WO2008028662A1 - N-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés associés utilisés en tant qu'inhibiteurs dpp-iv pour le traitement du diabète sucré de type 2 - Google Patents

N-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés associés utilisés en tant qu'inhibiteurs dpp-iv pour le traitement du diabète sucré de type 2 Download PDF

Info

Publication number
WO2008028662A1
WO2008028662A1 PCT/EP2007/007786 EP2007007786W WO2008028662A1 WO 2008028662 A1 WO2008028662 A1 WO 2008028662A1 EP 2007007786 W EP2007007786 W EP 2007007786W WO 2008028662 A1 WO2008028662 A1 WO 2008028662A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
independently
group
cycloalkyl
Prior art date
Application number
PCT/EP2007/007786
Other languages
English (en)
Inventor
Per-Olof Edelund
Stephan Bulat
Original Assignee
Santhera Pharmaceuticals (Schweiz) Ag
Biovitrum Ab (Publ)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP06018795A external-priority patent/EP1905759A1/fr
Application filed by Santhera Pharmaceuticals (Schweiz) Ag, Biovitrum Ab (Publ) filed Critical Santhera Pharmaceuticals (Schweiz) Ag
Publication of WO2008028662A1 publication Critical patent/WO2008028662A1/fr

Links

Classifications

    • 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
    • C07D207/12—Oxygen or sulfur atoms
    • 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

