WO2011092671A1 - Dérivés de la proline à utiliser dans le traitement du diabète - Google Patents

Dérivés de la proline à utiliser dans le traitement du diabète Download PDF

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WO2011092671A1
WO2011092671A1 PCT/IB2011/050424 IB2011050424W WO2011092671A1 WO 2011092671 A1 WO2011092671 A1 WO 2011092671A1 IB 2011050424 W IB2011050424 W IB 2011050424W WO 2011092671 A1 WO2011092671 A1 WO 2011092671A1
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amino
compound
butanoyl
proline
trifluorophenyl
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PCT/IB2011/050424
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English (en)
Inventor
Jitendra A. Sattigeri
Shahadat Ahmed
Sachin Sethi
Anil Gorakshnath Gadhave
Kirandeep Kaur
Lalima Sharma
Balasaheb Gangadhar Jadhav
Dhrubajyoti Datta
Satyanarayan Murthy Chilla
Pradip Kumar Bhatnager
Abhijit Ray
Vinay Bansal
Joseph Alexanand Davis
Geeta Vani Rayasam
Vamshi Krishna Tulasi
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Ranbaxy Laboratories Limited
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Publication of WO2011092671A1 publication Critical patent/WO2011092671A1/fr

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    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention provides novel heterocyclic compounds and methods of preparing such compounds.
  • the compounds of the invention are useful for palliative, curative or prophylactic treatment of diseases or conditions of diabetes and/or
  • This invention also relates to pharmaceutical compositions containing the compounds of the present invention, and methods for palliative, curative or prophylactic treatment of diseases or conditions of diabetes and/or hypertension.
  • the present invention also provides pharmaceutical compositions consisting of the heterocyclic compounds along with one or more dyslipidemic agents, antiobesity agents, anti-hyperglycemic agents, antihypertensive agents and anti-inflammatory agents.
  • Metabolic syndrome also called insulin resistance syndrome or syndrome X
  • the major characteristics of metabolic syndrome include insulin resistance, abdominal obesity, elevated blood pressure, and lipid abnormalities (i.e., elevated levels of triglycerides and low levels of high-density lipoprotein [HDL] cholesterol).
  • lipid abnormalities i.e., elevated levels of triglycerides and low levels of high-density lipoprotein [HDL] cholesterol.
  • the NCEP-ATP III Initially defined by an expert panel of the World Health Organization in 1998, the NCEP-ATP III has created an operational definition of metabolic syndrome: the co-occurrence of any three of the abnormalities mentioned above.
  • no study has been carried out which specifically examines the treatment of metabolic syndrome.
  • Type 2 diabetes mellitus also known as "non-insulin dependent diabetes mellitus” (NIDDM), accounts for 90% of all diabetes. This afflicts an estimated 6% of the adult population in western society and is expected to continue to grow at a rate of 6% per annum worldwide.
  • Type-2 diabetes is a complex metabolic disorder, characterized by hyperglycemia and hyperinsulinemia. This results from contribution of impaired insulin secretion from ⁇ -cells in pancreas and insulin resistance mainly in muscle and liver.
  • Uncontrolled hyperglycemia can further lead to late stage microvascular and
  • ASCVD cardiovascular disease
  • pharmacological agents are available as antihyperglycemic agents to mitigate the conditions manifested in NIDDM (Lancet, 2005, 365, 1333-1346).
  • insulin secretagogues which increase insulin secretion from pancreatic cells [e.g., sulphonyl urea's (glimeperide) and non-sulphonyl ureas (repaglinide)]
  • biguanides which lower hepatic glucose production (e.g., metformin)
  • a-glucosidase inhibitors which delay intestinal absorption of carbohydrates [e.g., acarbose] (Lancet, 2005, 365, 1333-1346).
  • the insulin sensitizers like pioglitazone and rosiglitazone (TZDs), which exhibit their effect by PPARy agonism, control hyperglycemia by improving peripheral insulin sensitivity without increasing circulating insulin levels.
  • all these agents are associated with one or more of side effects like hypoglycaemia, gastrointestinal side effects including abdominal discomfort, bloating, flatulence, hepatotoxicity, weight gain, dilutional anemia and peripheral edema (Endocrine Rev., 2000, 21, 585-618).
  • DPP-IV, CD26, EC 3.4.14.5 dipeptidyl peptidase IV
  • DPP-IV dipeptidyl peptidase IV
  • DPP-rV inhibitor sitagliptin (Januvia ® )
  • vildagliptin vildagliptin (Galvus ® )
  • DPP-IV diminishes the physiological level of active incretin (stimulating insulin secretion) hormone, glucagon-like peptide- 1 (GLP-1) ⁇ tin. ⁇ 2 min ⁇ by proteolytic deactivation.
  • the inhibition of DPP-IV elevates the level of active GLP-1 by 2-3 folds.
  • GLP-1 targets multiple pathways of glucose regulation. It augments insulin secretion in glucose-dependent manner, thereby avoiding hypoglycemic episodes. Importantly, GLP-1 is shown to increase ⁇ -cell mass in animal models, which offers the potential to prevent or reverse the progression of the disease. DPP-IV is a ubiquitous serine protease, which exists as both the soluble and membrane-bound forms with identical structure and function. It is clinically proven that DPP-IV inhibition leads to increase of GLP-1 to therapeutically beneficial levels and thus enhances the body's own normal glucose homeostatic mechanism. (/. Clin. Investig., 2007, 117, 24-32).
