WO2005040095A1 - Inhibiteurs de la dipeptidyl-peptidase iv - Google Patents

Inhibiteurs de la dipeptidyl-peptidase iv Download PDF

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WO2005040095A1
WO2005040095A1 PCT/GB2004/004283 GB2004004283W WO2005040095A1 WO 2005040095 A1 WO2005040095 A1 WO 2005040095A1 GB 2004004283 W GB2004004283 W GB 2004004283W WO 2005040095 A1 WO2005040095 A1 WO 2005040095A1
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alkyl
phenyl
hydrogen
amino
hetl
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PCT/GB2004/004283
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Roger John Butlin
Gordon Stuart Currie
Harold Gaskin
Rodney Brian Hargreaves
Paul David Kemmitt
Nathaniel George Martin
Richard Andrew Ward
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2005040095A1 publication Critical patent/WO2005040095A1/fr

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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/14—The ring being saturated
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to compounds which inhibit dipeptidyl peptidase IV (DPP-IV) activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, methods for the treatment of disease states associated with DPP- IV activity, to their use as medicaments and to their use in the manufacture of medicaments for use in the inhibition of DPP-IV in warm-blooded animals such as humans.
  • this invention relates to compounds useful for the treatment of diabetes mellitus in warmblooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of diabetes mellitus in warm-blooded animals such as humans.
  • DPP-IV is a serine protease found throughout the body, which degrades and regulates the activity of several regulatory peptides in man including glucagon-like peptide-1 (GLP-1), GLP-2, GHRH (growth hormone releasing hormone) and GIP (glucagon interacting peptide).
  • GLP-1 is a peptide hormone which is released from the intestinal tract wall into the bloodstream in response to a meal and strongly influences post-prandial glucose metabolism. As post-prandial glucose levels rise, GLP-1 acts directly on pancreatic ⁇ -cells to augment insulin release and also promote new insulin biosynthesis. Simultaneously, GLP-1 delays gastric emptying, further suppressing meal-related rise in plasma glucose. It has been shown (Rachman, J. et al, (1997), Diabetologia, 40, 205-211; Nauck, M.A. et al, (1996),
  • GLP-1 administration either subcutaneously or by intravenous infusion improves glucose tolerance in diabetic patients, however daily administration of GLP-1 is not generally considered to be a desirable form of therapy.
  • DPP-IV degrades GLP-1 circulating in the bloodstream and inhibition of DPP-IV activity causes an increase in the half life, and therefore activity, of GLP-1. Additionally DPP- IV inhibitors have beneficial effects on pancreatic failure: Ribel U.
  • DPP-IV inhibitor valine pyrrolidide (VP) promoted differentiation of new beta cells in 60% pancreatectomised rats. Therefore, administration of a DPP-IV inhibitor should result in prolongation of endogenous GLP-1 activity and thus potentially in a clinically significant lowering of diabetic hyperglycemia.
  • a DPP-IV inhibitor may potentially be useful for the prevention, delay or treatment of Type 2 (non-insulin dependent) diabetes mellitus. Novel DPP-IV inhibitors have been described in the art.
  • 2- cyanopyrrolidines derivatives with a significant range of substituents bonded to the ring nitrogen (see for example WO 98/19998, WO 00/34241, WO 01/96295, WO 01/40180), or contain this structure (see for example WO 01/68603 which discloses cyclopropyl fused cyano pyrrolidines).
  • Others are cyanothiazolidines (see for example US 6110949, US 6107317, WO 99/61431), also with a variety of substituents bonded to the ring nitrogen.
  • the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof,
  • -(l-6C)alkylCO 2 ARl -(l-6C)alkylCO 2 HETl, -(l-6C)alkylOCO(l-6C)alkyl, -(l-6C)alkylOCO(3-8C)cycloalkyl, -(l-6C)alkylOCOARl, -(l-6C)alkylOCOHETl, -(l-6C)alkylCO(l-6C)alkyl, -(l-6C)alkylCO(3-8C)cycloalkyl, -(l-6C)alkylCOARl, -(l-6C)alkylCOHETl , -(l-6C)alkylNHCO(l-6C)alkyl, -(l-6C)alkylNHCO(3-8C)cycloalkyl, -(l-6C)alkylNHCOARl,
  • R 1 and R 2 may together with the nitrogen to which they are attached form a ring defined by HETl or HET3; wherein a ring
  • R 2 , R 3 or R 4 is optionally substituted;
  • AR1 is optionally substituted phenyl;
  • AR2 is an optionally substituted 8-, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic carbocylic ring;
  • HETl is an optionally substituted 3-, 4-, 5- or 6-membered, unsaturated, partially or fully saturated monocyclic heterocyclyl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised, and wherein any available carbon, sulfur or nitrogen atom may be oxidised;
  • HET2 is an optionally substituted 8-, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic heterocyclyl ring containing up to four heteroatoms independently selected from O, N and S (but
  • a further embodiment of the invention comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof wherein: Ar is phenyl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R 9 ; R 9 is selected from halo, (l-6C)alkyl (optionally substituted with 1-5 halo), (l-6C)alkoxy (optionally substituted with 1-5 halo) and cyano; R 1 is selected from hydrogen and (l-6C)al yl; R 2 is selected from hydrogen, (l-6C)alkyl, C3-8C)cycloalkyl , (5-12C)bicycloalkyl, (6-12C)tricycloalkyl, ARl, HETl, -(l-6C)alkylARl,
  • -(l-6C)alkylAR2 -(l-6C)alkyl(3-8C)cycloalkyl, -(l-6C)alkylHETl, -(l-6C)alkylHET2, -(l-6C)alkylCO 2 (l-6C)alkyl, -(l-6C)alkylCO 2 (3-8C)cycloalkyl, -(l-6C)alkylCO 2 ARl, -(L6C)alkylCO 2 HETl, -(l-6C)alkylOCO(l-6C)alkyl, -(l-6C)alkylOCO(3-8C)cycloalkyl, -(l-6C)alkylOCOARl, -(l-6C)alkylOCOHETl, -(l-6C)alkylCO(l-6C)alkyl, -(l-6C)alkylCO(3-8C)cycloalkyl,
  • -(l-6)alkylNHSO2(l-6C)alkyl includes -methylaminosulphonylmethyl, -methylaminosulphonylethyl, -ethylaminosulphonylmethyl, and -propylaminosulphonylbutyl.
  • substituents are chosen from "0, 1, 2 or 3" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
  • An analogous convention applies to substituents chose from "0, 1 or 2" groups, "0 or 1" groups and "1 or 2" groups.
  • Substituents may be present at any suitable position on, for example, an alkyl group.
