7-deazaguanines as immunomodulators

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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544280, 544316, 544330, 544331, A61K 31505, C07D48704

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active

049218581

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The pyrrolo[2,3-d]pyrimidin-4-ones of the following formula 2, 3 and 4 ##STR1## 2, R is n-C.sub.3 H.sub.7 3, R is CH.sub.2 C.sub.6 H.sub.5 3 as reported in J. Het. Chem., 1964, 34, but gave no biological activity for either compound. M. Legraverend, et al, reported the synthesis of the compounds of formula 3 and 4 in Tetrahedron Letters, 1985, 2001, but again gave no biological activity for either compound.
Of lesser interest the following references provide a background in which a 7-(substituted phenyl)pyrrolo[2,3-d]pyrimidin-4-one having a methyl at each of the five (5) and six (6) positions for treating CNS illnesses or inflammations is disclosed generically in U.S. Pat. No. 4,229,453. Similarly, 4-mercapto-7-(phenyl substituted or unsubstituted)pyrrollo [2,3-d]pyrimidine derivatives requiring an alkyl or phenyl at the five (5) and six (6) positions are disclosed in German 3145287 (Derwent Abstract No. 49344 K/21). Other pyrrolo [2,3-d]pyrimidin-4-one or thione, distinguished by having various substituents at the five (5) position, are found in U.S. Pat. Nos. 4,435,570 and 4,140,851; European publications 160,910 (Derwent Abstract No. 85-284574/46); 89,055 (corresponding to U.S. Pat. No. 4,571,423); 119,591 (Derwent Abstract No. 84-238735/39); 79,447 (corresponding to U.S. Pat. No. 4,435,569); German 3,306-390 (Derwent Abstract No. 39438 E/20); German 3145287 (Derwent Abstract No. 49344 K/21); British Pat. No. 981,458 (Derwent Abstract No. 15,454); Japanese J6 0204,788 (Derwent Abstract No. 85/298810/48); and Japanese J5 9036615 (Derwent Abstract No. 84-086061/84).
Finally, hydroxy and mercapto analogs of the antibiotic sparsomycin A are pyrrolo[2,3-d]pyrimidin-4-one or thione having a sugar moiety in the seven (7) position are disclosed by Upjohn in Netherlands 6,407,785 (Derwent Abstract No. 15,466) and similarly by Warner Lambert in European publication 57,548 (Derwent Abstract No. 68572 E/33).
Copending Applications Ser. No. PD-3557 and Ser. No. 767,202 filed Aug. 22, 1985, now U.S. Pat. No. 4,772,606, which is a continuation-in-part of U.S. Ser. No. 660,152 filed Oct. 12, 1984, now abandoned, disclose similar activity as now found in the present invention for different ring systems.


SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula (I) ##STR2## wherein R.sub.6 is OH or SH, R.sub.2 is hydrogen or NH.sub.2, R.sub.7 and R.sub.8 are independently hydrogen or NH.sub.2 with the proviso that both cannot be NH.sub.2 at once, n is an integer of from one through four, Ar is (i) phenyl unsubstituted or substituted by halogen, trifluoromethyl, alkyl of one to four carbon atoms, hydroxy, or alkoxy of from one to four carbon atoms, (ii) 2- or 3-thienyl, or (iii) 2- or 3-furanyl with the proviso that when R.sub.6 is OH, and R.sub.2 is H.sub.2 N, and R.sub.7 and R.sub.8 are both hydrogen then Ar cannot be unsubstituted phenyl; or a pharmaceutically acceptable base or acid addition salt thereof.
The present invention also includes methods of manufacturing and novel intermediates therein, and a pharmaceutical composition for treating autoimmune diseases such as arthritis, systemic lupus erythematosus, inflammatory bowel diseases, juvenile diabetes, myasthenia gravis, multiple sclerosis, gout and gouty arthritis, as well as psoriasis, viral infections and cancer, or rejection of transplantation, comprising an anti-psoriatic, immunomodulator or antirejection effective amount such as an advantageously cytotoxic to T-cell amount, of a compound of the formula (I) ##STR3## or a pharmaceutically acceptable base or acid addition salt thereof wherein R.sub.6 is OH or SH, R.sub.2 is hydrogen or NH.sub.2, R.sub.7 and R.sub.8 are independently hydrogen and NH.sub.2 with the proviso that both cannot be NH.sub.2 at once, n is an integer of from one to four, Ar is (i) phenyl unsubstituted or substituted by halogen, trifluoromethyl, alkyl of one to four carbon atoms, hydroxy, alkoxy of from one to four carbon atoms, (ii) 2- or 3-thienyl, or (iii) 2- or 3-furanyl with

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