5-substituted derivatives of mycophenolic acid

A compound of the formula:

• ##STR68## wherein:
• R.sup.1 is H or C(O)R.sup.10, where R.sup.10 is lower alkyl, aryl or NH--aryl;
• and
• Z is selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH:
• ##STR69## wherein:
• Z.sup.1 is H, lower alkyl, halo or CF.sub.3 ;
• Z.sup.2 is H, OH, lower alkyl, lower alkoxy, aryl, or CH.sub.2 --Z.sup.13, where
• Z.sup.13 is halo, CN, aryl or heteroaryl;
• Z.sup.3 is H, OH, lower alkyl, lower alkenyl, lower alkoxy, halo, phenyl, P(O)(OCH.sub.3).sub.2, P(O)(OH)(OCH.sub.3), NHZ.sup.11, SH or S(O).sub.m Z.sup.12, where
• Z.sup.11 is H, alkyl, acyl, or lower alkyl sulfonyl,
• Z.sup.12 is lower alkyl, and
• m is 0, 1 or 2;
• Z.sup.4 is H, OH, lower alkyl, halo, or phenyl,
• provided, however that Z.sup.4 is not OH or halo when Z.sup.3 is OH, halo, P(O)(OCH.sub.3).sub.2, P(O)(OH)(OCH.sub.3), NHZ.sup.11, or SZ.sup.12 ;
• 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 --NG.sup.1 G.sup.2, or O--(CH.sub.2).sub.n --N.dbd.G.sup.3, where
• n is an integer from 1 to 6,
• G.sup.1 is H or lower alkyl,
• G.sup.2 is H 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 H or lower alkyl;
• provided that when Z.sup.1 is methyl, Z.sup.2, Z.sup.3 and Z.sup.4 are not all H, and
• provided that when R.sup.1, Z.sup.3 and Z.sup.4 are all H and Z.sup.1 is methyl, Z.sup.2 is not H or OH;
• or ##STR70## wherein:
• Z.sup.5 is H or lower alkyl;
• Z.sup.8 is H, lower alkyl or forms a double bond with D.sup.2 ;
• 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 ##STR71## wherein:
• Z.sup.8 is H or lower alkyl;
• and
• Z.sup.5 and G are as defined above;
• or ##STR72## wherein:
• D.sup.3 is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --;
• and
• G is as defined above;
• or ##STR73## wherein:
• Z.sup.6 is H, lower alkyl, lower alkoxy, COOH, NH.sub.2, azido or halo;
• Z.sup.7 is H, lower alkyl, lower alkoxy or halo;
• and
• Z.sup.5 and G are as defined above;
• or ##STR74## wherein:
• Z.sup.1 and G are as defined above;
• or ##STR75## wherein:
• D.sup.3, Z.sup.2, Z.sup.3, Z.sup.4 and G are as defined above;
• or ##STR76## 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 --O--CH.sub.2 --;
• and
• Z.sup.1 and G are as defined above;
• or a pharmaceutically acceptable salt thereof.