  • hydroxy substituted (l-6C)alkyl includes hydroxymethyl, 1-hy roxyethyl, 2-hydroxyethyl and 3-hydroxypropyl.
  • Examples of (l-4C)aIkyl include methyl, ethyl, propyl and isopropyl; examples of (l-6C)alkyl include methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, iso-pentyl, 1-2- dimethylpropyl and hexyl; examples of (3-8C)cy oalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of (3-8C)cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl; examples of (5-12C)bicycIoalkyl include norbornyl, decalinyl (bicyclo[4,4,0]decyl (cis and trans), bicyclo[5,3,0]decyl and hydrindanyl (bicyclo[4,3,
  • Examples of -(l-6C)alkyIARl include (each example being optionally substituted) benzyl, phenylethyl and phenylbutyl.
  • Examples of -(l-6C)alkylCOARl include (each example being optionally substituted) phenylcarbonylmethyl, phenylcarbonylethyl, phenylcarbonylpropyl and phenylcarbonylbutyl.
  • Examples of -(l-6C)alkylCO 2 ARl include (each example being optionally substituted) phenoxycarbonylmethyl, phenoxycarbonylethyl, phenoxycarbonylpropyl and phenoxycarbonylbutyl.
  • Examples of -(l-6C)alkylOCOARl include (each example being optionally substituted) phenylcarbonyloxymethyl, phenylcarbonyloxyethyl, phenylcarbonyloxypropyl and phenylcarbonyloxybutyl.
  • Examples of -(l-6C)alkyINHCOARl include (each example being optionally substituted) phenylcarbonylaminomethyl, phenylcarbonylaminoethyl, phenylcarbonylaminopropyl and phenylcarbonylaminobutyl.
  • Examples of -(l-6C)alkylCONHARl include (each example being optionally substituted) phenylaminocarbonylmethyl, phenylaminocarbonylethyl, phenylaminocarbonylpropyl and phenylaminocarbonylbutyl. Examples of -(1-
  • 6C)aIkylNHARl include (each example being optionally substituted) phenylaminomethyl, phenylaminoethyl, phenylaminopropyl and phenylaminobutyl.
  • Particular values for AR2 include, for example, naphthyl, indanyl, indenyl, dihydronaphthyl and 1,2,3,4-tetrahydronaphthyl.
  • Examples of -(l-6C)alkyIAR2 include (each example being optionally substituted) naphthylmethyl, naphthylethyl, indanylmethyl, indanylethyl, indanylpropyl, indanylbutyl, indenylmethyl, indenylethyl, dihydronaphthylmethyl, dihydronaphthylpropyl and 1,2,3,4- tetrahydronaphthylmethyl .
  • HETl particularly values for HETl include, for example (each example being optionally substituted) furyl, pyrrolyl, thiophenyl (thienyl), pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-trazinyl, 1,3,5-trazinyl, 1,2,3- & 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxazinyl, oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- and 1,3,4- thiadiazolyl, oxazoline, thiazoline, dihydropyrrolyl (especially 2,5-dihydropyrrol-4-yl), tetrahydropyridyl (especially l,2,5,6-tetrahydr
  • HETl include (each value being optionally substituted) furyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,3- & 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxazinyl, oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4- and 1,3,4-thiadiazolyl, oxazoline, thiazoline, piperazinyl and imidazolyl.
  • HETl include (each value being optionally substituted) dihydropyrrolyl (especially 2,5-dihydropyrrol-4-yl), tetrahydropyridyl (especially 1,2,5,6- tetrahydropyrid-4-yl), tetrahydrofuranyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1- dioxotetrahydrothienyl, pyrrolidinyl, oxazolidine, thiazolidine, morpholinyl, thiomorpholinyl, piperidyl, l,3-dioxolan-4-yl, l,3-dioxan-4-yl, l,3-dioxan-5-yl and l,4-dioxan-2-yl.
  • dihydropyrrolyl especially 2,5-dihydropyrrol-4-yl
  • HETl includes (each value being optionally substituted) furyl, thiophenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, 2- oxopyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidyl and 2-oxopiperidyl.
  • HETl includes (each value being optionally substituted) furyl, thiophenyl, pyridyl, thiazolyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1- dioxotetrahydrothienyl, pyrrolidinyl, 2-oxopyrrolidinyl, morpholinyl, thiomorpholinyl, and piperidyl.
  • HETl include (each value being optionally substituted) furyl, thiophenyl, pyridyl, thiazolyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, 2- oxopyrrolidinyl, morpholinyl and piperidyl. It will be appreciated that, when R 1 and R 2 together with the nitrogen to which they are attached form a ring HETl, the ring HETl must be one which allows the ring to be linked through a nitrogen atom to the carbonyl group to which it is attached and which when linked the nitrogen atom is not quaternised.
  • Suitable values within the particular values for HETl set out herein include, for example, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidyl or 2-oxopiperidyl.
  • Examples of -(l-6C)a!kyIHETl include any one of the above particular values for HETl attached to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl and pyridylhexyl.
  • Examples of -(l-6C)alkylCOHETl include any one of the above particular values for HETl attached through a carbonyl group to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) pyridylcarbonylmethyl, pyridylcarbonylethyl, pyridylcarbonylpropyl, pyridylcarbonylbutyl and pyridylcarbonylhexyl.
  • Examples of -(l-6C)alkylCO 2 HETl include any one of the above particular values for HETl attached through an oxycarbonyl group to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) pyridyloxycarbonylmethyl, pyridyloxycarbonylethyl, pyridyloxycarbonylpropyl, pyridyloxycarbonylbutyl and pyridyloxyc arbonylhexyl .
  • Examples of -(l-6C)alkylOCOHETl include any one of the above particular values for HETl attached through an carboxy group to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) pyridylcarboxymethyl, pyridylcarboxyethyl, pyridylcarboxypropyl, pyridylcarboxybutyl and pyridylcarboxyhexyl.
  • Examples of -(l-6C)alkylNH(HETl) include any one of the above particular values for HETl attached through an amino group to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) pyridylaminomethyl, pyridylaminoethyl, pyridylaminopropyl, pyridylaminobutyl and pyridylaminohexyl.
  • HET2 particularly values for HET2 include for example indole, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, isochromanyl, 2,3-dihydrobenzthiazolyl, 2,3-dihydrobenzimidazolyl, benzodioxolanyl, purinyl and naphthyridinyl.
  • HET2 include for example, indole, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.
  • HET2 include bicyclic heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen.
