WO2006090244A1 - Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant - Google Patents

Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant Download PDF

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WO2006090244A1
WO2006090244A1 PCT/IB2006/000363 IB2006000363W WO2006090244A1 WO 2006090244 A1 WO2006090244 A1 WO 2006090244A1 IB 2006000363 W IB2006000363 W IB 2006000363W WO 2006090244 A1 WO2006090244 A1 WO 2006090244A1
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substituted
unsubstituted
compound
formula
cyano
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PCT/IB2006/000363
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Balasubramanian Gopalan
Abraham Thomas
Daisy Manish Shah
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Glenmark Pharmaceuticals S.A.
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Publication of WO2006090244A1 publication Critical patent/WO2006090244A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • 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

Definitions

  • the present invention relates to adamantane derivatives which are 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) patients produce little or no insulin, the hormone which regulates glucose utilization.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • i 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.
  • Therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • 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 result 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-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. Additional methods of treating the disease are still under investigation. 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
  • Probiodrug "P32/98” which has the formula B
  • Novartis "NVP-LAF-237” which has the formula C .
  • B represents a group of formula (I), (II), (III), (IV) or (V):
  • Z represents a group of formula (i), (ii), (iii), (iv) or (v):
  • the present invention relates to dipeptidyl peptidase IV (DPP-IV) inhibitors of the formula (A):
  • Y is -S (O) m , -CH 2 -, CHF, or -CF 2 ;
  • R 1 is hydrogen, nitrile (-CN), COOH, or an isostere of a carboxylic acid, such as SO 3 H, CONOH, B(OH) 2 , PO 3 R 3 R 4 , SO 2 N R 3 R 4 , tetrazole, COOR 3 , -CONR 3 R 4 - NR 3 COR 4 , and -COOCOR 3 ;
  • R 2 is substituted 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 , -NR 3 R 4 , -NH-S(O) 1n -R 3 , -NH-CR 3 R 4 - C(O)-R 5 , -C(O)O-R 3 ,
  • R f and R s are hydrogen or R f and R s together represent C 2 -C 7 alkylene
  • R 4 does not represent substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing mono- or bicyclic aromatic moiety, substituted or unsubstituted arylalkyl, substituted
  • the aforementioned generic formula also has the proviso that: c) when n is O and R 2 is NR f -(CH 2 ) a -C(O)-R g (where R f is hydrogen, alkylcarbonyl, alkoxycarbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or
  • R g is not
  • R h is hydrogen or cyano
  • 30 Y is CH 2 , CHF, CF 2 , O, or S(0) m (where m is 0, 1 , or 2);
  • W and Z are independently CH 2 , CHF, or CF 2 ; and the ring formed by N, W, Y, and Z and the carbon atoms to which they are attached is saturated or optionally contains one double bond; and d) when n is 0 and R 1 is H or cyano, then R 2 does not represent NR 3 R 4 wherein R 3 and R 4 are the same as defined above.
  • R 1 is cyano
  • R 2 is -NHR 4 then R is not substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or - COR 5 .
  • R 2 when n is 0 and R 1 is H or cyano, then R 2 does not represent NR 3 R 4 .
  • R 2 when n is 0 and R 1 is cyano, then R 2 is not -NHR 4 .
  • Preferred is a compound of general formula (A) where Y is CH 2 .
  • R 2 is -NH- S(O) m -R 3 , wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
  • R 2 is -NH- S(O) m -R 3 , wherein R 3 is methyl, n-butyl, 4-fluoro phenyl, 4-methyl phenyl, 4- sulfonylmethyl phenyl, or pyrid-3-yl.
  • R 2 is -NR 3 R 4 , wherein R 3 and R 4 are taken together with the atom to which they are attached to form a 3-7 member optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR 5 or S(O) m .
  • R 2 is -NR 3 R 4 ; wherein R 3 and R 4 together along with the nitrogen atom to which they are attached form a 1 , 1 -dioxo-2-isothiazolidinyl ring.
  • R 2 is -NH- CR 3 R 4 -C(O)-R 5 ;
  • R 3 and R 4 are hydrogen; and
  • R 5 is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • the invention also encompasses active metabolites of the compounds of formula (A).
  • the present invention also provides 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).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • Another embodiment of the present invention is a method for the treatment of a condition that may be regulated or normalized via inhibition of DPP-IV (e.g., type II diabetes) in a subject in need thereof, by administering a therapeutically effective amount of a compound of the present invention to the subject.
  • DPP-IV e.g., type II diabetes
  • 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- 1 -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 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.
  • Non-limiting examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or 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 HsC 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-oxopi ⁇ erazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom 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 1 stable structure.
  • 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.
  • 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-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.
  • 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.”
  • Pharaiaceutically 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 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.
  • 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,
  • 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.
  • Delivery" a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished , e.g., by local or by systemic administration of the active ingredient to the host.
  • 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-FV or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or formulations for topical applications.
  • the pharmaceutical composition includes a compound of the invention (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.
  • 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 pharmaceutical compositions may also include auxiliary agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, flavoring agents, salt for influencing osmotic pressure, buffers and/or coloring substances.
  • auxiliary agents wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, flavoring agents, salt for influencing osmotic pressure, buffers and/or coloring substances.
  • the pharmaceutical compositions 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 methods known in the art.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The
  • the active compound may be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a 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.
  • the route of administration may be by any route, which effectively transports the active compound of the invention which inhibits the enzymatic activity of DPP-FV to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. 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 Colloidal silicon dioxide (Aerosil ® ) 1.5 mg Cellulose, microcryst. (Avicel ® ) 70 mg j Modified cellulose gum (Ac-Di-Sol ® ) 7.5 mg Magnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg *Acylated monoglyceride used as plasticizer for film coating.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • a further aspect of the present invention is the use of a compound of formula
  • a further aspect of the present invention is the use of a compound of formula (A) in 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 (A) in 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 formula (A) in 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 (A) in 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 formula (A) in 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
  • a further aspect of the present invention is the use of a compound of formula (A) in a pharmaceutical composition in a therapeutically effective amount for delaying the progression of impaired glucose tolerance (IGT) to Type II diabetes.
  • ITT impaired glucose tolerance
  • a further aspect of the present invention is the use of a compound of formula (A) in 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.
  • a further aspect of the present invention is the use of a compound of formula (A) in 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.
  • a further aspect of the present invention is the use of a compound of formula (A) in 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.
  • a further aspect of the present invention is the use of a compound of formula
  • (A) in 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 (A) in 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 (A) in 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 formula (A) in 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 (A) in 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 (A) in 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 (A) in a pharmaceutical composition in a therapeutically effective amount for the treatment of functional dyspepsia, in particular irritable bowel syndrome.
