WO2007099385A1 - Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes - Google Patents

Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes Download PDF

Info

Publication number
WO2007099385A1
WO2007099385A1 PCT/IB2006/000442 IB2006000442W WO2007099385A1 WO 2007099385 A1 WO2007099385 A1 WO 2007099385A1 IB 2006000442 W IB2006000442 W IB 2006000442W WO 2007099385 A1 WO2007099385 A1 WO 2007099385A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
ethyl
compound
amine
Prior art date
Application number
PCT/IB2006/000442
Other languages
English (en)
Inventor
Abraham Thomas
V.S. Prasada Rao Lingam
Daisy Manish Shah
Original Assignee
Glenmark Pharmaceuticals S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glenmark Pharmaceuticals S.A. filed Critical Glenmark Pharmaceuticals S.A.
Priority to PCT/IB2006/000442 priority Critical patent/WO2007099385A1/fr
Publication of WO2007099385A1 publication Critical patent/WO2007099385A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/42—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/52—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/54—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
    • C07C251/60—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile 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
    • C07D213/24—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
    • C07D213/78—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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/18—Oxygen or sulfur atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors, pharmaceutical compositions containing them, processes for their preparation, and methods for treating disorders mediated by DPP-IV inhibition, such as diabetes, especially Type II diabetes, with them.
  • 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. 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.
  • 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.
  • tolbutamide and glipizide which stimulate the pancreatic ⁇ -cells to secrete more insulin, and/or by injection of insulin when sulphonylureas or meglitinide becomes ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistance tissues.
  • dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur.
  • 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 are a more recently described class of compounds with potential for ameliorating many symptoms of Type II diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type II diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype.
  • PPAR-gamma 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
  • DPP-IV dipeptidyl peptidase-IV
  • DPP-IV dipeptidyl peptidase-IV
  • WO 97/40832 WO 98/19998
  • U.S. Patent No. 5,939,560 Bioorg. Med. Chem. Lett, 6(10), 1163-1166 (1996)
  • DPP-IV inhibitors in the treatment of Type II diabetes is based on the fact that DPP- 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 incretins stimulate production of insulin. Inhibition of DPP-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 the pancreas. DPP-IV inhibition therefore results in an increased level of serum insulin.
  • DPP-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 DPP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues.
  • DPP-IV inhibitors may also have other therapeutic utilities, as discussed herein. DPP-IV inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DPP-IV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions.
  • NDP-DPP-728 which has the formula A
  • Probiodrag " P32/98 which has the formula B
  • Novartis "NVP-LAF-237” which has the formula C .
  • DPP-IV inhibitors are described in PCT Patent publication WO 03/084940, JMC (2003), 46(13), 2774-2789, PCT Patent publication WO 03/037327, EP Patent publication EP 1 354 882 Al, PCT Patent publication WO 98/19998, U.S. Patent No. 6,011,155.
  • 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 Dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (I):
  • Ri is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl;
  • R 2 is hydrogen or C 1-6 alkyl;
  • Y is -S(O)" 1 , -CH 2 -, -CHF or CF 2 ;
  • R 3 is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid, such as SO 3 H,
  • R 4 and R 5 may be same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-
  • a compound of formula (I), wherein R 1 is cyanomethyl. Further preferred is a compound of formula (I), wherein R 1 is ethyl. Further preferred is a compound of formula (I), wherein R 1 is methoxyethyl. Further preferred is a compound of formula (I), wherein R 1 is propyl.
  • a compound of formula (I), wherein R 1 is butyl.
  • Preferred is a compound of formula (I), wherein R 1 is cycloalkyl.
  • Preferred is a compound of formula (I), wherein R 1 is substituted or unsubstituted arylalkyl.
  • Preferred is a compound of formula (I), wherein R 2 is substituted or unsubstituted C 1-6 alkyl.
  • Preferred is a compound of formula (I), wherein R 3 is nitrile.
  • the compounds of the present invention may be prepared as a mixture of enantiomers as well as single enantiomers. Mixtures as well as single enantiomers of the above mentioned isomers are within the scope of this invention.