Definitions

  • the present invention relates to a novel class of dipeptidyl peptidase inhibitors, including pharmaceutically acceptable salts and prodrugs thereof, which are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes mellitus (NIDDM), and of conditions that are often associated with this disease, such as obesity and lipid disorders.
  • NIDDM non-insulin dependent diabetes mellitus
  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at an increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • Type 1 insulin-dependent, diabetes mellitus
  • IDDM insulin-dependent, diabetes mellitus
  • Type 2 noninsulin dependent, diabetes mellitus
  • NIDDM noninsulin dependent, diabetes mellitus
  • these patients develop a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, namely the muscle, liver and adipose tissues. Further, the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • Type 2 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 sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant 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/diarrhoea.
  • Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type 2 diabetes.
  • the glitazones are a recently described class of compounds with potential for ameliorating many symptoms of Type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype.
  • PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones.
  • Newer PPAR agonists that are being tested for treatment of Type 2 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 glitazones, 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., acarbose) and protein tyrosine phosphatase-IB (PTP-1 B) inhibitors.
  • alpha-glucosidase inhibitors e.g., acarbose
  • PTP-1 B protein tyrosine phosphatase-IB
  • DPP-IV dipeptidyl peptidase-IV
  • WO-A-97/40832 WO-A-98/19998
  • WO-A-03/00180 WO-A-03/00181.
  • the usefulness of DPP-IV inhibitors in the treatment of Type 2 diabetes is based on the fact that DPP-IV in vivo readily inactivates glucagon like peptide-1 (GLP-1 ) and gastric inhibitory peptide (GIP).
  • GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin.
  • DPP-IV 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 since the incretins are produced by the body only when food is consumed, 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 elsewhere in this application.
  • 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 disease and conditions.
  • the object of the present invention is to provide a new class of DPP-IV inhibitors which is effective in the treatment of Type 2 diabetes and other DPP-IV modulated diseases.
  • the present invention provides novel compounds of formula (I) and formula (II) as defined in claims 1 to 26.
  • the present invention provides novel compounds of formula (I):
  • Ci- 6 alkyl optionally substituted with one or more F
  • 0-C 1-6 alkyl optionally substituted with one or more F
  • R 1 , R 2 , R 4 , and R 5 are independently from each other selected from the group consisting of
  • R 3 is H or C 1-6 alkyl
  • n O, 1 or 2;
  • a 1 is -C(R 6 R 7 J-Y-T;
  • R 6 andR 7 are independently from each other selected from the group consisting of H;
  • Ci- 6 alkyl optionally substituted with one or more F
  • R 6 and R 7 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F;
  • Y is selected from the group consisting of
  • R 8 and T are independently from each other T 1 -T 2 or T 2 ;
  • T 1 is selected from the group consisting of
  • each C 1-6 alkyl is optionally substituted with one or more F;
  • R 9 and R 10 are independently from each other H or C 1-6 alkyl, optionally substituted with one or more F;
  • T 2 is selected from the group consisting of H; F;
  • C 1-6 alkyl optionally substituted with one or more halogen atoms; phenyl; naphthyl; wherein phenyl and naphthyl are optionally substituted with one, or independently from each other, more of halogen; CN; R 11 ;
  • NHT 3 NHT 3 ; or T 3 ;
  • R 8 is T 1 -T 2 and represents -Ci -6 alkyl and T is T 1 -T 2 and represents - CC 1 i --66 aallkkyyll tthheenn RR 88 aanndd TT mm ⁇ ay form together a 3 to 7 membered cyclic group containing one nitrogen atom;
  • R 11 is selected from the group consisting of Ci -6 alkyl; O-Ci -6 alkyl; COO-Ci -6 alkyl; OC(O)-Ci -6 alkyl;
  • Ci -6 alkyl is optionally substituted with one, or independently from each other, more of F, COOR 18 , C(O)N(R 19 R 20 ), S(O) 2 N(R 21 R 22 ), OR 23 , N(R 24 R 25 ), T 3 , O-T 3 or N(R 26 )-T 3 ;
  • R 12 is selected from the group consisting of Ci -6 alkyl; O-Ci -6 alkyl; N(R 13 J-C 1-6 alkyl; COO-Ci -6 alkyl; OC(O)-C 1-6 alkyl;
  • Ci -6 alkyl is optionally substituted with one, or independently from each other, more of F, COOR 18 , C(O)N(R 19 R 20 ), S(O) 2 N(R 21 R 22 ), OR 23 , N(R 24 R 25 ), T 3 , O-T 3 or N(R 26 )-T 3 ;
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are independently from each other H or Ci -6 alkyl;
  • T 3 is selected from the group consisting of phenyl; naphthyl; wherein phenyl and naphthyl are optionally substituted with one, or independently from each other, more of halogen; CN;
  • O-Ci -6 alkyl O-Ci -6 alkyl; COO-C 1-6 alkyl; OC(O)-Ci -6 alkyl; C(O)N(R 27 J-C 1-6 alkyl; S(O) 2 N(R 28 J-Ci -6 alkyl;
  • R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 and R 34 are independently from each other H or C 1-6 alkyl.
  • Preferred compounds of formula (I) or (Ia) are those compounds in which one or more of the residues contained therein have the meanings given below. It is understood, that the claimed compounds cover any compound obtained by combining any of the definitions disclosed within this description for the various substituents. With respect to all compounds of the formulas (I) or (Ia) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.