  • Another embodiment of the present invention is a method for the treatment of a condition that may be regulated or normalized via inhibition of DPP-IV in a subject in need thereof, by administering a therapeutically effective amount of a compound of the present invention to the subject.
  • a further aspect of the present invention is a method for the treatment and/or prophylaxis of a disease selected from diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis,, ' Crohn's disease, obesity, and metabolic syndrome in a subject in need thereof, by administering to the subject a therapeutically effective amount of a compound according to Formula (A).
  • a disease selected from diabetes, non-insulin dependent diabetes mellitus, impaired glucose tolerance, inflammatory bowel disease, ulcerative colitis,, ' Crohn's disease, obesity, and metabolic syndrome
  • the compounds of the invention maybe 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.
  • 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.
  • the compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1000
  • the compounds of the present invention are dispensed in a unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier.
  • 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 a compound of the present invention admixed with a pharmaceutically acceptable carrier or diluent.
  • G is a leaving group (preferably a halogen such as bromine, chlorine or iodine).
  • Compounds of formula (A) can be obtained by the condensation of compound of formula (1) with a compound of formula (2), optionally in the presence of a suitable base such as triethylamine or K 2 CO 3 , and in an appropriate solvent, such as tetrahydrofuran acetonitrile, or dichloromethane.
  • the intermediate of formula (4) can be synthesized by reacting the intermediate of formula (3) (wherein n is 0 or 1) with a sulfonyl halide of the formula R SO 2 G (wherein R is as defined above and G is a leaving group such as a halogen (preferably chloro) optionally in the presence of a suitable organic base (such as pyridine or triethylamine).
  • a suitable organic base such as pyridine or triethylamine
  • Ritter reaction of the intermediate of formula (4) with acetonitrile or chloroacetonitrile optionally in the presence of a suitable mineral acid (preferably sulfuric acid) can provide an intermediate of formula (5).
  • the intermediate of formula (5) can then be converted to the intermediate of formula (1) by cleaving the haloacetyl group, such as with thiourea under acidic conditions (as described in Jirgensons, A et al. Synthesis 2000, No. 12, 1709-1712).
  • the intermediate of formula (1) where R 2 is -NR 3 R 4 , R 3 and R 4 together along with the nitrogen atom to which they are attached form a l,l-dioxo-2-isothiazolidinyl ring or l,l-dioxo-2-isothiazinyl ring and n is as defined above, can be synthesized as shown in scheme II.
  • the intermediate (6) can be synthesized by reacting the intermediate of formula (3) wherein n is 0 or 1, with, for example, chloropropylsulfonyl chloride or chlorobutylsulfonyl chloride optionally in the presence of a suitable amine (such as triethylamine or N,N-diisopropylethylamine) followed by Ritter reaction on the resultant sulfonamide, such as with a haloacetonitrile (XCH 2 CN where X is halogen) (preferably chloroacetonitrile) optionally in the presence of a suitable mineral acid (preferably sulfuric acid).
  • a suitable amine such as triethylamine or N,N-diisopropylethylamine
  • XCH 2 CN where X is halogen
  • a suitable mineral acid preferably sulfuric acid
  • the intermediate of formula (6) can then be cyclised, for example, in the presence of a strong base (such as metal alkoxides (e.g., sodium ethoxide) and in a protic solvent (such as ethanol or isopropanol), to provide the intermediate of formula (7).
  • a strong base such as metal alkoxides (e.g., sodium ethoxide) and in a protic solvent (such as ethanol or isopropanol
  • the intermediate of formula (7) can then be converted to the intermediate of formula (1) by the cleavage of the haloacetyl group, for example, with thiourea under acidic conditions (as described in Jirgensons, A et al., supra).
  • the intermediate of formula (8) is converted to the intermediate of formula (9), for example by the two step process shown above.
  • the intermediate of formula (8) is subjected to a Ritter reaction with, for example, a haloacetonitrile (XCH 2 CN where X is halogen) (preferably chloroacetonitrile) optionally in the presence of a suitable mineral acid (preferably sulfuric acid) followed by esteriflcation, such as with ethanol under acidic conditions.
  • a haloacetonitrile XCH 2 CN where X is halogen
  • a suitable mineral acid preferably sulfuric acid
  • esteriflcation such as with ethanol under acidic conditions.
  • the haloacetyl group from the intermediate of formula (9) can be cleaved (such as described above) and followed by protection of the free amino group, with for example di-tert-butyldicarbonate, to provide the intermediate of formula (10), where PG is a protecting group.
  • a preferred protecting group PG is t-butoxycarbonyl (BOC).
  • the intermediate of formula (10) can then be hydrolysed and converted into an amide of formula (11).
  • the intermediate of formula (11) can then be converted to the intermediate of formula (12) such as by standard functional group transformations, (e.g., conversion of -CONH 2 to a CN group in the presence of TFAA/TEA).
  • the intermediate of formula (12) can then be deprotected under acidic conditions to obtain the intermediate of formula (1).
  • R 2 has the formula
  • D is absent is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, can be synthesized as shown in scheme IV.
  • the intermediate of formula (14) can be synthesized by reacting the intermediate of formula (3), wherein n is 0-3, with an intermediate of formula (13) (where the D ring is absent or is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl (such as phenyl, cyclohexyl, pyridyl) and each occurrence of G is a leaving group) optionally under basic reaction conditions.
  • an intermediate of formula (13) where the D ring is absent or is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl (such as phenyl, cyclohexyl, pyridyl) and each occurrence of G is a leaving group
  • Ritter reaction on the intermediate of formula (14) with, for example, a haloacetonitrile (XCH 2 CN where X is halogen) (preferably chloroacetonitrile) optionally in the presence of a suitable mineral acid (preferably sulfuric acid) can provide the intermediate of formula (15).
  • a suitable mineral acid preferably sulfuric acid
  • the intermediate of formula (15) can then be converted to the intermediate of formula (1) by the cleavage of the haloacetyl group, for example with thiourea optionally under acidic conditions (as described in Jirgensons, A et al., supra).
  • a compound of the present invention having the structure of formula (19) below, wherein n, R 1 , and Y are as defined above, can be prepared as shown in scheme V.
  • the intermediate of formula (16) can be synthesized by reacting the intermediate of formula (3); wherein n is O or 1, with, for example, acetic anhydride optionally in the presence of a base such as pyridine.