  • the optically active compounds of the present invention may be obtained by resolution, asymmetric synthesis or by other methods known to those skilled in the art.
  • Another embodiment is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition includes a therapeutically effective amount of the compound(s) of the present invention.
  • Yet another embodiment is a method of treating a condition that may be regulated or normalized through inhibition of DPP-IV, such as diabetes (especially type II diabetes) in a subject in need thereof by administering to the subject an effective amount of a compound of the present invention
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting 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-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.
  • 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 about 2 up to 10 carbon atoms presently being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy refers to an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -OCH 3 and -OC 2 H 5 .
  • alkylcarbonyl refers to an alkyl group as defined above attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(O)CH 3 and -C(O)C 2 H 5 .
  • alkoxycarbonyl refers to an alkoxy group as defined above attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(O)-OCH 3 and -C(O)-OC 2 H 5 .
  • alkylcarbonyloxy refers to an alkylcarbonyl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -0-C(O)CH 3 and - 0-C(O)C 2 H 5 .
  • alkylamino refers to an alkyl group as defined above attached via an amino linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -NH 2 CH 3 , -NH(CH 3 ) 2 , and -N(CH 3 ) 3 .
  • cycloalkyl refers to 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 groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms directly attached to an alkyl group which are then attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms with at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl and cyclopentenyl.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical containing in the range of about 3 up to 8 carbon atoms with at least one carbon- carbon double bond directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropenylmethyl, cyclobutenylethyl and cyclopentenylethyl.
  • aryl refers to an aromatic radical having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • 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).
  • 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, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl
  • heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocylcyl 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 heterocylic ring radical as defined above directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • 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 the alkyl group that results in the creation of a stable structure.
  • cyclic ring refers to a cyclic ring containing 3-10 carbon atoms.
  • protecting group or “PG” refers to a substituent that is employed to block or protect a particular functionality while 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, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • 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, benzyl, tetrahydropyranyl 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-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl.
  • halogen refers to a radical of fluorine, chlorine, bromine or iodine.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be “substituted alkenyl”.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and the like), salts of chiral bases (such as 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), salts of non-
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • salts include, but are not limited to, quaternary ammonium salts of the compounds of the present invention with alkyl halides or alkyl sulphates (such as MeI and (Me) 2 SO 4 ).
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • solvates include hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • treating or “treatment” of a state, disorder or condition includes:
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • prodrug refers to a compound that is transformed in vivo to yield a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series; Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; and "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • Pharmaceutical Compositions ed. H. Bundgaard, Elsevier, 1985.
  • 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.
  • Pharmaceutical compositions containing a compound of the invention of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19 th Supp. Ed., 1995.
  • the 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.
  • compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsif ⁇ ers, 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 the present invention 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 the present invention 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 the present invention as a pharmaceutical composition in a therapeutically effective amount for blood glucose lowering.
  • a further aspect of the present invention is the use of a compound of the present invention 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 the present invention as a pharmaceutical composition in a therapeutically effective amount for the treatment of impaired glucose tolerance (IGT).