  • the substituents R 1 - R 5 , Z, X, W, n and A 1 of the formula (I) or (Ia) independently from each other have the following meaning.
  • one or more of the substituents R 1 - R 5 , Z, X, W, n and A 1 can have the preferred or more preferred meanings given below.
  • Z is preferably phenyl or heterocycle and Z is optionally substituted independently from each other with 1 , 2 or 3, more preferably with 2 or 3 substituents selected from Cl, F 1 CN, CH 3 or OCH 3 . In one embodiment Z is substituted with 1 , 2 or 3 F.
  • R 1 , R 2 , R 4 and R 5 are independently from each other selected from the group consisting of H, F, OH, CH 3 and OCH 3 .
  • R 3 is preferably H.
  • X is preferably H or F.
  • W is preferably H. In an other embodiment, W and X both represent F. In a preferred embodiment, W and X both represent F and are both attached to the same carbon atom.
  • n is 1. In other embodiments, n is 0 or 2.
  • Y is preferably -O-, -N(R 8 ) or -S(O) 2 -, more preferably -O- or -N(R 8 )-. Most preferably, Y is -N(R 8 )-.
  • R 8 is selected from the group consisting of H, CH 3 , COOH 1 COOCH 3 , C(O)NH 2 , C(O)N(CH 3 J 2 , and S(O) 2 CH 3 , more preferably H, CH 3 , most preferably H.
  • T is T 1 -T 2 or T 2 , wherein T 1 is selected from the group consisting of
  • T 1 selected from the group consisting of -C(O)-; -CH 2 -; -S(O) 2 -; and -C(O)NH-.
  • T is T 1 -T 2 .
  • T 1 -T 2 is preferably a group as defined below.
  • T 1 -T 2 is preferably CH 2 -phenyl, whereby phenyl may be substituted with 1 to 3, preferably 1 or 2, substituents selected from halogen, CN, O-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably CH 2 -C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1 or 2, preferably 1 , substituents selected from halogen, CN, OH, NH 2 , COOH, C(O)NH 2 or S(O) 2 NH 2 , more preferably COOH or C(O)NH 2 .
  • T 1 -T 2 is preferably Ci -4 alkyl, preferably methyl, ethyl or propyl, most preferably methyl.
  • T 1 -T 2 is preferably C(O)-phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, O-Ci -4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably C(O)-C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1 to 3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl and Ci -4 alkyl, whereby alkyl may be further substituted with 1 to 3 F. More preferably, cycloalkyl may be substituted with one C 1-4 alkyl substituted with 1 to 3 F.
  • T 1 -T 2 is preferably C(O)-heterocycle, whereby heterocycle may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 ; preferably, the heterocycle is aromatic, more preferably containing 1 or 2 heteroatoms selected from N and O, most preferably N.
  • T 1 -T 2 is preferably S(0) 2 -phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably S(O) 2 -C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl, whereby alkyl may be further substituted with 1 to 3 F; more preferably cycloalkyl may be substituted with one C 1-4 alkyl substituted with 1 to 3 F.
  • T 1 -T 2 is preferably S(O) 2 -C 1-4 alkyl, preferably S(O) 2 CH 3 .
  • T 1 -T 2 is preferably C(O)-NH-phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 .
  • T 2 is preferably a group as defined below.
  • T 2 is preferably H.
  • T 2 is preferably phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3
  • T 2 is preferably heterocycle, whereby heterocycle may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, phenyl, heterocycle, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 ; preferably, the heterocycle is aromatic, more preferably containing 1 , 2 or 3 heteroatoms selected from N and O, most preferably N.
  • the heterocycle is preferably aromatic, more preferably containing 1 , 2 or 3 heteroatoms selected from N and O, most preferably N, and the phenyl or heterocycle may be further substituted by 1 or 2 F or S(O) 2 CH 3 .
  • T 2 is preferably CF 3 .
  • T 2 is phenyl or heterocycle.
  • a 1 is -CH 2 -N(R 8 )-T, wherein R 8 is H, S(O) 2 CH 3 or S(O) 2 -C 3-7 cycloalkyl, most preferably H.
  • a 1 is -CH 2 -O-T.
  • R 8 is T 1 -T 2 and represents -Ci -6 alkyl and T is T 1 -T 2 and represents -Ci -6 alkyl then R 8 and T may form together a 3 to 7 membered cyclic group containing one nitrogen atom, preferably a 5 or 6 membered cyclic group.
  • the invention further relates to a compound of formula (II)
  • Z is selected from the group consisting of phenyl; naphthyl; C 3-7 cycloalkyl; heterocycle; and heterobicycle; wherein Z is optionally substituted with one, or independently from each other, more of halogen; CN; OH;
  • Ci -6 alkyl optionally substituted with one or more F
  • R 1 , R 2 , R 4 and R 5 are independently from each other selected from the group consisting of
  • R 1 and R 2 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F; and/or R 2 and R 3 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F; and/or R 3 and R 4 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F; and/or R 4 and R 5 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F;
  • R 3 is H or C 1-6 alkyl
  • R' and R may form together a C 3-7 cycloalkyl, which is optionally substituted with one or more F;
  • X are independently from each other selected from H; F;
  • W are independently from each other H or F;
  • n 0,1 or 2;
  • a 1 is -C(R 6 R 7 J-Y-T;
  • R 6 and R 7 are independently from each other selected from the group consisting of H; F; and
  • Ci- 6 alkyl optionally substituted with one or more F
  • R 6 and R 7 optionally form together C 3-7 cycloalkyl, which is optionally substituted with one or more F
  • Y is selected from the group consisting of
  • R 8 and T are independently from each other T 1 -T 2 or T 2 ;