  • Ritter reaction on the intermediate of formula (16) with, for example, acetonitrile optionally in the presence of a suitable mineral acid (preferably sulfuric acid) can provide the intermediate of formula (17).
  • the intermediate of formula (17) can then be converted to the intermediate of formula (18) by hydrolysis, for example with concentrated HCl optionally at an elevated temperature (e.g., 80-100 0 C).
  • the intermediate of formula (3) wherein n is O or 1, with, for example, acetic anhydride optionally in the presence of a base such as pyridine.
  • Ritter reaction on the intermediate of formula (16) with, for example, acetonitrile optionally in the presence of a suitable mineral acid (preferably sulfuric acid) can provide the intermediate of formula (17).
  • the intermediate of formula (17) can then be converted to the
  • the compounds of the invention can be isolated and purified in a manner known in the art, 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 (such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (such as ethanol or 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, re-precipitating, 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.
  • Suitable ethereal solvents for use in the above described processes for the preparation of compounds of the formula (A) include, but are not limited to, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, and 1,4 dioxane.
  • Suitable chlorinated solvents which may be employed include, but are not limited to, dichloromethane, 1,2-dichloroethane, chloroform, and carbontetrachloride.
  • Suitable aromatic solvents which may be employed include, but are not limited to, benzene and toluene.
  • Suitable alchoholic solvents which may be employed include, but are not limited to, methanol, ethanol, n-propanol, iso propanol, and tert-butanol.
  • Suitable aprotic solvents which may be employed include, but are not limited to, N, N- dimethylformamide and dimethyl sulfoxide.
  • the compounds prepared in the above described processes can be obtained in pure form by using techniques known in the art 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,
  • polymorphs of a compound of formula (A) forming part of this invention may be prepared by crystallization of a compound of formula (A) under different conditions, for example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, and 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 calorinietry, powder X-ray diffraction or such other techniques.
  • some of the compounds of formula (A) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in the compounds of formula (A) 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 and Z geometrical isomers wherever possible in the compounds of formula (A) which includes the single isomer or mixture of both the isomers.
  • 3-Amino-l-adamantanol is commercially available. Alternatively, it may be prepared by nitration of adamantane-1 -amine with concentrated HNO 3 and H 2 SO 4 to 3- nitroadamantan-1 -amine followed by its in situ hydrolysis according to a literature procedure (PCT application No.WO2000/034241).
  • Step 1 1-Adamantanecarboxamide: To a stirred and cooled (-10 °C) solution of adamantane-1 -carboxylic acid (5.0 g, 27.74 mmol) and triethylamine (3.61 g, 33.27 mmol) in THF (80 ml) was added ethyl chloroformate (3.65 g, 36.06 mmol) to result in a white precipitate. The mixture was stirred at the same temperature for 30 min and 30 % NH 4 OH (20 ml) was added. The reaction mixture was gradually warmed to room temperature and further stirred for 30 min.
  • Step 2 1-Adamantylmethylamine: To a stirred and cooled (0 °C) suspension of lithium aluminium hydride (846 mg, 22.29 mmol) in dry THF (10 ml) was added dropwise a solution of Step 1 intermediate (1.0 g, 5.58 mmol) in dry THF (15 ml). The reaction mixture was gently refiuxed overnight. The mixture was cooled to 10 0 C and then quenched with a few drops of ethyl acetate followed by addition of a saturated solution of Na 2 SO 4 . The mixture was filtered over celite, the filtrate was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the product as a pale yellow semisolid (737 mg, 80%).
  • Step 3 1-Adamantylmethylamine hydrochloride: Dry HCl gas was bubbled into a solution of Step 2 intermediate (737 mg, 4.46 mmol) in dichloromethane (10 ml) at 0 0 C. The solvent was removed under reduced pressure and the solid so obtained was triturated with dry diethyl ether to afford the pure product as a white solid (540 mg, . 60 %); 1 H NMR (300 MHz, DMSO-J 6 ) ⁇ 1.50-1.69 (m, 12 H), 1.96 (brs, 3H), 2.46- 2.51 (m, 2H), 7.85 (brs, 3H).
  • Step 4 3-Aminomethyl-l-adamantanol: Step 3 intermediate (300 mg, 1.49 mmol) was added in portions to concentrated H 2 SO 4 (1.5 ml) under stirring at 0 0 C. Concentrated HNO 3 (0.3 ml) was added dropwise to the above reaction mixture. Stirring was continued overnight. The reaction mixture was added to ice cold water, basified to pH 10 and extracted with dichloromethane.
  • Step 1 (25 r ,45)-iV-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 (2 ⁇ S',4 ⁇ )-iV-BOC-4-Fluoro ⁇ yrrolidme-2-carbonitrile: To a stirred and cooled (0 0 C) solution of Step 1 intermediate (10 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 (26',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. The white crystalline product separated out was collected by filtration and dried under vacuum to give 10.5 g (87 %) of the product as a pale pink solid.
  • Step 4 (2S,4S) ⁇ l-(2-Chloroacetyl)-4-fiuoropyrrolidine-2-carbonitrile:
  • a solution of step 3 intermediate (10 g, 32.89 mmol) and triethylamine (4.32 g, 42.77 mmol) in dichloromethane (200 ml) was added drop wise 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 (45)-l,3-Thiazolane-4-carboxylic acid: This intermediate was prepared from
  • Step 2 (4,S)-JV-BOC-1, 3-Thiazolane-4-carboxylic acid: A solution of di-tert-butyl dicarbonate (21.3 g, 0.977 mol) in acetonitrile (20 ml) was added to a stirred solution of Step 1 intermediate (10.0 g, 0.075 mol) and triethylamine (18.98 g, 0.188 mol) in 50 % aqueous acetonitrile (100 ml) and the solution was stirred at room temperature for 18 h. Acetonitrile was evaporated under reduced pressure and the residual aqueous solution was acidified with IN HCl to pH 3-4.
  • Step 3 (4,S)-N-BOC-1, 3 -TMazolane-4-carboxamide: To a stirred and cooled (-15 0 C) solution of Step 2 intermediate (10 g, 42.918 mmol) and triethylamine (7.15 g, 70.79 mmol) in dry tetrahydrofuran (100 ml) was added ethyl chloroformate (7.68 g, 70.79 mmol) under nitrogen atmosphere to result a white precipitate. The mixture was stirred at the same temperature for 30 min and 30 % aqueous NH 4 OH (100 ml) solution was added drop-wise over a period of 20 min.
  • the reaction mixture was gradually allowed to warm to room temperature and stirring was continued for another 18 h.
