Immunosuppressive effects of pteridine derivatives

• US 7,501,513 B2
• Filed: 08/27/2004
• Issued: 03/10/2009
• Est. Priority Date: 12/28/1998
• Status: Expired due to Fees

• Current Assignee: 4 AZA Bioscience NV
• Original Assignee: 4 AZA Bioscience NV
• Inventors: Herdewijn, Piet Andre Maurits Maria, De Jonghe, Steven Cesar Alfons, Marchand, Arnaud Didier Marie, Pfleiderer, Wolfgang Eugen, Waer, Mark Jozef Albert
• Primary Examiner(s): Saeed; Kamal A
• Assistant Examiner(s): Young; Shawquia
• Application Number:
  US10/595,126
• Publication Number:
  US 20060287314A1
• Time in Patent Office: 1,656 Days
• Field of Search: 544/258, 544/162
• US Class Current: 544/258
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 475/04 with a nitrogen atom directly attached in position 2
• CPC Class Codes: C07D 475/08 with a nitrogen atom directly attached in position 2
• CPC Class Codes: C07D 475/10 with an aromatic or hetero-aromatic ring directly attached in position 2

Abstract

This invention relates to a group of trisubstituted and tetrasubstituted pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydro-derivatives 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 compounds are also useful in preventing or treating cardiovascular disorders, allergic conditions, disorders of the central nervous system and cell proliferative disorders.

Claims

1. A pteridine derivative selected from the group consisting of:

2-amino-4-morpholino-6-(4-acetanilide)pteridine,

2-amino-4-morpholino-6-(3-acetanilide)pteridine,

2-amino-4-morpholino-6-(4-aminophenyl)pteridine,

2-amino-4-morpholino-6-(3-aminophenyl)pteridine,

2-amino-4-morpholino-6-(4-benzoylaminophenyl)pteridine,

2-amino-4-morpholino-6-(4-phenoxyacetylaminophenyl)pteridine,

2-amino-4-morpholino-6-(4-propionylaminophenyl)pteridine,

2-amino-4-morpholino-6-(4-furoylaminophenyl)pteridine,

2-amino-4-morpholino-6-(4-cyclohexanoylaminophenyl)pteridine,

2-amino-4-morpholino-6-[4-(4-chlorobenzoyl)aminophenyl]pteridine,

2-amino-4-morpholino-6-(4-benzyloxyacetylaminophenyl)pteridine,

2-amino-4-morpholino-6-(4-isonicotinoylaminophenyl)pteridine;

2-amino-4-morpholino-6-(4-naphtoylaminophenyl)pteridine;

2-amino-4-morpholino-6-(4-methylsulfonylaminophenyl)pteridine;

2-amino-4-morpholino-6-(4-ethylsuccinylaminophenyl)pteridine;

2-amino-4-morpholino-6-[4-(4-methylbenzoate)aminophenyl)pteridine;

2-amino-4-morpholino-6-(3-benzoylaminophenyl)pteridine;

2-amino-4-morpholino-6-(3-benzensulfonylaminophenyl)pteridine,

2-amino-4-morpholino-6-(3-phenoxyacetylaminophenyl)pteridine;

2-amino-4-morpholino-6-(3-isonicotinoylaminophenyl)pteridine;

2-amino-4-morpholino-6-(3-cyclohexanoylaminophenyl)pteridine;

2-amino-4-morpholino-6-[3-(4-methylbenzoate)aminophenyl]pteridine;

2-amino-4-morpholino-6-(3-ethylsuccinylaminophenyl)pteridine;

2-amino-4-morpholino-6-(3-ethylmalonylaminophenyl)pteridine;

2-amino-4-morpholino-6-(3-benzyloxyacetylaminophenyl)pteridine,

2-amino-4-morpholino-6-(3-ethylsulfonylaminophenyl)pteridine,

2-amino-4-morpholino-6-[3-Boc-(L)-phenylalanine-aminophenyl]pteridine;

2-amino-4-morpholino-6-[3-Boc-(D)-phenylalanine-aminophenyl]pteridine;

2-amino-4-morpholino-6-[3-Boc-(L)-tryptophane-aminophenyl]pteridine;

2-amino-4-morpholino-6-[3-Boc-(D)-tryptophane-aminophenyl]pteridine,

2-amino-4-morpholino-6-(4-hydroxyphenyl)pteridine,

2,4-di-(thienyl-2-methylarnino)-6-(3,4-dimethoxy-phenyl)pteridine,

2-amino-4-morpholino-6-(4-benzyloxyphenyl)pteridine,

2-amino-4-morpholino-6-(4-(phenethyloxy)-phenyl)pteridine,

2-amino-4-morpholino-6-(4-phenoxy-butyronitrile)pteridine,

2-amino-4-morpholino-6-(4-propoxy-phenyl)pteridine,

2-amino-4-morpholino-6-(4-phenoxy-butyric acid ethyl ester)pteridine,

2-amino-4-morpholino-6-(4-phenoxy-acetic acid ethyl ester)pteridine,

2-amino-4-morpholino-6-(4-(2-methoxyethoxy)-phenyl)pteridine,

2-amino-4-morpholino-6-(4-butoxy-phenyl)-pteridine,

2-amino-4-(diethanolamino)-6-[[3,4-(dimethoxyphenyl)]pteridine,

2-amino-4-(benzylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine;

2-amino-4-(phenylethylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine,

2-amino-4-(2-thienylmethylamino)-6-[[3,4-(dimethoxyphenyl)]pteridine,

2-amino-4-thiomorpholine-6-[[3,4-(dimethoxyphenyl)]pteridine.

2. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 1.

3. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 1, and further comprising one or more biologically active drugs selected from the group consisting of immuno-suppressant and/or immunomodulator drugs.

4. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 1, and further comprising one or more immunosuppressant drugs selected from the group consisting of cyclosporin A;

pentoxyfylline;

daltroban, sirolimus, tacrolimus;

rapamycin;

leflunomide;

mycophenolic acid and salts thereof;

azathioprine, brequinar;

gusperimus;

6-mercaptopurine;

mizoribine;

chloroquine;

hydroxy-chloroquine;

etanercept;

infliximab; and

kineret.

5. A pharmaceutical composition comprising as an active principle at least onepteridine derivative according to claim 1 and further comprising one or more immunomodulator drugs selected from the group consisting of acemannan, amiprilose, bucillamine, ditiocarb sodium, imiquimod, Inosine Pranobex, interferon-β

, interferon-γ

, lentinan, levamisole, pidotimod, romurtide, platonin, procodazole, propagermanium, thymomodulin, thymopentin and ubenimex.

6. A pharmaceutical composition comprising as an active principle at least one pteridine derivative according to claim 1 and further comprising one or more pharmaceutically acceptable carriers or excipients.