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

• US 20090036430A1
• Filed: 06/20/2008
• Published: 02/05/2009
• Est. Priority Date: 12/30/2004
• Status: Abandoned Application

• Current Assignee: Eduard Dolusic, Ling-Jie Gao, Piet Andre Maurits Maria Herdewijn, Steven Cesar Alfons De Jonghe, Wolfgang Eugen Pfleiderer
• Original Assignee: Eduard Dolusic, Ling-Jie Gao, Piet Andre Maurits Maria Herdewijn, Steven Cesar Alfons De Jonghe, Wolfgang Eugen Pfleiderer
• Inventors: De Jonghe, Steven Cesar Alfons, Dolusic, Eduard, Pfleiderer, Wolfgang Eugen, Maria Herdewijn, Piet Andre Maurits, Gao, Ling-Jie
• Application Number:
  US12/143,652
• Publication Number:
  US 20090036430A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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:

wherein;

R₁ is selected from the group consisting of hydrogen, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C_1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C_1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C_3-10 cycloalkylamino, (mono- or di) hydroxy C_1-7 alkylamino, (mono- or di) C_1-4 alkyl-arylamino, mercapto C_1-7 alkyl, C_1-7 alkyloxy, and groups of the formula R₆—

NR₇R₁₂, wherein R₆ is a bond or C_1-3 alkylene, wherein R₇ and R₁₂ are independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, aryl, arylalkyl, C_3-10 cycloalkyl and heteroaryl, or wherein R₇ and R₁₂ together form a heterocycle,

R₂ is selected from the group consisting of (mono- or di-) C_1-12 alkylamino;

monoarylamino;

diarylamino;

(mono- or di-) C_3-10 cycloalkylamino;

(mono- or di-) hydroxyC_1-7 alkylamino;

(mono- or di-) C_1-4 alkylarylamino;

(mono- or di-) arylC_1-4 alkylamino;

morpholinyl;

mercapto C_1-7 alkyl;

C_1-7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R₅ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_3-10 cycloalkyl-alkyl, C_3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω

-cyanoalkyl, ω

-carboxylic ester-alkyl, halo C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R₃ and R₄ are independently selected from the group consisting of hydrogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino, provided that R₃ and R₄ are not both hydrogen, and further provided that R₄ is hydrogen when R₂ is monoarylamino,

or a pharmaceutical acceptable addition salt or a stereochemical isomeric form thereof or a N-oxide thereof or a solvate thereof.

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-dimethoxy-phenyl)-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-dimethoxy-phenyl)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-dimethoxy-phenyl)-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,

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

4-[6-(4-Fluoro-phenyl)-2-imidazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-pyrrolidin-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-[1,2,3]triazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-y]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-pyrazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

2-(4-Chloro-phenoxy)-N-[4-{4-[2-(4-chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide,

4-[2-(N′

,N′

-Dimethyl-hydrazinomethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid ethyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid ethyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid amide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid methylamide,

4-[2-Cyanomethyl-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid propylamide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid (2-methoxy-ethyl)-amide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid dimethylamide,

2-(4-Chloro-phenoxy)-1-{4-[6-(4-fluoro-phenyl)-2-(pyrrolidine-1-carbonyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanone,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid cyclopropylamide,

4-(2-{4-[2-Amino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}2-oxo-ethoxy)-benzoic acid methyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carbonitrile,

4-(6-Pyridin-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Thiophen-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[2-Amino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1,3-dicarboxylic acid 3-tert-butylamide 1-m-tolylamide,

4-(6-Chloro-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Pyridin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(2-Chloro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-(6-o-Tolyl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Furan-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(2-Cyano-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid (4-chloro-2-trifluoromethyl-phenyl)-amide, and

4-[6-(2-Cyano-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid (4-tert-butyl-phenyl)-amide.

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

wherein;

R₁ is selected from the group consisting of hydrogen, halogen, C_1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C_1-7 alkylamino, (mono- or di) C_1-4 alkyl-arylamino, C_1-7 alkyloxy, and groups of the formula R₆—

NR₇R₁₂, wherein R₆ is a bond or C_1-3 alkylene, wherein R₇ and R₁₂ together form a heterocycle,

R₂ is selected from the group consisting of (mono- or di-) C_1-12 alkylamino;

monoarylamino;

diarylamino;

(mono- or di-) C_1-4 alkylarylamino;

(mono- or di-) arylC_1-4 alkylamino;

morpholinyl;

mercapto C_1-7 alkyl;

C_1-7 alkoxy;

homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted, with a substituent R₅ selected from the group consisting of acyl, heterocyclic-substituted alkyl, heterocyclic, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen and C_1-7 alkyl;

R₃ and R₄ are independently selected from the group consisting of hydrogen, heteroaryl and aryl groups, wherein said or aryl, groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, hydroxyl, C_1-7 alkoxy, C_3-10 cycloalkoxy,

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

or a N-oxide thereof or a solvate thereof.