  • the mixture was then extracted into dichloromethane (2 x 100 ml) and the combined organic extracts were washed with water (100 ml), brine (100 ml) and dried (Na 2 SO 4 ).
  • the residue obtained after evaporation of the solvent was triturated with n-pentane (50 ml) to give 7.1 g (71 %) of the product as a white solid.
  • Step 4 (45)-iV-BOC-l,3-Thiazolane-4-carbonitrile: To a stirred and cooled (0 0 C) solution of Step 3 intermediate (7.0 g, 30.04 mmol) and triethylamine (9.2 g, 91.09 mmol) in dry tetrahydrofuran (35 ml) was added trifluoroacetic anhydride (9.46 g, 45.05 mmol) and the mixture was stirred at the same temperature for 1 h. The reaction, mixture was diluted with water (50 ml) and extracted with chloroform (2 x 50 ml).
  • Step 5 (45)-l,3-Thiazolane-4-carbonitrile jt?-methylbenzenesulfonate: 4- Methylbenzene-sulfonic acid monohydrate (7.73 g, 40.68 mmol) was added to a stirred solution of Step 4 intermediate (5.8 g, 27.10 mmol) in dry acetonitrile (50 ml) and the mixture was stirred at room temperature for 24 h under nitrogen atmosphere.
  • Step 6 (4 > S)-3-(2-Chloroacetyl)-l,3-tliiazolane-4-carbonitrile: A mixture of Step 5 intermediate (7.0 g, 23.03 mmol) and triethylamine (3.02 g, 29.90 mmol) in dry dichloromethane (25 ml) was added drop wise (10 min) to a stirred and cooled (0 0 C) solution of chloroacetyl chloride (2.58 g, 23.03 mmol) in dry dichloromethane (25 ml) over 20 min. The resulting mixture was stirred at 0 0 C for 2 h and diluted with water (100 ml).
  • Step 1 iV-(3-Hydroxy-l-adamantyl)methanesulfonamide: To a stirred and cooled (0 °C) solution of Intermediate 1 (2.0 g, 11.03 mmol) in pyridine (10 ml) was added methanesulfonyl chloride (1.39 g, 12.14 mmol) under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 h. The mixture was further diluted with dichloromethane (100ml) and washed with IN HCl, brine and dried over anhydrous Na 2 SO 4 .
  • Step 2 M-(3-Methylsulfonamido-l-adamantyl)-2-chloroacetamide: Concentrated H 2 SO 4 (1 ml) was added dropwise to chloroacetonitrile (2 ml) at 0 °C under stirring. Step 1 intermediate (400 mg, 1.54 mmol) was then added in one portion. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for 2 h. The reaction mixture was added onto ice cold water and extracted into dichloromethane (2 x 50 ml). Combined organic extracts were dried over anhydrous Na 2 SO 4 and the solvent was evaporated under reduced pressure to afford a pale brown residue.
  • Step 3 iV-(3-Amino-l-adamantyl)methanesulfonamide: A solution of Step 2 intermediate (406 mg, 1.21 mmol) and thiourea (111 mg, 1.46 mmol) in a mixture of ethanol (5 ml) and acetic acid (1 ml) was refluxed overnight. The reaction mixture was diluted with water (25 ml), basified with 10 % KOH solution to pH 10 and extracted with dichloromethane (2 x 50 ml).
  • Step 4 7V-(3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2-oxoethylammo ⁇ -l- adamantyl)methane-sulfonamide: To a stirred and cooled (10 °C) suspension of Step 3 intermediate (140 mg, 0.57 mmol), potassium carbonate (158 mg, 1.15 mmol) and sodium iodide (86 mg, 0.57 mmol) in dry THF (3 ml) was added drop-wise to a solution of Intermediate 3 (99 mg, 0.57 mmol) in dry
  • Step 1 iVl-(3-Hydroxy-l-adamantyl)-3-chloro-l-propanesulfonamide: To a stirred and cooled (0 °C) suspension of Intermediate 1 (5.0 g, 29.90 mmol) and NJSf- diisopropylethylamine (7.70 g, 59.79 mmol) in dichloromethane (50 ml) was added a solution of 3-chloropropanesulfonyl chloride (7.9 g, 44.84 mmol) in dichloromethane (50 ml). Stirring was continued for 4 h.
  • Step 3 iVl-[3-Tetrahydro-2-(l,l-dioxo-2-isothiazolidinyl)-l-adamantyl]-2- chloroacetamide: A solution of Step 2 intermediate (500 mg, 1.30 mmol) and sodium methoxide (141 mg, 2.61 mmol) in dry methanol (10 ml) was refluxed overnight. The solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane (50 ml) and washed with IN HCl, brine and dried over anhydrous Na 2 SO 4 .
  • Step 5 iV-(3- ⁇ 2-[(2,S)-2-Cyanopyrrolidin- 1 -yl]-2-oxoethylamino ⁇ - 1 -(1 , 1 -dioxo-2- isothiazolidinyl)adamantane: Coupling reaction of Step 4 intermediate (140 mg, 0.52 mmol) with Intermediate 3 (90 mg, 0.52 mmol) in dry THF (6 ml) in the presence of potassium carbonate (143 mg, 1.04 mmol) and NaI (77 mg, 0.52 mmol) as described in Example 1, Step 4 gave 90 mg of the product as an off-white solid; IR (neat) 3310, 2912, 2855, 2240, 1659, 1416, 1059 cm 4 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.88-1.96 (m, 7H), 2.04-2.09 (m, 6H), 2.16-2.28 (m, 8H), 3.15-3.
  • Step 1 l-(4-Fluorophenylsulfonamido)-3-hydroxyadamantane: To a stirred and cooled (0 °C) suspension of Intermediate 1 (1.0 g, 5.98 mmol) and triethylamine (0.65 g, 6.58 mmol) in dichloromethane (5 ml) was added a solution of p- fmorobenzenesulfonyl chloride (1.16 g, 6.58 mmol) in dichloromethane (5 ml). Stirring was continued for 2 h. The reaction mixture was further diluted with dichloromethane and washed with IN HCl, water, brine and dried over anhydrous Na 2 SO 4 .
  • Step 2 M-[3-(4-Fluorophenylsulfonamido)l-adamantyl]acetamide: Concentrated H 2 SO 4 (3 ml) was added dropwise to acetonitrile (3 ml) under stirring at 0 0 C. Step 1 intermediate (500 mg, 1.54 mmol) was then added in one portion. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for 3 h. The reaction mixture was added onto ice cold water, basif ⁇ ed with saturated NaHCO 3 solution to pH 8 and extracted into dichloromethane (2 x 50 ml).