  • T 1 is selected from the group consisting of
  • R 9 and R 10 are independently from each other H or C 1-6 alkyl, optionally substituted with one or more F;
  • T 2 is selected from the group consisting of H; CF 3 ; phenyl; naphthyl; wherein phenyl and naphthyl are optionally substituted with one, or independently from each other, more of halogen;
  • NHT 3 NHT 3 ; or T 3 ;
  • R 8 is T 1 -T 2 and represents -C 1-6 alkyl and T is T 1 -T 2 and represents - Ci- 6 alkyl then R 9 and T may form together a 3 to 7 membered cyclic group containing one nitrogen atom;
  • R 11 is selected from the group consisting of
  • N(R 17 JS(O) 2 -C 1-6 alkyl wherein each C 1-6 alkyl is optionally substituted with one, or independently from each other, more of F, COOR 18 , C(O)N(R 19 R 20 ), S(O) 2 N(R 21 R 22 ), OR 23 , N(R 24 R 25 ), T 3 , O-T 3 or N(R 26 )-T 3 ;
  • R 12 is selected from the group consisting of C 1-6 alkyl; 0-C 1-6 alkyl; N(R 13 J-C 1-6 alkyl; COO-C 1-6 alkyl; OC(O)-C 1-6 alkyl; C(O)N(R 14 )-C 1-6 alkyl; N(R 15 J-C(O)-C 1-6 alkyl; S(O) 2 N(R 16 )-C 1-6 alkyl; S(O)-C 1-6 alkyl; S(O) 2 -C 1-6 alkyl; and -N(R 17 JS(O) 2 -C 1-6 alkyl; wherein each C 1-6 alkyl is optionally substituted with one, or independently from each other, more of F, COOR 18 , C(O)N(R 19 R 20 ), S(O) 2 N(R 21 R 22 ), OR 23 ,
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are independently from each other H or C 1-6 alkyl;
  • T 3 is selected from the group consisting of phenyl; naphthyl; wherein phenyl and naphthyl are optionally substituted with one, or independently from each other, more of halogen;
  • R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 and R 34 are independently from each other H or C 1-6 alkyl.
  • Preferred compounds of formula (II) or (Ma) are those compounds in which one or more of the residues contained therein have the meanings given below. It is understood, that the claimed compounds cover any compound obtained by combining any of the definitions disclosed within this description for the various substituents. With respect to all preferred compounds of the formulas (II) or (Ha) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.
  • the substituents R 1 - R 5 , Z, X, m and A 1 of the formula (II) or (Ha) independently from each other have the following meaning.
  • one or more of the substituents R 1 - R 5 , Z, X, m and A 1 can have the preferred or more preferred meanings given below.
  • Z is preferably is phenyl or heterocycle and Z is optionally substituted independently from each other with 1 , 2 or 3, more preferably up to 2 or 3, of Cl, F, CN, CH 3 or OCH 3 . In one embodiment Z is substituted with up to 3 F.
  • R 1 , R 2 , R 4 and R 5 are independently from each other selected from the group consisting of H, F, OH 1 CH 3 , and OCH 3 .
  • R 3 is preferably H.
  • X is preferably H or F.
  • W is preferably H. In another embodiment, W and X both represent F. In a preferred embodiment, W and X both represent F and are both attached to the same carbon atom.
  • m is 1.
  • Y is preferably -O-, -N(R 8 )- or -S(O) 2 -, more preferably -O- or -N(R 8 )-. Most preferably,
  • Y is -N(R 8 )-.
  • R 8 is selected, from the group consisting of H, CH 3 , COOH, COOCH 3 , C(O)NH 2 , C(O)N(CH 3 ) 2 , and S(O) 2 CH 3 , more preferably H and CH 3 , most preferably H. It is preferred that T is T 1 -T 2 or T 2 , wherein T 1 is selected from the group consisting of
  • T 1 selected from the group consisting of -C(O)-, -CH 2 -, -S(O) 2 - and -C(O)NH-.
  • T is T 1 -T 2 .
  • T 1 -T 2 is preferably a group as defined below.
  • T 1 -T 2 is preferably CH 2 -phenyl, whereby phenyl may be substituted with 1 to 3, preferably 1 or 2, substituents selected from halogen, CN, O-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, 0-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably CH 2 -C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1 or 2, preferably 1 , substituents selected from halogen, CN, OH, NH 2 , COOH, C(O)NH 2 or S(O) 2 NH 2 , more preferably COOH or C(O)NH 2 .
  • T 1 -T 2 is preferably C 1-4 alkyl, preferably methyl, ethyl or propyl, most preferably methyl.
  • T 1 -T 2 is preferably C(O)-phenyl, whereby phenyl may be substituted with 1 to 3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably C(O)-C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1 to 3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, C 1-4 alkyl, whereby alkyl may be further substituted with 1 to 3 F; more preferably cycloalkyl may be substituted with one C 1-4 alkyl substituted with 1 to 3 F.
  • T 1 -T 2 is preferably C(0)-heterocycle, whereby heterocycle may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-C 1-4 alkyl, Ci -4 alkyl or S(O) 2 CH 3 ; preferably, the heterocycle is aromatic, more preferably containing 1 or 2 heteroatoms selected from N and O, most preferably N.
  • T 1 -T 2 is preferably S(O) 2 -phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-Ci -4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 1 -T 2 is preferably S(O) 2 -C 3-7 cycloalkyl, more preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl, whereby cycloalkyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-Ci -4 alkyl, Ci -4 alkyl, whereby alkyl may be further substituted with 1 to 3 F; more preferably cycloalkyl may be substituted with one C 1-4 alkyl substituted with 1 to 3 F.
  • T 1 -T 2 is preferably S(O) 2 -C 1-4 alkyl, preferably S(O) 2 CH 3 .
  • T 1 -T 2 is preferably C(O)-NH-phenyl, whereby phenyl may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, 0-Ci -4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 .
  • T is T 2
  • T 2 is preferably a group as defined below.
  • T 2 is preferably H.