  • HT Hypertension
  • blood pressure is abnormally high with undue stress on heart, blood vessels and other organs such as kidney and brain.
  • ACEIs ACE inhibitors
  • ARBs angiotensin receptor blockers
  • beta-blockers e.g., atenolol, propranolol, nandolol, etc.
  • CBs calcium channel blockers
  • RAAS plays a pivotal role in the development of hypertension by regulating pressure/volume homeostasis as well as in the development of hypertension.
  • RAAS is activated by the enzyme renin secreted from juxtaglomerular cells in the kidney. Renin releases a decapeptide angiotensin I (ANG I) from angiotensinogen, the naturally occurring substrate of renin, synthesized in the liver.
  • ANG I is cleaved by angiotensin converting enzyme (ACE) to give the octapeptide, angiotensin II (ANG II).
  • ACE angiotensin converting enzyme
  • ANG II is the active species of the RAAS system, which mediates various physiological functions, which include vasoconstriction, stimulating aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, stimulating vasopressin secretion, causing cardiac inotropic effect and modulating other hormone system.
  • ANG II also increases hepatic glucose production and decreases insulin sensitivity. Therefore, pharmacological inhibition of RAAS may not only exert antihypertensive effects but also improves insulin resistance and glucose metabolism.
  • ACEIs improve insulin sensitivity also. ⁇ Hypertension, 2002, 40, 329-334; JRAAS, 2008, 9, 75-88).
  • ACEIs are thought to be beneficial in improving ventricular remodeling following myocardial infarction, reducing mortality in patients with heart failure and prevent the progression of diabetic nephropathy (Diabetes Care, 2003, 26, 2421-2425).
  • the American Heart Association and American College of Cardiology recommend ACEIs as standard therapy in patients with recent myocardial infarction, systolic heart failure and patients at high risk of cardiovascular events.
  • U.S. Publication No. 2006/0046978 discloses novel compounds that inhibit dipeptidyl peptidase (DPP r ) and/or neprilysin (NEP) and/or angiotensin converting enzyme (ACE).
  • DPP r dipeptidyl peptidase
  • NEP neprilysin
  • ACE angiotensin converting enzyme
  • the present invention provides novel heterocyclic compounds, which can be useful for palliative, curative or prophylactic treatment of diseases or conditions of diabetes and/or hypertension. Also provided herein, are processes for synthesizing such compounds.
  • compositions containing such compounds are provided together with the pharmaceutically acceptable carriers or diluents, which can be used for palliative, curative or prophylactic treatment of diseases or conditions of diabetes and/or
  • compositions may be administered or coadministered by a wide variety of routes including, for example, oral or parenteral.
  • compositions comprise one or more compound of Formula I and at least one other active ingredient include, but are not limited to, anti-hypertensive agents, dyslipidemic agents, anti-obesity agents, anti-hyperglycemic agents and anti-inflammatory agents.
  • racemates The racemates, enantiomers, diastereomers, and pharmaceutically acceptable salts as well as pharmaceutical compositions comprising the compounds, their racemates, enantiomers, pharmaceutically acceptable salts thereof, in combination with a
  • n is an integer 0-2;
  • R is hydrogen or alkyl
  • Y is -CH- or -N-;
  • G can independently be hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carbonyl, thiocarbonyl or oxo ; f can be 0-3; R j is alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or NR x R y (wherein R x and R y are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl); and R t is alkylene or -NH- alkylene;
  • R 3 is aralkyl, (CH 2 ) q SR u ,
  • R u is hydrogen, alkyl, -CO-alkyl, -CO-aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl;
  • q is an integer 1-3;
  • R d is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, Ci_ 6 alkylamine, aralkyl, heterocyclylalkyl, cycloalkylalkyl, heteroarylalkyl, alkyl-COOR, (CH2) q SR u , alkyl-OR f ; wherein R f is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloclkylalkyl,
  • R p is direct bond, alkylene;
  • R q can be NHCOR e (wherein R e is aryl, heteroaryl, heterocyclyl, cycloalkyl);
  • R s and R r are independently hydrogen, alkyl, aralkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl or can join together along with the carbon and nitrogen to which they are attached to form a ring system;
  • R d and R r can also join together along with the carbon to which they are attached to form a ring system and
  • p is an integer 0-2;
  • R 4 and R5 are independently hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aralkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl, Ci_ 6 alkylamine, alkyl-COR, alkyl-OR f ; wherein R is hydroxy, alkoxy, NHR and R and R f are as defined earlier or R4 and R5 can join together along with the carbon to which they are attached to form a ring system or R s andRs can join together along with the carbon and nitrogen to which they are attached to form a ring system;
  • R6 can be OH , aralkyl or (CH 2 ) q SR u wherein R u , Rd, q and p are as defined above.
  • P q is N- protecting group
  • R, G, f and R 2 is as defined earlier.
  • the invention encompasses compounds of Formula I that include, for example:
  • composition comprising therapeutically effective amount of compound of Formula I described herein together with one or more pharmaceutically acceptable carrier(s), excipients(s) or diluent(s).
  • the methods may include one or more of the following embodiments.