  • ring systems include, for example, 3H-pyrrolo[l,2-a]pyrrolyl, pyrrolo[2,l-b]thiazolyl, lH-imidazo[l,2-a]pyrrolyl, lH-imidazo[l,2-a]imidazolyl, lH,3H-pyrrolo[l,2-c]oxazolyl, lH-imidazo[l,5-a]pyrrolyl, pyrrolo[l,2-b]isoxazolyl, imidazo[5,l-b]thiazolyl, imidazo[2,l-b]thiazolyl, indolizinyl, imidazo[l ,2-a]pyridyl, imidazo[l ,5-a]pyridyl, pyrazolo[ 1 ,5-a]pyridyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2-c]pyr
  • ring systems include, for example, [lH]-pyrrolo[2,l-c]oxazinyl, [3H]-oxazolo[3,4-a]pyridyl, [6H]-pyrrolo[2,l-c]oxazinyl and pyrido [2, l-c][ 1,4] oxazinyl.
  • 5/5- bicyclic ring systems are imidazooxazolyl or imidazothiazolyl, in particular imidazo[5,l-b]thiazolyl, imidazo[2,l-b]thiazolyl, imidazo[5,l-b]oxazolyl or imidazo[2,l-b]oxazolyl.
  • Examples of -(l-6C)alkylHET2 include any one of the above particular values for HET2 attached to any value of (l-6C)alkyl, and thus includes for example (optionally substituted) indolylmethyl, indolylethyl, indolylpropyl, indolylbutyl and indoylhexyl.
  • the nomenclature used is that found in, for example, "Heterocyclic Compounds (Systems with bridgehead nitrogen)", W.L.Mosby (Interscience Publishers Inc., New York), 1961, Parts 1 and 2.
  • Particuler values for HET3 include, for example, indolyl, benzimidazolyl, indolinyl, 1,2,3,4-tetrahydroquinolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzimidazolyl and purinyl.
  • Particular values for optional substituents on AR1, AR2, HETl and HET2 are 1, 2, 3,
  • substituents on AR1, AR2, HETl and HET2 are 1, 2 or 3, substituents independently selected from cyano, halo, (l-6C)alkyl, halo(l-6C)alkyl, dihalo(l-6C)alkyl, trifluoromethyl, (l-6C)alkoxy, carboxy(l-4C)alkyl, carboxy(l-6C)alkoxy, hydroxy, amino, (l-6C)alkylamino, -CONH 2 , -CONH(l-6C)alkyl, -CONdi(l-6C)alkyl, - NHCO(l-6C)alkyl, -S(O) 2 NH 2 , -SO 2 NH(l-6C)alkyl, -NHSO 2 (l-6C)alkyl.
  • substituents on AR1, AR2, HETl and HET2 are 1 or 2 substituents independently selected from cyano, halo, methyl, ethyl, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, methoxy, carboxymethyl, carboxymethoxy, hydroxy, amino, methylamino, ethylamino, -CONH 2 , -CONHMe, -NHCOMe, -S(O) 2 NH 2 , -SO 2 NHMe and -NHSO 2 Me.
  • optional substituents on AR1, AR2, HETl and HET2 are 1 or 2 substituents independently selected from cyano, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, methoxy, carboxymethyl, carboxymethoxy, hydroxy, -CONH 2 and -S(O) 2 NH 2 .
  • suitable optional substituents for a particular group are those as stated for similar groups herein.
  • a compound of formula (I) may form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following.
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, -glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine.
  • a preferred pharmaceutically-acceptable salt is the sodium salt.
  • salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DPP-IV activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings.
  • the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the inhibition of DPP-IV activity, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the inhibition of DPP-IV activity by the standard tests described hereinafter.
  • optically-active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase
  • compounds having the (R)- configuration at the carbon atom bearing R 3 and R 4 are preferred.
  • Particular aspects of the invention comprise a compound of formula (I), or a pharmaceutically-acceptable salt thereof, wherein the substituents Ar, R 1 to R 9 and other substituents mentioned above have values defined hereinbefore, or any of the following values (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter):
  • compounds of formula (I) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I).
  • Particular values of variable groups are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Ar is phenyl substituted with 1 group R 9 3) Ar is phenyl substituted with 2 groups independently selected from R 9
  • Ar is phenyl substituted with 4 groups independently selected from R 9
  • R 9 is halo, preferably fluoro
  • R 9 is (l-6C)alkyl (optionally substituted with 1-5 halo), for example (l-4C)alkyl (optionally substituted with 1-5 halo), such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl
  • R 9 is (l-6C)alkoxy (optionally substituted with 1-5 halo), for example (l-4C)alkoxy (optionally substituted with 1-5 halo), such as methoxy, fluoromethoxy, difluoromethxoy or trifluoromethoxy
  • R 9 is cyano 9)
  • R 1 is hydrogen
  • R is (l-6C)alkyl, for example (l-4C)alkyl, such as methyl
  • R > 5 is hydrogen or methyl
  • R 5 is hydrogen 13)
  • R 6 is hydrogen or methyl 14)
  • R 6 is hydrogen 15)
  • R 7 is hydrogen or methyl 16)
  • R 7 is hydrogen 5 17)
  • R 8 is hydrogen or methyl 18)
  • R 8 is hydrogen 19)
  • R 3 and R 4 together form a ring as defined by AR2, HETl or HET2 20)
  • R 3 and R 4 together form a ring as defined by AR2 21)
  • R 3 and R 4 together form a ring as defined by HETl 10 22)
  • R 3 and R 4 together form a ring as defined by HET2 23)
  • R 3 and R 4 are independently selected from hydrogen, (l-6C)alkyl, -(l-6C)alkyl(3-8C)cycloalkyl, -(l-6C)alkyl(3-8C)cycloalkenyl, -(l-6C)alkylARl, -(l-6C)alkylAR2, -(l-6C)alkyl
  • R 3 is hydrogen and R 4 is selected from -(l-6C)alkyl(3-8C)cycloalkyl, -(l-6C)alkyl(3-8C)cycloalkenyl, -(l-6C)alkylARl, -(l-6C)alkylAR2, -(l-6C)alkylHETl and -(l-6C)alkylHET2 30)
  • R 1 is hydrogen and R 2 is a (3-8C)cycloalkyl, (5-12C)bicycloalkyl,
  • a ring comprising R 1 and R 2 is optionally substituted by 1 or 2 substituents independently selected from halo, (l-6C)alkyl, halo(l-6C)alkyl, (l-6C)alkoxy, cyano, carboxy, carboxy(l-6C)alkyl, -CO(l-6C)alkyl, - CO 2 (l-6C)alkyl, (l-6C)alkylamino, di-(l-6C)alkylamino, -NHCO(l-6C)alkyl, -CONH(l- 6C)alkyl, -CONdi-(l-6C)alkyl and HETl
  • R 2 is selected from hydrogen, (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl, and (6-12C)tricycloalkyl 32) R 2 is selected from AR1, HETl, -(l-6C)alkylARl, -(l-6C)alkylAR2, -(1- 6C)alkyl(3-8C)cycloalkyl, -(l-6C)alkylHETl and -(l-6C)alkylHET2 33) R 2 is selected from -(l-6C)alkylCO 2 (l-6C)alkyl, -(l-6C)alkylCO 2 (3-8C)cycloalkyl, -(l-6C)alkylCO 2 ARl, -(l-6C)alkylCO 2 HETl, -(l-6C)alkylOCO(l-6C)alkyl, -(l-6C)alkylOCO(3
