US 6,297,250 B1 · Pyrimidopyrimidine compounds

Abstract

A range of dipyridamole analogues useful for inhibiting transport of nucleosides or purines across cell membranes, thereby to potentiate the activity of various cytotoxic antitumor drugs, is disclosed. These analogues comprise compounds having general structural formula (I) or pharmaceutically acceptable salts thereof; wherein R1 is chloro and R3 is diethanolamino, or R1 and R3 are identical and are selected from allyl, halo, diethanolamino, solketalo and a group having the formula: —O—Rz or —NHRz, Rz being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and R2 and R4 are identical and are selected from piperidino, N-tetrahydroisoquinolyl, and a benzylamino group having structural formula (II) wherein R5 is H, or an optionally substituted alkyl or benzyl group, and R6 and R7 represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NRxRy where Rx and Ry each represent hydrogen or alkyl, subject to the provisos that (a) if R1 and R3 are both chloro or diethanolamino, R2 and R4 are not both benzylamino, i.e. R2 and R4 do not correspond to structure II with R5, R6 and R7 each being hydrogen, and (b) if R2 and R4 are both piperidino, R1 and R3 are not both chloro, diethanolamino, solketalo or (2,3-dimethoxy)propoxy

Claims18

Dependent claims

A pyrimidopyrimidine compound which is a compound having the structural formula I

or a pharmaceutically acceptable salt thereof,
characterised in that in structural formula I
R1 and R3 are identical and are selected from allyl, diethanolamino, solketalo and a group having the formula —O—RZ or —NHRz,
RZ being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and
R2 and R4 are identical and are selected from N-tetrahydroisoquinolyl, and a benzylamino group having the structural formula II
where
R5 is H, or an optionally substituted alkyl or benzyl group, and
R6 and R7 represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NRxRy where Rx and Ry each represent hydrogen or alkyl,
subject to the proviso that
if R1 and R3 are both diethanolamino, R2 and R4 do not correspond to structure II with R5, R6 and R7 each being hydrogen and provided further that, if R1 and R3 are —NHRz and R2 and R4 are both benzylamino groups of formula II, R5 is hydrogen.

7 more elements

A pyrimidopyrimidine compound which is one of the following:

2,6-di-(3-hydroxypropoxy)-4,8-di-(N 4-methoxybenzyl-N-methylamino)pyrimidopyrimidine;
2,6-bis-diethanolamino-4,8-di-(4-methoxybenzylamino)pyrimidopyrimidine;
2,6-bis-diethanolamino-4,8-bis-(3,4-dimethoxybenzylamino)pyrimidopyrimidine;
2,6-di-(2-hydroxypropoxy)-4,8-di-(4-methoxybenzylamino)pyrimidopyrimidine;
2,6-di(−3-hydroxypropoxy)-4,8-di(−4-methoxybenzylamino)pyrimidopyrimidine;
2,6-di-(2-hydroxyethoxy)-4,8-di-(N-4-methoxybenzyl-N-methylamino)pyrimidopyrimidine;
2,6-di(−3-hydroxypropoxy)-4,8-bis[(−3,4-dimethoxybenzyl)-N-methylamino]pyrimidopyrimidine;
2,6-bis(diethanolamino)-4,8-di(4-chlorobenzylamino)pyrimidopyrimidine;
2,6-di-(3-hydroxypropoxy)-4,8-di-(N-benzylmethylamino)pyrimidopyrimidine;
2,6-di(−2-hydroxyethoxy)-4,8-di(N-methylbenzylamino)pyrimidopyrimidine;
2,6-di(−2-methoxyethoxy)-4,8-dibenzylaminopyrimidopyrimidine;
2,6-di-(2-methoxyethoxy)-4,8-di-(N-benzyl-N-methylamino)pyrimidopyrimidine;
2,6-disolketalo-4,8-dibenzylaminopyrimidopyrimidine;
2,6-bis-diethanolamino-4,8-di-(4-trifluoromethylbenzylamino)pyrimidopyrimidine;
2,6-di(−2-methoxyethoxy)-4,8-bis(dibenzylamino)pyrimidopyrimidine;
2,6-dipropoxy-4,8-di-(N-benzyl-N-methylamino)pyrimidopyrimidine;
2,6-di(−2-hydroxyethyl)amino-4,8-di(4-methoxybenzyl)aminopyrimidopyrimidine;
2,6-di(−2-hydroxyethylamino)-4,8-dibenzylaminopyrimidopyrimidine;
2,6-bis-diethanolamino-4,8-di-(N-methyl-N-[4-methoxybenzyl])aminopyrimidopyrimidine;
2,6-di-(2-hydroxyethyl)amino-4,8-bis-(3,4-dimethoxybenzyl)aminopyrimidopyrimidine;
2,6-Di-(3-hydroxypropoxy)-4,8-di-(N-[4-methoxybenzyl]-N-methyl)aminopyrimidopyrimidine;
2,6-Di-(2-hydroxyethoxy)-4,8-di-(N-benzyl-N-methyl)aminopyrimidopyrimidine.

19 more elements

A method of inhibiting nucleoside or purine cell membrane transport, in a mammal said method comprising administering to said mammal an effective nucleoside or purine membrane transport-inhibiting amount of a compound having the formula I

or a pharmaceutically acceptable salt thereof,
characterised in that in structural formula I
R1 and R3 are identical and are selected from allyl, diethanolamino, solketalo and a group having the formula —O—RZ or —NHRz,
RZ being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and
R2 and R4 are identical and are selected from N-tetrahydroisoquinolyl, and a benzylamino group having the structural formula II
where
R5 is H, or an optionally substituted alkyl or benzyl group, and
R6 and R7 represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NRxRy where Rx and Ry each represent hydrogen or alkyl,
subject to the proviso that
if R1 and R3 are both diethanolamino, R2 and R4 do not correspond to structure II with R5, R6 and R7 each being hydrogen.

7 more elements

Dependencies are inferred from the claim text.

Pyrimidopyrimidine compounds

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Pyrimidopyrimidine compounds

Life of this patent

Abstract

Claims18