US 5,232,917 AGranted

Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series

AssigneeUniversity of Southern California

InventorsMichael Bolger, Kelvin W. Gee, Nancy C. Lan, Delia Belelli, Seid Mirsadeghi, Robert Purdy

Life of this patent

Estimating the term…

Abstract

Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, insomnia and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-aminobutyric acid receptor-chloride ionophore (GR) complex.

Claims119

Dependent claims

A method for modulating excitability of the central nervous system as mediated by the ability to regulate chloride ion channels associated with the GABA-benzodiazepine receptor complex comprising administering to an animal subject an amount, effective to modulate said central nervous system excitability, of a 3.alpha.-hydroxylated-5-reduced neuroactive steroid compound or derivative thereof, that activates the GABA-benzodiazepine receptor complex by attaching to a brain receptor site, of the formula ##STR64## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenate C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15.dbd. listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR65## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethanesulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and
wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen;
and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
and
(4) an R14 group;
and
(5) ##STR66## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14 or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR67## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN,--CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups;
##STR68## and (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the ##STR69## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR70## ;
and (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, acetyl ##STR71## 2-hydroxyethanoyl ##STR72## 1-hydroxyethyl ##STR73## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR74## ;
and (3) pharmaceutically acceptable ##STR75## groups;
and (4) pharmaceutically acceptable ##STR76## groups;
(5) pharmaceutically acceptable ##STR77## ;
and (6) pharmaceutically acceptable oxime ##STR78## ;
and (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR79## wherein one of R20 and R21 is ##STR80## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen
;
and
(8) pharmaceutically acceptable ##STR81## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group ;
and
(9) pharmaceutically acceptable carboxylate ##STR82## ;
and (10) pharmaceutically acceptable ##STR83## (11) pharmaceutically acceptable ##STR84## groups;
and (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and
(13) ##STR85## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR86## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR87## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR88## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14 ', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR89## ;
and (3) and R14 group
;
and
(4) pharmaceutically acceptable ##STR90## ;
and (5) pharmaceutically acceptable ##STR91## groups;
and (6) a pharmaceutically acceptable ##STR92## wherein R26 is selected from ##STR93## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR94## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR95## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

80 more elements

A compound of the formula ##STR99## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 cyclic aliphatic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 cyclic aliphatic radical, or C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR100## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethanesulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotonic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR101## (6) --SCN;
B) is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14' or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR102## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN, --CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR103## (3) pharmaceutically acceptable cleavable ester of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR104## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR105## (5) pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) ##STR106## wherein R23' is as previously defined;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR107## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR108## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR109## (5) pharmaceutically acceptable ##STR110## groups;
and (6) a pharmaceutically acceptable ##STR111## wherein R26 is selected from ##STR112## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR113## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR114## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

52 more elements

A compound of the formula ##STR115## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR116## radical where n is 1-10, R16' is previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethanesulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen;
and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
and
(4) an R14 group;
and
(5) ##STR117## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14 or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR118## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN, --CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR119## ;
and (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR120## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR121## ;
and (5) a pharmaceutically acceptable ester of an acid A;
D) R7 and R8 combined are .dbd.CH--O--R14;
E) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
F) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR122## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
G) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR123## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR124## ;
and (5) pharmaceutically acceptable ##STR125## (6) a pharmaceutically acceptable ##STR126## wherein R26 is selected from ##STR127## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR128## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR129## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

48 more elements

A compound of the formula ##STR130## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR131## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotonic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) an R14 group;
and
(5) ##STR132## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14 or --CH.sub.2 --Y--CH.sub.2 --R14';
and
an R15 group;
and
(5) ##STR133## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN, --CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable and thioester groups ##STR134## ;
and (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR135## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR136## ;
and (5) a pharmaceutically acceptable ester of an acid A;
E) R8 is a pharmaceutically acceptable thiazolidine derivative having the formula:
##STR137## wherein one of R20 and R21 is ##STR138## any to of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen;
and
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR139## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR140## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR141## ;
and (5) pharmaceutically acceptable ##STR142## groups;
and (6) a pharmaceutically acceptable ##STR143## wherein R26 is selected from ##STR144## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR145## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR146## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

49 more elements

A compound of the formula ##STR147## wherein when R1, R2, R4, R4, R6, R7, R11 and R12 are H and R10 and R13 are CH.sub.3, is not hydroxyl, otherwise wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR148## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotonic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR149## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14' or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR150## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN, --CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR151## (3) pharmaceutically acceptable cleavable ester of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR152## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR153## (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is a pharmaceutically acceptable ##STR154## F) R9 is selected from the group consisting of (1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR155## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR156## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR157## (5) pharmaceutically acceptable ##STR158## groups;
and (6) a pharmaceutically acceptable ##STR159## wherein R26 is selected from ##STR160## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR161## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR162## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