  • a method for palliative, curative or prophylactic treatment of diseases or conditions of a mammal suffering from diabetes and/or hypertension wherein the diabetes is treated by Dipeptidyl peptidases-IV (DPP-IV) inhibition and also benefited by ACE inhibition and hypertension is treated by angiotensin converting enzyme (ACE) inhibition.
  • DPP-IV Dipeptidyl peptidases-IV
  • ACE angiotensin converting enzyme
  • the diseases or conditions of diabetes are selected from the type 2 diabetes, prediabetes, dyslipidemia, metabolic syndrome, metabolic acidosis, ketosis, and satiety disorders, diabetic nephropathy and end organ damage such as kidney and brain and diseases or conditions of hypertension are selected from hypertension with or without incipient nephropathy, myocardial infarction, stroke, increased collagen formation, fibrosis, remodeling following hypertension, congestive heart failure, left ventricular hypertrophy, survival post myocardial infarction (MI), coronary artery diseases, atherosclerosis, angina pectoris or thrombosis
  • methods for palliative, curative or prophylactic treatment of diseases or conditions of diabetes and/or hypertension comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of Formula I in combination with one or more therapeutic agents selected from anti-hypertensive agents, dyslipidemic agents, anti-obesity agents, anti-hyperglycemic agents and anti-inflammatory agents.
  • alkyl refers to a branched or unbranched saturated hydrocarbon chain having 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, w-propyl, zso-propyl, w-butyl, zso-butyl, t- butyl, w-hexyl, w-decyl, w-tetradecyl and the like.
  • R «i ⁇ is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl or heteroaryl, heteroarylalkyl, heterocyclylalkyl) .
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g.,
  • cycloalkyl refers to a cyclic alkyl group of 3 to 20 carbon atoms having a monocyclic ring or polycyclic (fused, spiro and bridged rings) ring, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopentenyl and the like, and multiple ring structures such as adamantyl and bicyclo[2.2.1]heptanyl.
  • cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • aromatic -alkyl or "arylalkyl” refers to alkyl- aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-8 carbon atoms and aryl is as defined below.
  • heteroaryl groups are pyridinyl, quinolinyl, oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl refers to a non-aromatic monocyclic or polycyclic (multiple condensed, spiro or bridged) cycloalkyl group of 5 to 16 atoms in which 1 to 4 carbon atoms in the ring are replaced by a heteroatom selected from the group comprising of O, S and N, wherein the optionally-fused ring may, in turn, be saturated or unsaturated and may further contain 1-4 heteroatoms selected from the group comprising of N, O, and S.
  • the said heterocyclyl ring may optionally contain one or more olefinic bonds.
  • heterocyclyl groups are oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl,
  • dihydrobenzofuryl azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl, tetrahydroquinolinyl, pyrrolidinyl, morpholinyl, piperizinyl, azepinyl, azetidinyl, azeridinyl, tetrahydropyridinyl, benzthiazinyl, benzoxazinyl, isoindolinyl, phenoxazine and the like.
  • heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.
  • heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.
  • amino refers to -N(RJ0 2 , (wherein ⁇ is the same as defined earlier).
  • i alkylamine refers to alkyl-amino group linked through alkyl portion, wherein the alkyl and amino are as defined earlier.
  • halo or halogen refers to -F, -CI, -Br, and -I.
  • leaving group generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions.
  • the examples of such leaving groups include, but are not limited to, halide (F “ , CI “ , Br “ , ⁇ ), triflate, tosylate, mesylate radical and the like.
  • protecting group is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification.
  • protecting group may be used with groups such as hydroxy, amino, and carboxy. The examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 3 ed., John Wiley and Sons Inc., New York, 1999.
  • salts refers to the inorganic and organic base or acid addition salts of compounds of present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic base or acid and isolating the salt thus obtained.
  • Representative salts include, but not limited to, trifluoroacetate, hydrochloride, acetate, fumarate, phosphate, tosylate, hydrobromide, sulfate, bisulfate, nitrate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, succinate, tartrate, naphthylate, mesylate,
  • the salts derived from inorganic bases include, but not limited to, lithium, sodium, potassium, calcium, magnesium, zinc, aluminium as well as non-toxic
  • ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, triethylamine, ethylamine, diethylamine, and the like.
  • the salts derived from organic bases include, but not limited to, salts of natural or synthetic amino acids, betaine, caffeine, 2- diethylaminoethanol, N-ethylmorpholine, glucosamine, dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, piperazine, procaine, purine, tromethamine and the like.
  • the free base form may be regenerated by contacting the salt form with a base. While the free base form may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the compounds of present invention include stereoisomers.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomers and comformational isomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Racemic mixtures are also encompassed within the scope of this invention.
  • the enantiomeric compounds of the invention may be obtained by a) the separation of the components of the corresponding racemic mixture, for example, by chiral chromatography, enzymatic resolution methods or preparing and separating suitable diastereoisomers, which can then be converted to required isomer and b) by asymmetric synthesis route either by using chiral starting materials, chiral reagents and catalysts.
