 1.
  • Step 2 (l 1 S,4i?)-(-)-2-N-BOC-Azabicyclo[2,2,l]heptan-3-one:
  • the Step 1 intermediate (9.0 g, 43.26 mmol) from Method B was hydrogenated using 5 % Pd/C (1.0 g) to give 9.0 g of the product as a white solid;
  • IR and 1 H NMR spectra of the product were identical with that of (li?,45)-(+)-2-7V-BOC-Azabicyclo[2,2,l]heptan-3- one (see Step 2, Method B, Intermediate 3).
  • Step 3 (li?,3iS)-(-)-3 -N-BOC- Aminocyclopentane-1-carboxylic acid: Hydrolytic cleavage of Step 2 intermediate (8.5 g, 40.26 mmol) using IN sodium hydroxide (80 ml) in THF as described in Intermediate 1, Step 2 gave 8.0 g of the product as a white solid, which was identical in all respects with the product isolated by Method A.
  • Step 1 (35,li?)-(-)-3-N-BOC-Aminocyclopentylmethanol: Reductive cleavage of (15,47?)-(-)-2-N-BOC-Azabicyclo[2,2,l]he ⁇ tan-3-one (10.0 g, 47.33 mmol) using sodium borohydride (3.58 g, 94.6 mmol) in 10 % aqueous THF (100 ml) as described in Intermediate 4, Method A gave 8.5 g of the product as a white solid.
  • Method B The mixed anhydride of Intermediate 2 (8.5 g, 37.07 mmol) prepared using ethyl chloroformate (4.43 g, 40.78 mmol) and triethylamine (4.13 g, 40.78 mmol) in dry THF was treated with NaBH 4 (4.21 g, 111.21 mmol) in 20 % aqueous THF as described in Intermediate 2, Step 1 to give 7.0 g of the alcohol as a white solid, which was identical in all respects with the product obtained by Method A.
  • Step 2 (35',li?)-(-)-3-N-BOC-Aminocyclopentylmethyl methanesulfonate: Reaction of Intermediate 1 (6.5 g, 30.2 mmol) with methanesulfonyl chloride (3.8 g, 33.18 mmol) in the presence of triethylamine (3.97 g, 39.2 mmol) in dry dichloromethane (100 ml) under a nitrogen atmosphere as described in Intermediate 4 gave 8.5 g (96.5 %) of the product as a white solid.
  • Step 3 (3S, ⁇ R)-3 -N-BOC- Aminocyclopentylmethyl azide:
  • the Step 2 intermediate (8.0 g, 27.3 mmol) was treated with sodium azide (3.5 g, 54.4 mmol) in DMF (150 ml) as described in Intermediate 4, Step 3 to give 6.5 g (100 %) of the azide as an oil.
  • IR and 1 H NMR spectra of the product were identical with that of the racemic product from Intermediate 2, Step3.
  • Step 4 (3S,l ⁇ )-3-Aminocyclopentylmethylamine:
  • the azide (6.0 g, 25.0 mmol) from Step 3 in methanol (150 ml) was reduced with 5 % Pd/C (300 mg) as described in Intermediate 4, Step 4 to give 5.35 g (100 %) of the amine as a semisolid, which was used as such for the coupling reaction.
  • This intermediate was prepared from L-(-)-proline using a literature procedure (J. Med. Chem., 2003, 46, 2774-2789).
  • Step 1 (25',45)-N-BOC-4-Fluoropyrrolidine-2-carboxamide: This intermediate was prepared in 5 steps from L-(-)-4-hydroxyproline using a literature procedure (WO 03/002553 A2)
  • Step 2 (25 r ,45)-N-BOC-4-Fluoropyrrolidine-2-carbonitrile: To a stirred and cooled (0 0 C) solution of Step 1 intermediate (10.0 g, 43.10 mmol) in dry THF (50 ml) was added triethylamine (13.93 g, 138 mmol) and trifluoroacetic anhydride (14.5 g, 69.05 mmol). The resulting clear solution was stirred at the same temperature for 1 h. The reaction was quenched with water (100 ml) and extracted with chloroform (2 x 100 ml).
  • Step 3 (25',4iS)-4-Fluoropyrrolidine-2-carbonitrile />-methylbenzenesulfonate: 4- Methyl-benzenesulfonic acid monohydrate (15.2 g, 79.91 mmol) was added to a solution of step 2 intermediate (8.5 g, 39.72 mmol) in acetonitrile (170 ml) and the mixture was stirred at room temperature for 48 h. The solvent was then evaporated under reduced pressure to afford a brown residue which was taken up in dry diethyl ether (200 ml) and stirred for 1 h.
  • Step 4 (25 I ,45)-l-(2-Chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile:
  • a solution of step 3 intermediate (10.0 g, 32.89 mmol) and triethylamine (4.32 g, 42.77 mmol) in dichloromethane (200 ml) was added dropwise to a stirred and cooled (0 0 C) solution of chloroacetyl chloride (4.81 g, 32.95 mmol) in dichloromethane (50 ml) over a period of 10 min.
  • the mixture was stirred at the same temperature for 2 h and diluted with dichloromethane (100 ml) and water (100 ml) under stirring.
  • the layers were separated.
  • Step 1 ⁇ -[(l ⁇ S ⁇ -S-TV-BOC-AminocyclopentylmethylJmethanesulfonamide: A solution of methanesulfonyl chloride (1.04 g, 9.09 mmol) in dichloromethane (15 ml) was added (5 min) to a stirred solution of Intermediate 4 (1.95 g, 9.09 mmol) and TEA (2.75 g, 27.27 mmol) in dichloromethane (15 ml) at 10 0 C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 2 h and diluted with DCM and water. The layers were separated and the organic layer was washed with water, brine and dried (Na 2 SO 4 ).