50 more elements

A compound of the formula ##STR163## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR164## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(b 1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR165## (6) --SCN;
B) R2 is a --CH.sub.2 --O--CH.sub.2 --R14' or --CH.sub.2 --O--R14;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR166## (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR167## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR168## (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, ##STR169## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR170## (3) pharmaceutically acceptable ##STR171## groups;
(4) pharmaceutically acceptable ##STR172## groups;
(5) pharmaceutically acceptable ##STR173## (6) pharmaceutically acceptable oxime ##STR174## (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR175## wherein one of R20 and R21 is ##STR176## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen;
and
(8) pharmaceutically acceptable ##STR177## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
and
(9) pharmaceutically acceptable carboxylate ##STR178## (10) pharmaceutically acceptable ##STR179## (11) pharmaceutically acceptable ##STR180## groups;
and (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and
(13) ##STR181## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR182## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR183## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR184## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR185## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR186## (5) pharmaceutically acceptable ##STR187## (6) a pharmaceutically acceptable ##STR188## wherein R26 is selected from ##STR189## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR190## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR191## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

54 more elements

A compound of the formula ##STR192## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR193## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(b 1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR194## (6) --SCN;
B) R2 is --CH.sub.2 T or --CT.sub.3 wherein T is a halide;
C) R3 is selected from the group consisting of:
(1)hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR195## (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR196## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR197## (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, ##STR198## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR199## (3) pharmaceutically acceptable ##STR200## (4) pharmaceutically acceptable ##STR201## (5) pharmaceutically acceptable ##STR202## (6) pharmaceutically acceptable oxime ##STR203## (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR204## wherein one of R20 and R21 is ##STR205## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, and R19, R20 and R21 is hydrogen;
and
(8) pharmaceutically acceptable ##STR206## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
and
(9) pharmaceutically acceptable carboxylate ##STR207## (10) pharmaceutically acceptable ##STR208## groups;
and (11) pharmaceutically acceptable ##STR209## (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and (13) ##STR210## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR211## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR212## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR213## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR214## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR215## (5) pharmaceutically acceptable ##STR216## (6) a pharmaceutically acceptable ##STR217## wherein R26 is selected from ##STR218## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR219## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR220## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

52 more elements

A compound of the formula ##STR221## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR222## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR223## (6) --SCN;
B) R2is CH.sub.3
C) R3 is ##STR224## start D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, ##STR225## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR226## (3) pharmaceutically acceptable ##STR227## (4) pharmaceutically acceptable ##STR228## (5) pharmaceutically acceptable ##STR229## (6) pharmaceutically acceptable oxime ##STR230## (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR231## wherein one of R20 and R21 is ##STR232## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen;
and
(8) pharmaceutically acceptable ##STR233## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
and
(9) pharmaceutically acceptable carboxylate ##STR234## (10) pharmaceutically acceptable ##STR235## (11) pharmaceutically acceptable ##STR236## (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and (13) ##STR237## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR238## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR239## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR240## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR241## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR242## (5) pharmaceutically acceptable ##STR243## (6) a pharmaceutically acceptable ##STR244## wherein R26 is selected from ##STR245## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR246## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR247## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

47 more elements

A compound of the formula ##STR248## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR249## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(b 1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR250## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14' or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR251## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN, --CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is ##STR252## D) R7 is selected from the group consisting of (1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, ##STR253## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR254## (3) pharmaceutically acceptable ##STR255## (4) pharmaceutically acceptable ##STR256## (5) pharmaceutically acceptable ##STR257## (6) pharmaceutically acceptable oxime ##STR258## (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR259## wherein one of R20 and R21 is ##STR260## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen;
and
(8) pharmaceutically acceptable ##STR261## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
and
(9) pharmaceutically acceptable carboxylate ##STR262## (10) pharmaceutically acceptable ##STR263## (11) pharmaceutically acceptable ##STR264## (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and (13) ##STR265## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR266## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR267## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR268## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR269## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR270## (5) pharmaceutically acceptable ##STR271## (6) a pharmaceutically acceptable ##STR272## wherein R26 is selected from ##STR273## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR274## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR275## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

55 more elements

A compound of the formula ##STR276## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR277## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(b 1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR278## (6) --SCN;
B) R2 is R17
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR279## (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR280## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR281## (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when the bond between carbons C16-C17 in formula i is a double bond, R7 is not substituted;
E) R8 is ##STR282## F) R9 is selected from the group consisting of (1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR283## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR284## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR285## (5) pharmaceutically acceptable ##STR286## groups;
and (6) a pharmaceutically acceptable ##STR287## wherein R26 is selected from ##STR288## (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR289## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR290## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