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-dimethoxy-phenyl)-pyrido[3,2-d]pyrimidine

2-(p-tolylamino)-4-[(N-3-methylphenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxy-phenyl)-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-methoxy-phenyl)-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-(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-methylphenylcarbamoyl)piperidin-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-o]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-o]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:

wherein;

R₁ is selected from the group consisting of hydrogen, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C_1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C_1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C_3-10 cycloalkylamino, (mono- or di) hydroxy C_1-7 alkylamino, (mono- or di) C_1-4 alkyl-arylamino, mercapto C_1-7 alkyl, C_1-7 alkyloxy, and groups of the formula R₆—

NR₇R₁₂, wherein R₆ is a bond or C_1-3 alkylene, wherein R₇ and R₁₂ are independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, aryl, arylalkyl, C_3-10 cycloalkyl and heteroaryl, or wherein R₇ and R₁₂ together form a heterocycle,

R₂ is selected from the group consisting of (mono- or di-) C_1-12 alkylamino;

monoarylamino;

diarylamino;

(mono- or di-) C_3-10 cycloalkylamino;

(mono- or di-) hydroxyC_1-7 alkylamino;

(mono- or di-) C_1-4 alkylarylamino;

(mono- or di-) aryl C_1-4 alkylamino;

morpholinyl;

mercapto C_1-7 alkyl;

C_1-7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R₅ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_3-10 cycloalkyl-alkyl, C_3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, w-cyanoalkyl, w-carboxylic ester-alkyl, halo C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R₃ and R₄ are independently selected from the group consisting of hydrogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino, provided that R₃ and R₄ are not both hydrogen, and further provided that R₄ is hydrogen when R₂ is monoarylamino,

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

or a N-oxide thereof or a solvate thereof.

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:

wherein;

R₁ is selected from the group consisting of hydrogen, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C_1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C_1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C_3-10 cycloalkylamino, (mono- or di) hydroxy C_1-7 alkylamino, (mono- or di) C_1-4 alkyl-arylamino, mercapto C_1-7 alkyl, C_1-7 alkyloxy, and groups of the formula R₆—

NR₇R₁₂, wherein R₆ is a bond or C_1-3 alkylene, wherein R₇ and R₁₂ are independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, aryl, arylalkyl, C_3-10 cycloalkyl and heteroaryl, or wherein R₇ and R₁₂ together form a heterocycle,

R₂ is selected from the group consisting of (mono- or di-) C_1-12 alkylamino;

monoarylamino;

diarylamino;

(mono- or di-) C_3-10 cycloalkylamino;

(mono- or di-) hydroxyC_1-7 alkylamino;

(mono- or di-) C_1-4 alkylarylamino;

(mono- or di-) arylC_1-4 alkylamino;

morpholinyl;

mercapto C_1-7 alkyl;

C_1-7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R₅ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_3-10 cycloalkyl-alkyl, C_3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω

-cyanoalkyl, ω

-carboxylic ester-alkyl, halo C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R₃ and R₄ are independently selected from the group consisting of hydrogen halogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino, provided that R₃ and R₄ are not both hydrogen,

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

or a N-oxide thereof or a solvate thereof.

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)

or the structural formula (III)

or the structural formula (IV)

wherein:

R₁ is selected from the group consisting of hydrogen, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C_1-7 alkyl, aryl, amino, acetamido, N-protected amino, (mono- or di) C_1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C_3-10 cycloalkylamino, (mono- or di) hydroxy C_1-7 alkylamino, (mono- or di) C_1-4 alkyl-arylamino, mercapto C_1-7 alkyl, C_1-7 alkyloxy, and groups of the formula R₆—

NR₇R₁₂, wherein R₆ is a bond or C_1-3 alkylene, wherein R₇ and R₁₂ are independently selected from the group consisting of hydrogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, aryl, arylalkyl, C_3-10 cycloalkyl and heteroaryl, or wherein R₇ and R₁₂ together form a heterocycle;

R₂ is selected from the group consisting of (mono- or di-) C_1-12 alkylamino;

monoarylamino;

diarylamino;

(mono- or di-) C_3-10 cycloalkylamino;

(mono- or di-) hydroxyC_1-7 alkylamino;

(mono- or di-) C_1-4 alkylarylamino;

(mono- or di-) arylC_1-4 alkylamino;

morpholinyl;

mercapto C_1-7 alkyl;

C_1-7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R₅

R₅ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_3-10 cycloalkyl-alkyl, C_3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω

-cyanoalkyl, ω

-carboxylic ester-alkyl, halo C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R₃ is independently selected from the group consisting of hydrogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C_1-7 alkyl, C_2-7 alkenyl, C_2-7 alkynyl, halo C_1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_1-7 alkoxy, C_3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_1-7 alkyl, thio C_3-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R₂′

is selected from the group consisting of;

piperazinyl or homopiperazinyl wherein one or more carbon atoms of said piperazinyl or homopiperazinyl are independently substituted with C_1-4 alkyl, or two carbon atoms of said piperazinyl or homopiperazinyl together with their alkyl substituent form a C_1-4 alkylene group, and wherein said piperazinyl or homopiperazinyl is optionally N-substituted with R₅;