  • Step 3 3-Amino-l-(4-fluorophenylsulfonamido)adamantane: A solution of Step 2 intermediate (250 mg, 0.68 mmol) in concentrated HCl (10 ml) was refmxed overnight. The reaction mixture was cooled to 0 °C, basif ⁇ ed with saturated KOH solution and extracted with dichloromethane (2 x 50 ml). The combined organic extracts were dried over anhydrous Na 2 SO 4 .
  • Step 4 iV-(3- ⁇ 2-[(25)-2-cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l-(4-fluorophenyl- sulfonamido)adamantane: Coupling reaction of Step 3 intermediate (130 mg, 0.40 mmol) with Intermediate 3 (69 mg, 0.40 mmol) in dry THF (6 ml) in the presence of potassium carbonate (110 mg, 0.80 mmol) and NaI (60 mg, 0.40 mmol) as described in Example 1, Step 4 gave 70 mg of the product as an off-white solid; IR (KBr) 3437,
  • Step 1 4-Methylsulfanyl-l-benzenesulfonyl chloride: To a cooled (0 0 C) and stirred solution of thioanisole (1.0 g, 8.05 mmol) in chloroform (10 ml) was added cautiously chlorosulfonic acid (2.81 g, 24.15 mmol) in one portion. Stirring was continued for 3 h. The reaction mixture was then added to ice cold water and extracted with dichloromethane (2 x 50 ml). The combined organic extracts were washed with water, brine and dried over anhydrous Na 2 SO 4 .
  • Step 3 3 -Hydroxy- l-(4-methylsulfonylphenylsulfonamido)adamantane: To a cooled (0 °C) solution of Step 2 intermediate (150 mg, 0.425 mmol) in chloroform (8 ml) was added m-chloroperbenzoic acid (293 mg, 1.70 mmol) in portions. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with chloroform (50 ml) and washed with saturated NaHCO 3 solution, water and dried over anhydrous Na 2 SO 4 .
  • Step 4 Nl-[3-(4-Methylsulfonylphenylsulfonamido)-l-adamantyl]acetamide: This compound was prepared from Step 3 intermediate (180 mg, 0.47 mmol) by Ritter reaction using acetonitrile (3.0 ml) in the presence of concentrated H 2 SO 4 (3.0 ml) as* described in Example 6, Step 2 to afford 181 mg of the desired product as an off- white solid; IR (KBr) 3441, 3376, 2909, 2871, 1656, 1597, 1547, 1318, 1157 cm 1 ; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.60-1.79 (m, 9H), 1.97-2.07 (m, 8H), 3.31 (s, 3H), 7.38 (s, IH), 7.94 (s, IH), 8.05-8.14 (m, 4H).
  • Step 5 3-Amino-l-(4-methylsulfonylphenylsulfonamido)adamantane: This compound was prepared by the hydrolysis of Step 4 intermediate (350 mg, 0.821 mmol) using concentrated HCl (10 ml) according to the procedure described in Example 6, Step 3 to afford 85 mg of the amine as a yellow solid; IR (KBr) 3434, 3446, 2871, 1594, 1532, 1313, 1150 cm “1 ; 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.33- 1.58 (m, 9H), 1.73-1.78 (m, 2H) 1.88-2.00 (m, 4H), 2.10-2.15 (m, IH), 3.16 (s, 3H), 4.18 (brs, IH), 8.05-8.15 (m, 4H).
  • Step 6 3 - ⁇ 2- [(25)-2-Cyanopyrrolidin- 1 -yl] -2-oxoethylamino ⁇ - 1 -(4-methylsulfonyl- phenylsulfonamido)adamantane: Coupling reaction of Step 5 intermediate (80 mg, 0.208 mmol) with Intermediate 3 (36 mg, 0.208 mmol) in dry THF (6 ml) in the presence of potassium carbonate (57 mg, 0.416 mmol) and NaI (31 mg, 0.208 mmol) as described in Example 1, Step 4 gave 23 mg of the product as a yellow solid; IR (KBr) 3267, 2924, 2856, 2241, 1651, 1591, 1417, 1316, 1154 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.65-1.79 (m, 6H), 1.90-1.98 (m, 6H), 2.19-2.26 (m, 7H
  • Step 4 7V3-(3- ⁇ 2-[(2,S)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l-adamantyl)-3- pyridinesulfonamide: Coupling reaction of Step 3 intermediate (60 mg, 0.20 mmol) with Intermediate 3 (35 mg, 0.20 mmol) in dry THF (6 ml) in the presence of potassium carbonate (55 mg, 0.40 mmol) and NaI (30 mg, 0.20 mmol) as described in Example 1, Step 4 gave 35 mg of the pure product as a yellow solid; IR (KBr) 3435, 2922, 2242, 1648, 1416, 1162 cm- 1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.26-1.80 (m, 12H), 2.09-2.31 (m, 7H), 3.38-3.64 (m, 4H), 4.77-4.79 (m, IH), 5.34 (brs, IH), 7.44
  • Step 2 M-(3-Butylsulfonamidomethyl-l-adamantyl)acetamide: This compound was prepared from Step 1 intermediate (505 mg, 1.68 mmol) by Ritter reaction using acetonitrile (4.0 ml) in the presence of concentrated H 2 SO 4 (4.0 ml) as described in Example 6, Step 2 to afford 550 mg of the desired product as a yellow semi-solid; IR (KBr) 3288, 2937, 2850, 1650, 1450, 1315, 1132 cm 4 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 0.95 (t, J- 7.2 Hz, 3H), 1.41-1.64 (m, 6H), 1.76-2.09 (m, 13H), 2.18 (brs, 2H), 2.82 (s, 2H), 2.98-3.03 (s, 2H), 4.80 (brs, IH), 6.07 (brs, IH).
  • Step 4 M-(3- ⁇ 2-[(2»S)-2-Cyano ⁇ yrrolidin-l-yl]-2-oxoethylamino ⁇ -l- adamantylmethyl)-l-butanesulfonamide: Coupling reaction of Step 3 intermediate (76 mg, 0.25 mmol ) with Intermediate 3 (44 mg, 0.25 mmol) in dry THF (6 ml) in the presence of potassium carbonate (70 mg, 0.51 mmol) and NaI (38 mg, 0.25 mmol) as described in Example 1, Step 4 gave 100 mg of the product as an off-white solid; IR
  • Step 1 M-(3-Hydroxy-l-adamantylmethyl)-3-chloiO-l-propanesulfonamide: This compound was prepared from Intermediate 2 (500 mg, 2.76 mmol) and 3- chloropropanesulfonyl chloride (730 mg, 4.12 mmol) using N,N- diisopropylethylamine (700 mg, 5.42 mmol) in dichloromethane (10 ml) according to the procedure described in Example 4, Step 1 to afford 640 mg of the product as an off-white solid; IR (KBr) 3435, 2903, 2857, 1464, 1309, 1138, 1028, 857 cm "1 ;.
