Purine and guanine derivatives as PNP inhibitors

Details Purine and guanine derivatives as PNP inhibitors Purine and guanine derivatives as PNP inhibitors

1997-05-19

1999-06-15

Berch, Mark

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544255, 544276, 544277, 544319, 544320, 544321, C07D47318, C07D47330, C07D49804, A61K 3152

Patent

active

059122528

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to purine and guanine derivatives and their use purine nucleoside phosphorylase (PNP) inhibitors, for treating conditions in mammals which are responsive to purine nucleoside phosphorylase inhibition.


BACKGROUND OF THE INVENTION

9-Arylmethyl-substituted purines (including guanines) have been reported as PNP inhibitors in EP-A-0,178,178 substantially corresponding to U.S. Pat. No. 4,772,606. 9-arylmethyl-substituted purines (including guanines), in which the aryl ring contains phosphonic acid groups, have also been reported as PNP inhibitors in EP-A-0,465,297 WO-A-92/05180. Modified purines, namely 9-deazapurines, have also been reported as PNP inhibitors in U.S. Pat. No. 4,985,434; U.S. Pat. No. 5,008,265; U.S. Pat. No. 4,985,433; U.S. Pat. No. 5,236,926; U.S. Pat. No. 5,236,926 and U.S. Pat. No. 5,008,270.
PNP inhibitory data cited in Drugs of the Future, 13, 654 (1988), Agents and Actions, 21, 253 (1987), Proc Natl Acad Sci USA, 88, 11540 (1991) and U.S. 90/01021 indicate that modifications to the guanine base markedly alter the PNP inhibitory ability of such compounds. Also, modifications to the aryl ring of the 9-deaza (9-arylmethyl) purines can markedly alter PNP inhibitory activity. Namely replacement of a pyridine ring with piperidine greatly reduces activity as illustrated in IL Farmaco, 48 (2), 297 (1993).


SUMMARY OF THE INVENTION

The compounds of the invention are particularly useful in mammals as purine nucleoside phosphorylase (PNP) inhibitors, as selective inhibitors of T-cells and for suppressing cellular immunity. They can thus be used for the treatment of autoimmune diseases, transplant rejection, psoriasis or gout in mammals. They can also be used to potentiate the antiviral and antitumor effect of antiviral or antitumor purine nucleosides.
The present invention relates to the compounds of formula (I), their tautomers, salts, solvates and hydrates. ##STR1## wherein n=1,2; R.sup.7 and R.sup.8 may be the same of different, and may be H or the group C.sub.1-6 alkyl or C.sub.1-6 haloalkyl. CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, NHSO.sub.2 CF.sub.3 tetrazole or (CR.sup.9 R.sup.10)p(Y)q(CR.sup.9 R.sup.10)tZ where the group (CR.sup.9 R.sup.10)p or (CR.sup.9 R.sup.10)t may be straight or branched chain bearing the substituents R.sup.9 and R.sup.10 when p or t>1. group C.sub.0-6 alkyl Z NHSO.sub.2 CF, tetrazole, triazole, CONH.sub.2, CON(C.sub.1-6 alkyl).sub.2, CONH(C.sub.1-6 alkyl), SO.sub.2 N H (C.sub.1-6 alkyl), SO.sub.2 N(C.sub.1-6 alkyl).sub.2. combinations result in stable compounds; thus t>0 when q=1.


DESCRIPTION OF THE INVENTION

It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
In the formulae herein, the .about. line is used at a potential asymmetric centre to represent the possibility of R- and S-configurations, and the < line and the . . . line to represent a unique configuration at an asymmetric centre.
As used in this specification, alone or in combination, the term "C.sub.1-6 alkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like.
As used in this specification, alone in combination, the term "C.sub.1-6 haloalkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms optionally substituted with one or more halogen atoms including for example trifluoromethyl, pentafluoroethyl, trifluorodichloroethyl and the like.
As used in this specification, alone or in combination, the term "C.sub.0-6 alkyl" refers to a straight chain alkyl moiety having from zero to six carbon atoms, including

REFERENCES:
Reily, Inorg. Chem 24, 37-43, 1985.
Montgomery, J. Med. Chem 15, 1189, 1972.
Otsuka, Chem Abs 77, 101650g, 1972.
Michael, J. Med Chem 36, 3431, 1993.
Baker, J. Med Chem. 10, 62-4 1967.
Schaeffer, J. Pharm. Sci 60, 1204 1971.

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