Pyrazolo[3,4-d]pyrimidineone compounds

Details Pyrazolo[3,4-d]pyrimidineone compounds Pyrazolo[3,4-d]pyrimidineone compounds

1998-05-07

2000-02-22

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

544262, A61K 31505, C07D48704

Patent

active

060280743

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to pharmaceutically useful pyrazolo[3,4-d]pyrimidinedione compounds, processes for their production, pharmaceutical compositions containing them and their use for the treatment of various diseases.
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 EL-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.
According to the invention there is provided a compound of formula (I): ##STR1## in which: R.sup.1 is C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 cycloalkyl; 9-fluorenyl, acenaphthyl or CHR.sup.4 (CH.sub.2).sub.n Ar where n is 0 or 1, R.sup.4 is hydrogen or C.sub.1-6 alkyl and Ar is quinolinyl, naphthalenyl, benzodioxolinyl optionally susbstituted by one or more halogen atoms, or phenyl optionally substituted by one or more substituent groups selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and phenylsulfonylmethyl; NR.sup.5 R.sup.6, CONR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl, or together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic ring optionally further containing an oxygen atom or a group NR.sup.7 where R.sup.7 is hydrogen or C.sub.1-6 alkyl, or W is pyridyl or phenyl, each of which may be optionally substituted by one or more substituent groups selected from halogen, hydroxyl, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; X is a bond or C, .sub.5 alkylene; CH.dbd.CH; and alkyl, CH.sub.2 NR.sup.5 R.sup.6 or CONR.sup.5 R.sup.6 and Y is sulfur.
Alkyl and alkenyl groups whether alone or as part of another group, may be linear or branched. As defined herein alkenyl groups are those where the double bond is not adjacent to a heteroatom.
Suitably R.sup.1 is C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 cycloalkyl. Preferably R.sup.1 is a C.sub.1-4 alkyl or C.sub.3-4 alkenyl group such as methyl, ethyl, propyl, butyl, 2-methyl-1-propyl, propenyl, butenyl or 2-methyl-2-propenyl.
Suitably R.sup.2 is C.sub.1-4 alkyl (e.g. methyl, ethyl, propyl, butyl or 2-methyl-1-propyl) or C.sub.3-6 alkenyl (e.g. propenyl, butenyl, pentenyl, hexenyl or 2-methyl-2-propenyl). Preferably R.sup.2 is C.sub.1-4 alkyl, most preferably methyl.
Suitably R.sup.3 is 1- or 2-indanyl, 1- or 2-(1,2,3,4-tetrahydronaphthalenyl), 9-fluorenyl, acenaphthyl or CHR.sup.4 (CH.sub.2).sub.n Ar where n is 0 or 1, R.sup.4 is hydrogen or C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) and Ar is quinolinyl, naphthalenyl, benzodioxolinyl optionally susbstituted by one or more, e.g. one, two or three, halogen atoms (e.g. fluorine, chlorine or bromine), or phenyl optionally substituted by one or more, e.g. one to four, preferably one or two, substituent groups selected from halogen (e.g. fluorine, chlorine or bromine), C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), C.sub.1-6 alkoxy (e.g. methoxy, ethoxy, propoxy or butoxy) and phenylsulfonylmethyl.
Preferably R.sup.3 is CHR.sup.4 (CH.sub.2).sub.n Ar where n is 0, R.sup.4 is hydrogen and Ar is quinolinyl, naphthalenyl, benzodioxolinyl substituted by one or more halogen atoms, or phenyl substituted by one or more substituent groups selected from halogen atoms and phenylsulfonylmethyl.
Suitably W is H, CH.sub.2 OH, CO.sub.2 H, CO.sub.2 C.sub

REFERENCES:
patent: 4824848 (1989-04-01), Naka et al.
Michne et al. Novel inhibitors of the Nuclear Factor of . . . J. Med. Chem. 38, 2557-2569, 1995.

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