  • Step 2 M-[(15,3/?)-3-Aminocyclopentylmethyl]methanesulfonamide trifluoroacetate: To a stirred solution of Step 1 intermediate (900 mg, 3.08 mmol) in dichloromethane (3.0 ml) was added trifluoroacetic acid (3.0 ml) at 10 0 C and the solution was maintained at the same temperature for 1 h under a nitrogen atmosphere. The mixture was evaporated under reduced pressure to give 946 mg of the amine as its TFA salt which was used as such for the next step.
  • Step 3 M-((15,3i?)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)methanesulfonamide: K 2 CO 3 (1.7 g, 12.32 mmol) was added to a stirred and cooled (10 0 C) suspension of Step 2 intermediate (946 mg, 3.08 mmol) in dry THF (25 ml) and the mixture was stirred for 30 min to generate the free base. To this mixture was added NaI (231 mg, 1.54 mmol) followed by dropwise addition (2 h) of Intermediate 7 (266 mg, 1.54 mmol) in dry THF (10 ml).
  • the temperature of the reaction mixture was raised to room temperature and further stirred for 18 h.
  • the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in water and extracted with CHCl 3 .
  • the combined organic layers were dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • Step 2 M-[(157?,3i?5)-3-Aminocyclopentylmethyl]butanesulfonamide: To a stirred solution of Step 1 intermediate (1.5 g, 4.49 mmol) in dichloromethane (4.0 ml) was added trifluoroacetic acid (4.0 ml) at 10 0 C and the solution was maintained at the same temperature for 30 min under a nitrogen atmosphere. Trifluoroacetic acid and dichloromethane were removed under reduced pressure. The residue obtained was dissolved in water (8 ml), basified to pH 10 with 2 N NaOH and extracted with dichloromethane (2 x 50 ml).
  • Step 3 M-((15 ⁇ ,3i?5)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ cyclo- pentylmethyl)-l-butanesulfonamide: A solution of Intermediate 7 (184 mg, 1.07 mmol) in dry THF (10 ml) was added to a stirred and cooled (10 °C) mixture of Step 2 intermediate (500 mg, 2.14 mmol), K 2 CO 3 (246 mg, 2.134 mmol) and NaI (160 mg, 1.07 mmol) in dry THF (10 ml) over a period of 2 h.
  • Step 2 Nl-[(15',3i?)-3-Aminocyclopentylmethyl]butanesulfonamide: Deprotection of Step 1 intermediate (1.5 g, 4.49 mmol) using TFA (4 ml) in dichloromethane (4 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 972 mg of the free base which was used as such for the next step.
  • Step 3 7Vl-((l 1 S,3 ⁇ )-3- ⁇ 2-[(25,45)-2-Cyano-4-fluoropyrrolidin-l-yl]-2- oxoethylamino ⁇ -cyclopentyl-methyl)- 1 -butanesulfonamide: Coupling reaction of Step 2 intermediate (400 mg, 1.71 mmol) with Intermediate 8 (162 mg, 0.85 mmol) in the presence Of K 2 CO 3 (236 mg, 1.71 mmol) and NaI (127 mg, 0.85 mmol) as described in Example 2, Step 3 gave 210 mg of the product as a semisolid; IR (neat) 3293, 2958, 2242, 1664, 1415, 1320, 1141, 1077, 958 cm “1 ; 1 U NMR (CDCl 3 , 300 MHz) ⁇ 0.85- 0.97 (m, 4H), 1.25-1.50 (m, 3H), 1.54-2.02 (m, 7H), 2.25-2.72
  • Step 1 Nl-[(15',3i?)-3-jV-BOC-Aminocyclo ⁇ entylmethyl]-4-methyl-l-benzene- sulfonamide: This compound was prepared from Intermediate 4 (1.1 g, 5.14 mmol) and />-toluenesulfonyl chloride (1.17 g, 6.17 mmol) in the presence of triethylamine (624 mg, 6.17 mmol) in dichloromethane (20 ml) as described in Example 1, Step 1 to give 1.37 g of the product as a white solid; IR (KBr) 3366, 3297, 2957, 1686, 1524, 1300, 1154, 1074 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.92-1.02 (m, IH), 1.27-1.40 (m, 2H), 1.42 (s, 9H), 1.66-1.75 (m, IH), 1.91-2.07 (m, 2H), 2.1
  • Step 2 Nl-[(15,3i?)-3-Aminocyclopentylmethyl]-4-methyl-l-benzenesulfonamide: Deprotection of Step 1 intermediate (1.0 g, 2.72 mmol) using TFA (4 ml) in dichloromethane (4 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 600 mg of the free base which was used as such for the next step.
