Substituted Pyrido(2,3-D) Pyrimidine Derivatives Useful as Medicines for the Treatment of Autoimmune Disorders

• US 20080312227A1
• Filed: 02/21/2006
• Published: 12/18/2008
• Est. Priority Date: 02/21/2005
• Status: Abandoned Application

• Current Assignee: 4 Aza IP NV
• Original Assignee: 4 AZA Bioscience NV
• Inventors: De Jonghe, Steven Cesar Alfons, Gao, Ling-Jie, Herdewijn, Piet Andre Maurits Maria
• Application Number:
  US11/816,086
• Publication Number:
  US 20080312227A1
• Time in Patent Office: Days
• US Class Current: 514/234.2
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

This invention relates to a group of trisubstituted pyrido(2,3-d)pyrimidine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates and enantiomers, possessing unexpectedly desirable pharmaceutical properties, in particular which are highly active immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. These derivatives are also useful in preventing or treating cardiovascular disorders, disorders of the central nervous system, TNF-α related disorders and cell proliferative disorders.

Claims

1-25. -25. (canceled)

26. A pyrido(2,3-d)pyrimidine derivative represented by the structural formula:

wherein

R₁ is amino;

R₂ is selected from the group consisting of hydroxy, halogen, mono-C_1-7-alkylamino, mono-arylamino, mono-aryl-C_1-7-alkylamino, morpholinyl, N-piperidinyl, triazolyl, heterocyclic-substituted amino, C_1-7 alkoxy, oxyheterocyclic, piperazinyl, and homopiperazinyl, wherein said piperazinyl is optionally N-substituted with acyl C_1-7 alkyl or arylalkyl;

R₃ is selected from aryl or heteroaryl groups optionally substituted with one or more substituents selected from the group consisting of halogen, halo C_1-7 alkyl, C_1-7 alkoxy, and alkylamino;

R₄ is hydrogen,

or a pharmaceutically acceptable addition salt thereof, a dihydro-derivative thereof, a tetrahydro-derivative thereof, a stereochemical isomeric form thereof, a N-oxide thereof, or a solvate thereof.

27. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is halogen or triazolyl.

28. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₃ is a monosubstituted or polysubstituted phenyl group.

29. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₃ is a phenyl group having no more than two substituents and wherein one substituent is in a para position on said phenyl ring.

30. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₃ is thienyl.

31. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is tetrahydro-pyranyloxy or methylpiperidinoxy.

32. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is C_1-4 alkoxy.

33. A pyrido(2,3-d)pyrimidine derivative according to claim 28, wherein R₂ is C_1-4 alkoxy.

34. A pyrido(2,3-d)pyrimidine derivative according to claim 29, wherein R₂ is C_1-4 alkoxy.

35. A pyrido(2,3-d)pyrimidine derivative according to claim 30, wherein R₂ is C_1-4 alkoxy.

36. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is monopropylamino, anilino, bromoanilino, benzylamino, or phenylethylamino.

37. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is a piperazin-1-yl group, said group being optionally substituted in the 4 position with a substituent R₅, wherein R₅ is selected from the group consisting of:

COR₈ wherein R₈ is selected from hydrogen, C_1-7 alkyl, aryl optionally substituted with one or more substituents, aryloxy, or arylamino; and

R₁₁, wherein R₁₁ is arylalkyl.

38. A pyrido(2,3-d)pyrimidine derivative according to claim 26, wherein R₂ is methylphenylcarbamoylpiperazin-1-yl, N-phenoxyacetyl-N-piperazin-1-yl, (N-benzyloxycarbonyl)piperazin-1-yl, or N-benzylpiperazin-1-yl.

47. A process for making the pyrido(2,3-d)pyrimidine derivative of claim 26, comprising a step of reacting a 2-R₁-substituted-6-bromo-pyrido[2,3-d]pyrimidine or a 2-R₁-substituted-6-chloro-pyrido[2,3-d]pyrimidine, wherein R₁ is as defined in the structural formula (I), with an aryl boronic acid including the radical R₃, wherein R₃ is an aryl or heteroaryl group as defined in the structural formula (I).

48. A method of treatment or prevention of a disease selected from the group consisting of immune disorders, autoimmune disorders, cardiovascular disorders, disorders of the central nervous system, TNF-alpha related disorders, and cell proliferative disorders, comprising the step of administering to a person in need thereof, a therapeutically effective amount of the pyrido(2,3-d)pyrimidine derivative of claim 26.

39. A pyrido(2,3-d)pyrimidine derivative, selected from the group consisting of:

2-amino-4-isopropoxy-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-isopropoxy-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-morpholino-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-morpholino-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-N-piperazino-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-[N-4-methylphenylcarbamoyl-piperazin-1-yl]-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-[N-4-methylphenylcarbamoyl-piperazin-1-yl]-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-[(N-phenoxyacetyl)-N-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-(N-phenoxyacetyl-N-piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[2,3d]pyrimidine;

2-pivaloylamino-4-[N-4-methylphenylcarbamoyl-piperazin-1-yl]-6-(3,4-dimethoxy-phenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(N-4-methylphenylcarbamoyl-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-[(N-benzyloxycarbonyl)-piperazin-1-yl]-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-[(N-benzyloxycarbonyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-6-(3,4-dimethoxyphenyl)-4-[(N-benzyloxycarbonyl)-piperazin-1-yl]-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-isopropoxy-6-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-isopropoxy-6-(4-trifluoromethylphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-isopropoxy-6-(2-thienyl)pyrido[2,3-d]pyrimidine;

