PYRIDO(3,2-D)PYRIMIDINES AND PHARMACEUTICAL COMPOSITIONS USEFUL FOR MEDICAL TREATMENT

• US 20080004285A1
• Filed: 06/29/2007
• Published: 01/03/2008
• Est. Priority Date: 12/30/2004
• Status: Abandoned Application

• Current Assignee: 4 Aza IP NV
• Original Assignee: 4 Aza IP NV
• Inventors: Herdewijn, Piet Andre, Pfleiderer, Wolfgang, Dolusic, Eduard, De Jonghe, Steven, Gao, Ling-Jie
• Application Number:
  US11/771,924
• Publication Number:
  US 20080004285A1
• Time in Patent Office: Days
• US Class Current: 514/252.16
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

This invention relates to substituted pyrido(3,2-d)pyrimidine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, pro-drugs 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, viral diseases (including hepatitis C), erectile dysfunction and cell proliferative disorders.

Claims

1. A pyrido(3,2-d)pyrimidine derivative having the general formula:

2. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₄ is hydrogen.

3. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₁ is not hydrogen.

4. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₁ is amino or acetamido.

5. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₁ is amino or acetamido, and further wherein R₃ is a substituted aryl group.

6. A pyrido(3,2-d)pyrimidine derivative according to claim 1, wherein R₁ is amino or acetamido, wherein R₃ is a substituted aryl group and wherein R₄ is hydrogen.

7. A pyrido(3,2-d)pyrimidine derivative according to claim 1, 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;

C_3-10 cycloalkyl;

aryl optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, cyano and C_1-7 alkoxy;

heterocyclic optionally substituted with one or more halogen atoms;

arylalkyl;

aryloxyalkyl;

arylalkoxyalkyl;

alkoxyalkyl;

arylalkoxy;

aryloxy;

arylalkenyl;

heterocyclic-substituted alkyl;

alkylamino, arylamino and alkylarylamino;

CSR₉, wherein R₉ is selected from the group consisting of alkylamino and aryloxy;

SO₂R₁₀, wherein R₁₀ is selected from the group consisting of aryl and arylalkyl; and

R₁₁, wherein R₁₁ is selected from the group consisting of C_1-7 alkyl, aryl, arylalkyl, arylalkenyl, alkoxyalkyl, heterocyclic-substituted alkyl, cycloalkylalkyl, hetero-cyclic, C_3-10 cycloalkyl, alkylaminoalkyl, aryloxyalkyl, alkoxyaryl, ω

-cyanoalkyl, ω

-carboxylatoalkyl and carboxamidoalkyl.

10. A pyrido(3,2-d)pyrimidine derivative according to claim 1, being selected from the group consisting of:

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

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

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

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

2-[(N-hydroxyethyl)morpholino]-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine,

2-(1-methyl-2-pyrrolidino-ethoxy)-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine,

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

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

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

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

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

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

2-amino-4-[(4-carboxylic ethyl ester)-piperidin-1-yl]-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine,

2-amino-4-(m-tolylamino)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine,

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

2-amino-4-(m-bromophenylamino)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine,

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

2-amino-4-(thien-2-ylmethyl)amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine,

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

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

2-amino-4-(pyridin-2-ylmethyl)amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine,

2-amino-4-(2-chloro-5-methoxyphenyl)amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine,

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

2-N-morpholinylethoxy-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-chloro-pyrido[3,2-d]pyrimidine, and

2-chloro-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine.

8. A pyrido(3,2-d)pyrimidine derivative having the general formula:

9. A pyrido[3,2-d]pyrimidine derivative selected from the group consisting of:

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

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

2-[(N-hydroxyethyl)morpholino]-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-(1-methyl-2-pyrrolidino-ethoxy)-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

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

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

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

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

2-amino-4-[3,4-(methylenedioxy)aniline]-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

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

2-amino-4-(thienyl-2-methylamino)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine-2,4-diamine

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

2-amino-4-[2-(aminomethyl)pyridino]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2,4-diamino-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-amino-4-(4-{[(3-methylphenyl)amino]carbonyl}piperazin-1-yl)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[2-(piperazin-1-yl)-acetic acid N-(2-thiazolyl)-amide]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-morpholino-4-[(N-3-methyl-phenylcarbamoyl-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-butoxy-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-methoxy-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

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

2-[(3-chloro-4-fluoro-anilino)-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2,4-diamino-6-(4-hydroxy-3-methoxyphenyl)-pyrido[3,2-d]pyrimidine

2,4-diamino-6-(3-chloro-4-methoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[(N-4-fluoro-phenyl-carbamoyl)-piperazin-1-yl]-6-(4-hydroxy-3-methoxyphenyl)-pyrido[3,2-d]pyrimidine

4-(4-methyl-phenyl-piperazin-1-yl)-6-(3,4-dimethoxy-phenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-(N-piperazin-1-yl)-6-(1,4-benzodioxane-phenyl)pyrido[3,2-d]pyrimidine