  • Step 1 Nl -[(li?,35)-3-N-BOC-Aminocyclopentylmethyl]-4-methyl-l -benzene- sulfonamide: This compound was prepared from Intermediate 4 (1.1 g, 5.14 mmol) and /7-toluenesulfonyl chloride (1.17 g, 6.17 mmol) in the presence of triethylamine (624 mg, 6.17 mmol) in dichloromethane (20 ml) as described in Example 1, Step 1 to give 1.35 g of the product as a white solid; IR (KBr) 3365, 3296, 2957, 1685, 1524, 1299, 1154, 1074 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.92-1.02 (m, IH), 1.26-1.40 (m, 2H), 1.42 (s, 9H), 1.66-1.75 (m, IH), 1.91-2.20 (m, 3H), 2.43
  • Step 2 M-[(li?,3-S)-3-Aminocyclopentylmethyl]-4-methyl-l-benzenesulfonamide: Deprotection of Step 1 intermediate (1.0 g, 2.72 mmol) using TFA (4 ml) in dichloromethane (4 ml) followed by workup of the reaction mixture as described in Example 2, Step 2 gave 684 mg of the free base which was used as such for the next step.
  • Step 1 Nl -[(35 1 , li?)-3-N-BOC-Aminocyclopentylmethyl]-4-trifluoromethyl-l - benzenesulfonamide: This compound was prepared from Intermediate 6 (508 mg, 2.38 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (581 mg, 2.38 mmol) in the presence of triethylamine (288 mg, 2.85 mmol) in dichloromethane (15 ml) as described in Example 1, Step 1, to give 1.1 g of the product as a white solid; IR (KBr) 3360, 2977, 2239, 1685, 1529, 1317, 1158 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.97- 1.07 (m, IH), 1.22-1.41 (m, 2H), 1.43 (s, 9H), 1.64-1.80 (m, 2H), 1.93-2.23 (m, 2H),
  • Step 2 M -[(3S, 17?)-3-Aminocyclopentylmethyl]-4-trifluoromethyl- 1 -benzene ⁇ sulfonamide:
  • Acetonitrile was removed under reduced pressure and the residue obtained was dissolved in water (20 ml) and neutralized with saturated NaHCO 3 solution.
  • the mixture was extracted with dichloromethane (3 x 50 ml) and the combined organic extracts were washed with water, brine and dried over anhydrous Na 2 SO 4 .
  • the solvent was evaporated under reduced pressure to afford 375 mg of the free amine as a viscous residue.
  • Step 3 Nl-((3S,l£)-3- ⁇ 2-[(2S)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-4-trifluoromethyl-l -benzenesulfonamide: Coupling reaction of Step 2 intermediate (370 mg, 1.15 mmol) with Intermediate 7 (99 mg, 0.58 mmol) in the presence Of K 2 CO 3 (159 mg, 1.15 mmol) and NaI (86 mg, 0.58 mmol) as described in Example 2, Step 3 gave 113 mg of the product as a semisolid; IR (neat) 3289, 2953, 2242, 1659, 1405, 1324, 1163 cm '1 ; 1 H ⁇ MR (CDCl 3 , 300 MHz) ⁇ 1.24-1.49 (m, 2H), 1.64-1.92 (m, 4H), 2.05-2.70 (m, 5H), 2.86- 3.16 (m, 7H), 4.75
  • Step 1 JVl -[(15,3 ⁇ )-3-N-BOC-Aminocyclopentylmethyl]-4-methoxy- 1 -benzene- sulfonamide:
  • This compound was prepared from Intermediate 4 (2.5 g, 7.57 mmol) and 4-methoxybenzenesulfonyl chloride (1.87 g, 9.05 mmol) in the presence of triethylamine (2.29 g, 22.60 mmol) as described in Example 1, Step 1 to give 2.8 g of the product as a white solid;
  • Step 2 ⁇ [(l ⁇ S ⁇ -S-Aminocyclopentylmethy ⁇ -methoxy-l-benzenesulfonamide: Deprotection of Step 1 intermediate (600 mg, 1.56 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 443 mg of the free base which was used as such for the next step.
  • Step 3 M-((lS,3 ⁇ -3- ⁇ 2-[(2S)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-4-methoxy- 1 -benzenesulfonamide: Coupling reaction of Step 2 intermediate (443 mg, 1.56 mmol) with Intermediate 7 (135 mg, 0.78 mmol) in the presence Of K 2 CO 3 (216 mg, 1.56 mmol) and NaI (117 mg, 0.78 mmol) as described in Example 2, Step 3 gave 90 mg of the product as a yellow semisolid; IR (neat) 3292, 2951, 2871, 2241, 1659, 1597, 1497, 1414, 1324, 1303, 1258, 1154, 1096 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.41-1.83 (m, 7H), 2.17-2.28 (m, 5H), 2.41 (brs, IH
  • Step 2 M -[(lS,3/?)-3-Aminocyclopentylmethyl]-4-fluoro-l -benzenesulfonamide: Deprotection of Step 1 intermediate (900 mg, 2.42 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 591 mg of the free base which was used as such for the next step.
  • Step 1 M-[(35',li?)-3-N-BOC-Aminocyclopentylmethyl]-2,4-dichloro-l-benzene- sulfonamide: This compound was prepared from Intermediate 6 (508 mg, 2.38 mmol) and 2,4-dichlorobenzenesulfonyl chloride (583 mg, 2.38 mmol) using triethylamine (288 mg, 2.85 mmol) in DCM (10 ml) as described in Example 1, Step 1, to give 1.0 g of the product as a white solid; IR (KBr) 3376, 3305, 2969, 1682, 1515, 1330, 1160 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.99-1.05 (m, IH), 1.26-1.40 (m, IH), 1.43 (s, 9H), 1.64-1.80 (m, 2H), 1.93-2.23 (m, 4H), 2.86-2.90 (m, 2H),
  • Step 2 M-[(3S,li?)-3-Aminocydopentylmethyl]-2,4-dichloro-l- benzenesulfonamide: Deprotection of Step 1 intermediate (500 mg, 1.18 mmol) with /j-toluenesulfonic acid monohydrate (337 mg, 1.77 mmol) as described in Example 8, Step 2 gave 375 mg of the free amine as an off-white solid.