  • ITT impaired glucose tolerance
  • a further aspect of the present invention is the use of a compound of the present invention as a pharmaceutical composition in a therapeutically effective amount for the treatment of impaired fasting glucose (IFG).
  • IGF impaired fasting glucose
  • a further aspect of the present invention is the use of a compound of the present invention 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 the present invention 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 the present invention as a pharmaceutical composition in a therapeutically effective amount for delaying the progression of non-insulin requiring Type II diabetes to insulin requiring Type II diabetes.
  • ITT impaired glucose tolerance
  • a further aspect of the present invention is the use of a compound of the present invention 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 the present invention 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 the present invention as a pharmaceutical composition in a therapeutically effective amount for the treatment of disorders of food intake.
  • a further aspect of the present invention is the use of a compound of the present invention 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 the present invention 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 the present invention 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 the present invention 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 subject, 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.
  • 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 more 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 as a unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier or diluent.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about
  • the compounds of formula (1) 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.
  • the intermediate of formula (2) can be converted to the intemediate of formula (3), by, for example, reacting the compound of formula (2) with N,O-dimethylhydroxylamine hydrochloride in presence of an alkylchloroformate and a base (such as triethylamine) which can then be treated with acompound of formula R 2 MgX where X is halogen to give the intermediate of formula (3).
  • the compound of formula (3) ca be converted to a formula of formula (4) by reacting the compound of formula (3) with hydroxylamine hydrochloride, optionally in the presence of a base, to give the intermediate of formula (4).
  • the intermediate of formula (4) can be coupled with an intermediate of formula (5), optionally in the presence of a base, and the coupled product can then be deprotected, for exapmple, with a suitable reagent such as EtOAcHCl gas or trifluoroacetic acid, or by hydrogenation to yield the intermediate of formula (6).
  • the intermediate of formula (7) can be prepared by methods known in the art such as in J. Med. Chem., 2003, 46, 2774-2789; International publication No. WO 03/002553. Desired compounds of formula (1) can be obtained by coupling of the intermediates of general formula (6) and (7) optionally in the presence of a base such as triethylamine or K 2 CO 3 .
  • a base such as triethylamine or K 2 CO 3
  • 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. The solvent was evaporated under reduced pressure.
  • Step 2 cz5 r -( ⁇ )-4-iV-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 czs-( ⁇ )-3-N-BOC-Aminocyclopentane-l-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 (15",4i?)-(+)-2-iV-BOC-Azabicyclo[2.2.1]hept-5-ene-3-one: This intermediate was synthesized from (l£4i?)-(+)-2-Azabicyclo[2.2.1]hept-5-ene-3-one (10.0 g, 91.74 mmol) and di-tert-butyl 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-iV-BOC-Azabicyclo[2.2.1]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;
  • Step 3 (15 r ,3i?)-(+)-3 -N-BOC- Aminocyclopentane-1-carboxylic acid: To a stirred solution of Step 2 intermediate (8.5 g, 40.26 mmol) in THF (40 ml) was added IN sodium hydroxide (80 ml) and the mixture was stirred at 50 0 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 1 (li?,4S)-(-)-2-N-BOC-Azabicyclo[2.2.1]hept-5-ene-3-one: This intermediate was synthesized from (li?,45)-(-)-2-Azabicyclo[2.2.1]hept-5-ene-3-one (10.0 g, 91.74 mmol) and di-fert-butyl dicarbonate (23.9 g, 119.26 mol) 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 (15',4i?)-(-)-2-N-BOC-Azabicyclo[2.2.1]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?,4,S)-(+)-2-7V-BOC-Azabicyclo[2.2.1]heptan-3- one (see Step 2, Method B, Intermediate 2).
  • Step 3 (li?,35)-(-)-3-N-BOC-Aminocyclopentane-l-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 l-[(l)S,3i?)-3-N-BOC-aminocyclopentyl]-l-ethanone: A solution of Intermediate 4 (2.0 g, 7.35 mmol) in dry ether (15 ml) was added to a 1 M solution of methyl magnesium iodide in ether (5.5 ml, 5.51 mmol). The resultant mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The reaction was quenched with saturated aqueous NH 4 Cl solution and the product was extracted into ethyl acetate (2 x 100 ml).