2-amino-4-isopropoxy-6-(4-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-isopropoxy-6-(4-trifluoromethylphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-isopropoxy-6-(2-thienyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(piperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-(4-benzylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(1,2,4-triazolyl)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-n-propylamino-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-isopropylamino-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(1-piperidino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(tetrahydro-2H-pyran-4-yloxy)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-6-(3,4-dimethoxyphenyl)-4-(4-N-methylpiperidinoxy)pyrido[2,3-d]pyrimidine;

2-amino-4-n-propylamino-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-isopropylamino-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(1-piperidino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(tetrahydro-2H-pyran-4-yloxy)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-6-(3,4-dimethoxyphenyl)-4-(4-N-methylpiperidinoxy)pyrido[2,3-d]pyrimidine;

2-amino-4-methoxy-6-(3,4-dimethoxyphenyl)pyrido[2, 3d]pyrimidine;

2-pivaloylamino-4-N-homopiperazino-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-N-homopiperazino-6-(3,4-dimethoxy-phenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-N-homopiperazino-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-N-homopiperazino-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-(sec-butoxy)-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-(sec-butoxy)-6-(3,4-dimethoxyphenyl)-pyrido[2,3-d]pyrimidine hydrochloride salt;

2-amino-4-isopropoxy-6-(3,4-dimethylphenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(3-bromo-anilino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(benzylamino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(phenylethylamino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(3-bromo-anilino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(benzylamino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(phenylethylamino)-6-(3,4-dimethoxyphenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-N-homopiperazino-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-N-homopiperazino-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-N-homopiperazino-6-(3,4-dimethoxy-phenyl)-pyrido[2,3-d]pyrimidine;

2-amino-4-N-homopiperazino-6-(3,4-dimethoxy-phenyl)-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidin-4-(3H)-one;

2-pivaloylamino-4-(1,2,4-triazolyl)-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(3-methylanilino)-6-bromo-pyrido[2,3-d]pyrimidine;

2-amino-4-(3-methylanilino)-6-bromo-pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(N-piperidino)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(N-morpholino)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(N-acetyl-N-piperazin-1-yl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-(N-methyl-N-piperazin-1-yl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(N-piperidino)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(N-morpholino)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(N-acetyl-N-piperazin-1-yl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-(N-methyl-N-piperazin-1-yl)-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-ethoxy-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-pivaloylamino-4-isopropoxy-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine;

2-amino-4-ethoxy-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine; and

2-amino-4-isopropoxy-6-(4-fluorophenyl)pyrido[2,3-d]pyrimidine.

40. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(2,3-d)pyrimidine derivative represented by the structural formula:

wherein;

R₁ is amino,

R₂ is selected from the group consisting of hydroxy, halogen, mono C_1-7-alkyl amino, mono-arylamino, mono-arylC_1-7-alkylamino, morpholinyl, N-piperidinyl, triazolyl, heterocyclic-substituted amino, C_1-7 alkoxy, oxyheterocyclic, piperazinyl, and homopiperazinyl, wherein said piperazinyl is optionally N-substituted with acyl C_1-7 alkyl or arylalkyl;

R₃ is selected from the group consisting of aryl and heteroaryl groups optionally substituted with one or more substituents selected from the group consisting of halogen, halo C_1-7 alkyl, C_1-7 alkoxy, and alkylamino; and

R₄ is hydrogen

or a pharmaceutically acceptable addition salt thereof, a dihydro-derivative thereof, a tetrahydro-derivative thereof, a stereochemical isomeric form thereof, a N-oxide thereof, or a solvate thereof.

41. A pharmaceutical composition according to claim 40, wherein R₃ is a monosubstituted or polysubstituted phenyl group, or R₃ is thienyl.

42. A pharmaceutical composition according to claim 40, wherein R₃ is a phenyl group having no more than two substituents, and wherein one substituent is in a para position on said phenyl ring.

43. A pharmaceutical composition according to claim 40, wherein R₂ is selected from the group consisting of C_1-4 alkoxy, tetrahydro-pyranyloxy, methylpiperidinoxy, monopropylamino, anilino, bromoanilino, benzylamino, and phenylethylamino.

44. A pharmaceutical composition according to claim 40, wherein R₂ is a piperazin-1-yl group optionally substituted in the 4 position with a substituent R₅, wherein R₅ is selected from the group consisting of:

COR₈ wherein R₈ is selected from hydrogen, C_1-7 alkyl, aryl optionally substituted with one or more substituents, aryloxy, and arylamino; and

R₁₁, wherein R₁₁ is arylalkyl.

45. A pharmaceutical composition according to claim 40, further comprising one or more biologically active drugs selected from the group consisting of immunosuppressant, immunomodulator drugs, and antineoplastic drugs.

46. A pharmaceutical composition according to claim 40, wherein R₂ is methylphenylcarbamoylpiperazin-1-yl, N-phenoxyacetyl-N-piperazin-1-yl, (N-benzyloxycarbonyl)piperazin-1-yl, or N-benzylpiperazin-1-yl.