  • Step 3 Nl-((35,li?)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-2,4-dichloro-l -benzenesulfonamide: Coupling reaction of Step 2 intermediate (370 mg, 1.46 mmol) with Intermediate 7 (99 mg, 0.57 mmol) in the presence Of K 2 CO 3 (158 mg, 1.15 mmol) and NaI (86 mg, 0.57 mmol) gave 133 mg of the product as a semisolid; IR (neat) 3307, 2953, 2246, 1658, 1573, 1412, 1163 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.41-1.55 (m, IH), 1.65-1.92 (m, 9H), 2.05-2.63 (m, 5H), 2.78-3.01 (m, IH), 3.12-3.32 (m, 2H),
  • Step 2 Nl-[(15 r ,3i?)-3-Aminocyclopentylmethyl]-3,4-dichloro-l- benzenesulfonamide: Deprotection of Step 1 intermediate (900 mg, 2.13 mmol) with /7-toluenesulfonic acid monohydrate (809 mg, 4.26 mmol) as described in Example 8, Step 2, gave 687 mg of the free amine as a yellow solid which was used as such for the next step.
  • Step 1 4-Methylsulfanyl-l-benzenesulfonyl chloride: To a cooled (0 °C) and stirred solution of thioanisole (1.0 g, 8.05 mmol) in chloroform (10 ml) was cautiously added chlorosulfonic acid (2.81 g, 24.15 mmol) in one portion. Stirring was continued for 3 h. The reaction mixture was added to ice-cold water and extracted with dichloromethane. Combined organic extracts were washed with water, brine and dried (Na 2 SO 4 ).
  • Step 2 M-[(15',3i?)-3-N-BOC-Aminocyclo ⁇ entylmethyl]-4-methylsulfanyl-l- benzenesulfonamide:
  • This compound was prepared from Step 1 intermediate (2.0 g, 8.98 mmol) and Intermediate 4 (2.89 g, 13.50 mmol) in the presence of triethylamine (3.6 g, 35.57 mmol) as described in Example 1, Step 1, to give 1.9 g of the product as a pale yellow solid;
  • Step 3 M -[( 1 £,3i?)-3-Aminocyclopentylmethyl]-4-methylsulfanyl- 1 -benzene- sulfonamide: Deprotection of Step 2 intermediate (600 mg, 1.50 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 450 mg of the free base which was used as such for the next step.
  • Step 4 iVl-((l 1 S,3i?)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2- oxoethylaminojcyclopentyl-methyl ⁇ -memylsulfanyl-l-beiizenesulfonamide:
  • Step 1 M-CCl ⁇ S ⁇ -S-iV-BOC-Aminocyclopentylmethy ⁇ -methylsulfonyl-l- benzene-sulfonamide: To a cooled (0 0 C) solution of Step 2 intermediate, Example 13 (1.0 g, 2.50 mmol) in chloroform (20 ml) was added /n-chloroperbenzoic acid (1.73 g, 10 mmol) in portions. The temperature was gradually allowed to rise to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO 3 solution, water, brine and dried (Na 2 SO 4 ).
  • Step 2 M-[(15',3/?)-3-Aminocyclopentylmethyl]-4-methylsulfonyl-l-benzene- sulfonamide: Deprotection of Step 1 intermediate (500 mg, 1.15 mmol) using TFA (3 ml) in dichloromethane (3 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 385 mg of the free base which was used as such for the next step.
  • Step 3 Nl-((lS,3 ⁇ )-3- ⁇ 2-[(2S>2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-4-methylsulfonyl-l-benzenesulfonamide: Coupling reaction of Step 2 intermediate (385 mg, 1.16 mmol) with Intermediate 7 (100 mg, 0.58 mmol) in the presence Of K 2 CO 3 (160 mg, 1.16 mmol) and NaI (87 mg, 0.58 mmol) gave 60 mg of the product as a semisolid; IR (neat) 3306, 2927, 2224, 1657, 1416, 1315, 1156, 1092 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.42-1.64 (m, 4H), 1.74-1.81 (m, 4H), 2.23-2.30 (m, 4H), 2.42-2.60 (m, IH), 2.69 (dd, J
  • Step 2 ⁇ G-[(157?,3i?5)-3-Aminocyclopentylmethyl]-3-pyridinesulfonamide trifluoroacetate: Deprotection of Step 1 intermediate ((700 mg, 1.97 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 gave 730 mg of the amine as its TFA salt which was used as such for the next step.
  • Step 3 7V3 -(( 1 SR,3RS)-3 - ⁇ 2-[(2.S)-2-cyanopyrrolidin- 1 -yl] -2-oxoethylamino ⁇ cyclo- pentylmethyl)-3-pyridinesulfonamide: Coupling reaction of Step 2 intermediate (725 mg, 1.96 mmol) with Intermediate 7 (170 mg, 0.99 mmol) in the presence Of K 2 CO 3 (544 mg, 3.94 mmol) and NaI (147 mg, 0.99 mmol) gave 150 mg of the product as a semisolid; IR (neat) 3290, 2962, 2243, 1657, 1414, 1321, 1162, 1108 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.25-1.96 (m, 6H), 2.07-2.50 (m, 6H), 2.73-2.78 (m, IH), 2.88- 3.75 (m, 7H), 4.76-4.84 (m, I
  • Step 1 intermediate (650 mg, 1.83 mmol) using TFA (3 ml) in dichloromethane (3 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 467 mg of the free base which was used as such for the next step.