  • Step 2 l-[(16',3i?)-3-N-BOC-aminocyclopentyl]-l-ethanone oxime: Hydroxylamine hydrochloride (336 nig, 4.83 mmol) was added to a solution of Step 1 intermediate (1.0 g, 4.39 mmol) in water (10 ml), followed by the addition of saturated sodium carbonate solution (10 ml). The resultant solution was stirred at room temperature for 4 h. The product was extracted into ethyl acetate (200 ml), washed with water (2 x 100 ml), brine (100 ml), dried (Na 2 SO 4 ) and concentrated.
  • Step 1 l-fpSjl ⁇ -S-iV-BOC-aminocyclopentylJ-l-ethanone: This compound was synthesized using Intermediate 5 (2.0 g, 7.35 mmol) and 1 M methylmagnesium iodide (5.5 ml, 5.51 mmol) in dry ether (15 ml) as described in Intermediate 6, Step 1 to afford 1.2 g of the product as a white solid; IR (KBr) 3359, 2973, 1705, 1683, 1527, 1367, 1253, 1166 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.43 (s, 9H), 1.50-1.72 (m, 2H), 1.82-1.94 (m, 3H), 2.06-2.16 (m, IH), 2.19 (s, 3H), 2.99-3.03 (m, IH), 4.02 (brs, IH), 4.86 (brs, IH).
  • Step 2 l-[(l 1 S',3i?)-3-N-BOC-aminocyclopentyl]-l-ethanone oxime: This compound was synthesized using the Step 1 intermediate (1.0 g, 4.39 mmol), hydroxylamine hydrochloride (336 mg, 4.83 mmol) and saturated aqueous sodium carbonate solution (10 ml) as described in Intermediate 6, Step 2 to afford 900 mg of the product as a white solid; IR (KBr) 3358, 3261, 2962, 1679, 1530, 1391, 1369, 1287, 1172, 1045 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.45 (s, 9H), 1.48-1.57 (m, 2H), 1.67-1.85 (m, 2H), 1.88 (s, 3H), 1.93-2.07 (m, IH) 5 2.18 (brs, IH), 2.65-2.73 (m, IH), 4.02 (brs, IH),
  • This intermediate was prepared from L-(-)-proline using a literature procedure (J. Med. Chem., 2003, 46, 2774-2789).
  • Step 1 (2£45)-N-BOC-4-Fluoropyrrolidme-2-carboxamide: This intermediate was prepared in 5 steps from L-(-)-4-hydroxyproline using a literature procedure (WO 03/002553 A2)
  • Step 2 (2.S',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',45)-4-Fluoropyrrolidine-2-carbonitrile p-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 (26',4iS)-l-(2-Chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile:
  • a solution of step 3 intermediate (10.0g, 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 (3 J S', ⁇ -)-3-(l-Ethoxyiminoethyl)cyclopentan-l-N-BOC-amine: To a stirred and cooled (-10 °C) suspension of 60 % sodium hydride (99 mg, 2.45 mmol) in N 1 N- dimethylacetamide (10 ml) was added Intermediate 6 (600 mg, 2.48 mmol) in dimethylacetamide (5 ml) and the mixture was stirred for 20 min at the same temperature. Ethyl bromide (540 mg, 4.95 mmol) was then added and the resultant mixture was stirred for 12 h under nitrogen atmosphere during which time the temperature increased to room temperature.
  • reaction mixture was quenched with ice-cold water and the product was extracted into ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (2 x 50 ml), brine (50 ml) and dried (Na 2 SO 4 ).
  • Step 2 (35',li-)-3-(l-Ethoxyiminoethyl)cyclopentan-l-amine: To a stirred and cooled (0-10 0 C) solution of Step 1 intermediate (590 mg, 2.18 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3 ml) and the mixture was stirred for 1 h under nitrogen atmosphere. The mixture was evaporated under reduced pressure. The residue obtained was diluted with water (10 ml), basif ⁇ ed to pH 12 using solid potassium carbonate and extracted with dichloromethane (3 x 50 ml).
  • Step 3 (2S,4S)- 1 - ⁇ 2-[(3S, li?)-3-(l -Ethoxyiminoethyl)cyclopentylamino]acetyl ⁇ -4- fluoropyrrolidine-2-carbonitrile: A solution of Intermediate 9 (207 mg, 1.08 mmol) in dry THF (10 ml) was added dropwise to a stirred and cooled (10 0 C) mixture of the amine from Step 2 (365 mg, 2.14 mmol), K 2 CO 3 ( 299 mg, 2.16 mmol) and NaI (163 mg, 1.08 mmol) in dry THF(15 ml) under nitrogen atmosphere.
  • Step 2 (lS,3i?)-3-(l-Ethoxyiminoethyl)cyclopentan-l-amine: This compound was prepared from Step 1 intermediate (590 mg, 2.18 mmol) using trifluoroacetic acid (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to give 366 mg of the free amine, which was used as such for the next step.
  • Step 3 (26',4 ⁇ S)-l- ⁇ 2-[(l ( S',3i?)-3-(l-Ethoxyiminoethyl)cyclopentylamino]acetyl ⁇ -4- fluoropyrrolidine-2-carbonitrile:
  • This product was prepared from Step 2 intermediate (366 mg, 2.14 mmol) and Intermediate 9 (207 mg, 1.08 mmol) using K 2 CO 3 ( 299 mg, 2.16 mmol) and NaI (163 mg, 1.08 mmol) in dry THF (10 ml) as described in Example 1, Step 3 to give 100 mg of the product as a white solid;
  • Step 2 (3»S',li?)-3-(l-Propyloxyiminoethyl)cyclopentan-l-amine: This compound was prepared from Step 1 intermediate (700 mg, 2.46 mmol) using TFA (4 ml) in dichloromethane (4 ml) as described in Example 1, Step 2 to afford 450 mg of the amine, which was used as such for the next step.
  • Step 2 (3 1 S',li?)-3-(l-Butyloxyiminoethyl)cyclopentan-l-amine: This was prepared from Step 1 intermediate (700 mg, 2.35 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 459 mg of the amine, which was used as such for the next step.
  • Step 1 (35',li?)-3-(l-Cyclopentyloxyiminoethyl)cyclopentan-l-N-BOC-amine: This was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and cyclopentyl bromide (738 mg, 4.95 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to afford 830 mg of the product as a white solid; IR