  • R 2 is selected from (l-6C)alkyl, cyclohexyl, norbonyl, adamantyl, phenyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -S ⁇ 2 NHMe), benzyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -SO 2 NHMe), -(l-4C)alkylCONH(l-
  • R 1 is H and and R 2 is a furyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, oxazoline, thiazoline, dihydropyrrolyl (especially 2,5-dihydropyrrol-4-yl), tetrahydropyridyl (especially l,2,5,6-tetrahydropyrid-4-yl), tetrahydrofuranyl, , tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, oxazolidine, thiazolidine, morpholinyl, thiomorpholinyl, piperazinyl, imidazolyl or piperidyl
  • 25 ring optionally substituted by 1 or 2 substituents independently selected from cyano, halo, (1- 6C)alkyl, halo(l-6C)alkyl, dihalo(l-6C)alkyl, trifluoromethyl, (l-6C)alkoxy, carboxy(l- 4C)alkyl, carboxy(l-6C)alkoxy, hydroxy, amino, (l-6C)alkylamino, -CONH 2 , -CONH(l- 6C)alkyl, -CONdi(l-6C)alkyl, -NHCO(l-6C)alkyl, -S(O) 2 NH 2 , -SO 2 NH(l-6C)alkyl and- NHSO 2 (l-6C)alkyl
  • R 1 and R 2 together with the nitrogen to which they are attached form a tetrahydropyridyl (especially l,2,5,6-tetrahydropyrid-4-yl), tetrahydrofuranyl, pyrrolidinyl, oxazolidine, thiazolidine, morpholinyl, thiomorpholinyl, piperazinyl or piperidyl ring optionally substituted by 1 or 2 substituents independently selected from cyano, halo, (1- 6C)alkyl, halo(l-6C)alkyl, dihalo(l-6C)alkyl, trifluoromethyl, (l-6C)alkoxy, carboxy(l- 4C)alkyl, carboxy(l-6C)alkoxy, hydroxy, amino, (l-6C)alkylamino, -CONH 2 , -CONHQ- 6C)alkyl, -CONdi(l-6C)alkyl, -NH
  • R 1 is hydrogen 50)
  • R 1 is methyl 51)
  • Ar is phenyl substituted with 3 groups independently selected from R 9 , and particularly three fluoro groups
  • Ar is 2-fluorophenyl 53) Ar is 2,4-difluorophenyl 54) Ar is 2,5-difluorophenyl 55)
  • R 2 is (l-4C)alkyl, for example methyl 56)
  • R 2 is hydrogen, (l-6C)alkyl, (l-6C)alkylSO 2 (l-6C)alkyl, (l-6C)alkylCONH(l-
  • R 3 is hydrogen or (l-6C)alkyl and R 4 is a group 30 other than hydrogen or (l-6C)alkyl, and wherein the carbon atom bearing R 3 and R 4 has the (R)-configuration.
  • R 4 is a group 30 other than hydrogen or (l-6C)alkyl, and wherein the carbon atom bearing R 3 and R 4 has the (R)-configuration.
  • Further particular groups of compounds of the invention within any of the groups of compounds defined herein are those containing a group HETl in which HETl contains a single heteroatom.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof wherein
  • Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R 9 ;
  • R 9 is selected from halo, methyl, methoxy and trifluoromethyl
  • R 1 is hydrogen or methyl;
  • R 5 is hydrogen;
  • R 6 is hydrogen
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 3 and R 4 together form a ring as defined by AR2, HETl or HET2;
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl,
  • Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R 9 ;
  • R 9 is selected from halo, methyl, methoxy and trifluoromethyl;
  • R 1 is hydrogen or methyl;
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is hydrogen
  • R 8 is hydrogen; R 3 and R 4 together form a ring as defined by AR2; R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl,
  • -(l-6C)alkylNHCOARl -(l-6C)alkylCONH(l-6C)alkyl, -(l-6C)alkylCONHARl, -Q-6C)alkylNH(l-6C)alkyl, -(l-6C)alkylNHARl, -(l-6C)alkylNH(HETl), -(l-6C)alkylNHS0 2 (l-6C)alkyl and -(l-6C)alkylSO 2 NH(l-6C)alkyl.
  • Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R 9 ;
  • R 9 is selected from halo, methyl, methoxy and trifluoromethyl
  • R 1 is hydrogen or methyl
  • R 5 is hydrogen; R is hydrogen;
  • R 7 is hydrogen
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl, (6-12C)tricycloalkyl, ARl, HETl, -(l-6C)alkylARl, -(l-6C)alkylNHCO(l-6C)alkyl,
  • R 1 is hydrogen
  • R 8 is hydrogen
  • R 3 and R 4 together form an indanyl ring
  • R 2 is selected from (l-6C)alkyl, cyclohexyl, norbonyl, adamantyl, phenyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -SO 2 NHMe), benzyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -SO 2 NHMe), -(l-4C)alkylCONH(l-
  • R 9 is selected from halo, methyl, methoxy and trifluoromethyl
  • R 1 is hydrogen or methyl
  • R 6 is hydrogen; R is hydrogen;
  • R 8 is hydrogen
  • R 3 is hydrogen and R 4 is selected from -(l-4C)alkyl(3-8C)cycloalkyl,
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl,
  • R 9 is selected from halo, methyl, methoxy and trifluoromethyl;
  • R 1 is hydrogen or methyl;
  • R 6 is hydrogen
  • R 7 is hydrogen
  • R 8 is hydrogen; R 3 is hydrogen and R 4 is selected from -(l-4C)alkylARl, -(l-4C)alkylAR2, -(1-
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl,
  • Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R 9 ;
  • R is selected from halo, methyl, methoxy and trifluoromethyl
  • R 1 is hydrogen or methyl;
  • R 5 is hydrogen;
  • R is hydrogen
  • R 8 is hydrogen
  • R 3 is hydrogen and R 4 is selected from benzyl, (optionally substituted with 1 or 2 substituents selected from cyano, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, methoxy, carboxymethyl, carboxymethoxy, hydroxy, -CONH 2 and -S(O) 2 NH 2;
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl,
  • Ar is phenyl, fluorophenyl or difluorophenyl
  • R 1 is hydrogen
  • R 5 is hydrogen
  • R 8 is hydrogen
  • R 3 is hydrogen
  • R 4 is benzyl;
  • R 2 is selected from (l-6C)alkyl, cyclohexyl, norbonyl, adamantyl, phenyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -SO 2 NHMe), benzyl (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and -SO 2 NHMe), -(l-4C)alkylCONH(l- 4C)alkyl, -(l-4C)alkylCONHPh (optionally substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methanesulfonamido, carboxymethyl, -SO 2 NH 2 and
  • Ar is phenyl substituted with 1, 2 or 3 fluoro
  • R 2 is selected from (l-6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl, (6-12C)tricycloalkyl, ARl, HETl, -(l-6C)alkylARl, -Q-6C)alkylNHCO(l-6C)alkyl,
  • R 3 is hydrogen;
  • R 4 is CH 2 -AR1, CH 2 -HETI or CH 2 -HET2;
  • R 5 , R 6 , R 7 and R 8 are all hydrogen.