  • T 2 is preferably phenyl, whereby phenyl may be substituted with 1- 3, preferably 1 or 2, substituents selected from halogen, CN, O-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 , preferably F, Cl, O-Me, Me or S(O) 2 CH 3 .
  • T 2 is preferably heterocycle, whereby heterocycle may be substituted with 1-3, preferably 1 or 2, substituents selected from halogen, CN, phenyl, heterocycle, 0-C 1-4 alkyl, C 1-4 alkyl or S(O) 2 CH 3 ; preferably, the heterocycle is aromatic, more preferably containing 1 , 2 or 3 heteroatoms selected from N and O, most preferably N.
  • the heterocycle is preferably aromatic, more preferably containing 1 , 2 or 3 heteroatoms selected from N and O, most preferably N, and the phenyl or heterocycle may be further substituted by 1 or 2 F or S(O) 2 CH 3 .
  • T 2 is preferably CF 3 .
  • T 2 is preferably phenyl or heterocycle.
  • a 1 is -CH 2 -N(R 8 )- " ! " , wherein R 8 is H, S(O) 2 CH 3 or S(O) 2 -C 3-7 cycloalkyl, most preferably H.
  • a 1 is -CH 2 -O-T.
  • R 8 contains the group R 8
  • R 8 and T may form together a 3 to 7 membered cyclic group containing one nitrogen atom, preferably a 5 or 6 membered cyclic group.
  • the present invention provides prodrug compounds of the compounds of the invention as described above.
  • Prodrug compound means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of the prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g.
  • Metabolites of compounds of formula (I), (Ia), (II) and (Ha) are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • compounds of general formula (I), (Ia), (II) or (Ma) or their prodrugs may occur
  • the individual forms like e.g. the keto and enol form, and together as mixtures in any ratio are also within the scope of the invention.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases.
  • enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue.
  • any enantiomer of a compound of formula (I), (Ia), (II) or (Ha) may be obtained from stereoselective synthesis using optically pure starting materials.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I), (Ia), (II) or (Ma) which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • acids examples include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I), (Ia), (II) or (Ma) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I), (Ia), (II) or (Ha) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • C 1-6 Alkyl means a straight-chain or branched carbon chain having 1 - 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentane, or n-hexane. If the alkyl group is used as a bridging moiety between two substituents, the term "alkyl” comprises e.g.
  • Each hydrogen of a C 1-6 alkyl carbon may be replaced by a substituent.
  • C 3-7 Cycloalkyl means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples for a heterocycle are furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, tri
  • Heterobicycle means a heterocycle which is condensed with phenyl or an additional heterocycle to form a bicyclic ring system.
  • Condensed to form a bicyclic ring means that two rings are attached to each other by sharing two ring atoms.
  • heterobicycle examples include indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • DPP-IV is a cell surface protein that has been implicated in a wide range of biological functions. It has a broad tissue distribution
  • DPP-IV is identical to the T cell activation marker CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological peptides in vitro.
  • the present invention provides compounds of formula (I), (Ia), (II) or (Ma) or their prodrugs or pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention provides the use of compounds of formula (I), (Ia), (II) or (Ma) or their prodrugs or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of non-insulin dependent
  • Type II diabetes mellitus hyperglycemia; obesity; insulin resistance; lipid disorders; dyslipidemia; hyperlipidemia; hypertriglyceridemia; hypercholestrerolemia; low HDL; high LDL; atherosclerosis; growth hormone deficiency; diseases related to the immune response; HIV infection; neutropenia; neuronal disorders; anxiety; depression; tumor metastasis; benign prostatic hypertrophy; gingivitis; hypertension; osteoporosis; diseases related to sperm motility; low glucose tolerance; insulin resistance; ist sequelae; vascular restenosis; irritable bowel syndrome; inflammatory bowel disease; including Crohn's disease and ulcerative colitis; other inflammatory conditions; pancreatitis; abdominal obesity; neurodegenerative disease; retinopathy; nephropathy; neuropathy; Syndrome X; ovarian hyperandrogenism (polycystic ovarian syndrome;
  • Type n diabetes or growth hormone deficiency.
  • Preferred is non-insulin dependent
  • compositions comprising at least one compound of formula (I), (Ia) 1 (II) or (Ha), a prodrug compound thereof, or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like other DPP-IV inhibitors.
  • Other active ingredients are disclosed in WO-A-03/000181 under the paragraph "Combination Therapy" which is herewith incorporated by reference. Accordingly, other active ingredients may be insulin sensitizers; PPAR agonists; biguanides; protein tyrosinephosphatase-IB (PTP-1 B) inhibitors; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; a-glucosidase inhibitors; glucagon receptor antagonists; GLP-1 , GLP-1 mimetics, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents; HMG-CoA reductase inhibitors; sequestrants; nicotinyl alcohol; nicotinic acid or a