  • Step 3 ⁇ G-[(3S,li?)-3- ⁇ 2-[(2S)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-3-pyridinesulfonamide: Coupling reaction of Step 2 intermediate (467 mg, 1.83 mmol) with Intermediate 7 (158 mg, 0.91 mmol) in the presence of K 2 CO 3 (253 mg, 1.83 mmol) and NaI (137 mg, 0.93 mmol) as described in Example 2, Step 3 gave 90 mg of the product as a semisolid; IR (neat) 3624, 3019, 2400, 1644, 1521, 1476, 1416, 1215, 1164, 1045 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.25-1.34 (m, 2H), 1.52-1.85 (m, 6H), 2.23-2.29 (m, 4H), 2.49 (brs, IH), 2.71- 2.76
  • Step 1 M -(( 1 S,3R)-3 -N-BOC- Aminocyclopentylmethyl)- 1 -adamantanecarboxamide: A solution of adamantane-1-carbonyl chloride (2.19 g, 11.10 mmol) in dichloromethane (10 ml) was added to a stirred and cooled (10 0 C) solution of Intermediate 4 (4.76 g, 22.20 mmol) and triethylamine (6.74 g, 66.60 mmol) in dichloromethane (20 ml) over 5 min under a nitrogen atmosphere. The reaction mixture was stirred for 3 h at the same temperature.
  • Step 2 Nl-((15',3i?)-3-Aminocyclopentylmethyl)-l-adamantanecarboxamide trifluoroacetate: Deprotection of Step 1 intermediate (1.0 g, 2.66 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described Example 1, Step 2 gave 1.10 g of the amine as its TFA salt which was used as such for the next step.
  • Step 3 7Vl-((15,3i?)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2- oxoethylaminojcyclopentyl-methyty-l-adamantanecarboxamide: Coupling reaction of Step 2 intermediate (1.10 mg, 2.66 mmol) with Intermediate 7 (230 mg, 1.33 mmol) using K 2 CO 3 (1.47 g, 10.64 mmol) and NaI (200 mg, 1.33 mmol) as described in Example 1, Step 1 gave 150 mg of the product as a colourless oil; IR (neat) 3460, 2906, 2242, 1638, 1449, 1264, 770 cm “1 ; 1 H NMR (CDCI 35 SOO MHZ) S 1.11-1.26 (m, 2H), 1.46-1.60 (m, 2H), 1.64-1.87 (m, 14H), 1.96-2.08 (m, 4H), 2.14-2.32 (m, 5
  • Step 1 M-[(157?,3/?5)-3-N-BOC-Aminocyclopentylmethyl]benzamide: This compound was prepared from Intermediate 2 (2.4 g, 11.0 mmol) and benzoyl chloride (1.57 g, 11.0 mmol) using triethylamine (1.25 g, 12.3 mmol) as described in Example
  • Step 2 M-[(l.S7?,3i?S)-3-aminocyclopentylmethylamino]benzamide: Deprotection of Step 1 intermediate (810 mg, 2.55 mmol) using TFA (4 ml) in dichloromethane (4 ml) followed by workup of the reaction mixture as described Example 2, Step 2 gave 555 mg of the free base which was used as such for the next step.
  • Step 3 M-((157?,37?5)-3- ⁇ 2-[(2-S)-2-cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ cyclo- pentylmethyl)benzamide: Coupling reaction of Step 2 intermediate (553 mg, 1.74 mmol) with Intermediate 7 (150 mg, 0.87 mmol) using K 2 CO 3 (240 mg, 1.74 mmol) and NaI (130 mg, 0.87 mmol) as described in Example 2, Step 3 gave 108 mg of the product as a semisolid; IR (neat) 3318, 2945, 1660, 1628, 1416, 1340, 1166 cm '1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.13-1.99 (m, 6H), 2.10-2.50 (m, 7H), 3.10-3.73 (m, 6H), 3.98 (brs, IH), 4.75 (brs, IH), 7.38 (s, 5H).
  • Step 1 M -(( ⁇ S,3R)-3 -N-BOC- Aminocyclopentylmethyl)-2-fluorobenzamide: This compound was prepared from Intermediate 4 (5.64 g, 17.09 mmol) and 2- fluorobenzoyl chloride (2.26 g, 14.2 mmol) using triethylamine (5.76 g, 56.9 mmol) as described in Example 17, Step 1 to give 2.86 g of the product as an off-white solid; IR (KBr) 3358, 2968, 2924, 1675, 1642, 1520, 1484, 1366, 1310, 1170, 1017 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.10-1.14 (m, IH), 1.26-1.55 (m, 3H), 1.44 (s, 9H), 1.98- 2.06 (m, IH), 2.17-2.29 (m, 2H), 3.45-3.49 (m, 2H), 3.95 (brs, IH
  • Step 2 M-((15,3i?)-3-Aminocyclopentylmethyl)-2-fluorobenzamide: Deprotection of Step 1 intermediate (1.0 g, 2.97 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described in Example 2, Step 2 gave 702 mg of the free base which was used as such for the next step.