  • Step 2 (3S,li?)-3-(l-Cyclopentyloxyimmoemyl)cyclopentan-l-amine: This compound was prepared from Step 1 intermediate (830 mg, 2.67 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 555 mg of the amine, which was used as such for the next step.
  • Step 3 (2 1 S,4,S)-l-(2- ⁇ (3 ⁇ 1i?)-3-
  • Step 1 (36", li?)-3-[l -(2-Adamantyloxyimino)ethyl]cyclopentan- 1 -N-BOC-amine:
  • Step 2 (3iS l ,li?)-3-[l-(2-Adamantyloxyimino)ethyl]cyclopentan-l-amine: This product was prepared from Step 1 intermediate (650 mg, 1.73 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 470 mg of the amine, which was used as such for the next step.
  • Step 1 (3S, IR)S-[I -(2-Methoxyethoxyimino)ethyl]cyclopentan- 1 -N-BOC-amine: This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 2- bromoethyl methyl ether (689 mg, 5.07 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to afford 1.10 g of the product as a semisolid; IR (KBr) 3342, 2973, 2931, 1711, 1519, 1454, 1365, 1248 cm "1 ; 1 H
  • Step 2 (35', ⁇ -)-3-[l-(2-Methoxyethoxyimino)ethyl]cyclopentan-l-amine: This compound was prepared from Step 1 intermediate (1.1 g, 3.66 mmol) using TFA (2.5 ml) in dichloromethane (2.5 ml) as described in Example 1, Step 2 to afford 483 mg of the free amine, which was used as such for the next step.
  • Step 3 (25)- 1 -(2- ⁇ (35", lR)-3 -(I -(2-Methoxyethoxyimino)ethyl]cyclopentylamino ⁇ - acetyl)pyrrolidine-2-carbonitrile:
  • This product was prepared from Step 2 (728 mg, 3.63 mmol) and Intermediate 8 (316 mg, 1.83 mmol) using K 2 CO 3 (506 mg, 3.66 mmol) and NaI (275 mg, 1.83 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • Step 1 (3iS',li?)-3-(l-Cyanomethoxyoxyiminoethyl)cyclopentan-l-N-BOC-amine: This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and bromoacetonitrile (743 mg, 6.19 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to afford 800 mg of the product as a white solid; IR (KBr) 3340, 2967, 2116, 1681, 1536, 1168 cm '1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.44 (s, 9H), 1.49-1.64 (m, 3H), 1.71-1.84 (m, IH), 1.86 (s, 3H), 1.88-2.21 (m, 2H), 2.69-2.74 (m, IH), 4.01 (brs, IH), 4.67 (s, 2H), 4.74 (b
  • Step 2 (35',li?)-3-(l-Cyanomethoxyoxyiminoethyl)cyclopentan-l-amine: This was prepared from Step 1 intermediate (750 mg, 2.67 mmol) using TFA (2.5 ml) in dichloromethane (2.5 ml) described in Example 1, Step 2 to afford 477 mg of the free amine, which was used as such for the next step.
  • Step 3 (25 1 ,45)-l-(2- ⁇ (3»S,li?)-3-[l-(Cyanomethoxyimmo)ethyl]cyclopentylamino ⁇ - acetyl)-4-fluoropyrrolidine-2-carbonitrile: This was prepared from Step 2 intermediate (477 mg, 2.63 mmol) and Intermediate 9 (254 mg, 1.33 mmol) using K 2 CO 3 (368 mg, 3.66 mmol) and NaI (200 mg, 1.33 mmol) in dry THF (30 ml) as described in Example 1, Step 3.
  • Step 1 (35 r ,li?)-3-(l-Benzyloxyoxyiminoethyl)cyclopentan-l-N-BOC-amme: This compound was prepared from Intermediate 6 (1.0 g, 3.90 mmol) and benzyl bromide (848 mg, 4.95 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to give 1.0 g of the product as a white solid; IR (KBr) 3372, 2980, 2874, 1682, 1527, 1454, 1390, 1273, 1171, 1068 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.44 (s, 9H), 1.47-1.53 (m, IH), 1.57-1.83 (m, 2H), 1.86 (s, 3H), 1.89-1.99 (m, 2H), 2.04-2.13 (m, IH), 2.65-2.75 (m, IH),
  • Step 2 (3»S',li?)-3-(l-Benzyloxyoxyiminoethyl)cyclopentan-l-amine: This was prepared from Step 1 intermediate (1.1 g, 4.13 mmol) using TFA (2.5 ml) in dichloromethane (2.5 ml) as described in Example 1, Step 2 to afford 691 mg of the free amine which was used as such for the next step.
  • Step 3 (25,45)- 1- ⁇ 2-[(35',li?)-3-(l-Benzyloxyimino)ethyl]cyclopentylamino ⁇ acetyl)- 4-fluoropyrrolidine-2-carbonitrile:
  • This compound was prepared from Step 2 intermediate (691 mg, 2.97 mmol) and Intermediate 9 (286 mg, 1.50 mmol) using K 2 CO 3 (414 mg, 3.00 mmol) and NaI (225 mg, 1.50 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • Step 1 (3S, li?)-3-[l -(4-tert-butylbenzyloxyoxyimino)ethyl]cyclopentan- 1 -N-BOC- amine:
  • This product was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and t-butyl benzyl chloride (980 mg, 5.36 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.1 g of the product as a white solid;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.32 (s, 9H), 1.44 (s, 9H), 1.60 (s, 3H), 1.65-1.83 (m, 2H), 1.85-1.99 (m, 3H), 2.04-2.14 (m, IH),
  • Step 2 (35 l ,li?)-3-[l-(4-tert-butylbenzyloxyoxyimino)ethyl]cyclopentan-l-amine: This compound was prepared from the Step 1 intermediate (1.0 g, 2.57 mmol) using TFA (2.5 ml) in dichloromethane (2.5 ml) as described in Example 1, Step 2 to afford 736 mg of the free amine, which was used as such for the next step.
  • Step 3 (2S)-l-(2- ⁇ (35,li2)-3-[l-(4-tert- butylbenzyloxyimino)ethyl]cyclopentylammo ⁇ -acetyl)pyrrolidine-2-carbonitrile: This was prepared from Step 2 intermediate (736 mg, 2.55 mmol) and Intermediate 8 (222 mg, 1.29 mmol) using K 2 CO 3 (355 mg, 2.57 mmol) and NaI (193 mg, 1.28 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • Step 1 (35,lJ?)-3-[l-(4-Cyanobenzyloxyoxyimmo)ethyl]cyclopentan-l-iV-BOC- amine:
  • This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 4- cyanobenzyl bromide (972 mg, 4.96 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to afford 800 mg of the product;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.44 (s, 9H), 1.48-1.61 (m, 2H), 1.68-1.85 (m, IH), 1.88 (s, 3H), 1.94-2.00 (m, IH), 2.06-2.19 (m, 2H), 2.67-2.72 (m, I
  • Step 2 (3 ⁇ S',li?)-3-[l-(4-Cyanobenzyloxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (780 mg, 2.18 mmol) using trifluoroacetic acid (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 554 mg of the free amine, which was used as such for the next step.
  • Step 1 (36 r ,li?)-3-[l-(4-Trifluorobenzyloxyimmo)ethyl]cyclopentan-l-N-BOC- amine: This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 4- (trifluoro methyl)benzyl bromide (1.18 g, 4.93 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.3 g of the product as a white solid; IR (KBr) 3377, 2982, 2872, 1680, 1515, 1417, 1325, 1162, 1067 cm - 1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.44 (s, 9H), 1.47-1.76 (m, 3H), 1.78-1.85 (m, IH), 1.88 (s, 3H), 1.91-2.15 (m, 2H), 2.65-2.75 (
  • Step 2 (35',li?)-3-[l-(4-Trifluorobenzyloxyoxyimino)ethyl]cyclopentan-l-amme: This was prepared from Step 1 intermediate (1.3 g, 3.25 mmol) using trifluoroacetic acid (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 970 mg of the free amine, which was used as such for the next step.
  • Step 3 (25',4 i S)-4-Fluoro-l-(2- ⁇ (3i?,15)-3-[(l-(4-trifluorobenzyloxyimino)ethyl]cyclo- pentylamino ⁇ acetyl)pyrrolidine-2-carbonitrile:
  • This compound was prepared from Step 2 intermediate (970 mg, 3.22 mmol) and Intermediate 9 (309 mg, 1.62 mmol) using K 2 CO 3 (448 mg, 3.24 mmol) and NaI (243 mg, 1.62 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • Step 1 (3(S',li?)-3-[l-(4-Fluorobenzyloxyimino)ethyl]cyclopentan-l-iV-BOC-amine: This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 4- fluorobenzyl bromide (937 mg, 4.95 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.2 g of the product as a pale yellow solid; IR (KBr) 3346, 2970, 1682, 1513, 1217 cm "1 J 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.28-1.39 (m, IH), 1.44 (s, 9H), 1.47-1.77 (m, 3H), 1.80-2.17 (m, 4H), 2.19- 2.36 (m, IH), 3.35-3.47 (m, IH), 3.96 (brs, IH), 4.52
  • Step 2 (35',li-)-3-[l-(4-Fluorobenzyloxyoxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (1.0 g, 2.85 mmol) using trifluoroacetic acid (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 707 mg of the free amine, which was used as such for the next step.
  • Step 3 (25,45')-4-Fluoro-l-(2- ⁇ (3 1 S,li?)-3-[l-(4- fluorobenzyloxyimino)ethyl]cyclopentyl-amino ⁇ acetyl)pyrrolidme-2-carbonitrile:
  • This compound was prepared from Step 2 intermediate (707 mg, 2.81 mmol) and Intermediate 9 (272 mg, 1.42 mmol) using K 2 CO 3 (394 mg, 2.85 mmol) and NaI (214 mg, 1.42 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • Step 2 This was prepared from Step 2 intermediate (600 mg, 2.34 mmol) and 4-chlorobenzyl bromide (578 mg, 2.81mmol) using 60 % NaH (140 mg, 3.51 mmol) in dry DMA (15 ml) as described in Example 1, Step 1 to afford 860 mg of the product as an off white solid;
  • Step 4 (36',li?)-3-[l-(4-Chlorobenzyloxyimino)propyl]cyclopentan-l-amine: This was prepared from the Step 3 intermediate (850 mg, 2.23 mmol) using trifluoroacetic acid (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 620 mg of the free amine, which was used as such for the next step.
  • Step 5 (2S,4S)-l-(2- ⁇ (3S,lR)-3-[l-(4-
  • Step 1 (3S, li?)-3-[l -(3-Phenylpropyloxyimino)ethyl]cyclopentan- 1 -N-BOC-amine: This was prepared from Intermediate 6 (1.0 g, 3.90 mmol) and l-bromo-3- phenylpropane (933 mg, 4.68 mmol) using 60 % NaH (146 mg, 6.08 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 830 mg of the product as a semisolid; IR (neat) 3338, 2960, 1680, 1530, 1190, 1020 cm - 1 ; 1 H NMR (300 MHz, CDCl 3 ) 0.84-0.96 (m, IH), 1.43 (s, 9H), 1.49-1.79 (m, 2H), 1.83 (s, 3H), 1.87-2.14 (m, 6H), 2.67-2.76 (m, 2H), 3.98 (brs, IH),
  • Step 2 (35,li?)-3-[l-(3-Phenylpropyloxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (800 mg, 2.14 mmol) using trifluoroacetic acid (2.5 ml) in dichloromethane (2.5 ml) as described in Example 1, Step 2 to afford 586 mg of the free amine, which was used as such for the next step.
  • Step 3 (26',45)-4-Fluoro-l-(2- ⁇ (35',li?)-3-[l-(3-phenylpro ⁇ yloxyimmo)ethyl]cyclo- pentylamino ⁇ acetyl)pyrrolidine-2-carbonitrile:
  • This compound was prepared from Step 2 intermediate (579 mg, 2.11 mmol) and Intermediate 9 (203 mg, 1.06 mmol) using K 2 CO 3 (294 mg, 2.13 mmol) and NaI (160 mg, 1.06 mmol) in dry THF (40 ml) as described in Example 1, Step 3.
  • Step 1 (35',li?)-3-[l-(2-Pyridylmethoxyimino)ethyl]cyclo ⁇ entan-l-N-BOC-amine:
  • This compound was prepared from Intermediate 6 (1.5 g, 6.19 mmol) and 2- picolylchloride hydrochloride (1.2 g, 4.68 mmol) using 60 % NaH (372 mg, 9.29 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 2.0 g of the product as a colourless liquid;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.43 (s, 9H), 1.47-1.89 (m, 5H), 1.92 (s, 3H), 1.96-2.32 (m, IH), 2.66-2.73 (m, IH), 3.99 (brs, IH), 4.90 (brs