  • Step 5 (25)- 1 -[2-(3 -Tetrahydro-2-( 1 , 1 -dioxo-2-isothiazolidinylmethyl)- 1 -adamantyl- amino)acetyl]pyrrolidine-2-carbonitrile: Coupling reaction of Step 4 intermediate (84 mg, 0.30 mmol) with Intermediate 3 (50 mg, 0.30 mmol) in dry THF (6 ml) in the presence of potassium carbonate (81 mg, 0.60 mmol) and NaI (44 mg, 0.30 mmol) as described in Example 1, Step 4 gave 90 mg of the product; IR (neat) 2918, 2852, 2400, 1663, 1417, 1308, 1215, 1137, 756 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.46 (brs, 6H), 1.59-1.71 (m, 6H), 2.21-2.40 (m, 9H), 2.78-2.79 (m, 2H), 3.10 (
  • Step 4 3- ⁇ 2-[(2 ( S)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l-(4- methylphenylsulfo-namidomethyl)adamantane: Coupling reaction of Step 3 intermediate (45 mg, 0.14 mmol) with Intermediate 3 (23 mg, 0.14 mmol) in dry THF (6 ml) in the presence of potassium carbonate (37 mg, 0.27 mmol) and NaI (20 mg, 0.14 mmol) as described in Example 1, Step 4 gave 30 mg of the product as an off- white solid; IR (KBr) 3422, 2922, 2850, 2241, 1737, 1654, 1326, 1157 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.34-1.37 (m, 7H), 1.56 (brs, 6H), 2.15-2.30 (m, 6H), 2.42 (s, 3H), 2.59-2.60 (m
  • Step 3 3-Amino-l-(4-fluorophenylsulfonamidomethyl)adamantane: This compound was prepared from Step 2 intermediate (400 mg, 0.93 mmol) using thiourea (85 mg, 1.11 mmol) in a mixture of ethanol (5 ml) and acetic acid (1 ml) according to the procedure described in Example 1, Step 3 to afford 280 mg of the product as a yellow solid; IR (KBr) 3325, 2377, 2900, 2849, 1591, 1490, 1326, 1168, 1092 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.23-1.57 (m, 14H), 2.12-2.13 (m, 2H), 2.64 (s, 2H), 4.60 (brs, IH), 7.16-7.22 (m, 2H), 7.84-7.88 (m, 2H).
  • Step 4 3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l-(4-fluorophenyl- sulfonamidomethyl)adamantane: Coupling reaction of Step 3 intermediate (120 mg, 0.34 mmol) with Intermediate 3 (60 mg, 0.34 mmol) in dry THF (6 ml) in the presence of potassium carbonate (93 mg, 0.68 mmol) and NaI (50 mg, 0.34 mmol) as described in Example 1, Step 4 gave 127 mg of the pure product as an off-white solid; IR (KBr) 3437, 2906, 2850, 2243, 1653, 1592, 1420, 1166, 1092 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.32-1.37 (m, 7H), 1.57 (brs, 7H), 2.16-2.31 (m, 6H), 2.60-2.66 (m,
  • Step 2 3 -Hydroxy- l-(4-methylsulfonylphenylsulfonamidomethyl)adamantane: This compound was prepared by the oxidation of Step 1 intermediate (570 mg, 1.55 mmol) using m-chloroperbenzoic acid (1.07 g, 6.20 mmol) in chloroform (10 ml) according to the procedure described in Example 7, Step 3 to afford a crude residue which was purified by silica gel column chromatography using 5 % methanol in dichloromethane to give the product as a white solid (545 mg, 88 %); IR (KBr) 3315, 2905, 2851, 1594, 1451, 1309, 1162 cm “1 , 1 H NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 1.28 (brs, 6 H), 1.44- 1.54 (m, 6H), 2.07 (brs, 2H), 2.46-2.49 (m, 2H), 3.31 (s
  • Step 5 3- ⁇ 2-[(25)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l-(4-methylsulfonyl- phenylsulfonamidomethyl)adamantane: Coupling reaction of Step 4 intermediate (56 mg, 0.14 mmol) with Intermediate 3 (24 mg, 0.14 mmol) in dry THF (6 ml) in the presence of potassium carbonate (39 mg, 0.28 mmol) and NaI (21 mg, 0.14 mmol) as described in Example 1, Step 4 gave 52 mg of the product as an off-white solid; IR (KBr) 3282, 2907, 2850, 2241, 1656, 1417, 1314, 1155 cm '1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.32-1.45 (m, 6H), 1.56-1.61 (m, 6H), 2.02-2.30 (m, 8H), 2.65-2.68 (m, 2H
  • Step 1 3 -Hydroxy- 1-adamantanecarboxylic acid: Adamantane-1-carboxylic acid (5.0 g, 27.70 mmol) was added in portions to concentrated H 2 SO 4 (25 ml) under stirring at 0 °C. Concentrated HNO 3 (5 ml) was added dropwise to the above reaction mixture.
  • Step 2 3-Chloromethylcarboxamido-l-adamantanecarboxylic acid: This compound was prepared from Step 1 intermediate (4.0 g, 20.38 mmol) by Ritter reaction using chloroacetonitrile (13 ml) in the presence of concentrated H 2 SO 4 (17 ml) as described in Example 1, Step 2 to afford 5.0 g of the compound as a white solid; IR (KBr) 3344, 2911, 1688, 1645, 1550, 1269 cm '1 ; 1 H NMR (300 MHz, DMSO-J 6 ,) ⁇ 1.59-2.18 (m, 14H), 3.96 (s, 2H), 7.80 (s, IH), 12.20 (brs, IH).
  • Step 3 Methyl S-chloromethylcarboxamido-l-adamantanecarboxylate: Thionyl chloride (2.63 g, 22.08 mmol) was added dropwise to a cooled (0 0 C) solution of Step 2 intermediate (3.09 g, 11.04 mmol) in methanol (25 ml) under stirring. The reaction mixture was further refluxed for 6 h. Methanol was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated NaHCO 3 solution, brine and dried over anhydrous Na 2 SO 4 .
