Pro-drugs for the improved delivery of certain selected anti-inflammatory steroids

A pharmaceutical composition of matter comprising an anti-inflammatory effective amount of a pro-drug compound of the formula:

• ##STR45## wherein Z represents a member selected from the group consisting of .dbd.O, .beta.--OH and .beta.--O--R.sub.1, wherein R.sub.1 represents ##STR46## wherein R.sub.4 represents a member selected from the group consisting of H and straight or branched C.sub.1 -C.sub.4 alkyl, and wherein R.sub.2 and R.sub.3 which may be the same or different, represent a member selected from the group consisting of H, straight or branched C.sub.1 -C.sub.8 alkyl, substituted C.sub.1 -C.sub.8 alkyl, wherein at least one of the hydrogen atoms therein is substituted by a member selected from the group consisting of --N(R.sub.4).sub.2, --CON(R.sub.4).sub.2, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub.4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined as above, and wherein R.sub.2 and R.sub.3 further represent a member selected from the group consisting of ##STR47## wherein W represents a member selected from the group consisting of --N(R.sub.4).sub.2, --CON(R.sub.4).sub.2, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub.4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined as above, with the proviso that R.sub.2 and R.sub.3 cannot simultaneously be H or wherein R.sub.2 and R.sub.3 taken together further represent a member selected from the group consisting of cyclic alkyl [--(CH.sub.2).sub.n --] and cyclic heteroalkyl, wherein one of the carbon atoms is substituted by a member selected from the group consisting of <N--R.sub.4, <--COR.sub.4 and --CO, wherein n is an integer of 5 to 7 and wherein R.sub.4 is defined as above;
• wherein Q represents ##STR48## wherein R.sub.4 is defined as above, and R.sub.5 represents H, COOR.sub.4 and --CON(R.sub.4).sub.2, wherein R.sub.4 is defined as above, provided that the C.sub.4 -C.sub.5 double bond in formula (I) is subject to migration to the C.sub.5 -C.sub.6 position;
• and wherein with respect to ring (A) in formula (I), the bond between C.sub.1 and C.sub.2 can be a single or double bond. ##STR49## wherein Z represents a member selected from the group consisting of .dbd.O and .beta.--OH;
• wherein R.sub.6 represents a member selected from the group consisting of H and ##STR50## with the proviso that one of said R.sub.6 is H, wherein R.sub.7 represents a member selected from the group consisting of a C.sub.1 -C.sub.12 straight, branched or cycloalkyl, a C.sub.1 -C.sub.12 straight, branched or cycloalkenyl, a substituted C.sub.1 -C.sub.12 straight, branched or cycloalkyl or alkenyl, ##STR51## --(CH.sub.2).sub.n --CON(R.sub.2).sub.2, wherein n is an integer of 1 to 6, a 2, 3 or 4 pyridyl, wherein at least one of the hydrogen atoms therein can be substituted by a member selected from the group consisting of --N(R.sub.4).sub.2, --CON(R.sub.4).sub.2, --SOR.sub.4, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub.4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined above, ##STR52## wherein W is defined above;
• wherein Q represents ##STR53## wherein R.sub.4 is defined as above and R.sub.5 represents a member selected from the group consisting of H, COOR.sub.4 and --CON(R.sub.4).sub.2, wherein R.sub.4 is defined as above;
• wherein the bond between C.sub.1 and C.sub.2 in ring "A" of formula (II) can be a single or a double bond;
• and wherein, with respect to ring "A" in formula (II), the double bond between C.sub.4 and C.sub.5 is subject to migration to the C.sub.5 -C.sub.6 position.

A method for alleviating inflammation in or on a warm-blooded aniamal exhibiting an inflammatory response which comprises administering thereto, an anti-inflammatory effective amount of a pro-drug compound of the formula:

• ##STR54## wherein Z respresents a member selected from the group consisting of .dbd.O, .beta.--OH and .beta.--O--R.sub.1, wherein R.sub.1 represents ##STR55## wherein R.sub.4 represents a member selected from the group consisting of H and straight or branched C.sub.1 -C.sub.4 alkyl, and wherein R.sub.2 and R.sub.3 which may be the same or different, represent a member selected from the group consisting of H, straight or branched C.sub.1 -C.sub.8 alkyl, substituted C.sub.1 -C.sub.8 alkyl, wherein at least one of the hydrogen atoms therein is substituted by a member selected from the group consisting of --N(R.sub.4).sub.2, --CON(R.sub. 4).sub.2, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub.4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined as above, and wherein R.sub.2 and R.sub.3 further represent a member selected from the group consisting of ##STR56## wherein W represents a member selected from the group consisting of --N(R.sub. 4 .sub. 2, --CON(R.sub. 4).sub.2, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub. 4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined as above, with the proviso that R.sub.2 and R.sub.3 cannot simultaneously be H or wherein R.sub.2 and R.sub.3 taken together further represent a member selected from the group consisting of cyclic alkyl [--(CH.sub.2).sub.n --] and cyclic heteroalkyl, wherein one of the carbon atoms is substituted by a member selected from the group consisting of N--R.sub.4, N--COR.sub.4 and --CO, wherein n is an integer of 5 to 7 and wherein R.sub.4 is defined as above;
• wherein O represents ##STR57## wherein R.sub.4 is defined as above, and R.sub.5 represents H, COOR.sub.4 and --CON(R.sub. 4).sub.2, wherein R.sub.4 is defined as above, provided the C.sub.4 -C.sub.5 double bond in formula (I) is subject to migration to the C.sub.5 -C.sub.6 position;
• and wherein with respect to ring (A) formula (I), the bond between C.sub.1 and C.sub.2 can be a single or double bond. ##STR58## wherein Z represents a member selected from the group consisting of .dbd.O and .beta.--OH;
• wherein R.sub.6 represents a member selected from the group consisting of H and ##STR59## with the proviso that one of said R.sub.6 is H, wherein R.sub.7 represents a member selected from the group consisting of a C.sub.1 -C.sub.12 straight, branched or cycloalkyl, a C.sub.1 -C.sub.12 straight, branched or cycloalkenyl, a substituted C.sub.1 -C.sub.12 straight, branched or cycloalkyl or alkenyl, ##STR60## --(CH.sub.2).sub.n --CON(R.sub.2).sub.2, wherein n is an integer of 1 to 6, a 2, 3 or 4 pyridyl, wherein at least one of the hydrogen atoms therein can be substituted by a member selected from the group consisting of --N(R.sub.4).sub.2, --CON(R.sub.4).sub.2, --SOR.sub.4, a halogen atom, --COOR.sub.4, --COOCH.sub.2 N(R.sub.4).sub.2 and --COOCH.sub.2 --S--R.sub.4, wherein R.sub.4 is defined above, ##STR61## wherein W is defined above;
• wherein Q represents ##STR62## wherein R.sub.4 is defined as above and R.sub.5 represents a member selected from the group consisting of H, COOR.sub.4 and --CON(R.sub.4).sub.2, wherein R.sub.4 is defined as above;
• wherein the bond between C.sub.1 and C.sub.2 in ring "A" of formula (II) can be a single or a double bond;
• and wherein, with respect to ring "A" in formula (II), the double bond between C.sub.4 and C.sub.5 is subject to migration to the C.sub.5 -C.sub.6 position.