  • R 1 is hydrogen
  • R 2 is hydrogen, (l-4C)alkyl, -(l-4C)alkylARl or -(l-4C)alkylCONH(l-4C)alkyl;
  • R 3 is hydrogen
  • R 4 is CH 2 -AR1 or CH2-HET1; and R 5 , R 6 , R 7 and R 8 are all hydrogen.
  • Particular compounds of the invention are of the formula (IA):
  • compounds of the invention are any one of the Examples, or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) and its pharmaceutically-acceptable salts may be prepared by any process known to be applicable to the preparation of chemically related compounds.
  • Such processes, when used to prepare a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention.
  • the present invention also provides that the compounds of the formulae (I) and pharmaceutically-acceptable salts thereof, can be prepared by a process comprising the following steps (wherein the variables are as defined hereinbefore or after unless otherwise stated) : a) coupling of a compound of formula (II) (or an activated derivative thereof) (wherein P is a suitable protecting groups) with a compound of formula (IH), followed by removal of the protecting group P;
  • Suitable coupling conditions for step b) or step c) are any of those known in the art for coupling together acids and bases for example standard peptide coupling reagents known in the art, or for example carbonyldiimidazole, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI), optionally in the presence of a catalyst such as 1-hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, di-isopropylethylamine, pyridine, or 2,6-di-a-/ y.-pyridmes such as 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • a catalyst such as 1-hydroxybenzotriazole, dimethylaminopyridine or 4-pyrrolidin
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
  • the coupling reaction may conveniently be performed at a temperature in the range of -40 to 40°C.
  • Reference to an "activated derivative" of a compound of formula (II) or (IV) means for example, a derivative such as an anhydride or acid halide suitable for such coupling reactions.
  • Removal of the proptecting group P 1 may be achieved by any suitable method known in the art. Where P 1 is an alkyl group, the ester may be hydrolysed under acid or basic conditions, for example using alkali bases such as sodium hydroxide or lithium hydroxide. Removal of the proptecting group P may be achieved by any suitable method known in the art.
  • hydrolysis of the BOC group may be achieved using aqueous acid, for example a solution of aqueous HC1 in dioxane.
  • aqueous acid for example a solution of aqueous HC1 in dioxane.
  • Conditions suitable for removing the protecting group P such as treatment with an acid such as HC1, may result in formation of a salt of a compound of the formula (I), which may optionally be treated to give the free base form or to give an alternative (pharmaceutically acceptable) salt form.
  • the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, techniques which are described or illustrated in the references given above, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 4 th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents.
  • Particular compounds of formula (II), (III), (IV) and (V) are those wherein Ar is phenyl substituted with 1, 2 or 3 fluoro; R 5 , R 6 , R 7 and R 8 are all hydrogen; R 3 is hydrogen and R 4 is CH 2 -AR1, CH 2 -Hetl or CH 2 -Het2, R 1 is hydrogen and R 2 is selected from (1- 6C)alkyl, (3-8C)cycloalkyl , (5-12C)bicycloalkyl, (6-12C)tricycloalkyl, ARl, HETl, -(l-6C)alkylARl, -(l-6C)alkylNHCO(l-6C)alkyl, -(l-6C)alkylNHCOARl, -(l-6C)alkylCONH(l-6C)alkyl, -(l-6C)alkylCONHARl, -(l-6C)alkylNH(l-6C)alkyl, -(l-6C
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • a suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxyca-rbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
  • an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • an optically active form of a compound of the invention it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced).
  • Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • a pure regioisomer of a compound of the invention when required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable excipient or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the composition of the inventions is in a form suitable for oral use.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
  • a further feature of the present invention is a compound of formula (I) and pharmaceutically-acceptable salts thereof for use as a medicament.
  • this is a compound of formula (I), or a pharmaceutically-acceptable salt thereof, for use as a medicament for producing an inhibition of DPP-IV activity in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof for use as a medicament for treating diabetes mellitus in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof in the manufacture of a medicament for use in the production of an inhibition of DPP-IV activity in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically-acceptable salt thereof in the manufacture of a medicament for use in the treatment of diabetes mellitus in a warm-blooded animal such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable excipient or carrier for use in producing an inhibition of DPP-IV activity in an warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable excipient or carrier for use in the treatment of diabetes mellitus in an warm-blooded animal, such as a human being.
  • a method for • producing an inhibition of DPP-IV activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt thereof as defined hereinbefore.
  • a method of treating diabetes mellitus in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt thereof as defined hereinbefore.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • compounds defined in the present invention are of interest for their ability to inhibit the activity of DPP-IV.
  • a compound of the invention may therefore be useful for the prevention, delay or treatment of a range of disease states including diabetes mellitus, more specifically type 2 diabetes mellitus (T2DM) and complications arising there from (for example retinopathy, neuropathy and nephropathy), impaired glucose tolerance (IGT), conditions of impaired fasting glucose, metabolic acidosis, ketosis, dysmetabolic syndrome, arthritis, osteoporosis, obesity and obesity related disorders, peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperfusion, muscle weakness, hyperlipidaemias, Alzheimer's disease , atherosclerosis, infertility, polycystic ovary syndrome, various immunomodulatory diseases (such as psoriasis), HIV infection, inflammatory bowel syndrome, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis.
