Pyrrolo[3,4-D] pyrimidinone derivatives and their use as medicam

Details Pyrrolo[3,4-D] pyrimidinone derivatives and their use as medicam Pyrrolo[3,4-D] pyrimidinone derivatives and their use as medicam

1998-02-24

2000-04-04

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514258, 544238, 544280, A61K 3150, A61K 31505, C07D48704

Patent

active

060462043

DESCRIPTION:

BRIEF SUMMARY
The present invention provides certain novel 5-substituted pyrrolo[3,4-d]-pyrimidine-2,4-diones, processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and methods of treatment involving their use.
T-cells play an important role in the immune response, however in autoimmune disease T-cells are activated against particular tissues, e.g. causing the inflammation associated with rheumatoid arthritis. Interleukin-2 (IL-2) is an essential autocrine growth factor for T-cells and hence inhibition of IL-2 transcription is beneficial in the modulation of autoimmune disease. Formation of a transcriptional complex of the protein nuclear factor of activated T-cells-1 (NFAT-1) on the IL-2 promoter is essential for IL-2 transcription. NFAT-1 mediated transcription has therefore been proposed as appropriate molecular target for immunomodulation, Y. Baine et al., J. Immunol., 1995, 154, 3667-3677.
W. F. Michne et al., in J. Med. Chem. (1995) 38, 2557-2569 disclose a number of quinazoline-2,4-diones and pyrrolo[3,4-d]pyrimidine-2,4-diones which inhibit transcription regulated by the DNA region bound by the NFAT-1 protein.
WO 96/17610 discloses the use of compounds of the following general formula and their salts as anti-ischaemic agents, ##STR1## wherein R1, R2 and R3 which may be the same or different are N or CH; X1 and X2 which may be the same or different are hydrogen, hydroxy or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group and Z1 and Z2 which may be the same or different are hydrogen, hydroxy, keto or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group or one of Z1 and X1 and Z2 and X2 form the second bond of a double bond at the 1,6 or 2,3 positions, with the proviso that at least one of the groupings R1Z1X1, R2Z2X2 and R1X1Z2 form a hydroxamate moiety (--N(OH)C(.dbd.O)--) in which R1 and/or R2 is N, Z1 and/or Z2 is .dbd.O and X1 and/or X2 is OH or R1 is N, Z2 is .dbd.O and X1 is OH and B is a 5- or 6-membered ring of formula ##STR2## in which R4, R5, R6, R7, R8, R9 and R10 which may be the same or different are CH or N with the proviso that ring B cannot contain more than 3 ring members which are nitrogen and the ring B may optionally be substituted by one or more of hydroxy, keto and an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group. Preferred compounds of WO 96/17610 include those compounds in which the ring B contains no substituent groups.
In accordance with the present invention, there is provided a compound according to the general formula: ##STR3## wherein W represents --CH.sub.2 -- or a bond; Q represents Ar.sup.1 or Ar.sup.2 ; in the case where W represents --CH.sub.2 --, Q represents an aryl group Ar.sup.1 wherein Ar.sup.1 represents naphthyl, phenyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl; in the case where W represents a bond, Q represents an aryl group Ar.sup.2 wherein Ar.sup.2 represents acenaphthenyl, fluorenyl or indanyl; wherein the ring systems which Ar.sup.1 and Ar.sup.2 represent may all be optionally substituted by one or more substituents selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halogen, or trifluoromethyl; R.sup.10 represents X--(A).sub.p --Y; X represents S(O).sub.n, C.tbd.C, (CH.sub.2).sub.2, CH.dbd.CH or CH.sub.2 CH.dbd.CH; n represents 0, 1 or 2; A represents C.sub.1-6 alkylene; p is 0 or 1; Y represents CN, OR.sup.11, CO.sub.2 R.sup.12, CONR.sup.13 R.sup.14, NR.sup.15 R.sup.16, NHSO.sub.2 R.sup.17, NHCOR.sup.18 or an optionally substituted aryl or heteroaryl group, provided that when X represents S(O).sub.n and Y is other than an optionally substituted aryl or heteroaryl group, then p is 1 and also provided that when X represents S(O).sub.n, p is 1 and Y represents OH, then n is not 0; R.sup.13 and R.sup.14 independently represent H, C.sub.1-5 alkyl or phenyl, which latter group may be substituted by one or more substituents selected from C.sub.1-4 alkyl, C.su

REFERENCES:
Michne et al, "Novel Inhibitors of the Nuclear Factor of Activated T Cells (NFAT)-Mediated . . . ," J. Med. Chem., vol. 38, pp. 2557-2569 (1995).
Noguchi et al, "A Facile Preparation of 7-(Substituted amino)-6H-pyrrolo[3,4-d]-pyrimidine Derivatives.sup.1," Bull. Chem. Soc. Jpn., vol. 62, pp. 3043-3045 (1989).
Hirota et al, "Pyrimidine Derivatives and Related Compounds. XXXIII..sup.1) Reactions of . . . ," Chem. Pharm. Bull., vol. 29, No. 6, pp. 1525-1532 (1981).
Senda et al, "A Facile Synthesis of Pyrrolo[3,4-d]pyrimidines and Pyrimido[4,5-d]pyridazines," Communications, "Synthesis," pp. 463-465 (1978).
Baine et al, "Functional Characterization of Novel IL-2 Transcriptional Inhibitors," The Journal of Immunology, vol. 154, pp. 3667-3677 (1995).

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