  • Anti-hypertensive agents can be selected from, but are not limited to: renin inhibitors, angiotensin receptor blockers, beta blockers, diuretics class of compounds, calcium channel blockers, aldosterone receptor blockers or other
  • “Dyslipidemic agents” described herein can be selected from, but are not limited to: cholesteroyl ester transfer protein (CETP) inhibitors, fibric acid derivatives/fibrates, bile acid sequestrants, Acyl CoA-cholesterol acyltransferase inhibitors, HMG CoA reductase inhibitors, cholesterol absorption inhibitors or other dyslipidemic agents.
  • CETP cholesteroyl ester transfer protein
  • Anti-obesity agents can be selected from, but are not limited to, 5-HT reuptake inhibitors, pancreatic lipase inhibitors, cannabinoid antagonists or recombinant human ciliary neutrotropic factors.
  • Anti-hyper glycemic agents can be selected from, but are not limited to insulin sensitizing agents/PPAR agonists, sulphonyl ureas, hepatic glucose lowering agents like metformin, a glucosidase inhibitors, GLP-1 analogs or receptor agonists, glucagon receptor antagonists, AMPK activators, glucokinase activators, insulin receptor agonists or activators, silence information regulator-1 activators (SIRT-1), stearoyl CoA desaturase inhibitors, fatty acid synthase inhibitors or protein tyrosine phosphatase inhibitors or other anti-hyperglycemic agents.
  • SIRT-1 silence information regulator-1 activators
  • Anti-inflammatory agents can be selected from, but not limited to, ⁇ 2 agonists, COX-2 inhibitors, 5-lipoxygenase inhibitors, phosphodiesterase IV inhibitors, MMP inhibitors, TNF-oc inhibitors, caspase inhibitors, p38 MAPkinase inhibitors, VLA-4 antagonists, PAF antagonists and other anti-inflammatory agents.
  • the compounds disclosed herein may be prepared by the following reaction sequences as depicted in Schemes 1-4.
  • Path A Compound of Formula II can be N-protected to give a compound of Formula III (wherein R pr is carboxy-protecting group, for example, methyl, ethyl i-butyl, benzyl, trimethylsilyl, R c is a amine-protecting group such as benzyloxycarbonyl, ⁇ -Boc and F- moc).
  • Path B Compound of Formula IV can be N-protected to give a compound of Formula V, which is then O-protected to give a compound of Formula III (wherein R c and R pr are as defined earlier).
  • N-protection of compound of Formula II to give a compound of Formula III can be carried out with amine-protecting reagents, for example, benzylchloroformate, Boc anhydride or Fmoc chloride in one or more solvents, for example, dichloromethane, dioxane, water, dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran in the presence of a base, for example, triethylamine, sodium bicarbonate, N,N- diisopropylethylamine or potassium carbonate.
  • amine-protecting reagents for example, benzylchloroformate, Boc anhydride or Fmoc chloride
  • solvents for example, dichloromethane, dioxane, water, dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran in the presence of a base, for example, triethylamine, sodium
  • N-protection of compound of Formula IV to give a compound of Formula V can be carried out in the similar way as the conversion of compound of Formula II to compound of Formula III.
  • Carboxy protection of compound of Formula V to give a compound of Formula III can be carried out with carboxy-protecting reagent, for example, i-butyl bromide in a solvent, for example, N,N-dimethylacetamide, N,N-dimethylformamide in presence of a base, for example, potassium carbonate, sodium carbonate, triethylamine, N,N- diisopropylethylamine or mixtures thereof.
  • a phase transfer catalyst for example, trimethylbenzylammonium chloride
  • benzethonium chloride cetrimonium bromide or cetylpyridinium chloride.
  • O-activation of compound of Formula III to give a compound of Formula VI can be carried out using suitable sulfonyl chloride, for example, methane sulfonyl chloride, p- toluene sulfonyl chloride in one or more solvents, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in presence of one or more base, for example, triethylamine, N,N-diisopropylethylamine or potassium carbonate.
  • suitable sulfonyl chloride for example, methane sulfonyl chloride, p- toluene sulfonyl chloride in one or more solvents, for example, dichloromethane, dichloroethane, chloroform or carbon tetrachloride in presence of one or more base, for example, triethylamine, N,N-diisopropylethylamine or potassium
  • Azidation of compound of Formula VI to give a compound of Formula VII can be carried out in the presence of sodium azide or lithium azide in one or more solvent, for example, dimethylformamide, 1,4-dioxane, tetrahydrofuran or dimethylsulfoxide.
  • solvent for example, dimethylformamide, 1,4-dioxane, tetrahydrofuran or dimethylsulfoxide.
  • Reduction of compound of Formula VII to give a compound of Formula VIII can be carried out with a reducing reagent, for example, triphenylphosphine, Fe/AlCl 3 , Fe/BiCl 3 , sodium amalgam or sodium sulfide hydrate in presence of one or more solvent, for example, tetrahydrofuran, water, ethanol, dioxane, acetonitrile, acetone or
  • a reducing reagent for example, triphenylphosphine, Fe/AlCl 3 , Fe/BiCl 3 , sodium amalgam or sodium sulfide hydrate in presence of one or more solvent, for example, tetrahydrofuran, water, ethanol, dioxane, acetonitrile, acetone or
  • Coupling of compound of Formula VIII with a compound of Formula IX to give a compound of Formula X can be carried out using a coupling agent, for example, l-ethyl-3- (3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexyl
  • a coupling agent for example, l-ethyl-3- (3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,3-dicyclohexyl
  • the hydrogenolysis of compound of Formula X to a compound of Formula XI can be carried out with one or more reducing agent, for example, palladium on carbon or platinum/hydrogen in one or more solvent, for example, methanol, ethanol, 1-propanol, 2- propanol or water.