  • T2DM type 2 diabetes mellitus
  • ITT impaired glucose tolerance
  • ITT impaired fasting
  • compounds of the formula (I) or their pharmaceutically acceptable salts may be administered in combination with other therapeutic agents in order to prevent, delay or treat the various disease states in which DPP-IV activity is implicated, including but not limited to those disease states listed above
  • the compounds of the present invention or their pharmaceutically-acceptable salts may be administered in combination with a therapeutically effective amount of one or more other compounds of the formula (I) and/or one or more of the following agent(s): 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas, prandial glucose regulators and glucokinase activators; 3) Agents that improve incretin action (for example GLP-1 agonists); 4) Insulin sensitising agents including PPARgamma agonists and agents with combined PPARalpha and gamma activity; 5) Agents that modulate hepatic glucose balance (for example biguanides, fruct, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite,
  • compounds of formula (I) and their pharmaceutically-acceptable salts are also useful as pharmacological tools in the development and standardisation of in-vitro and in- vivo test systems for the evaluation of the effects of inhibitors of DPP-IV activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • all of the compounds, and their corresponding pharmaceutically- acceptable salts are useful in inhibiting DPP-IV.
  • the ability of the compounds of formula (I), and their corresponding pharmaceutically-acceptable acid addition salts, to inhibit DPP-IV may be demonstrated employing the caco-2 DPP-IV Assay which measures the ability of test compounds to inhibit DPP--V activity from human colonic carcinoma cell extracts.
  • the human colonic carcinoma cell line Caco-2 was obtained from the American Type Culture Collection (ATCC HTB 37). Differentiation of the cells to induce DPP-IV expression was accomplished as described by Reisher, et al. (Proc. Natl. Acad. Sci., Vol. 90, pgs. 5757-5761 (1993)).
  • Cell extract is prepared from cells solubilized in lOmM Tris HCI, 0.15 M NaCI, 0.04 t.i.u.aprotinin, 0.5% nonidet-P40, pH 8.0, which is centrifuged at 35,000 g for 30 min at 4°C to remove cell debris.
  • the colorimetric assay is conducted by adding 20 ⁇ g solubilized Caco-2 protein, 20 ng of recombinant human DPPIV or purified porcine kidney DPP-IV, in a final volume of lOul in assay buffer (25 mM Tris HCI pH 7.4, 140mM NaCI, 10 mM KCI,0.1% Triton-x-100) to microtiter plate wells. After a 10 min.
  • reaction is initiated by adding 10 ⁇ l of 0.5 mM substrate (H-Glycine -Proline-pNA; pNA is p- nitroaniline).
  • substrate H-Glycine -Proline-pNA; pNA is p- nitroaniline.
  • the final assay volume is lOO ⁇ l.
  • the reaction is carried out at room temperature for 10 minutes after which time a 10 ⁇ l volume of sodium acetate buffer pH 4.5 is added to stop the reaction.
  • Test compounds are typically added as 10 ⁇ l additions
  • a standard curve of free p-nitroaniline is generated using 0-500 ⁇ M solutions of free pNA in assay buffer. The curve generated is linear and is used for interpolation of substrate consumption (catalytic activity in nmoles substrate cleaved/min).
  • the endpoint is determined by measuring absorbance at 405 nm in a Labsystems microtiter plate reader. Activity of CaCo2 extract is also measured employing a modified version of the assay described in Kubota, et al. (Clin. Exp.Immunol., Vol.89, pgs. 192-197 (1992)). The assay is conducted by adding 10 ⁇ g solubilized Caco-2 protein, in a final volume of 10 ul assay buffer (25 mMHEPES, 140 mM NaCI, 80 mM MgC12, 0.1% Triton X-100, pH 7.4) to micro titer plate wells.
  • 10 ul assay buffer 25 mMHEPES, 140 mM NaCI, 80 mM MgC12, 0.1% Triton X-100, pH 7.4
  • the reaction is initiated by the addition of 10 ⁇ l of incubation buffer containing 0.5 mM substrate (H-Glycine-Proline-AMC; AMC is 7-amino-40-methylcoumarin).
  • the plates are at room temperature (in the dark) for 10 min.
  • Test compounds are typically added as 10 ⁇ l additions and the final assay buffer volume is lOO ⁇ l.
  • the reaction is initiated by adding 10 ⁇ l of 0.5 mM substrate Gly-Pro-7-amino-4- trifluoromethylcoumarin for 10 minutes after which time a 10 ⁇ l volume of sodium acetate buffer pH4.5 is added to stop the reaction. After the 10 min.
  • the ability of the compounds of formula I, and their corresponding pharmaceutically acceptable acid addition salts, to inhibit DPP-IV may also be demonstrated by measuring the effects of test compounds on DPP-IV activity in human and rat plasma employing a modified version of the assay described above. Briefly, 5-10 ⁇ l of plasma are added to 96-well flat- bottom microtiter plates instead of CaCo2 extract, final assay volume is lOO ⁇ l. As with the previous assay, the potency of the test compounds as DPP-IV inhibitors, expressed as IC 50 , is calculated from 11 -point, dose-response curves using a 4 parameter logistic function.
  • temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C and under an atmosphere of an inert gas such as argon;
  • NMR data (1H) is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz (unless otherwise stated) using perdeuterio dimethyl sulphoxide
  • Example 1 The following examples were made by an analogous method to Example 1.
  • the starting materials were obtained using an analogous procedure to that described below for the preparation of Intermediate 1, but using the appropriate amine starting materials (commercially available for Examples 3 and 4; for Example 2 see CAS no. [479586-24-8] reactant in Patent Application WO 2003045382) in place of benzylamine.
  • Example 2 r4- r(2-(r(3R)-3-Amino-4-(2-fluorophenyl)butanovnan ⁇ ino ⁇ -2.3-dihvdro- l_-ff-inden-2-yl)carbonyl1amino ⁇ methyl)phenyriacetic acid
  • Example 3 2- ⁇ .(3RV3-Amino-4-(2-fluorophenyl)butanoyl1amino ⁇ -N- ⁇ 2- f(propylsuIfonyl)amino1ethyl
  • Example 4 2- ⁇ r(3R)-3-Amino-4-(2-fluorophenyl)butanoyl1amino>-N- ⁇ 2-r4- (aminosulfonvI)phenyllethyl ⁇ indane-2-carboxamide
  • the hydrochloride salt was taken up in DCM (10 ml) and washed sequentially with 2M ⁇ aOH (2 x 20 ml) and water (20 ml) the organic layer was dried over MgSO 4 and the DCM was removed in vacuo to give the free bases as colourless solids.
  • reaction mixture was then washed sequentially with 2M HCI (50 ml), aqueous sodium bicarbonate (50 ml) and brine (100 ml).
  • the organic phase was separated, dried with magnesium sulphate and concentrated under reduced pressure to leave a pale yellow gum.
  • the residue was purified by flash silica gel chromatography (ethyl acetate) to give the title compound (325 mg, 69%) as a colourless solid.