  • Step 4 Methyl 3-amino-l-adamantanecarboxylate: This compound was prepared from Step 3 intermediate (500 mg, 1.74 mmol) using thiourea (160 mg, 2.10 mmol) in a mixture of ethanol (5 ml) and acetic acid (1 ml) according to the procedure described in Example 1, Step 3 to afford 230 mg of the product as an oil; IR (neat) 3389, 2921, 2859, 1710, 1672, 1532, 1123 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ,) ⁇ 1.44- 1.56 (m, 9H), 1.61-1.71 (m, 5H), 2.06-2.07 (m, 2H), 3.57 (s, 3H).
  • Step 5 Methyl 3-N-BOC-amino-l-adamantanecarboxylate: A solution of di-tert- butyl dicarbonate (263 mg, 1.21 mmol) in dichloromethane (5 ml) was added over 10 min to a stirred solution of Step 4 intermediate (230 mg, 1.10 mmol) and triethylamine (122 mg, 1.21 mmol) in dichloromethane (5 ml) at 0 0 C. The reaction mixture was gradually allowed to warm to room temperature and stirring was continued for 3 h. The reaction mixture was diluted with dichloromethane and washed with 10 % KHSO 4 solution, brine and dried over anhydrous Na 2 SO 4 .
  • Step 6 S-iV-BOC-Ammo-l-adamantanecarboxylic acid: A solution of Step 5 intermediate (2.3 g, 7.43 mmol) and KOH (2.6 g, 46.43 mmol) in methanol (50 ml) was refluxed for 15 h. Methanol was removed under reduced pressure and the residue was dissolved in minimum amount of water. The residual aqueous solution was acidified with 10 % KHSO 4 solution to pH 4 and extracted with dichloromethane. Combined organic extracts were washed with brine and dried over anhydrous Na 2 SO 4 .
  • Step 7 3-N-BOC-Amino-l-adamantanecarboxamide: To a stirred and cooled (-15 °C) solution of step 6 intermediate (1.0 g, 3.39 mmol) and triethylamine (445 mg, 4.40 mmol) in dry THF (10 ml) was added ethyl chloroformate (440 mg, 4.06 mmol) under a nitrogen atmosphere to result in a white precipitate. The mixture was stirred at the same temperature for 30 min and 30 % aqueous NH 4 OH (20 ml) solution was added in one portion. The reaction mixture was gradually allowed to warm to room temperature and stirring continued for another 30 min. THF was evaporated under reduced pressure and the solid so precipitated was filtered and washed with cold water to give the desired product as an off-white solid (800 mg); IR (KBr) 3510, 3320,
  • Step 8 S-iV-BOC-Amino-l-adamantanecarbonitrile: Phosphorus oxychloride (1.9 g, 12.40 mmol) was added carefully to a cooled (0 0 C) solution of Step 7 intermediate (730 mg, 2.48 mmol) in pyridine (10 ml) under stirring. The reaction mixture was further stirred for 30 min. The mixture was added to ice cold water and extracted with ethyl acetate (2 x 100 ml). Combined organic extracts were washed with water, brine and dried over anhydrous Na 2 SO 4 .
  • Step 9 3-Amino-l-adamantanecarbonitrile: Trifluoroacetic acid (3 ml) was added to a stirred and cooled (10 °C) solution of Step 8 intermediate (630 mg, 2.30 mmol) in dry dichloromethane (3 ml). The reaction mixture was stirred at the same temperature for another 2 h under a nitrogen atmosphere. The mixture was diluted with dichloromethane (100 ml) and washed with saturated NaHCO 3 solution, brine and dried over anhydrous Na 2 SO 4 .
  • Step 10 (2»S)-l-[2-(3-Cyano-l-adamantylamino)acetyl]pyrrolidme-2-carbonitrile: Coupling reaction of Step 9 intermediate (200 mg, 1.13 mmol) with Intermediate.3 (195 mg, 1.13 mmol) in dry THF (6 ml) in the presence of potassium carbonate (317 mg, 2.30 mmol) and NaI (170 mg, 1.13 mmol) as described in Example 1, Step 4 gave 250 mg of the product as a semisolid; IR (neat) 3440, 2948, 2832, 2241, 1651, 1526, 1405, 1113 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.64-1.70 (m, 4H), 1.90-1.95 (m, 8H), 2.15-2.19 (m, 7H), 3.39-3.47 (m, 3H), 3.57-3.60 (m, IH), 4.75-4.78 (m, IH).
  • Step 1 3-(2,3-Dihydro ⁇ lH-2-isoindolylmethyl)-l-adamantanol: A suspension of the Intermediate 2 (500 mg, 2.80 mmol), o-xylylene dibromide (739 mg, 2.80 mmol) and K 2 CO 3 (968 mg, 7.00 mmol) in dry DMF (10 ml) was stirred at room temperature for 24 h under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted into ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous Na 2 SO 4 .
  • Step 2 M -[3 -(2,3 -Dihydro- lH-2-isoindolylmethyl)- 1 -adamantyl]-2- chloroacetamide: This compound was prepared from Step 1 intermediate (600 mg, 2.10 mmol) by the Ritter reaction using chloroacetonitrile (2 ml) in the presence of concentrated H 2 SO 4 (1 ml) as described in Example 1, Step 2 to afford 305 mg of the compound as an off-white solid; IR (neat) 3265, 2915, 1657, 1566, 1236, 741 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.52-1.70 (m, 6H), 1.87 (s, 2H), 1.93-2.05 (m, 4H), 2.19 (brs, 2H), 2.52 (s, 2H), 3.93 (s, 2H), 4.05 (s, 4H), 6.26 (brs, IH), 7.18 (s, 4H).
  • Step 3 3-(2,3-Dihydro-lH-2-isoindolylmethyl)-l-adamantylamme: This compound was prepared from Step 2 intermediate (290 mg, 0.80 mmol) using thiourea (73 mg, 0.96 mmol) in a mixture of ethanol (5 ml) and acetic acid (1 ml) according to the procedure described in Example 1, Step 3 to afford 215 mg of the product as a semisolid; IR (neat) 3280, 2901, 1640, 1423, 1280, 1083 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.43-1.54 (m, 12H), 2.14 (brs, 2H), 2.49 (s, 2H), 3.48 (s, 2H), 4.05 (s, 4H), 7.17 (s, 4H).
