Claims
- 1. A compound represented by the formula: ##STR99## wherein: R.sup.1 is hydrogen or lower alkyl;
- R.sup.2 is hydrogen, lower alkyl, --C(O)R.sup.3, --C(O)NR.sup.4 R.sup.5, --CO.sub.2 R.sup.6, or --SO.sub.2 R.sup.3 ; in which:
- R.sup.3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl;
- R.sup.4 is hydrogen, lower alkyl or optionally substituted phenyl;
- R.sup.5 is hydrogen, lower alkyl or optionally substituted phenyl;
- R.sup.6 is lower alkyl or optionally substituted phenyl; and
- R.sup.7 is lower alkyl, cycloalkyl, fluorovinyl, difluorovinyl, trifluorovinyl, lower alkenyl, --C.dbd.C--R.sup.8, allyl, CHO, or CH.sub.2 OR.sup.9 ; in which:
- R.sup.8 is hydrogen or lower alkyl, and
- R.sup.9 is hydrogen or 4-methoxybenzyl; and
- Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH: ##STR100## wherein: Z.sup.1 is hydrogen, lower alkyl, halo or CF.sub.3 ;
- Z.sup.2 is hydrogen, lower alkyl, lower alkoxy, aryl, or --CH.sub.2 Z.sup.13, where Z.sup.13 is aryl or heteroaryl;
- Z.sup.3 is hydrogen, lower alkyl, lower alkenyl, lower alkoxy, phenyl, or --S(O).sub.m Z.sup.12, where
- Z.sup.12 is lower alkyl, and
- m is 0, 1 or 2;
- Z.sup.4 is hydrogen, lower alkyl, or phenyl, or Z.sup.3 and Z.sup.4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and
- G is OH, lower alkoxy, lower thioalkyl, --NG.sup.1 G.sup.2, --O(CH.sub.2).sub.n G.sup.1 G.sup.2, or --O(CH.sub.2).sub.n --G.sup.3, where
- n is an integer from 1 to 6,
- G.sup.1 is hydrogen or lower alkyl,
- G.sup.2 is hydrogen or lower alkyl, and
- .dbd.G.sup.3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is --O--, --S--, or --N(G.sup.4)-- where G.sup.4 is hydrogen or lower alkyl; ##STR101## wherein: Z.sup.5 is hydrogen or lower alkyl;
- Z.sup.6 is hydrogen or lower alkyl;
- D.sup.1 and D.sup.2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and
- G is as defined above; or ##STR102## wherein: Z.sup.5, Z.sup.6, and G are as defined above; or ##STR103## wherein: D.sup.3 is --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --; and
- G is as defined above; or ##STR104## wherein: Z.sup.6 is hydrogen, lower alkyl, lower alkoxy, --COOH, --NH.sub.2 or halo;
- Z.sup.7 is hydrogen, lower alkyl, lower alkoxy or halo; and
- Z.sup.5 and G are as defined above; or ##STR105## wherein: Z.sup.1 and G are as defined above; or ##STR106## wherein: D.sup.3, Z.sup.2, Z.sup.3, Z.sup.4 and G are as defined above; or ##STR107## wherein: D.sup.4 is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 --, --O--, or --OCH.sub.2 --; and
- Z.sup.1 and G are as defined above;
- or a pharmaceutically acceptable salt thereof.
- 2. The compound or salt of claim 1 wherein Z is selected from Formulae ZA, ZB, ZE and ZH.
- 3. The compound or salt of claim 1 wherein R.sup.1 is hydrogen and R.sup.2 is hydrogen or --C(O)CF.sub.3.
- 4. The compound or salt of claim 3 wherein G is OH.
- 5. The compound or salt of claim 4 where R.sup.7 is methyl, ethyl, vinyl or cyclopropyl.
- 6. The compound or salt of claim 3 wherein G is morpholinoethoxy.
- 7. The compound or slit of claim 1 comprising a single enantiomer, a diastereomer, a racemic mixture or a non-racemic mixture.
- 8. The compound or salt of claim 5 wherein Z is a side chain of Formula ZA.
- 9. The compound or salt of claim 8 wherein: Z.sup.1 is lower alkyl; Z.sup.2 is hydrogen or lower alkyl; Z.sup.3 is hydrogen or lower alkyl; and Z.sup.4 is hydrogen.
- 10. The compound or salt of claim 9 wherein Z.sup.1 is methyl.
- 11. The compound or salt of claim 10 wherein Z.sup.2 and Z.sup.3 are hydrogen.
- 12. The compound or salt of claim 11 wherein R.sup.2 is hydrogen and R.sup.7 is ethyl, namely (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
- 13. The compound or salt of claim 9 wherein Z.sup.2 is methyl and Z.sup.3 is hydrogen.
- 14. The compound or salt of claim 13 wherein R.sup.2 is hydrogen and R.sup.7 is ethyl, namely (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxo-isobenzofuran-5-yl)-3,4-dimethyl-4-hexenoic acid.
- 15. The compound or salt of claim 4 wherein Z is a side chain of Formula ZB.
- 16. The compound or salt of claim 15 wherein Z.sup.5 is H, methyl or ethyl, and Z.sup.8 is H.
- 17. The compound or salt of claim 16 wherein D.sup.1 -D.sup.2 is --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, or --CH.sub.2 --CH.sub.2 --O--CH.sub.2 --.
- 18. The compound or salt of claim 17 wherein R.sup.7 is methyl, ethyl, vinyl or cyclopropyl.
- 19. The compound or salt of claim 18 wherein Z.sup.5 and Z.sup.8 are H, D.sup.1 -D.sup.2 is --(CH.sub.2).sub.3 --, R.sup.2 is hydrogen, and R.sup.7 is ethyl, namely (E)-2-{2-[2-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-ethylidene]-cyclopent-1-yl}acetic acid.
- 20. The compound or salt of claim 4 wherein Z is a side chain of Formula ZE.
- 21. The compound or salt of claim 20 wherein Z.sup.5 and Z.sup.7 are hydrogen, and Z.sup.6 is hydrogen or lower alkyl.
- 22. The compound or salt of claim 4 wherein Z is a side chain of Formula ZH.
- 23. The compound or salt of claim 22 wherein Z.sup.1 is lower alkyl.
- 24. The compound or salt of claim 23 wherein D.sup.4 is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, or --OCH.sub.2 --.
- 25. A pharmaceutical composition comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a division of application Ser. No. 08/198,741, filed Feb. 18, 1994. This application is related to the following co-pending applications: Ser. Nos. 08/198,749, Attorney Docket No. 27960, entitled "5-Substituted Derivatives of Mycophenolic Acid"; 08/198,817, Attorney Docket No. 27970, entitled "4-Amino Derivatives of Mycophenolic Acid"; 08/198,732, Attorney Docket No. 27980, entitled "4-Amino Derivatives of 5-Substituted Mycophenolic Acid"; and 08/198,725, Attorney Docket No. 27990, entitled 6-Substituted Mycophenolic Acid and Derivatives"filed contemporaneously herewith and incorporated herein by reference.
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Nov 1973 |
JPX |
1290667 |
Nov 1989 |
JPX |
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Entry |
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Carman, et al., "Derivatives of Mycophenolic Acid", Aust. J. Chem., 1978, 31, pp. 353-64. |
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Divisions (1)
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Number |
Date |
Country |
Parent |
198741 |
Feb 1994 |
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