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of formula (I), (Ia), (II) or (Ha) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • compositions of formula (I), (Ia), (II) or (Ha) may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I), (Ia), (II) or (Ma) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of formula (I) or (II) of the present invention can be prepared from beta amino acid intermediates such as those of formula (XVIII) and substituted amine intermediates such as those of formula (IX) and (XVII), using standard peptide coupling conditions followed by deprotection reactions.
  • beta amino acid intermediates such as those of formula (XVIII)
  • substituted amine intermediates such as those of formula (IX) and (XVII
  • Suitable starting materials for keto compounds for Scheme C are mostly commercial or may be prepared by either a Dieckmann Cyclization, as described in Pellegrini, et al Tetrahedron Lett. 2002, 3243-3246 or by a rhodium mediated ring closing reaction, as reported by Moyer, et al in J. Org. Chem. 1985, 5223-5230 as shown in Scheme D.
  • diamines (VII) may be prepared by the reaction sequence shown in Scheme E.
  • PG 2 a suitable protecting group
  • PG 2 preferably a silyl group.
  • the reaction sequence further comprises the reduction of the ester, followed by transformation of the resulting alcohol into a good leaving group and subsequent nucleophilic displacement with sodium azide.
  • a Gabriel synthesis may be performed to synthesize compounds of the type (VII), which uses potassium phthalimide as nucleophile and hydrazine to liberate the primary amine.
  • the azide may be reduced to the primary amine (VII) by either a Staudinger reaction with triphenylphosphane (see: Tian, Wang, J. Org. Chem. 2004, 69, 4299. or Lin, et al J. Am. Chem. Soc, 2005, 127, 2686.) or hydrogen reduction with palladium on charcoal as catalyst.
  • primary amines of the type (VII) may be reacted with a carboxylic acid under amide coupling conditions with e.g. EDC, HOBt and a base (e.g. triethylamine) to form amides of the type (VIII).
  • Sulfonamides of the type (IX) can result from the reaction of diamines (VII) with sulfonylchlorides and amines of the type (X) can be the product of a nucleophilic substitution reaction of diamine (VII) with activated aryl halogenides or alkyl halogenides as shown in Scheme F or other suitable methods.
  • the alcohol may be converted into the azide after activation with, e.g. methane sulfonylchloride, followed by a nucleophilic substitution with sodium azide.
  • the azide can be transformed into the primary amine (XII) by either the Staudinger reaction (triphenylphosphine, water) or catalytic hydrogenation.
  • the Gabriel sequence may be employed to yield diamines of the type (XII), as described earlier.
  • primary amines of the type (XII) may be reacted with a carboxylic acid under amide coupling conditions with e.g. EDC, HOBt and a base (e.g. triethylamine) to form amides of the type (XIII).
  • Sulfonamides of the type (XIV) can result from the reaction of diamines (XII) with sulfonylchlorides and amines of the type (XV) can be the product of a nucleophilic substitution reaction of diamine (XII) with activated aryl halogenides or alkyl halogenides as shown in Scheme H.
  • XVIII may be commercially available, are known in the literature or may be conveniently synthesized using one of the methods already published and reviewed in e.g., Cole, Tetrahedron 1994, 32, 9517, Juaristi et al., Aldrichimica Acta 1994, 27, 3, or Juaristi, Enantioselective Synthesis of ⁇ -Amino Acids, Ed. Wiley-VCH, New York, 1997.
  • 3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid may be synthesized by a variety of methods as reported in the patent applications WO 2004069162, WO
  • EDC 1-hydroxybenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • a base triethylamine or diisopropylethylamine
  • solvents such as methylene chloride or ⁇ /, ⁇ /-dimethylformamide.
  • Scheme J outlines a procedure for using the amines formed according to Schemes A through F to synthesize compounds that are embodiments of the invention.
  • SiIyI protecting groups for alcohols may be removed with tetra ⁇ -butyl ammonium fluoride (TBAF) solution in THF or by reaction with hydrogenfluoride in pyridine.
  • the protective groups on the primary nitrogen may be removed with, for example, diethylamine in dichloromethane in the case of 9-fluorenylmethoxycarbonyl or using acidic conditions (such as trifluoroacetic acid in dichloro methane or hydrochloric acid in dioxane) in the case of te/t-butoxycarbonyl, as described in Greene, Wuts Protective Groups in Organic Synthesis 3rd ed., Ed. Wiley-VCH, New York; 1999.
  • amino building blocks (XVII) are coupled with beta amino acids (XVIII) to form the corresponding amides.
  • Suitable reaction conditions are for example, the use of 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in combination with 1- hydroxybenzotriazole (HOBt) and a base (triethylamine or diisopropylethylamine) or O- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in the presence of a base, in solvents such as methylene chloride or N 1 N- dimethylformamide.
  • EDC 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HOBt 1- hydroxybenzotriazole
  • HATU O- (7-azabenzotriazol-1-yl)
  • ester may be saponified with a hydroxide base, preferable lithium or sodium hydroxide in aqueous tetrahydrofurane, and the protecting group on the primary amine is removed.
  • a hydroxide base preferable lithium or sodium hydroxide in aqueous tetrahydrofurane
  • the protecting group on the primary amine is removed.
  • diethylamine in dichloromethane in the case of 9-fluorenylmethoxycarbonyl or acidic conditions (such as trifluoroacetic acid in dichloromethane or hydrochloric acid in dioxane) in the case of te/f-butoxycarbonyl