  • one or more reducing agent for example, palladium on carbon or platinum/hydrogen in one or more solvent, for example, methanol, ethanol, 1-propanol, 2- propanol or water.
  • the compound of Formula XI can react by 3 pathways (Scheme 2, Scheme 3 and Scheme 4).
  • the compounds of Formula XIV, XlVa and XVI can be prepared following Scheme 2.
  • Compound of Formula XI can react with a compound of Formula XII to give a compound of Formula XIII (where R m is sulfur-protecting group selected from the group consisting of acyl, thioacyl, alkyl, aryl, benzoyl and organothio groups comprising from 1 to about 10 carbon atoms or when taken together with the sulfur atom to be protected, is a hemithioacetal group, for example, tetrahydrofuranyl, 2-methyl tetrahydrofuranyl, tetrahydropyranyl, 2-methyl tetrahydropyranyl, ethoxyethyl, and methoxymethyl groups).
  • R m is sulfur-protecting group selected from the group consisting of acyl, thioacyl, alkyl, aryl, benzoyl and organothio groups comprising from 1 to about 10 carbon atoms or when taken together with the sulfur atom to be protected, is a hemithioacetal
  • the compound of Formula XIII can either be N-deprotected directly (Path A) (when R pr is not i-butyl) to give a compound of Formula XIV.
  • Compound of Formula XIII can be hydrolyzed to give a compound of Formula XlVa (Path C) (when R pr is i-butyl and P q is Boc) or the compound of Formula XIII can be deprotected to give a compound of Formula XV (Path B) (when R pr is not i-butyl), which can then beN-deprotected to give a compound of Formula XVI.
  • Path A The N-deprotection of compound of Formula XIII to give a compound of XIV can be carried out in one or more solvent, for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, water or carbon tetrachloride in the presence of an acid such as trifluoroacetic acid or hydrochloric acid.
  • solvent for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, water or carbon tetrachloride in the presence of an acid such as trifluoroacetic acid or hydrochloric acid.
  • Path B The deprotection of compound of Formula XIII to give a compound of Formula XV can be carried out in the presence of base, for example, lithium hydroxide
  • N-deprotection of compound of Formula XV to give a compound of Formula XVI can be carried out in similar way as the deprotection of compound of Formula XIII to a compound of Formula XIV.
  • Path C The hydrolysis of compound of Formula XIII to give a compound of Formula XlVa can be carried out in the presence of acid catalysts, for example, trifluoroacetic acid, hydrochloric acid in water, dichhoromethane, dichloroethane, chloroform or carbon tetrachloride.
  • acid catalysts for example, trifluoroacetic acid, hydrochloric acid in water, dichhoromethane, dichloroethane, chloroform or carbon tetrachloride.
  • Compound of Formula XI can react with a compound of Formula XVII (wherein Rd, R r , R s are as defined earlier; R w is alkyl, arylalkyl, CH 2 OR t , cycloalkylalkyl, heterocylcylalkyl or heteroarylalkyl where R t is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,
  • Path A The compound of Formula XVIII (when R pr is not i-butyl) can be hydrolyzed first to give a compound of Formula XIX, which can be then deprotected to give a compound of Formula XX.
  • Path B The compound of Formula XVIII (when R pr is i-butyl and P q is Boc) can be deprotected to give a compound of Formula XlXa, which can be hydrolyzed to give a compound of Formula XX.
  • Path C The compound of Formula XVIII (when R pr is not i-butyl) can be deprotected directly to give a compound of Formula XlXb.
  • the hydrolysis of compound of Formula XlXa to give a compound of Formula XX can be carried out in a similar way as the hydrolysis of compound of Formula XIII to a compound of Formula XV.
  • the deprotection of compound of Formula XVIII to give a compound of Formula XlXb (Path C) can be carried out in a similar way as the deprotection of a compound of Formula XIII to give a compound of Formula XIV.
  • Compound of Formula XI (wherein R pr and P q independently are as defined earlier) can be coupled with a compound of Formula XXI (wherein R w is as defined earlier) to give a compound of Formula XXII.
  • the compound of Formula XXII can then react with a compound of Formula XXIII (wherein R ⁇ j ; R r and R s are as defined earlier) to give a compound of Formula XXIV.
  • Path A The compound of Formula XXIV (when R pr is i-butyl and p q is Boc) can be deprotected and hydrolyzed directly to give a compound of Formula XXVI.
  • Path B The compound of Formula XXIV (when R pr is i-butyl and R pr ' is ethyl) can be deprotected first to give a compound of Formula XXV, which can then be hydrolyzed to give a compound of Formula XXVI.
  • Coupling of compound of Formula XI with a compound of Formula XXI to give a compound of Formula XXII can be carried out with dicyclohexylcarbodiimide in one or more solvent, for example, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or acetone.
  • solvent for example, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or acetone.
  • Compound of Formula XXII can be alkylated with a compound of Formula XXIII to give a compound of Formula XXIV in one or more solvents, for example, acetonitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dimethylformamide or acetone in the presence of a base, for example, potassium carbonate, triethylamine, diisopropylethylamine orN-methylmorpholine optionally in the presence of a catalyst, for example, potassium iodide.
