Immunosuppressive effects of pteridine derivatives

a technology of pteridine and derivatives, which is applied in the direction of biocide, plant growth regulators, cyclic peptide ingredients, etc., can solve the problems of high turn-over rate, marrow depression and liver damage, and severe toxic effects on normal cells

Inactive Publication Date: 2006-08-24
4 AZA IP NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0030] Compounds of formula (II) are highly active immunosuppressive agents, antineoplastic agents, anti-allergic agents or anti-viral agents which, together with one or more pharmaceutically acceptable carriers, may be formulated into pharmaceutical compositions for the prevention or treatment of pathologic conditions such as, but not limited to, immune and autoimmune disorders, organ and cells transplant rejections, allergic conditions, cell proliferative disorders, cardiovascular disorders, disorders of the central nervous system and viral diseases.
[0031] In a further embodiment, the present invention r

Problems solved by technology

Since these drugs affect mitosis and cell division, they have severe toxic effects on normal cells with high turn-over rate such as bone marrow cells and the gastrointestinal tract lining.
Accordingly, marrow depression and liver damage are common side effects of these antiproliferative drugs.
The common side effects observed with the use of these compounds are frequent infections, abnormal metabolism, hypertension, and diabetes.
However, cyclosporines suffer from a small therapeutic dose window and severe toxic effects including, nephrotoxicity, hepatotoxicity, hypertension, hirsutism, cancer, and neurotoxicity.
Introduction of

Method used

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  • Immunosuppressive effects of pteridine derivatives
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  • Immunosuppressive effects of pteridine derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 2-amino-4-n-pentyloxy-6-styrylpteridine

[0165] A mixture of 1.5 g (5.6 mmoles) 2-amino-6-chloro-4-n-pentyloxypteridine (e.g. available following the procedure disclosed by Mohr et al. in Helv. Chem. Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o-tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles), styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was stirred in dry acetonitrile (50 ml) under reflux for 90 hours. It was evaporated and the residue purified by silica gel column chromatography with chloroform. The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange powder exhibiting, after recrystallization from a EtOAc / hexane mixture, a melting point (m.p.) range of 127-128° C.

example 2

Preparation of 2-amino-6-(1,2-dibromophenethyl)-4-n-pentyloxy-pteridine

[0166] To a solution of the derivative of example 1 (1.0 g, 2.94 mmoles) in chloroform (50 ml) was added a 2 M bromine solution in chloroform (2.2 ml., 4.4 mmoles) and then the mixture was stirred at room temperature for 7 hours. It was diluted with chloroform (50 ml), washed with a saturated aqueous Na2SO3 solution (100 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue was treated with toluene, filtered, washed with ether and dried in a vacuum desiccator to give 0.84 g (yield: 57%) of a yellow powder.

example 3

Preparation of 2-amino-4,7-dimethoxy-6-styrylpteridine

[0167] A suspension of the derivative of example 2 (0.3 g, 0.6 mmoles) is methanol (10 ml) was treated with 1 M methanolic sodium methoxide (3 ml, 3 mmoles) and then refluxed for 4 hours. It was diluted with chloroform (100 ml), washed with a saturated aqueous ammonium chloride solution and water and then the solution was dried over sodium sulfate. The filtrate was evaporated and the residue was purified by silica gel column chromatography while using chloroform as the eluent. The product fraction was evaporated to give 50 mg (yield: 26%) of a yellow powder with a melting point range of 197-198° C.

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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 tetrahydroderivatives 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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of pending U.S. application Ser. No. 09 / 869,468, filed Oct. 10, 2001, which is the National Stage of International Application No. PCT / EP99 / 10320, filed Dec. 28, 1999, which was published in English under PCT Article 21(2), and which claims the benefit of U.S. provisional application No. 60 / 113,989 filed Dec. 28, 1998; the disclosures of which are incorporated by reference in their entirety. [0002] The invention relates to a class of novel pteridines. The invention further relates to pharmaceutical compositions including a broad class of pteridines especially for the prevention and / or the treatment of pathologic conditions such as, but not limited to, immune and auto-immune disorders, organ and cells transplant rejections, cell proliferative disorders, cardiovascular disorders, disorders of the central nervous system and viral diseases. [0003] The invention further relates to combined pharmaceu...

Claims

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Application Information

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IPC IPC(8): A61K31/525C07D475/12A61K31/519A61K31/5377A61K31/541A61K31/551C07D475/04C07D475/08C07D475/10
CPCA61K31/519A61K31/5377A61K31/541A61K31/551A61K38/13C07D471/04C07D475/04C07D475/08C07D475/10A61K2300/00
Inventor WAER, MARK JOZEF ALBERTHERDEWIJN, PIET ANDRE MAURITS MARIAPFLEIDERER, WOLFGANG EUGEN
Owner 4 AZA IP NV
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