  • diethylamine in dichloromethane in the case of 9-fluorenylmethoxycarbonyl or acidic conditions (such as trifluoroacetic acid in dichloromethane or hydrochloric acid in dioxane) in the case of te/f-butoxycarbonyl
  • acidic conditions
  • (2S.4R)-2-Azidomethyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylic acid terf-butyl ester 950 mg (2.87 mmol, 1.00 eq) of (2S,4fi)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy- methyl-pyrrolidine-1-carboxylic acid tert-butyl ester are dissolved in 16 mL of dichloromethane, 959 ⁇ l_ (696 mg, 6.89 mmol, 2.40 eq) triethylamine is added and the solution is cooled with an ice bath to 0 0 C.
  • the resulting mixture is heated for 3 h to 80 0 C and the reaction progress is monitored by TLC (silica gel, eluent: c-hexane:ethyl acetate 90:10). After completion of the reaction the mixture is poured into brine and extracted thrice with ethyl acetate. The combined organic layers are washed with water and brine, dried over sodium sulfate, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography on silica gel with c-hexane:ethyl acetate as eluent.
  • reaction is quenched by the addition of a saturated sodium bicarbonate solution and the organic layer is diluted with ethyl acetate and washed with water and brine. The organic layer is next dried with sodium sulfate and concentrated under vacuum. The crude product is used in the next step without further purification.
  • the title compound can be prepared according to example 1 , step 1 from (2S,4S)-4- hydroxy-pyrrolidine-1 , 2-dicarboxylic acid 1-te/t-butyl ester 2-methyl ester.
  • the title compound can be prepared according to example 1 , step 2 from (2S,4S)-4- (teAf-butyl-dimethyl-silanyloxy)-pyrrolidine-i , 2-dicarboxylic acid 1-terf-butyl ester 2- methyl ester.
  • the title compound can be prepared according to example 1 , step 5 from (2S,4S)-2- azidomethyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester.
  • the title compound can be prepared according to example 1 , step 6 from (2S,4S)-2- aminomethyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1 -carboxylic acid te/t-butyl ester.
  • the title compound can be prepared according to example 1 , step 7 from [(f?)-3- ⁇ (2S,4S)-2-[(2-fluoro-2-methyl-propionylamino)-methyl]-4-hydroxy-pyrrolidin-1-yl ⁇ -3- oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester.
  • the title compound can be prepared according to example 1 , step 9 from [(R)-3- ⁇ (2S,4S)-2-[(2-fluoro-2-methyl-propionylamino)-methyl]-4-hydroxy-pyrrolidin-1-yl ⁇ -3- oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid fert-butyl ester or step 8b from [(R)- 3- ⁇ (2S,4f?)-4-(tert-butyl-dimethyl-silanyloxy)-2-[(2-fluoro-2-methyl-propionylamino)- methyl]-pyrrolidin-1 -yl ⁇ -3-oxo-1 -(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-buty ⁇ ester.
  • the resulting solution is stirred for 1 h at 0 0 C, washed with saturated sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated to dryness.
  • the crude product is dissolved in 25 mL of dimethylformamide and 255 mg (3.93 mmol, 1.50 eq) of sodium azide are added.
  • the reaction mixture is heated to 80 0 C overnight, diluted with 100 mL of ethyl acetate and washed with brine, saturated sodium bicarbonate solution, water and brine. Afterwards the solution is dried with sodium sulfate, the solvent is removed under reduced pressure and the crude product is purified by flash chromatography on silica gel using c-hexane:ethyl acetat as eluent.
  • DPP-IV releasing free AMC.
  • the assay is carried out in 96-well microtiterplates. In a total volume of 100 ⁇ l, compounds are preincubated with 50 pM DPP-IV employing a buffer containing 1OmM Hepes, 15OmM NaCI, 0.005% Tween 20 (pH 7.4). The reaction is started by the addition of 16 ⁇ M substrate and the fluorescence of liberated AMC is detected for 10 minutes at 25 °C with a fluorescence reader (BMG-Fluostar; BMG-
  • DPP-IV activity assays were carried out with human and porcine DPP-IV (see below); both enzymes showed comparable activities.
  • Soluble human DPP-IV lacking the transmembrane anchor (Gly31-Pro766) was expressed in a recombinant YEAST-strain as Pre-Pro-alpha-mating fusion.
  • the secreted product (rhuDPP-IV-Gly31-Pro766) was purified from fermentation broth (>90% purity).
  • the examples 1-3 show a % inhibition of about 2 ⁇ M or less.
  • the compounds of the present invention also exhibit excellent physicochemical properties that are pharmacologically relevant such as aqueous solubility, plasma protein binding, metabolic stability and the like. Due to these properties, the claimed compounds show improved pharmacokinetic properties such as good absorption in the gastrointestinal tract, low first-pass metabolism and the like.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des composés représentés par la formule I et par la formule (II); dans ces formules, Z1 R1-5, R, W, X, Y, m, n et A1 sont tels que définis dans la description et dans les revendications. Ces composés sont utilisés en tant qu'inhibiteurs DPP-IV. Cette invention concerne également la préparation de tels composés ainsi que leur production et leur utilisation en tant que médicament.
PCT/EP2007/007786 2006-09-07 2007-09-06 N-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés associés utilisés en tant qu'inhibiteurs dpp-iv pour le traitement du diabète sucré de type 2 WO2008028662A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US84285206P 2006-09-07 2006-09-07
EP06018795A EP1905759A1 (fr) 2006-09-07 2006-09-07 Derivés n-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés similaires pour l'utilisation comme inhibiteurs dpp-iv pour le traitement de type 2 diabetes mellitus
EP06018795.2 2006-09-07
US60/842,852 2006-09-07

