A1 adenosine receptor antagonists

Abstract

A compound useful as an A1 adenosine receptor antagonist has formula (I), wherein R1 is selected from the group consisting of C1-C8alkyl; R2 is of formula (II), wherein n is an integer ranging from 1 to 8; R5 is H or CH3(CH2)p, wherein p is an integer ranging from 1 to 7; and R6 is H; (CH2)mH; or (CH2)mOH, wherein m is an integer ranging from 1 to 8; R3 is selected from the group consisting of: (a), (b), (c) and (d), wherein q is an integer ranging from 1 to 8; D is selected from the group consisting of NH, S, and O; wherein R7 is selected from the group consisting of H, OH, NH2, R9COOH, wherein R9 is an alkylene or alkenylene group having 1 to 8 carbon atoms, and (CH2)tOH, wherein t is an integer ranging from 1 to 8; R11 is selected from the group consisting of -CH2COOH and -CH2-CONH(CH2)wNHZ, wherein w is an integer ranging from 1 to 2 and Z is selected from the group consisting of hydrogen and acetate; and R4 is of formula (III), wherein R8 is selected from the group consisting of H; OH; (CH2)fNH2 wherein f is selected from the group consisting of 0 and an integer ranging from 1 to 8; (CH2)5OH, wherein s is an integer ranging from 1 to 8; and R10COOH, wherein R10 is an alkylene or alkenylene group having 1 to 8 carbon atoms; and r is an integer ranging from 1 to 8.

Description

[0001] The instant application is a continuation-in-part application of U.S. patent application Ser. No. 08 / 753,048 filed Nov. 19, 1996.FIELD AND BACKGROUND OF THE INVENTION[0002] The present invention relates to novel compounds useful as A.sub.1 adenosine receptor antagonists.[0003] Adenosine receptors are involved in a vast number of peripheral and central regulatory mechanisms such as, for example, vasodilation, cardiac depression, inhibition of lipolysis, inhibition of insulin release and potentiation glucagon release in the pancreas, and inhibition of neurotransmitter release from nerve endings.[0004] In general, adenosine: receptors can be divided into two main classes, A.sub.1 receptors which (,an inhibit, and A.sub.2 receptors which can stimulate adenylate cyclase activity. One of the best known classes of adenosine receptor antagonists are the xanthines which include caffeine and theophylline. See e.g., Muller et al., J. Med. Chem. 33: 2822-2828 (1990). In general, many of ...

AI Technical Summary

Problems solved by technology

In general, many of these antagonists often suffer from poor water solubility, and low potency or lack of selectivity for adenosine receptors.

Nonetheless, such developments have yet to fully address problems associated with potency and selectivity.

However, it is also acknowledged that such substituents may result in a decrease in solubility thus rendering the antagonists less soluble in vivo.

It is also stated that substitutions at the 7-position are typically not favorable.

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