  • solvents for example, acetonitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dimethylformamide or acetone
  • a base for example, potassium carbonate, triethylamine, diisopropylethylamine orN-methylmorpholine optionally in the presence of a catalyst, for example, potassium iodide.
  • Step III 1-benzyl 2-methyl (2S,4S)-4-azidopyrrolidine-l,2-dicarboxylate
  • Step IV 1-Benzyl 2-methyl (2S,4S)-4-aminopyrrolidine-l,2-dicarboxylate
  • Step V 1-Benzyl 2-methyl (25,4S)-4- ⁇ [(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoyl]amino ⁇ pyrrolidine-l,2-dicarboxylate
  • Step VI Methyl (45)-4- ⁇ [(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl) butanoyl]amino ⁇ -L-prolinate
  • Benzylchloroformate (224 ml, 1.2 mol) was added to the chilled solution of trans-4- hydroxy-L-proline (100 g, 0.76 mol) and sodium bicarbonate (128 g, 1.5 mol) in dioxane: water (1:1) mixture (750 ml) under nitrogen atmosphere over a period of about 15 minutes. After addition, the reaction mixture was stirred at ⁇ 25°C for about 12 hours and the solvent was recovered under reduced pressure. The aqueous layer was neutralized with chilled 30% HCI solution. The obtained product was extracted using ethyl acetate, dried over anhydrous sodium sulphate and concentrated.
  • Step II 1-benzyl 2-tert-butyl (IS, 4R)-4-hydroxypyrrolidine-l, 2-dicarboxylate
  • Step-Ill 1-benzyl 2-tert- butyl (2S, 4R)-4-[(methylsulfonyl) oxy] pyrrolidine- 1, 2- dicarboxylate
  • Step IV 1-Benzyl 2-tert-butyl (IS, 4S)-4-azidopyrrolidine-l, 2-dicarboxylate
  • Step V 1-Benzyl 2-tert-butyl (2S, 4S)-4-aminopyrrolidine-l, 2-dicarboxylate
  • Step VI 1-Benzyl 2-tert-butyl (25,4S)-4- ⁇ [(3R)-3-[(tert-butoxycarbonyl)amino]-4- (2,4,5-trifluorophenyl)butanoyl]amino ⁇ pyrrolidine-l,2-dicarboxylate
  • reaction mixture was stirred at - 25°C for about 12 hours, decomposed in excess of chilled water and then extracted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, 10% citric acid and finally with brine solution. Crude product was dried over anhydrous sodium sulphate, concentrated and then purified through column
  • Step I Methyl (45)-l-[(25)-3-(acetylsulfanyl)-2-methylpropanoyl]-4- ⁇ [(3R)-3-[(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-prolinate
  • Step II Methyl (4S)-l-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-4- ⁇ [(3R)-3-amino- 4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-prolinate
  • Step II (45)-4- ⁇ [(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5- trifluorophenyl)butanoyl] amino ⁇ -l-[(2S)-2-methyl-3-sulfanylpropanoyl]-L-proline
  • methyl (4S)-l-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-4- ⁇ [(3R)-3- [(iert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl] amino ⁇ -L-prolinate 0.6 g, 1.0 mmol
  • lithium hydroxide monohydrate (0.13 g, 3.0 mmol
  • Step III (4S)-4- ⁇ [(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -l-[(2S)-2- methyl-3-sulfanylpropanoyl]-L-proline trifluoroacetate salt
  • Step I t-Butyl (45)-l-[(25)-3-(acetylsulfanyl)-2-methylpropanoyl]-4- ⁇ [(3R)-3-[(tert- butoxycarbonyl) amino]-4-(2,4,5-trifluorophenyl) butanoyl] amino ⁇ -L-prolinate
  • Step II (4S)-l-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-4- ⁇ [(3R)-3-amino-4- (2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-proline ditrifluoroacetate salt (Compound no. 3)
  • Step I Methyl N-[(15)-l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-(45)-4- ⁇ [(3R)-3- [(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-prolinate
  • the reaction mixture was stirred at ⁇ 25°C for about 12 hours, decomposed in excess of chilled water and extracted out using ethyl acetate.
  • the organic layer was washed with 5% sodium bicarbonate, 10% citric acid and finally with brine solution.
  • the organic layer was dried over anhydrous sodium sulphate and concentrated.
  • the crude was then purified through column chromatography (silica gel 100-200 mesh) using 10% methanol:
  • Step II N-[(15)-l-carboxy-3-phenylpropyl]-L-alanyl-(45)-4- ⁇ [(3R)-3-[(tert-butoxy- carbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-proline
  • Step III N-[(15)-l-carboxy-3-phenylpropyl]-L-alanyl-(45)-4- ⁇ [(3R)-3-amino-4-(2,4,5- trifluorophenyl)butanoyl]amino ⁇ -L-proline ditrifluoroacetate salt (Compound No. 5)
  • Example 6A Synthesis of N-r(lS)-l-carboxy-3-phenylpropyll-L-alanyl-(4S)-4- ⁇ r(3R)-3- amino-4-(2A5-trifruorophenyl)butanoyl1 aminoj-L-proline dilithium salt (Compound No. 5 ⁇
  • Step I tert-butyl N-[(25)-l-ethoxy-l-oxo-4-phenylbutan-2-yl]-L-alanyl-(45)-4- ⁇ [(3R)- 3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-prolinate
  • the reaction mixture was stirred at - 25°C for about 12 hours, decomposed in excess of chilled water and extracted out using ethyl acetate.