  • Step 2 (35',li?)-3-[l-(2-Pyridylmethoxyimino)ethyl]cyclopentan-l-amine: This compound was prepared from Step 1 intermediate (1.0 g, 3.00 mmol) using TFA (4 ml) in dichloromethane (4 ml) as described in Example 1, Step 2 to afford 691 mg of the free amine, which was used as such for the next step.
  • Step 3 (2S)- 1-(2- ⁇ (3S t li?)-3-[l -(2-Pyridylmethoxyimino)ethyl]cyclopentylamino ⁇ - acetyl)pyrrolidine-2-carbonitrile: This compound was prepared from Step 2 intermediate (691 mg, 2.96 mmol) and Intermediate 8 (255 mg, 1.98 mmol) using K 2 CO 3 (408 mg, 2.95 mmol) and NaI (221 mg, 1.47 mmol) in dry THF (50 ml) as described in Example 1, Step 3.
  • This compound was prepared by the coupling reaction of Step 2 intermediate, Example 16 (690 mg, 2.95 mmol) and Intermediate 9 (285 mg, 1.49 mmol) using K 2 CO 3 (413 mg, 2.99 mmol) and NaI (224 mg, 1.49 mmol) in dry THF (40 ml) as described in Example 1, Step 3.
  • Step 1 (3S, lR)-3-[ l-(5-Cyano-2- ⁇ yridyloxyimino)ethyl]cyclopentan- 1 -N-BOC- amine:
  • This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 6- chloronicotinonitrile (686 mg, 4.95 mmol) using 60 % NaH (248 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.2 g of the product as a white solid;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.44 (s, 9H), 1.49-2.11 (m, 5H), 2.12 (s, 3H), 2.22-2.31 (m, IH), 2.84-2.92 (m, IH), 4.11 (brs, IH), 5.
  • Step 2 (35',li-)-3-[l-(5-Cyano-2-pyridyloxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (1.0 g, 2.90 mmol) using TFA (4 ml) in dichloromethane (4 ml) as described in Example 1, Step 2 to afford 701 mg of the free amine which was used as such for the next step.
  • Step 3 (25)-l-(2- ⁇ (35,li?)-3-[l-(5-Cyano-2- pyridyloxyirnino)ethyl] cyclopentylamino ⁇ -acetyl)pyrrolidine-2-carbonitrile :
  • This compound was prepared using Step 2 intermediate (701 mg, 2.85 mmol) and Intermediate 8 (250 mg, 1.46 mmol) using K 2 CO 3 (400 mg, 2.89 mmol) and NaI (217 mg, 1.46 mmol) in dry THF (40 ml) as described in Example 1, Step 3.
  • Step 1 (15 l ,3i?)-3-[l-(5-Cyano-2-pyridyloxyimino)ethyl]cyclopentan-l-N-BOC- amine: This compound was prepared from Intermediate 7 (800 mg, 3.30 mmol) and 6- chloronicotinonitrile (687 mg, 4.96 mmol) using 60 % NaH (198 mg, 4.95 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.0 g of the product as a pale yellow solid; IR (KBr) 3341, 2968, 2226, 1680, 1592, 1470, 1385, 1291 cm ' *; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.45 (s, 9H), 1.50-1.62 (m, 2H), 1.70-2.07 (m, 3H), 2.13 (s, 3H), 2.22-2.29 (m, IH), 2.87-2.92 (m, IH), 4.12 (br
  • Step 2 (liS,3i?)-3-[l-(5-Cyano-2-pyridyloxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (800 mg, 2.32 mmol) using TFA (4 ml) in dichloromethane (4 ml) as described in Example 1, Step 1 to afford 561 mg of the free amine, which was used as such for the next step.
  • Step 3 (2S)-l-(2- ⁇ (15,3i?)-3-[l-(5-Cyano-2- pyridyloxyimino)ethyl]cyclopentylamino ⁇ -acetyl)pyrrolidine-2-carbonitrile:
  • This compound was prepared from Step 2 intermediate (561 mg, 2.29 mmol) and Intermediate 8 (200 mg, 1.16 mmol) using K 2 CO 3 (320 mg, 2.32 mmol) and NaI (174 mg, 1.16 mmol) in dry THF (40 ml) as described in Example 1, Step 3.
  • Step 1 (3S, lR)-3-[ 1 -(2-Pyrimidinyloxyimino)ethyl]cyclopentan- 1 -N-BOC-amine :
  • This compound was prepared from Intermediate 6 (1.0 g, 4.13 mmol) and 2- chloropyrimidine (710 mg, 6.19 mmol) using 60 % NaH (246 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.1 g of the product as a white solid;
  • Step 2 (3)S',li?)-3-[l-(2-Pyrimidinyloxyimino)ethyl]cyclopentan-l-amine: This was prepared from Step 1 intermediate (800 mg, 2.50 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 1 to afford 544 mg of the free amine, which was used as such for the next step.
  • Step 3 (2 1 S)-l-(2- ⁇ (35 l ,li?)-3-[l-(2-Pyrimidinyloxyimino)ethyl]cyclo ⁇ entylamino ⁇ - acetyl)pyrrolidine-2-carbonitrile: This compound was prepared from Step 2 intermediate (544 mg, 2.47 mmol) and Intermediate 8 (215 mg, 1.24 mmol) using K 2 CO 3 (344 mg, 2.49 mmol) and NaI (187 mg, 1.24 mmol) in dry THF (40 ml) as described in Example 1, Step 3.
  • Step 1 (l 1 S',3i?)-3-[l-(2-Pyrazinyloxyimino)ethyl]cyclopentan-l-iV-BOC-amine:
  • This compound was prepared from Intermediate 7 (1.0 g, 4.13 mmol) and chloropyrazine (709 mg, 6.18 mmol) using 60 % NaH (246 mg, 6.16 mmol) in dry DMA (20 ml) as described in Example 1, Step 1 to afford 1.0 g of the product as a white solid;
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ 1.45 (s, 9H), 1.51-2.09 (m, 5H), 2.13 (s, 3H), 2.19-2.32 (m, IH), 2.86-2.93 (m, IH), 4.12 (brs, IH), 5.24 (brs, IH), 8.
  • Step 2 (liS',3i?)-3-[l-(2-Pyrazinyloxyimino)ethyl]cyclopentan-l-amine: This compound was prepared from Step 1 Intermediate (600 mg, 1.87 mmol) using TFA (3 ml) in dichloromethane (3 ml) as described in Example 1, Step 2 to afford 406 mg of the free amine, which was used as such for the next step.
  • DPP-IV 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, Inc of Minnea ⁇ olis,MN 55413, USA) in 50 ⁇ l of the assay buffer (25 mM Tris, pH 7.4, 140 mM 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.
  • 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 5 O values were calculated from 3 experiments using the prism software.