  • Example 14 (R)-3-Amino-4-(2-fluoro-phenyl)-N-((R)-l-methyIcarbamoyl-2- naphthalen-2-yl-ethyl)-butyramide Starting material (R)-2-tert-Butoxycarbonylamino-3-naphthalen-2-yl-propionic acid, commercially available
  • Example 19 (R)-3-Amino-4-(2,5-difluoro-phenyl)-N-((R)-l-methylcarbamovI-2-phenyl- ethvD-butyramide Starting material (R)-2-tert-Butoxycarbonylamino-3 -phenyl-propionic acid, commercially available.
  • the starting acid (3R)-3-[ftert-butoxycarbonyl)amino]-4-(2,5- difluorophenyl)butanoic acid was prepared according to the procedure described by ⁇ . Ikemoto et al, J.Amer.Chem.Soc, 2004, 126,(10) 3048-3049.
  • Example 20 The following examples were made as their hydrochloride salts by an analogous method to Example 11 from Intermediate 8 and the starting materials indicated below.
  • Example 21 (R)-3-Amino-4-(2-fluoro-phenyl)-N-((R)-l-methylcarbamoyl-2-pyridin-4- yj-ethvD-butyramide Starting material - see Intermediate 10
  • Example 22 (R)-3-Amino-N-r(R)-2-(4-bromo-phenyl)-l-methylcarbamoyl-ethyl1-4-(2- fluoro-phenvD-butyramide
  • This Example was prepared as the hydrochloride salt by an analogous method to Example 11 using Intermediate 8 and (S)-2-Amino-l-morpholin-4-yl-3-phenylpropan-l-one, hydrochloride.
  • This amine could be made by an analogous procedure to that used to synthesise the enantiomer (CAS no. 17186-57-1) in WO9528416.
  • Example 35 (R)-3-Amino-N-((R)-2-biphenyl-4-yl-l-carbamoyl-ethvI)-4-(2-fluoro- phenvD-butyramide Starting material - 4-biphenyl-D-alanine
  • Example 36 (R)-3-Amino-4-(2-fluoro-phenyl)-N-((R)-l-methylcarbamoyl-2-quinoIin-2- yl-ethvD-butyramide Starting material - 2-quinolyl-D-alanine
  • (R)-2-Amino-N-methyl-3-pyridin-2-yl-propionamide was made from (R)-2-tert- Butoxycarbonylamino-3-pyridin-2-yl-propionic acid as its TFA salt.
  • the procedure which was used was the same as that used for Intermediate 7 except a 2: 1 mixture of DCM:TFA was used in place of the 4M HCl/dioxan in the deprotection step.
  • a brown oil was obtained; MS m/z 202 (M+Na) + , 180 (MH) + .
  • the gum was further purified on an Isolute ® RNH 2 column washing with 20% methanol/DCM and eluting with 5% acetic acid : 10% methanol : 85% DCM.
  • the title product was obtained as a colourless solid (58mg, 25%) after reconcentration from ether.
  • Example 40 l- ⁇ r(3R)-3-amino-4-(2-fluorophenyl)butanovI.amino ⁇ -N- ⁇ 2- (propylsulfonvDaminolethyllcyclopentanecarboxamide
  • Example 39, 40 and 41 were made following the procedure described for Example 38, from
  • N-(2- aminoethyl)propane-l-sulfonamide could be made using an analogous procedure to that used to make ⁇ -(2-Aminoethyl)methanesulfonamide in Eur. Pat. Appl., EP259092.
  • Example 42 l-r(R)-3-Amino-4-(2-flnoro-phenyl)-butyrylamino1-cvclohexanecarboxylic acid 4-fluoro-benzylamide
  • Example 43 l-r(R)-3-Amino-4-(2-fluoro-phenyl)-butyrvIamino1-cycIohexanecarboxyIic acid isopropylamide
  • Example 44 l-r(R)-3-Amino-4-(2-fluoro-phenyl)-butyrylamino1-cyclohexanecarboxylic acid r2-(4-sulfamoyl-phenyl)-ethvn-amide
  • Example 45 l-r(RV3-A-- ⁇ ino-4-(4-fluoro-phenyl)-butyrylamino1-cyclohexanecarboxyIic acid r2-(4-sulfam
  • the reaction mixture was heated in a microwave for 5 minutes.
  • the mixture was diluted with ethyl acetate and washed with IN aqueous potassium hydrogen sulfate (100 ml).
  • the resulting suspension was filtered and the organic layer was washed successively with aqueous sodium bicarbonate and brine.
  • the solution was then dried with magnesium sulphate and evaporated to give a colourless solid (0.338 g, 80%).
  • Example 48 l- ⁇ r(3R)-3-Amino-4-(2-fluorophenyl)butanoyl1amino)-N-methyl-4- phenylcyclohexanecarboxamide
  • Example 48 was prepared from Intermediate 35 using the procedure described in Example 38 in 74 % yield.
  • Trimethylsilyldiazomethane (2M in hexanes; 2.3 ml, 4.59 mmol) was added to a solution of l- ⁇ [(9H-fluoren-9-ylmethoxy)carbonyl]amino ⁇ -4-phenylcyclohexanecarboxylic acid (Intermediate 31, 1.35 g, 3.06 mmol) in methanol (14 ml) and toluene (20 ml).
  • Example 51 was prepared as described for Example 38 from Intermediate 49 in 98 % yield.
  • (R)-2-Amino-l,2,3,4-tetrahvdro-naphthalene-2-carboxylic acid methylamide Prepared from (R)-2- Amino- 1, 2,3 ,4-tetrahydro-naphthalene-2-carboxylic acid using standard procedures known to those skilled in the art (described by M. Bodansky, 'Principles of Peptide Chemistry', Springer- Verlag, New York, 1984).
  • (R)-2-Amino-l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (CAS no.104974-44-9) could be prepared according to the literature procedure (J. Aldrich, Q Zheng, T.F. Murray,. Chirality (2001), 13(3), 125-129.)
  • Example 52 was prepared as described for Example 38 starting from ⁇ (R)-2-(2-Fluoro- phenyl)-l-[(l-methylcarbamoyl-cyclopropylcarbamoyl)-methyl]-ethyl ⁇ -carbamic acid tert- butyl ester.
  • Example 53 l- ⁇ r(3R)-3-A ⁇ ino-4-(2-fluorophenvDbutanoyl1amino ⁇ -N- ⁇ 2- KpropylsulfonvDaminolethyllcyclopropanecarboxamide hydrogen chloride
  • Example 53 was prepared as described for Example 38 from Intermediate 50 in 98 % yield.