  • Step 3 M-((15,3 ⁇ )-3- ⁇ 2-[(25)-2-Cyanopy ⁇ Olidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-2-fluorobenzamide: Coupling reaction of Step 2 intermediate (702 mg, 2.97 mmol) with Intermediate 7 (256 mg, 1.48 mmol) using K 2 CO 3 (409 mg, 2.96 mmol) and NaI (222 mg, 1.48 mmol) in THF (20 ml) gave 90 mg of the product as a white semisolid; IR (neat) 3444, 2952, 2872, 2242, 1645, 1541, 1482, 1430, 1315, 1221 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.19-1.31 (m, 2H), 1.50- 1.63 (m, 2H), 2.12-2.39 (m, 6H), 3.13-3.17 (m IH), 3.30-3.68 (m, 7H
  • Step 1 M -(( 1 S,3R)-3 -N-BOC- Aminocyclopentylmethyl)-3 ,4-di(difluoromethoxy)- benzamide: To a solution of 3,4-di(difluoromethoxy)benzoic acid (2.0 g, 7.87 mmol) in dichloromethane was added 1-hydroxybenzotriazole (HOBT) (1.80 g, 11.81 mmol) and l-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (EDCI) (2.26 g, 11.81 mmol) at room temperature and stirred for 30 min.
  • HOBT 1-hydroxybenzotriazole
  • EDCI 3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride
  • Step 2 iVl-((15,3i?)-3-Aminocyclopentylmethyl)-3,4-di(difluoromethoxy)benzamide trifluoroacetate: Deprotection of Step 1 intermediate (1.50 g, 3.33 mmol) using trifluoroacetic acid (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described Example 1, Step 2 gave 1.54 g of the amine as its TFA salt which was used as such for the next step.
  • Step 3 Nl-((15,3i?)-3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ cyclopentyl-methyl)-3,4-di(difluoromethoxy)benzamide: Coupling reaction of Step 2 intermediate (1.50 g, 3.33 mmol) with Intermediate 7 (0.35 g, 2.00 mmol) using K 2 CO 3 (1.37 g, 9.99 mmol) and NaI (0.30 g, 2.0 mmol) as described in Example 1, Step 3 gave 430 mg of the product as a white semisolid; IR (neat) 3310, 2952, 1652, 1414, 1274, 1137, 759 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.38-1.43 (m, IH), 1.68-1.75 (m, 5H), 1.93-2.28 (m, 6H), 2.63 (brs, IH), 3.05
  • Step 1 Benzyl (2S)-2-((l 85/ ⁇ -3 -N-BOC-aminocyclopentylmethylcarbamoyl)- pyrrolidine-1-carboxylate: Coupling reaction of N-Benzyloxycarbonyl-L-proline (2.0 g, 8.01 mmol) with Intermediate 4 (2.57 mg, 12.01 mmol) in the presence of HOBT (614 mg, 4.01 mmol), EDCI (2.3 g, 11.99 mmol) and triethylamine (1.62 g, 16.06 mmol) in dry dichloromethane (30 ml) as described in Example 20, Step 1 gave 2.8 g of the product as white solid; IR (KBr) 3338, 2970, 2955, 1711, 1681, 1655, 1536, 1489, 1413, 1363, 1316, 1247, 1167,1047 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.85- 0.99 (m,
  • Step 2 Benzyl (25)-2-((15',3/?)-3-aminocyclopentylmethylcarbamoyl)pyrrolidine-l- carboxylate: Deprotection of Step 1 intermediate (1.0 g, 2.24 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described in Example 2, Step 2 gave 775 mg (100 %) of the free base which was used as such for the next step.
  • Step 3 Benzyl (2S)-2-((lS,3i?)-3- ⁇ 2-[(2S)-2-cyanopvrrolidin-l-yl]-2- oxoethylamino ⁇ -cyclopentylmethylcarbamoytypyrrolidine- 1 -carboxylate: Coupling reaction of Step 2 intermediate (775 mg, 2.24 mmol) with Intermediate 7 (194 mg, 1.12 mmol) using K 2 CO 3 (310 mg, 2.24 mmol) and NaI (168 mg, 1.12 mmol) in THF (20 ml) as described in Example I, Step 1 gave 100 mg of the product as a semisolid; IR (neat) 3429, 2952, 2241, 1693, 1542, 1418, 1357, 1262, 1174, 1122, 1028 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.91-0.99 (m, IH), 1.23-1.62 (m, 4H), 1.80
  • Step 1 Benzyl (2S,45)-2-((l 1 S',3i?)-3-N-BOC-aminocyclo ⁇ entylmethylcarbamoyl)-4- fluoropyrrolidine-1 -carboxylate: Coupling reaction of N-Benzyloxycarbonyl-(2S,4S)- 4-fluoropyrrolidine-2-carboxylic acid (2.0 g, 6.06 mmol) with Intermediate 4 (1.94 g, 9.09 mmol) in the presence of EDCI (2.15 g, 11.21 mmol), HOBT (573 mg, 3.74 mmol) and triethylamine (1.22 g, 12.12 mmol) in dry dichloromethane (40 ml) as described Example 20, Step 1 gave 3.0 g of the product as a white solid; IR (KBr) 3418, 3358, 3034, 2970, 1705, 1682, 1661, 1527, 1407, 1365, 1299, 1248, 1170
  • Step 2 Benzyl (25,45)-2-((15,3/?)-3-aminocyclopentylmethylcarbamoyl)-4-fluoro- pyrrolidine-1-carboxylate: Deprotection of Step 1 intermediate (1.0 g, 2.15 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by work-up of the reaction mixture as described in Example 2, Step 2 gave 784 mg (100 %) of the free base which was used as such for the next step.