  • the organic layer was washed with 5% sodium bicarbonate, 10% citric acid and finally with brine solution.
  • the organic layer was dried over anhydrous sodium sulphate and concentrated.
  • the crude was then purified through column chromatography (silica gel 100-200 mesh) using 10% methanol:
  • Step II N-[(25)-l-ethoxy-l-oxo-4-phenylbutan-2-yl]-L-alanyl-(45)-4- ⁇ [(3R)-3-amino- 4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-proline ditrifluoroacetate salt
  • Step III N-[(15)-l-carboxy-3-phenylpropyl]-L-alanyl-(45)-4- ⁇ [(3R)-3-amino-4-(2,4,5- trifluorophenyl)butanoyl]amino ⁇ -L-proline dilithium salt (Compound no. 5)
  • ExampleLE 6B Synthesis of methyl N-r(2S)-l-ethoxy-l-oxo-4-phenylbutan-2-yll-L- alanyl-(4S)-4- ⁇ r(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyllamino
  • This compound was prepared by using cis-4-hydroxy proline as starting material.
  • Step-I tert-butyl (45)-l-(2(R)-bromopropanoyl)-4- ⁇ [(3R)-3-[(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-prolinate
  • Step-II tert-butyl N-[(15)-l-(tert-butoxycarbonyl)-3-methylbutyl]-L-alanyl-(45)-4- ⁇ [(3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4,5-trifluorophenyl) butanoyl] amino ⁇ -L- prolinate
  • the reaction mixture was stirred at 60-65°C for about 12 hours.
  • the reaction mixture was concentrated and then diluted with dichloromethane, washed with demineralized water and dried over anhydrous sodium sulphate, concentrated and then purified through preparative thin layer chromatography plates (2.0 mm) using 90% ethylacetate: hexane as eluent to get the title compound (Yield: 0.09 g).
  • Step-III N-[(15)-l-carboxy-3-methylbutyl]-L-alanyl-(45)-4- ⁇ [(3R)-3-amino-4-(2,4,5- trifluorophenyl)butanoyl]amino ⁇ -L-proline ditrifluoroacetate salt (Compound no. 24)
  • Example 7A Synthesis of N-r(lS)-l-carboxy-2-cvclopropylethyll-L-alanyl-(4S)-4- I r(3R)-3-amino-4-(2,4,5-trifluoro-phenyl)butanoyllamino
  • Step-I tert-butyl N-[(2S)-3-cyclopropyl-l-ethoxy-l-oxopropan-2-yl]-L-alanyl-(4S)-4-
  • Step-II N-[(2S)-3-cyclopropyl-l-ethoxy-l-oxopropan-2-yl]-L-alanyl-(4S)-4- ⁇ [(3R)-3- amino-4-(2,4,5-trifluorophenyl)butanoyl]amino ⁇ -L-proline
  • H-Gly-Pro-7-amido-methyl Coumarine (Gly-Pro-AMC; Cat. # G2761) and 7- amido-methyl Coumarine (AMC; Cat. # A9891) were purchased from Sigma.
  • 1 mM Gly- Pro-AMC stock solution was prepared in 50 mM HEPES buffer, pH 7.8 containing 80 mM MgC12, 140 mM NaCl and 1% BSA (working buffer).
  • 1 mM AMC was prepared in 10% dimethylsulfoxide (DMSO). Aliquots were stored at -20°C.
  • Assay The DPP IV assay was carried out as described earlier with slight modifications (/. Med. Chem. 2003, 46, 2774-2789).
  • test compounds were dissolved in 100% dimethylsulfoxide (DMSO) to get a final concentration of 10 mM.
  • DMSO dimethylsulfoxide
  • the compounds were diluted serially in 10% DMSO to get 10X concentrations of 10 nM, 100 nM, 1000 nM, 10 ⁇ , 100 ⁇ , and 1000 ⁇ .
  • the source of DPP IV was human plasma which was procured from local blood bank.
  • DPP ⁇ (10 ⁇ human plasma) was mixed in 96 well fluoroNunc plates with test compounds.
  • the final concentrations of the compounds were 1 nM, 10 nM, 100 nM, 1000 nM, 10 ⁇ and 100 ⁇ in working buffer and pre-incubated at 25 °C for 15 minutes.
  • the assay was also carried out without compound and with 1% DMSO (final concentration) as vehicle control.
  • the reaction was started by adding 20 ⁇ of 0.1 mM H-Gly-Pro AMC (40 ⁇ final concentration), mixed and incubated at 25°C for 20 minutes.
  • the reaction was arrested by adding 50 ⁇ of 25% acetic acid and read at 380 nm excitation and 460 nm emissions.
  • the DPP ⁇ releases AMC from Gly-Pro-AMC which was quantitated as relative fluorescence units (RFU).
  • the percentage of activity was calculated as follows:
  • the IC 50 is defined as the concentration of the inhibitor required to inhibit 50% of the human DPP IV activity under specific assay conditions.