Abstract

La présente invention concerne des inhibiteurs de dipeptidylpeptidase IV (DPP-IV) de formule (1), des compositions pharmaceutiques les incluant, leurs procédés de synthèse et des méthodes de traitement, à l'aide desdits composés et compositions, de troubles faisant intervenir l'inhibition de DPP-IV, par exemple le diabète, en particulier le diabète de type II, où Rj représente un groupement alkyle éventuellement substitué, alcényle éventuellement substitué, alcynyle éventuellement substitué, cycloalkyle éventuellement substitué, cycloalkylalkyle éventuellement substitué, aryle éventuellement substitué, arylalkyle éventuellement substitué, hétéroaryle éventuellement substitué, hétéroarylalkyle éventuellement substitué, hétérocycle éventuellement substitué, hétérocyclylalkyle éventuellement substitué ; R2 représente un atome d'hydrogène ou un groupement alkyle Q-β ; Y représente -S(O)m, -CH2-, -CHF ou CF2 ; R3 représente un atome d'hydrogène ou un groupement nitrile (-CN), COOH ou isostère d'acide carboxylique.
PCT/IB2006/000442 2006-03-01 2006-03-01 Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes WO2007099385A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2006/000442 WO2007099385A1 (fr) 2006-03-01 2006-03-01 Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2006/000442 WO2007099385A1 (fr) 2006-03-01 2006-03-01 Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes

Publications (1)

Publication Number Publication Date
WO2007099385A1 true WO2007099385A1 (fr) 2007-09-07

Family

ID=37467264

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/000442 WO2007099385A1 (fr) 2006-03-01 2006-03-01 Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes

Country Status (1)

Country Link
WO (1) WO2007099385A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014002105A1 (fr) * 2012-06-25 2014-01-03 Cadila Healthcare Limited Composés pour le traitement de la dyslipidémie et d'autres maladies
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
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
WO2014202827A1 (fr) 2013-06-11 2014-12-24 Orion Corporation Nouveaux inhibiteurs de cyp17/antiandrogènes
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011103A1 (fr) * 1996-09-10 1998-03-19 Astra Aktiebolag Nouveaux composes pharmaceutiquement actifs
US20030125389A1 (en) * 2001-07-25 2003-07-03 Raju Bore G. Beta-amino acid derivatives useful for the treatment of bacterial infections
WO2006011035A1 (fr) * 2004-07-23 2006-02-02 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011103A1 (fr) * 1996-09-10 1998-03-19 Astra Aktiebolag Nouveaux composes pharmaceutiquement actifs
US20030125389A1 (en) * 2001-07-25 2003-07-03 Raju Bore G. Beta-amino acid derivatives useful for the treatment of bacterial infections
WO2006011035A1 (fr) * 2004-07-23 2006-02-02 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAGATA H ET AL: "A convenient enantioselective synthesis of natural (1R,3S)-amidinomycin", TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 8, no. 16, 28 August 1997 (1997-08-28), pages 2679 - 2681, XP004090350, ISSN: 0957-4166 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
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
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014002105A1 (fr) * 2012-06-25 2014-01-03 Cadila Healthcare Limited Composés pour le traitement de la dyslipidémie et d'autres maladies
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2014202827A1 (fr) 2013-06-11 2014-12-24 Orion Corporation Nouveaux inhibiteurs de cyp17/antiandrogènes
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US10975096B2 (en) 2014-06-20 2021-04-13 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Similar Documents

Publication Publication Date Title
WO2007099385A1 (fr) Composés inhibiteurs de dipeptidylpeptidase iv et compositions correspondantes
EP1799639B1 (fr) Nouveaux inhibiteurs de dipeptidyle peptidase iv, compositions pharmaceutiques en contenant, et leur procédé de préparation
WO2005075426A1 (fr) Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
WO2006090244A1 (fr) Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant
US7893103B2 (en) Processes for the preparation of DPP IV inhibitors
JP5161869B2 (ja) １１−β−ヒドロキシステロイドデヒドロゲナーゼ１の阻害剤としての、シクロヘキシルピラゾール−ラクタム誘導体
JP4357293B2 (ja) ジペプチジルペプチダーゼ阻害剤としてのフルオロピロリジン類
WO2005033099A2 (fr) Nouveaux inhibiteurs de dipeptidylpeptidase iv, leurs procedes de preparation et compositions les contenant
WO2005058849A1 (fr) Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procede de preparation et compositions les contenant
US7230002B2 (en) Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
OA12659A (en) Urea-compounds active as vanilloid receptor antagonists for the treatment of pain.
AU2005247895A1 (en) Cyclohexylalanine derivatives as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
EP2004601A1 (fr) Nouveaux inhibiteurs de la dipeptidyl peptidase iv et procédés pour la préparation de ceux-ci et compositions pharmaceutiques contenant ceux-ci
WO2004013100A2 (fr) Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
WO2006011035A1 (fr) Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs
KR100523184B1 (ko) 아제티딘 및 피롤리딘의 유도체
RU2443687C2 (ru) Новые ингибиторы дипептидилпептидазы iv, способы их получения и содержащие их фармацевтические композиции
WO1999012914A1 (fr) Derives de thiouree
NO322011B1 (no) Aminometylpyrrolidin-derivater som har aromatiske substituenter
US7528151B2 (en) Heterocyclic urea derivatives for the treatment of pain
WO1995016674A1 (fr) Derives d'aminosulfonyl-phenyl-1h-pyrrole, leur procede de preparation et leur utilisation
CA2350429A1 (fr) Agents neurotrophiques de diamide et carbamate
JPH107652A (ja) ピロリジン誘導体の製造方法
WO2005066124A1 (fr) Procede de production de derive de pyrrolidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06727270

Country of ref document: EP

Kind code of ref document: A1