  • Step 4 (2S)-l- ⁇ 2-[3-(2,3-Dihydro-lH-2-isoindolylmethyl)-l- adamantylamino]acetyl ⁇ -pyrrolidine-2-carbonitrile: Coupling reaction of Step 3 intermediate (208 mg, 0.70 mmol) with Intermediate 3 (121 mg, 0.70 mmol) in dry THF (6 ml) in the presence of potassium carbonate (193 mg, 1.40 mmol) and NaI (105 mg, 0.70 mmol) as described in Example 1, Step 4 gave 125 mg of the product as a yellow semisolid; IR (neat) 3309, 2902, 2240, 1661, 1412, 746 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.46-1.61 (m, 12H), 2.07-2.30 (m, 7H), 2.52 (s, 2H), 3.41-3.69 (m, 4H), 4.08 (s, 4H), 4.76-5.02 (m
  • Step 1 Nl-(3-Hydroxy-l-adamantyl)acetamide: To a stirred suspension of Intermediate 1 (700 mg, 4.19 mmol) in pyridine (10 ml) was added acetic anhydride (514 mg, 5.03 mmol) at 0 °C. Stirring was continued for 1 h. The reaction mixture was poured onto ice cold water, acidified with IN HCl and extracted into dichloromethane (2 x 50 ml). The combined organic extracts were washed with water, brine and dried over anhydrous Na 2 SO 4 .
  • Step 2 M-(3-Methylcarboxamido-l-adamantyl)acetamide: This compound was prepared from Step 1 intermediate (390 mg, 1.87 mmol) by Ritter reaction using acetonitrile (5 ml) in the presence of concentrated H 2 SO 4 (5 ml) as described in Example 6, Step 2 to afford 366 mg of the desired product as a white solid; IR (KBr) 3299, 2913, 2853, 1645, 1548 cm “1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.70-1.73 (m, 2H), 1.90-2.00 (m, 14H), 2.21-2.29 (m, 4H), 5.26 (brs, 2H).
  • Step 3 1,3-Adamantanediamine: This compound was prepared by the hydrolysis of Step 2 intermediate (1.0 g, 3.98 mmol) using concentrated HCl (30 ml) according to the procedure described in Example 6, Step 3 to afford 600 mg of the diamine as a pale yellow solid; IR (KBr) 3295, 3226, 2910, 2847, 1562 cm '1 ; 1 H NMR (300 MHz, CDCl 3 ) ⁇ 1.42-1.53 (m, 16H), 2.17-2.18 (m, 2H).
  • Step 4 (26)-l-[2-(3- ⁇ 2-[(2S)-2-Cyanopyrrolidin-l-yl]-2-oxoethylamino ⁇ -l- adamantyl-amino)acetyl]pyrrolidine-2-carbonitrile: Coupling reaction of Step 3 intermediate (580 mg, 3.49 mmol) with Intermediate 3 (1.20 g, 6.98 mmol) in dry
  • DPPIV activity was determined by the cleavage rate of 7-amino-4-methyl coumarin (AMC) from synthetic substrate Glycyl-Prolyl-AMC.
  • the assay was conducted by adding 10 ng of human recombinant Dipeptidyl peptidase IV enzyme (DPPrV, available commercially from R & D Systems) 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 microliter 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 °C for 30 minutes.
  • 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

L'invention se rapporte à des inhibiteurs de dipeptidyl peptidase IV (DPP-IV) représentés par la formule (A) : R1, R2, Y, et n étant tels que définis ci-après, à des compositions pharmaceutiques les contenant, à des procédés de préparation associés, ainsi qu'à des méthodes de traitement de troubles médiés par l'inhibition DPP-IV, tels que les diabètes, notamment les diabètes de Type II, au moyen de ceux-ci.
PCT/IB2006/000363 2005-02-22 2006-02-22 Nouveaux derives d'adamantine utilises en tant qu'inhibiteurs de dipeptidyl peptidase iv, procedes de preparation associes, et compositions pharmaceutiques les contenant WO2006090244A1 (fr)

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WO2008120813A1 (fr) 2007-04-03 2008-10-09 Mitsubishi Tanabe Pharma Corporation Utilisation combinée de composé inhibiteur de dipeptidylpeptidase iv, et d'adoucisseur
WO2008135041A1 (fr) * 2007-05-08 2008-11-13 Schebo Biotech Ag Dérivés d'adamantyloxyamine et composés apparentés en tant que modulateurs de nmda et/ou dpp-4 pour traiter des maladies du snc et le diabète
WO2010011570A1 (fr) * 2008-07-25 2010-01-28 H. Lundbeck A/S Dérivés de diamide d'adamantyle, et utilisation de ceux-ci
WO2010076033A1 (fr) 2008-12-30 2010-07-08 European Molecular Biology Laboratory (Embl) Sulfamides de toluidine et leur utilisation
WO2010076034A1 (fr) 2008-12-30 2010-07-08 European Molecular Biology Laboratory (Embl) Toluidine sulfonamides et leur utilisation en tant qu'inhibiteurs
WO2010112946A1 (fr) 2009-03-31 2010-10-07 Rudjer Boskovic Institute Dérivés d'adamantane-bisurée, procédé de préparation et application à la détection d'anions
US8338450B2 (en) 2007-09-21 2012-12-25 Lupin Limited Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
CN103058826A (zh) * 2011-10-24 2013-04-24 上海博康精细化工有限公司 1-羟基-3-羟甲基金刚烷的合成方法
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
US8853385B2 (en) 2008-01-17 2014-10-07 Mitsubishi Tanabe Pharma Corporation Combination therapy comprising SGLT inhibitors and DPP4 inhibitors
CN104447704A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 一种腈基金刚烷四氮唑化合物、其制备方法和用途
CN104447703A (zh) * 2015-01-13 2015-03-25 佛山市赛维斯医药科技有限公司 一种硝基金刚烷四氮唑化合物、其制备方法和用途
CN104478859A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 一种羟基金刚烷四氮唑化合物、其制备方法和用途
CN104478861A (zh) * 2015-01-13 2015-04-01 佛山市赛维斯医药科技有限公司 一种硝基金刚烷四氮唑化合物、其制备方法和用途
WO2022159955A1 (fr) * 2021-01-21 2022-07-28 The Scripps Research Institute Régulateurs à petites molécules de prolifération cellulaire de type 2 alvéolaire pour le traitement de maladies pulmonaires

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WO2010011570A1 (fr) * 2008-07-25 2010-01-28 H. Lundbeck A/S Dérivés de diamide d'adamantyle, et utilisation de ceux-ci
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WO2010076034A1 (fr) 2008-12-30 2010-07-08 European Molecular Biology Laboratory (Embl) Toluidine sulfonamides et leur utilisation en tant qu'inhibiteurs
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WO2010112946A1 (fr) 2009-03-31 2010-10-07 Rudjer Boskovic Institute Dérivés d'adamantane-bisurée, procédé de préparation et application à la détection d'anions
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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