  • the activity obtained at different concentrations of the compound was plotted as log (X) vs % activity in y axis.
  • the data was analysed by GraphPad Prism 4.
  • the compounds provided herein showed activity (IC 50 ) between 0.057 ⁇ -2.2 ⁇ . More specifically, the compounds showed a range of activity between 0.057 ⁇ -1 ⁇ .
  • the ACE assay was carried out as described earlier with slight modifications (/. Biol. Chem. 2001, 276, 5525-5532) using purified human recombinant enzyme source.
  • the test compounds were dissolved in 100% dimethylsulfoxide (DMSO) to get a final concentration of 10 mM.
  • DMSO dimethylsulfoxide
  • the compounds were diluted serially in 10% DMSO to get 10X concentrations of ⁇ , 10 ⁇ , 100 ⁇ , 400 ⁇ , 800 ⁇ , 1 mM and 10 mM.
  • 20 ng ACE was mixed in 96 well fluronunc plates with test compounds.
  • the final concentrations of the compounds were 100 nM, 1 ⁇ , 10 ⁇ , 40 ⁇ , 80 ⁇ , 100 ⁇ and 1 mM in 50 mM MES working buffer pH 6.5 and pre-incubated at ⁇ 25°C for 10 minutes.
  • the standard compound captopril was diluted serially in milliQ to get final concentrations as 100 pM, 1 nM, 10 nM, 100 nM, 1 ⁇ , 10 ⁇ and 100 ⁇ .
  • the assay was also carried out without compound and with 1% DMSO (final concentration) as vehicle control.
  • the reaction was started by adding 10 ⁇ of 100 ⁇ Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys (Dnp)-OH (10 ⁇ final concentration) mixed and incubated at ⁇ 25°C for 20 minutes. The plate was read immediately after 20 minutes without stopping the reaction at 320 nm excitation and 405 nm emission in Sapphire attached to TECAN.
  • the IC 50 is defined as the concentration of the inhibitor required to inhibit 50% of the human ACE activity under specific assay conditions.
  • the activity obtained at different concentrations of the compound was plotted as log (X) vs % activity in y axis.
  • the data was analyzed by GraphPad Prism 4.
  • the compounds provided herein showed activity (IC 50 ) between 0.006 ⁇ -100 ⁇ . More specifically, the compounds showed a range of activity between 0.006 ⁇ - 10 ⁇ .

Abstract

La présente invention concerne de nouveaux composés hétérocycliques et des procédés de préparation de tels composés. Les composés de l'invention sont utiles pour le traitement palliatif, curatif ou prophylactique de maladies ou pathologies telles que le diabète et/ou l'hypertension. La présente invention concerne également des compositions pharmaceutiques contenant les composés de la présente invention, et des méthodes de traitement palliatif, curatif ou prophylactique de maladies ou pathologies telles que le diabète et/ou l'hypertension. La présente invention concerne également des compositions pharmaceutiques comprenant les composés hétérocycliques conjointement avec un ou plusieurs agent(s) dyslipidémiant(s), anti-obésité, anti-hyperglycémique(s), antihypertenseur(s) et anti-inflammatoire(s).
PCT/IB2011/050424 2010-01-29 2011-01-31 Dérivés de la proline à utiliser dans le traitement du diabète WO2011092671A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082817A2 (fr) * 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
DE10309005A1 (de) * 2003-03-01 2004-09-09 Morphochem Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen, die Dipetidyl Peptidase (DPPIV) und Neurale Endopeptidase (NEP) inhibieren
WO2005075426A1 (fr) * 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
US20060046978A1 (en) 2004-08-31 2006-03-02 Morphochem Ag Novel compounds that inhibit dipeptidyl peptidase (DPP-IV) and neprilysin (NEP) and/or angiotensin converting enzyme (ACE)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003082817A2 (fr) * 2002-03-25 2003-10-09 Merck & Co., Inc. Inhibiteurs de la dipeptidyl peptidase beta-amino heterocycliques pour le traitement ou la prevention du diabete
DE10309005A1 (de) * 2003-03-01 2004-09-09 Morphochem Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen, die Dipetidyl Peptidase (DPPIV) und Neurale Endopeptidase (NEP) inhibieren
WO2005075426A1 (fr) * 2004-02-03 2005-08-18 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de dipeptidyle peptidase iv, leur procedes de preparation et compositions en comportant
US20060046978A1 (en) 2004-08-31 2006-03-02 Morphochem Ag Novel compounds that inhibit dipeptidyl peptidase (DPP-IV) and neprilysin (NEP) and/or angiotensin converting enzyme (ACE)

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 4, 1994, pages 2673 - 76
DIABETES CARE, vol. 26, 2003, pages 2421 - 2425
ENDOCRINE REV., vol. 21, 2000, pages 585 - 618
EXPERT OPIN. INVESTIG. DRUGS, vol. 13, 2004, pages 1091 - 1102
HYPERTENSION, vol. 40, 2002, pages 329 - 334
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JIAANG W T ET AL: "Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 3, 1 February 2005 (2005-02-01), pages 687 - 691, XP025314573, ISSN: 0960-894X, [retrieved on 20050201], DOI: DOI:10.1016/J.BMCL.2004.11.023 *
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