41 more elements

A compound of the formula ##STR291## wherein each R14 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.6 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.6 cyclic radical, or C.sub.5 -C.sub.6 aromatic radical, and a 4, 5, or 6 membered C-- or N-- attached heterocyclic radical containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15' listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR292## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethane-sulfonic, oxalic, tartaric, salicyclic, acetyl salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
each Y is either a divalent oxygen or sulfur linkage;
and wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(b 1) hydrogen, and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
(4) a halogenated or unhalogenated C.sub.1 radical, C.sub.2 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated straight chain radicals, C.sub.3 -C.sub.8 saturated or unsaturated, halogenated or unhalogenated branched chain radicals, and C.sub.3 -C.sub.8 cyclic radicals;
(5) ##STR293## (6) --SCN;
B) R2 is --C.tbd.C--R14';
C) R3 is selected from the group consisting of:
(1)hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups ##STR294## (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the amino acid ##STR295## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR296## (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
##STR297## F) R9 is selected from the group consisting of (1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl,
except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR298## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR299## (3) an R14 group;
and (4) pharmaceutically acceptable ##STR300## (5) pharmaceutically acceptable ##STR301## groups;
and (6) a pharmaceutically acceptable ##STR302## wherein R26 is selected from ##STR303## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR304## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR305## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in the formula I is a double bond, then R12 is not substituted.

44 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/745,216Filed 13 Aug 1991 · continuation in part
Priority: 25 Aug 1987
Granted: 3 Aug 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 31/568
Not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol: substituted in positions 10 and 13 by a chain having at least one…
A61K 31/565
Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids: not substituted in position 17 beta by a…
A61K 31/57
Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids: substituted in position 17 beta by a chain…
A61K 31/573
Substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone: substituted in position 21, e.g. cortisone,…

Family

Serial89,362Parent of this continuation-in-part · filed 25 Aug 1987
Serial379,047Parent of this continuation-in-part · filed 13 Jul 1989
Serial521,724Parent of this continuation-in-part · filed 10 May 1990
US 5,120,723 AParent of this continuation-in-part
US 5,232,917 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