  • Step 3 Benzyl (25 l ,45)-2-((15,37?)-3- ⁇ 2-[(2,S)-2-cyanopyrrolidin-l-yl]-2-oxoethyl- amino ⁇ cyclopentylmethylcarbamoyl)-4-fluoropyrrolidine-l-carboxylate: Coupling reaction of Step 2 intermediate (784 mg, 2.16 mmol) with Intermediate 7 (186 mg, 1.08 mmol) using K 2 CO 3 (297 mg, 2.16 mmol) and NaI (161mg, 1.07 mmol) in THF (20 ml) as described in Example 2, Step 3 gave 100 mg of the product as a semisolid; IR (neat) 3436, 3018, 2953, 2929, 1704, 1661, 1533, 1411, 1350, 1216, 1117, 1074 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.99 (s, IH), 1.38-1.80 (m, 4H),
  • Step 2 7V2-[(15',3i?)-3-Aminocyclopentylmethyl]-l//-2-pyrrolecarboxamide trifluoroacetate: Deprotection of Step 1 intermediate (267 mg, 0.87) using TFA (3 ml) in dichloromethane (3 ml) as described Example 1, Step 2 give 268 mg of the amine as its TFA salt which was used as such for the next step.
  • Step 3 N2-((15',3/?)-3- ⁇ 2-[(2 ⁇ ',4 1 S)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ cyclo- pentylmethyl)-lH-2-pyrrolecarboxamide: Coupling reaction of Step 2 intermediate (268 mg, 0.87 mmol) with Intermediate 7 (75 mg, 0.44 mmol) using K 2 CO 3 (481 mg, 3.48 mmol) and NaI (66 mg, 0.44 mmol) as described in Example 1, Step 3 gave 50 mg of the product as a pale yellow semisolid; IR (neat) 3426, 2244, 1633, 1429, 1195, 750 cm “1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.40-1.44 (m, IH), 1.63-2.29 (m, 10H), 2.52 (brs, IH), 3.09-3.25 (m, 3H), 3.37-3.54 (m, 4H), 4.71
  • Step 1 Benzyl (2S)-2-((lS,3/?)-3-N-BOC-Aminocyclopentylmethylcarbamoyl)-2,3- dihydro-lH-1-indolecarboxylate: Coupling reaction of 7V-Benzyloxycarbonyl-2S-2,3- dihydroindole-2-carboxylic acid (3.0 g, 10.09 mmol) with Intermediate 4 (3.21 g, 15.00mmol) in the presence of EDCI (2.9 g, 15.12 mmol), HOBT (772 mg, 5.04 mmol) and triethylamine (2.04 g, 20.20 mmol) in dry dichloromethane (40 ml) as described in Example 20, Step 1 gave 4.0 g of the product as a white solid; IR (KBr) 3841, 3360, 3315, 2969, 2928, 1678, 1666, 1517, 1467, 1365, 1247, 1168, 1018 cm "
  • Step 2 Benzyl (2 1 S)-2-((15',3i?)-3-Aminocyclopentylmethylcarbamoyl)-2,3-dihydro- lH-1-indolecarboxylate: Deprotection of Step 1 intermediate (1.0 g, 2.02 mmol) using TFA (5 ml) in dichloromethane (5 ml) followed by workup of the reaction mixture as described in Example 2, Step 2 gave 797 mg (100 %) of the free base which was used as such for the next step.
  • Step 3 Benzyl (2 1 S)-2-((15,3i?)-3- ⁇ 2-[(25)-2-cyanopyrrolidin-l-yl]-2- oxoethylamino ⁇ -cyclopentylmethylcarbamoyl)-2,3-dihydro-17/-l-indolecarboxylate: Coupling reaction of Step 2 intermediate (797 mg, 2.02 mmol) with Intermediate 7 (174 mg, 1.01 mmol) using K 2 CO 3 (278 mg, 2.01 mmol) and NaI (151 mg, 1.01 mmol) in T ⁇ F (20 ml) as described in Example 2, Step 3 gave 200 mg of the product as a pale yellow solid; IR (KBr) 3293, 3067, 2951, 2240, 1714, 1657, 1563, 1487, 1408, 1364, 1277, 1150, 1050 cm '1 ; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 0.97-0.99 (m, IH),
  • Step 1 N3-[(15,3 ⁇ )-3-N-BOC-Aminocyclopentylmethyl]-lH " -3-indolecarboxamide: This compound was prepared from Intermediate 4 (942 mg, 4.40 mmol) and 1H-3- indolecarbonyl chloride hydrochloride salt (470 mg, 2.18 mmol) using triethylamine (334 mg, 3.30 mmol) in dichloromethane (20 ml) as described in Example 17, Step 1, to give 210 mg of the product as an off white solid; IR (neat) cm '1 3308, 2905, 1702, 1648, 1531, 1250, 1175, 1086, 664; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 1.16-1.29 (m, IH), 1.44 (s, 9H), 1.76-2.07 (m, 2H), 2.23-2.33 (m, 2H), 3.47-3.53 (m, 2H), 3.96 (brs, IH),
  • Step 2 ⁇ -[(lS ⁇ -S-Aminocyclopentylmethy ⁇ -lH-S-indolecarboxamide trifluoroacetate: Deprotection of Step 1 intermediate (586 mg, 1.64 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described Example 1, Step 2 gave 610 mg of the amine as its TFA salt which was used as such for the next step.
  • DPPIV activity was determined by the cleavage rate of 7-amino-4-methyl coumarin (AMC) from synthetic substrate Glycyl-Prolyl-AMC.