2-amino-4-(morpholino)-6-(1,4-benzodioxane-phenyl)pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3,4-dichloro-phenyl)pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(1,4-benzodioxane)-pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3,4-methylenedioxyphenyl)-pyrido[3,2-d]pyrimidine

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

2-amino-4-[2-(piperazin-1-yl acetic acid N-(2-thiazolyl)-amide)]-6-3,4-methylenedioxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[N-(3-methyl-phenyl-carbamoyl)-piperazin-1-yl]-6-(3,4-methylenedioxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[N-(3-methyl-phenyl-carbamoyl)-piperazin-1-yl]-6-(3,4-dichlorophenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[N-(3-methyl-phenyl-carbamoyl)-piperazin-1-yl]-6-(1,4-benzodioxane)-pyrido[3,2-d]pyrimidine

2-amino-4-[2-(piperazin-1-yl acetic acid N-(2-thiazolyl)-amide]-6-(1,4-benzodioxane)-pyrido[3,2-d]pyrimidine

2-amino-4-[2-(piperazin-1-yl acetic acid N-(2-thiazolyl)-amide]-6-(3,4-dichlorophenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-[(S)-3-(Boc-amino)pyrrolidine]-6-chloro-pyrido[3,2-d]pyrimidine

2-amino-4-[(S)-3-(Boc-amino)pyrrolidine]-6-chloro-pyrido[3,2-d]pyrimidine

2-amino-4-[(S)-3-(Boc-amino)pyrrolidine]-6-chloro-pyrido[3,2-d]pyrimidine

2-amino-4-[(S)-3-(Boc-amino)pyrrolidine]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[(S)-3-(amino)pyrrolidine]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[3-(S)-4-chloro-phenoxy-acetyl-amino)-pyrrolidin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[3-(S)-3-methyl phenyl carbamoyl pyrrolidin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-[(R)-3-Boc-aminopyrrolidin-1-yl]-6-chloro pyrido[3,2-d]pyrimidine

2-amino-4-[(R)-3-Boc-aminopyrrolidin-1-yl)]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

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

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

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

2-amino-4-[(R)-3-aminopyrrolidin-1-yl]-6-(3,4-dimethoxy-phenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[3-(R)-(3-methylphenylcarbamoyl)-pyrrolidin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

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

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

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

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

2-amino-4-[2-(4-chlorophenoxy-acetyl-ethylenediamine-1-N-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[3-N-(4-chlorophenoxy-acetyl)-3-amino-propane-amine-1-N-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[(3-(R)-(4-chlorophenoxyacetyl-amino)-pyrrolidin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[(3-carboxylic acid isobutylamide)-piperidin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-(4-chlorophenyl-4-hydroxypiperidin-1-yl)-6-(3,4-dimethoxy-phenyl)-pyrido[3,2-d]pyrimidine

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

2-amino-4-[3-(4-acetylpiperazin-1-yl)-propan-3-one-1-yl-amino]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

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

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

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

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

2-acetamido-4-[(N-pyridin-3-yl-acetamid)-2-yl-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-[(N-methyl-N-phenylacetamid)-2-yl-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-acetamido-4-benzyloxy-6-chloro-pyrido[3,2-d]pyrimidine

2-amino-4-benzyloxy-6-(o-fluorophenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-benzyloxy-6-(m-fluorophenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-benzyloxy-6-(p-fluorophenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-(1,8-diaminooctyl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-amino-4-(1,9-diaminononyl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-amino-4-(1,10-diaminodecyl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-amino-4-(1,12-diaminododecyl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3-methyl-4-methoxyphenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3-chloro-4-methoxy-phenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3-chloro-4-ethoxy-phenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3-fluoro-4-ethoxy-phenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3-methyl-4-fluoro-phenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3,4-dichloro-phenyl)pyrido-[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(3,4-(methylenedioxy)phenyl)pyrido[3,2-d]pyrimidine

2-acetamido-4-(1,2,4-triazolyl)-6-(1,4-benzodioxane-phenyl)pyrido[3,2-d]pyrimidin-4(3H)-one

11. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative having the general formula:

12. A pharmaceutical composition according to claim 11, further comprising one or more biologically-active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, phosphodiesterase-4 inhibitors and antiviral agents.

13. A method of treatment of a disease mediated by phosphodiesterase-4 activity in a patient, comprising the administration of an effective amount, preferably a phosphodiesterase-4 inhibiting amount, of a pyrido(3,2-d)pyrimidine derivative.