  • Example 54 l-r(R)-3-Amino-4-(2-iluoro-phenyI)-butyrylaminol-2-(4-chIoro-phenyI)- cyclopropanecarboxylic acid metlxylamide
  • Example 54 was made following the procedure as described for Example 38 from Intermediate 51 in 98% yield; MS rn/z 404 (MH+).
  • Example 55 (3R)-3-Amino-A- ⁇ (lR)-l-cyclohexyl-2-r(4-fluorobenzyl)amino1-2-oxoethyl)- 4-(2-fluorophenyI)butanamide
  • Example 56 (3R)-3-Amino--V-r(lR)-l-cvclohexyl-2-(isopropyIamino)-2-oxoethyn-4-(2- fluorophenvDbutanamide
  • Example 57 (3R)-3-Amino-iV-r(lR)-2-( ⁇ 2-r4-(aminosulfonyl)phenyllethyllamino)-l- cyclohexyl-2-oxoethvH-4-(2-fluorophenvI)butanamide
  • Example 58 (3R)-3-Amino-N- ⁇ (lR)-l-cvclohexyl-2-r(cvcloprop
  • Example 60 2- ⁇ r(3R)-3-amino-4-(2-fluorophenyl)butanovnamino)-N- ⁇ 2-r4- (methylsulfonyl)phenvHethyl ⁇ indane-2-carboxamide
  • Example 61 2- ⁇ r(3R)-3-amino-4-(2-fluorophenyl)butanoyI1an ⁇ ino ⁇ -N- ⁇ 3- r(methyIsulfonyI)amino1propyl>indane-2-carboxamide
  • Example 62 2- ⁇ r(3R)-3-amino-4-(2-fluorophenyl)butanovnamino ⁇ -N- ⁇ 3- r(propylsulfonyl)aminolpropyl
  • Example 63 2- ⁇ r(3R)-3-amino-4-(2-fluorophenyl)butanoyl1amino)-N-ITl- (
  • N-(3-aminopropyl)methanesuIfonamide hydrochloride salt N-(3-aminopropyl)methanesulfonamide hydrochloride salt (CAS No: 88334-76-3) was prepared as for N-(3-Aminopropyl)propane-l-sulfonamide hydrochloride salt except methanesulfonyl chloride was used in place of 1-propylsulphonyl chloride; MS m/z 153 (MH* " ).
  • Example 69 2-f f(3R)-3-a ⁇ nino-4-phenylbutanoyl1amino ⁇ -N-benzylindane-2- carboxamide
  • Example 70 2-f r(3R)-3-amino-4-phenvIbutanoyl1amino ⁇ -N-f2- 15 r(propylsulfonyl)amino1ethvI ⁇ indane-2-carboxamide
  • Examples 69 to 70 were prepared from Intermediates 61 and 62 respectively by the method described in Example 38.

Abstract

L'invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables de ces composés. Dans ladite formule (I), Ar, R1, R2, R3, R4, R5, R6, R7 et R 8 correspondent à une des significations définies dans la description. Les composés selon l'invention présentent une activité inhibitrice envers la dipeptidyl-peptidase IV (DPP-IV) et sont donc précieux pour traiter des états pathologiques qui sont associés à l'activité de la DPP-IV, tels que le diabète sucré. Cette invention concerne également des procédés de préparation desdits composés, des produits intermédiaires obtenus au cours de ces procédés, des compositions pharmaceutiques contenant lesdits composés ou sels, ainsi que l'utilisation desdits composés ou sels.
PCT/GB2004/004283 2003-10-16 2004-10-11 Inhibiteurs de la dipeptidyl-peptidase iv WO2005040095A1 (fr)

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WO2006118196A1 (fr) * 2005-04-27 2006-11-09 Ajinomoto Co., Inc. Inhibiteur dpp4 et son application pharmaceutique
WO2007063928A1 (fr) * 2005-11-30 2007-06-07 Toray Industries, Inc. Nouveau derive non cyclique d’amine carboxamide et sel de celui-ci
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
WO2007077508A2 (fr) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Dérivés de bêta-aminoacides comme inhibiteurs de la dipeptidylpeptidase iv
WO2007120702A2 (fr) 2006-04-11 2007-10-25 Arena Pharmaceuticals, Inc. Agonistes du récepteur de gpr119 dans des procédés d'augmentation de la masse osseuse et de traitement de l'ostéoporose et autres états se caractérisant par une masse osseuse faible, et thérapie de combinaison associée
WO2008028662A1 (fr) * 2006-09-07 2008-03-13 Santhera Pharmaceuticals (Schweiz) Ag 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
EP1905759A1 (fr) * 2006-09-07 2008-04-02 Santhera Pharmaceuticals (Schweiz) AG 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
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
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WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
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EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
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US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
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US8546429B2 (en) 2003-07-11 2013-10-01 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US7838525B2 (en) 2003-07-11 2010-11-23 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
EP2116235A1 (fr) 2005-01-10 2009-11-11 Arena Pharmaceuticals, Inc. Thérapie combinée pour le traitement des diabètes et des conditions associées, et pour le traitement des conditions améliorées par l'augmentation du niveau de sang GLP-1
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WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
WO2007077508A2 (fr) 2005-12-30 2007-07-12 Ranbaxy Laboratories Limited Dérivés de bêta-aminoacides comme inhibiteurs de la dipeptidylpeptidase iv
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WO2008028662A1 (fr) * 2006-09-07 2008-03-13 Santhera Pharmaceuticals (Schweiz) Ag 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
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
JP2010523502A (ja) * 2007-04-03 2010-07-15 北京摩力克科技有限公司 ジペプチジルペプチダーゼｉｖの阻害剤としてのｎ−置換チオモルホリン誘導体およびその医薬的使用
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues
WO2011005929A1 (fr) 2009-07-09 2011-01-13 Arena Pharmaceuticals, Inc. Dérivé de pipéridine et son utilisation pour le traitement du diabète et de l'obésité
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011127051A1 (fr) 2010-04-06 2011-10-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur de gpr119 et traitement de troubles associés
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012035549A2 (fr) 2010-09-13 2012-03-22 Panacea Biotec Ltd Procédé amélioré pour la synthèse de dérivés d'acides bêta-aminés
WO2012040279A1 (fr) 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
EP3323818A1 (fr) 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
WO2012145361A1 (fr) 2011-04-19 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145604A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US10555929B2 (en) 2015-03-09 2020-02-11 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US10772865B2 (en) 2015-03-09 2020-09-15 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11400072B2 (en) 2015-03-09 2022-08-02 Coherus Biosciences, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11253508B2 (en) 2017-04-03 2022-02-22 Coherus Biosciences, Inc. PPARy agonist for treatment of progressive supranuclear palsy
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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