US 7,501,513 B2Granted

Immunosuppressive effects of pteridine derivatives

Assignee4 AZA Bioscience NV

InventorsMark Jozef Albert Waer, Piet André Maurits Maria Herdewijn, Wolfgang Eugen Pfleiderer, Arnaud Didier Marie Marchand, Steven Cesar Alfons De Jonghe

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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.

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.

42 more elements

Facts

Application

10/595,126Filed 27 Aug 2004 · continuation in part

Priority

GB 0408955.322 Apr 2004

Published

US 2006/0287314 A121 Dec 2006

Granted

10 Mar 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 475/10
With a nitrogen atom directly attached in position 4: with an aromatic or hetero-aromatic ring directly attached in position 2
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/541
Having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame: non-condensed thiazines containing…

Family

Application10/651,604Parent of this continuation-in-part · filed 29 Aug 2003

US 2006/0287314 A1Pre-grant publication · published 21 Dec 2006

US 7,276,506 B2Parent of this continuation-in-part

US 2004/0077859 A1Published application

US 7,501,513 B2This patent

From the US filing history. Foreign family members aren’t listed.

Abstract

Claims6