  • AMC 7-amino-4-methyl coumarin
  • the assay was conducted by adding 10 ng of human recombinant Dipeptidyl peptidase IV enzyme (DPPIV, available commercially from R & D Systems) in 50 ⁇ l of the assay buffer (25 mM Tris, pH 7.4, 140 niM NaCl, 10 mM KCl, 1% BSA) to 96 well black flat bottom microtiter plates. The reaction was initiated by adding 50 ⁇ l of 100 ⁇ M substrate Gly-Pro-AMC. The incubation was carried out in the kinetic mode at 30 0 C for 30 minutes.
  • DPPIV Dipeptidyl peptidase IV enzyme
  • Test compounds dissolved in DMSO at 5-6 concentrations were tested in duplicate along with the solvent control and blank samples. Percent inhibition was calculated at each concentration with respect to the solvent control sample (no test compound added). IC 50 values were calculated from 3 experiments using the prism software.

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Abstract

La présente invention concerne de nouveaux composés organiques et plus particulièrement des inhibiteurs de la dipeptidyl peptidase IV (DPP-IV) représentés par la formule générale (I). Dans cette formule, Y désigne -S(O)m-, -CH2-, -CHF-, ou -CF2; X et Z désignent chacun -C(=O)-, -NR3-, - O- ou -S(O)m-; m vaut 0, 1 ou 2; a vaut 0, 1 ou 2; b vaut 0, 1 or 2; la ligne pointillée [----] dans le noyau carbocyclique désigne une double liaison facultative; R1 désigne un alkyle substitué ou non substitué, un alcényle substitué ou non substitué, un alcynyle substitué ou non substitué, un cycloalkyle substitué ou non substitué, un cycloalkylalkyle substitué ou non substitué, un cycloalcényle substitué ou non substitué, un aryle substitué ou non substitué, un arylalkyle substitué ou non substitué, un hétéroaryle substitué ou non substitué, un noyau hétérocyclique substitué ou non substitué, un hétérocyclylalkyle substitué ou non substitué, ou un hétéroarylalkyle substitué ou non substitué ; R2 désigne de l'hydrogène, un groupe nitrile (-CN), COOH, ou un isostère d'acide carboxylique. L'invention concerne également des produits analogues, des tautomères, des énantiomères, des diastéréomères, des régioisomères, des stéréoisomères, des polymorphes, des sels de qualité pharmaceutique, des N-oxydes, des solvates de qualité pharmaceutique et des compositions pharmaceutiques contenant ces composés.
PCT/IB2005/002146 2004-07-23 2005-07-22 Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs WO2006011035A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2007099385A1 (fr) * 2006-03-01 2007-09-07 Glenmark Pharmaceuticals S.A. Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2008001195A3 (fr) * 2006-06-27 2008-05-22 Glenmark Pharmaceuticals Sa Nouveaux procédés de synthèse d'inhibiteurs de dpp iv
WO2010079413A2 (fr) 2009-01-09 2010-07-15 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
WO2010098145A1 (fr) 2009-02-27 2010-09-02 Raqualia Pharma Inc. Dérivés d'oxyindole ayant une activité agoniste au récepteur de la motiline
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007099385A1 (fr) * 2006-03-01 2007-09-07 Glenmark Pharmaceuticals S.A. Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
EP2253311A2 (fr) 2006-04-11 2010-11-24 Arena Pharmaceuticals, Inc. Utilisation d'agonistes du récepteur de GPR119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose, et thérapie de combinaison associée
US7893103B2 (en) 2006-06-27 2011-02-22 Glenmark Pharmaceuticals, S.A. Processes for the preparation of DPP IV inhibitors
WO2008001195A3 (fr) * 2006-06-27 2008-05-22 Glenmark Pharmaceuticals Sa Nouveaux procédés de synthèse d'inhibiteurs de dpp iv
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
EP2376447A2 (fr) * 2009-01-09 2011-10-19 Orchid Research Laboratories Limited Inhibiteurs de l'enzyme dipeptidyl peptidase iv
WO2010079413A3 (fr) * 2009-01-09 2010-12-02 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
AU2010204144B2 (en) * 2009-01-09 2012-02-16 Orchid Research Laboratories Ltd. Dipeptidyl peptidase IV inhibitors
EP2376447A4 (fr) * 2009-01-09 2012-06-20 Orchid Res Lab Ltd Inhibiteurs de l'enzyme dipeptidyl peptidase iv
JP2012514630A (ja) * 2009-01-09 2012-06-28 オーキッド リサーチ ラボラトリーズ リミテッド ジペプチジルペプチダーゼｉｖ阻害剤
US8466145B2 (en) 2009-01-09 2013-06-18 Orchid Chemicals & Pharmaceuticals Limited Dipeptidyl peptidase IV inhibitors
WO2010079413A2 (fr) 2009-01-09 2010-07-15 Orchid Research Laboratories Ltd. Inhibiteurs de l'enzyme dipeptidyl peptidase iv
JP2015091889A (ja) * 2009-01-09 2015-05-14 オーキッド ケミカルズ アンド ファーマシューティカルズ リミテッド ジペプチジルペプチダーゼｉｖ阻害剤
WO2010098145A1 (fr) 2009-02-27 2010-09-02 Raqualia Pharma Inc. Dérivés d'oxyindole ayant une activité agoniste au récepteur de la motiline
US8748457B2 (en) 2009-06-18 2014-06-10 Lupin Limited 2-amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent DPP-IV inhibitors

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