Publications (1)

Publication Number Publication Date
WO2008028662A1 true WO2008028662A1 (fr) 2008-03-13

Family

ID=38965662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/007786 WO2008028662A1 (fr) 2006-09-07 2007-09-06 N-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés associés utilisés en tant qu'inhibiteurs dpp-iv pour le traitement du diabète sucré de type 2

Country Status (1)

Country Link
WO (1) WO2008028662A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040095A1 (fr) * 2003-10-16 2005-05-06 Astrazeneca Ab Inhibiteurs de la dipeptidyl-peptidase iv
WO2005056003A1 (fr) * 2003-12-09 2005-06-23 Santhera Pharmaceuticals (Schweiz) Gmbh Inhibiteurs dpp-iv

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040095A1 (fr) * 2003-10-16 2005-05-06 Astrazeneca Ab Inhibiteurs de la dipeptidyl-peptidase iv
WO2005056003A1 (fr) * 2003-12-09 2005-06-23 Santhera Pharmaceuticals (Schweiz) Gmbh Inhibiteurs dpp-iv

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
EP2669266A1 (fr) 2009-03-30 2013-12-04 Dong-A Pharmaceutical Co., Ltd. Procédé amélioré de préparation d'inhibiteur de dipeptidyl peptidase-IV et d'intermédiaire
WO2010114292A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2010114291A2 (fr) 2009-03-30 2010-10-07 동아제약 주식회사 Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2014064215A1 (fr) 2012-10-24 2014-05-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la kinase tpl2 pour prévenir ou traiter le diabète et favoriser la survie de cellules β
WO2016151018A1 (fr) 2015-03-24 2016-09-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthode et composition pharmaceutique destinées à être utilisées dans le traitement du diabète

Similar Documents

Publication Publication Date Title
WO2008028662A1 (fr) N-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés associés utilisés en tant qu'inhibiteurs dpp-iv pour le traitement du diabète sucré de type 2
EP1613304B1 (fr) Inhibiteurs de dpp-iv
EP1778682A1 (fr) Composés hétérocycliques utiles comme inhibiteurs de la dpp-iv
EP1593671A1 (fr) Inhibiteurs de la DPP-IV
EP1828138A1 (fr) Inhibiteurs de dpp-iv
EP1858846A1 (fr) Inhibiteurs de dpp-iv
CA2569535A1 (fr) Inhibiteurs de la dpp-iv
EP1604989A1 (fr) Inhibiteurs de DPP-IV
WO2005120494A1 (fr) Derives de 1-`(3r)-amino-4-(2-fluoro-phenyl)-butyl !-pyrrolidine-(2r)-acide carboxilique-benzylamine et composes apparentes utilises comme inhibiteurs de la dipeptidyl-peptidase iv (dpp-iv) destines au traitement du diabete non insulino-dependant
WO2009003681A1 (fr) Inhibiteurs de dpp-iv
WO2005056013A1 (fr) Inhibiteurs dpp-iv
EP1905759A1 (fr) Derivés n-[1-(3-amino-4-phenyl-butyryl)-4-hydroxy-pyrrolidin-2-ylmethyl}-propionamide et composés similaires pour l'utilisation comme inhibiteurs dpp-iv pour le traitement de type 2 diabetes mellitus
EP2019099A1 (fr) Inhibiteurs Dpp-IV

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07818064

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07818064

Country of ref document: EP

Kind code of ref document: A1