14. A method of treatment according to claim 13, wherein said pyrido(3,2-d)pyrimidine derivative has the general formula:

15. A method of treatment according to claim 13, wherein said disease is erectile dysfunction.

16. A method of treatment according to claim 13, wherein said administration is transurethral administration.

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

18. A pyrido(3,2-d)pyrimidine derivative according to claim 17, being selected from the group consisting of

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

(S)-2-amino-4-[4-(4-chlorophenoxyacetyl)-2-methylpiperazin-1-yl]-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

(S)-2-amino-4-{4-[3-(4-chlorophenyl)-2-aminopropionyl]piperazin-1-yl}-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

(R)-2-amino-4-(4-benzoyl-2-methylpiperazin-1-yl)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

(S)-4-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-3-methylpiperazine-1-carboxylic acid benzyl ester

(S,S)-5-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidine

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(3-fluoro-4-ethoxyphenyl)pyrido[3,2-d]pyrimidine

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(3-chloro-4-ethoxyphenyl)pyrido[3,2-d]pyrimidine

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(3,4,5-trifluorophenyl)pyrido[3,2-d]pyrimidine

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(2-thienyl)pyrido[3,2-d]pyrimidine

4-[(3-methylphenyl carbamoyl)-piperazin-1-yl]-6-(2-furanyl)pyrido[3,2-d]pyrimidine

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

2-amino-4-[N-(4-chlorophenoxyacetyl)-piperazin-1-yl]-6-(4-cyanomethylphenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[N-(4-chlorophenoxyacetyl)-piperazin-1-yl]-6-(3-methoxymethylphenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[N-(4-chlorophenoxyacetyl)-piperazin-1-yl]-6-(4-cyanomethoxyphenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[N-(4-chlorophenoxyacetyl)-piperazin-1-yl]-6-(4-acetoxyphenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[N-(4-chlorophenoxyacetyl)-piperazin-1-yl]-6-(3-methoxy-4-acetoxyphenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-(4-Hydroxy-piperidine-1-carboxylic acid m-tolylamide)-6-(4-fluorophenyl)-pyrido(3,2-d)-pyrimidine

2-amino-4-{4-[N-(tert-butoxycarbonyl)-glycyl]-piperazin-1-yl}-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-(4-(methanesulfonyl)-phenyl)pyrido-[3,2-d]pyrimidine

2-amino-4-{4-[N-(tert-butoxycarbonyl)-glycyl]-piperazin-1-yl}-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-[N-3-(methanesulfonamidophenyl)]-pyrido-[3,2-d]pyrimidine

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

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

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-[4-(hydroxymethyl)phenyl]pyrido-[3,2-d]pyrimidine

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-[4-(methylaminocarbonyl)phenyl]-pyrido-[3,2-d]pyrimidine

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

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-[4-(aminomethyl)phenyl]pyrido-[3,2-d]pyrimidine

2-amino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-6-[4-(cyclopropylaminocarbonyl)phenyl]-pyrido-[3,2-d]pyrimidine

2-amino-4-{4-[N-(1-adamantylcarbamoyl)]-piperazin-1-yl}-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

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

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

2-amino-4-[1-(tert-butoxycarbonyl)piperid-3-ylamino]-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

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

2-amino-4-[(R)-3-Boc-amino-pyrrolidin-1-yl]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine

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

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

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

2-amino-4-[(S)-3-Boc-amino-pyrrolidin-1-yl]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[(S)-3-Boc-amino-pyrrolidin-1-yl]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine

2-amino-4-[1-(tert-butoxycarbonyl)piperid-4-ylamino]-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

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

2-amino-4-[3-(R)-3-methyl phenyl carbamoyl pyrrolidin-1-yl]-pyrido(3,2-d)pyrimidine

2-amino-4-[3-(S)-3-methyl phenyl carbamoyl pyrrolidin-1-yl]-pyrido(3,2-d)pyrimidine

2-amino-4-[(S)-3-methyl-phenyl carbamoyl amino-pyrrolidin-1-yl]-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine

N-(2-{4-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-2-oxoethyl)-4-chlorobenzamide

(S)-[2-{4-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-1-(4-chlorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl ester

N-(2-{4-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-2-oxoethyl)benzamide

2-amino-4-[1-(4-chlorophenoxyacetyl)piperid-4-ylamino]-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine

(S,S)-1-{5-[2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-yl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-(4-chlorophenoxy)-ethanone, and

2-amino-4-[1-(phenoxyacetyl)piperid-4-ylamino]-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine,

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof

or a N-oxide thereof or a solvate thereof.

19. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative according to claim 17.

20. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative according to claim 17 and further comprising one or more biologically-active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, phosphodiesterase-4 inhibitors and antiviral agents.

21. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative according to claim 18.

22. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a pyrido(3,2-d)pyrimidine derivative according to claim 18 and further comprising one or more biologically-active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, antineoplastic drugs, phosphodiesterase-4 inhibitors and antiviral agents.

23. A method of treatment of a disease selected from the group consisting of rheumatoid arthritis, Crohn'"'"'s disease, ulcerative colitis, uveitis, multiple sclerosis, atopic dermatitis, psoriasis, lupus erythematosus, or prevention of transplant rejection in a patient, comprising the administration of an effective amount, of a pyrido(3,2-d)pyrimidine derivative according to claim 17.

24. A method of treatment of a disease selected from the group consisting of rheumatoid arthritis, Crohn'"'"'s disease, ulcerative colitis, uveitis, multiple sclerosis, atopic dermatitis, psoriasis, lupus erythematosus, or prevention of transplant rejection in a patient, comprising the administration of an effective amount, of a pyrido(3,2-d)pyrimidine derivative according to claim 18.