piperidin-4-yl-amino, piperidin-3-yl-amino, piperidin-4-yl-oxy, pyrrolidin-1-yl, 3-amino-pyrrolidin-1-yl, pyrrolidin-3-yl-amino or 2,6-diazabicyclo[3.2.0]heptan-2-yl, wherein said piperidin-4-yl, piperidin-3-yl, 3-amino-pyrrolidin-1-yl, pyrrolin-3-yl or 2,6-diazabicyclo[3.2.0]heptan-2-yl is optionally N-substituted with R₅ or C_1-4alkylarylcarbamoyl;

or wherein any carbon atom of said piperidin-1-yl may be further substituted with one or more substituent selected from the group consisting of hydrocy, aryl, C_1-4alkylcarbamoyl, C_1-4alkoxycarbonyl and C_1-4alkylarylcarbamoyl;

piperazinyl or homopiperazinyl being N-substituted with a substituent selected from the group consisting of C_1-4alkyl;

arylcarbamoyl-substituted alkanoyl;

arylalkanoyl wherein alkanoyl is substituted with one or more substituents selected from the group consisting of amino, hydroxy and halogen;

mono-C_1-4alkylaryl-carbamoyl;

di-C_1-4alkylaryl-carbamoyl;

tri-C_1-4alkylaryl-carbamoyl;

mono-C_1-4alkylaryl-C_1-4alkylcarbamoyl;

di-C_1-4alkylaryl-C_1-4alkylcarbamoyl;

tri-C_1-4alkylaryl-C_1-4alkylcarbamoyl;

alkoxycarbonyl;

alkanoyl substituted with one or more substituents independently selected from the group consisting of amino, alkoxycarbonyl, alkylcarbamate, arylamido and arylcarbamoyl;

arylalkanoyl substituted by alkylcarbamate;

cycloalkylcarbamoyl;

alkoxyalkanoyl;

dialkyl-carbamoyl;

heterocyclic carbamoyl C_1-4alkyl;

arylC_1-4alkylcarbamoyl;

heterocyclic carbonyl C_1-4alkyl and aryl C_1-4alkylcarbamoyl C_1-4alkyl;

triazolyl;

heterocyclic amino;

heterocyclic C_1-4alkylamino;

alkoxy C_1-4alkylamino;

amino cycloalkylamino;

amino C_2-14alkylamino;

amino C_1-6alkylamino wherein the N-atom is further substituted with C_1-4alkylarylcarbamoyl or aryloxy C_1-4alkanoyl;

aryl C_1-4alkoxy;

3-amino-pyrrolidin-1-yl;

N—

C_1-4alkyl-N-arylcarbamoyl; and

;

C_1-4alkyl or alkanoyl substituted heterocyclic carbonyl C_1-4alkylamino; and

,

R₃′

is an aryl group substituted with one or more substituents selected from the group consisting of heterocyclic;

C_3-10 cycloalkylcarbamoyl;

C_1-4 alkylcarbamoyl;

C_1-4 alkylsulfonyl;

C_1-4 alkylsulfonamido;

C_1-4 alkyl-carboxylate;

C_1-4 alkyl and C_1-4 alkoxy substituted with one or more substituents selected from the group consisting of amino, halogen, cyano and C_1-4alkoxy;

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

or a N-oxide thereof or a solvate thereof.

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-diazabicyclo[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-acetoxy-phenyl)-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-di-methoxyphenyl)-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-[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-{-[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-diazabicyclo[2.2.1]hept-2-yl}-2-(4-chlorophenoxy)-ethanone,

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

4-[6-(4-Fluoro-phenyl)-2-imidazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-pyrrolidin-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-[1,2,3]triazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(4-Fluoro-phenyl)-2-pyrazol-1-ylmethyl-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

2-(4-Chloro-phenoxy)-N-[4-{4-[2-(4-chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-yl]-acetamide,

4-[2-(N′ ,N′

-Dimethyl-hydrazinomethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid ethyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid ethyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid amide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid methylamide,

4-[2-Cyanomethyl-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid propylamide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid (2-methoxy-ethyl)-amide,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid dimethylamide,

2-(4-Chloro-phenoxy)-1-{4-[6-(4-fluoro-phenyl)-2-(pyrrolidine-1-carbonyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-ethanone,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid cyclopropylamide,

4-(2-{4-[2-Amino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazin-1-yl}-2-oxo-ethoxy)-benzoic acid methyl ester,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carboxylic acid,

4-{4-[2-(4-Chloro-phenoxy)-acetyl]-piperazin-1-yl}-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine-2-carbonitrile,

4-(6-Pyridin-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Thiophen-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[2-Amino-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1,3-dicarboxylic acid 3-tert-butylamide 1-m-tolylamide,

4-(6-Chloro-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Pyridin-4-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(2-Chloro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid m-tolylamide,

4-(6-o-Tolyl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-(6-Furan-3-yl-pyrido[3,2-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid m-tolylamide,

4-[6-(2-Cyano-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid (4-chloro-2-trifluoromethyl-phenyl)-amide, and

4-[6-(2-Cyano-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-piperazine-1-carboxylic acid (4-tert-butyl-phenyl)-amide,

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 dermatis, 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 dermatis, 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.