each R14' listed below is individually selected from the group R14 and hydrogen;
each R15 listed below is individually selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated straight chain radical, and a C.sub.3 -C.sub.4 saturated or unsaturated, halogenated or unhalogenated branched chain radical;
each R15.dbd. listed below is independently selected from the group R15 and hydrogen;
each R16 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.20 saturated, or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.20 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, or C.sub.5 -C.sub.10 aromatic radical, and a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms;
each R16' listed below is independently selected from the group R16 and hydrogen;
each R17 listed below is independently selected from the group consisting of a halogenated or unhalogenated C.sub.1 radical, a C.sub.2 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated straight chain radical, a C.sub.3 -C.sub.10 saturated or unsaturated, halogenated or unhalogenated branched chain radical, a C.sub.3 -C.sub.10 alicyclic radical, a C.sub.5 -C.sub.10 aromatic radical, a 4-, 5-, 6-, or 7-member, C-- or N-- attached, heterocyclic radical having one or more saturated or unsaturated rings containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, excluding heterocyclic radicals with two or more adjacent O or S atoms, and an amide ##STR65## radical where n is 1-10, R16' is as previously defined, and each R16' is independently determined;
each R17' listed below is independently selected from the group R17 and hydrogen;
each A is independently selected from the group consisting of acetic, propionic, normal and isomeric forms of butyric, valeric, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic and dodecanoic, cinnamic, benzylic, benzoic, maleic, fumaric, ascorbic, pimelic, succinic, bismethylene-salicyclic, methanesulfonic, ethanesulfonic, oxalic, tartaric, salicyclic, acetyl salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, cyclohexyl-sulfamic, gamma-amino-butyric, .alpha.-(2-hydroxyethylamino)-propionic, phosphoric, phosphonic, sulfuric, sulfonic, glucuronic and 1-methyl-1,4-dihydro nicotinic acids;
each X independently is oxygen, nitrogen, or sulfur;
each Y is either a divalent oxygen or sulfur linkage;
and
wherein
A) R1, R4, R5, and R6 are individually selected from the group consisting of:
(1) hydrogen;
and
(2) pharmaceutically acceptable ether and thioether groups --Y--R14';
and
(3) halogen atoms;
and
(4) an R14 group;
and
(5) ##STR66## (6) --SCN;
B) R2 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms except when R3 is hydroxyl;
and
(3) pharmaceutically acceptable --CH.sub.2 --Y--R14 or --CH.sub.2 --Y--CH.sub.2 --R14';
and
(4) an R15 group;
and
(5) ##STR67## --CH.sub.2 --C.tbd.N, --CH.sub.2 --SCN,--CH.sub.2 --N.dbd.N.dbd.N, --C.tbd.N, --SCN, and --N.dbd.N.dbd.N;
C) R3 is selected from the group consisting of:
(1) hydroxyl and thio;
and
(2) pharmaceutically acceptable ester and thioester groups;
##STR68## and (3) pharmaceutically acceptable cleavable esters of natural or synthetic amino acids of the formula --Y--Q wherein Q is a natural or synthetic amino acid and Q is attached to Y through the carbonyl carbon of the ##STR69## (4) pharmaceutically acceptable acyloxyalkyloxy or acyloxyalkylthio ##STR70## ;
and (5) a pharmaceutically acceptable ester of an acid A;
D) R7 is selected from the group consisting of
(1) hydrogen;
and
(2) halogen atoms;
and
(3) pharmaceutically acceptable ether and thioether groups --Y--R15';
and
(4) an R15 group;
except when R8 is hydroxyl, R7 is not hydroxyl, and when the bond between carbons C16-C17 in formula I is a double bond, R7 is not substituted;
E) R8 is selected from the group consisting of:
(1) hydroxyl, thio, acetyl ##STR71## 2-hydroxyethanoyl ##STR72## 1-hydroxyethyl ##STR73## and .dbd.O;
and (2) pharmaceutically acceptable ester or thioester groups ##STR74## ;
and (3) pharmaceutically acceptable ##STR75## groups;
and (4) pharmaceutically acceptable ##STR76## groups;
(5) pharmaceutically acceptable ##STR77## ;
and (6) pharmaceutically acceptable oxime ##STR78## ;
and (7) pharmaceutically acceptable thiazolidine derivatives having the formula:
##STR79## wherein one of R20 and R21 is ##STR80## any two of the remaining R18, R19, R20 and R21 are individually an R14' group, and the remaining of R18, R19, R20 and R21 is hydrogen
;
and
(8) pharmaceutically acceptable ##STR81## wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group ;
and
(9) pharmaceutically acceptable carboxylate ##STR82## ;
and (10) pharmaceutically acceptable ##STR83## (11) pharmaceutically acceptable ##STR84## groups;
and (12) cyano --C.tbd.N, acetyleno --C.tbd.CH, and --N.dbd.N.dbd.N;
and
(13) ##STR85## (14) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR86## wherein Q is a natural or synthetic amino acid, A and Q are attached to O through the carbonyl carbon of the acid or amino acid ##STR87## and wherein one of R22 and R23 is hydrogen or methyl and the other is an R17' group;
or R7 and R8 combined are .dbd.CH--R14 or .dbd.CH--O--R14;
F) R9 is selected from the group consisting of
(1) hydrogen, halogen;
and
(2) C.sub.1 -C.sub.6 alkyl, halo-, dihalo-, and trihaloalkyl, except if the bond between carbons C9-C11 in formula I is a double bond, in which case R9 is not substituted;
G) R10 and R13 are individually selected from the group consisting of
(1) hydrogen, halogen, --C.tbd.N, --CH.sub.2 --C.tbd.N, --CH.sub.2 --OH, ##STR88## (2) --CH.sub.3, --CH.sub.2 T, --CHT.sub.2 and --CT.sub.3 wherein T is a halide;
and
H) one of R11 and R12 is hydrogen, and the other is selected from the group consisting of
(1) hydrogen, hydroxy, and thio, and
(2) --Y--R14 ', --CH.sub.2 --Y--R14', --CH.sub.2 --Y--CH.sub.2 --R14', ##STR89## ;
and (3) and R14 group
;
and
(4) pharmaceutically acceptable ##STR90## ;
and (5) pharmaceutically acceptable ##STR91## groups;
and (6) a pharmaceutically acceptable ##STR92## wherein R26 is selected from ##STR93## and (7) a pharmaceutically acceptable cleavable ester of an acid or amino acid ##STR94## wherein Q is a natural or synthetic amino acid, and A and Q are attached to O through the carbonyl carbon of the amino acid ##STR95## or together R11 and R12 make a double bond to oxygen or sulfur to form the keto or sulfo;
except if the bond between carbons C9-C11 or C11-C12 in formula I is a double bond, then R12 is not substituted.

80 more elements

Facts

Application

07/745,216Filed 13 Aug 1991 · continuation in part

Priority

25 Aug 1987

Granted

3 Aug 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification28 codes

A61K 31/568
Not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol: substituted in positions 10 and 13 by a chain having at least one…
A61K 31/565
Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids: not substituted in position 17 beta by a…
A61K 31/57
Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids: substituted in position 17 beta by a chain…
A61K 31/573
Substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone: substituted in position 21, e.g. cortisone,…

Family

Serial89,362Parent of this continuation-in-part · filed 25 Aug 1987

Serial379,047Parent of this continuation-in-part · filed 13 Jul 1989

Serial521,724Parent of this continuation-in-part · filed 10 May 1990

US 5,120,723 AParent of this continuation-in-part

US 5,232,917 AThis patent

From the US filing history. Foreign family members aren’t listed.