Androstane and pregnane steroids with potent allosteric GABA receptor chloride ionophore modulating properties

A compound of structure 3′, wherein:

• R1is H or (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, 2-arylsubstituted ethynyl, arylsubstituted C1-4 alkyl, arylsubstituted C2-4-alkenyl, arylsubstituted C3-6 cycloalkyl, heterocycle, 2-heterocycle-substituted ethynyl, heterocycle-substituted C1-4 alkyl, heterocycle-substituted C2-4-alkenyl, or heterocycle-substituted C3-6 cycloalkyl;
• R2 group is OH or OR14, where R14 is HCO— or (optionally substituted) C2-18 alkyl-CO—, C2-18 alkenyl-CO—, C2-18 alkynyl-CO—, C6-10 aryl-CO— or heterocycle-CO—;
• or R14 is (optionally substituted) C1-18 alkyl-X—CO—, C2-18 alkenyl-X—CO—, C2-18 alkynyl-X—CO—, C6-10 aryl-X—CO— or heterocycle-X—CO—;
• or R14 is trimethylsilyl or triethylsilyl;
• or R14 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, or C2-4 alkynyl, or;
• or R14 is HO—SO2— or a salt thereof or R2 is NR15R16, where R15 is H, OH or (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, heterocycle or R15 is OR17, where R17 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, or heterocycle, C1-18 alkyl-CO—, C2-18 alkenyl-CO—, C2-18 alkynyl-CO—, C6-10 aryl-CO— or heterocycle-CO—;
• and where R16 is H or (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, or heterocycle, or R16 is H-CO— or (optionally substituted) C1-18 alkyl-CO—, C2-18 alkenyl-CO—, C2-18 alkynyl-CO—, C3-6 cycloalkyl-CO—, C6-10 aryl-CO— or heterocycle-CO—;
• where X is O or NR100, where R100 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl C6-10 aryl or heterocycle;
• or
• X is NOR110, where R110 is H or C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, or heteroaryl, any of which is optionally substituted;
• or
• X is
• where Y is —(CH2)m— where m is an integer of 0 to 3, or Y is —(CH2)n—Z—(CH2)p— where n is an integer of 0 to 2, p is an integer of 0 to 2 and Z is a heteroatom (optionally substituted) or Z is a carbon atom substituted with one or two C1-6 alkyl groups;
• R3 is H, halogen, cyano, azido or (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, or heterocycle;
• R4 is H or (optionally substituted) Me;
• R6 is H, or (optionally substituted) C1-8 alkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl or heterocycle;
• R8 is H, halogen, azido, cyano, thiocyano, ═O, OH, OR16 (where R16 is as defined above);
• or R8 is NH2 or NR15R16 (where R15 and R16 are as defined above);
• or R8 is (optionally substituted) C1-18 alkyl, C3-6 cycloalkyl, C2-18 alkynyl, C2-18 alkenyl, C6-10 aryl or heterocycle;
• or R8 is COOR18 where R18 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C6-10 aryl, or heterocycle;
• or R8 is S(O)nR16, where R16 is as defined above and n=0, 1, or 2;
• R9 is H, cyano, azido, halogen, thiocyano, OH, OR16, where R16 is as defined above, or R9 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl, 2-arylsubstituted ethynyl, arylsubstituted C1-4 alkyl, arylsubstituted C2-4-alkenyl, arylsubstituted C3-6 cycloalkyl, heterocycle;
• 2-heterocycle-substituted ethynyl, heterocycle-substituted C1-4 alkyl, heterocycle-substituted C2-4-alkenyl, heterocycle-substituted C3-6 cycloalkyl;
• R10 is H, keto, halogen, cyano, thiocyano, azido or NR15R16, where R15 and R16 are as defined above;
• or R10 is (optionally substituted) C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkynyl, C2-4 alkenyl, C6-10 aryl or heterocycle;
• or R10 is S(O)nR16, where R16 is as defined above and n=0, 1, or 2;
• or R10 is OR16 where R16 as defined above or R16 is trimethylsilyl or triethylsilyl;
• R11 is C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C3-8 cycloalkyl, C6-12 aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heteroaralkenyl or heteroaralkynyl any of which is optionally substituted;
• or
• R11 is
• where R50 and R60 are each independently H;
• halogen;
• (R70R80N(O)r)—, where r is 0 or 1 and R70 and R80 are each independently H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl, any of which is optionally substituted;
• substructure II,
• where q is 0 or 1, Y is —(CH2)m— where m is an integer of 0 to 5, or Y is —(CH2)n—Z—(CH2)p— where n is an integer of 0 to 2, p is an integer of 0 to 2, and Z is a heteratom (optionally substituted) and where the CH2 groups are optionally substituted;
• N-imidazolyl;
• —N-pyrrolyl-;
• HO—;
• CF3SO2O—;
• C1-6 alkyl-O—;
• C1-6 perfluoroalkyl-O—;
• C1-6 alkyl-S—;
• C1-6 alkyl-CH(OH)—;
• NC—;
• HCC—;
• C6H5CC—;
• 2′-furyl;
• 3′-furyl;
• 2′-thiophenyl;
• 3′-thiophenyl;
• 2′-pyridyl;
• 3′-pyridyl;
• 4′-pyridyl;
• 2′-thiazolyl;
• 2′-N-methylimidazolyl;
• 5′-pyrimidinyl;
• C6H5—;
• H2C═CH—;
• C1-6 alkyl;
• MeC(═CH2)—;
• C1-6 alkyl-CO;
• HCO;
• C1-6 alkyl;
• C═NOR120, or HC═NOR120, where R120 is H or C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-12 aryl, or heteroaryl, any of which is optionally substituted;
• or R50 and R60 combine to form a ring
• where W is CH2, CH, NH, N, O, or S, and R90 is H or C1-6 alkyl;
• or R50 and R60 combine to form a ring
• where A and B are each independently H, F or C1-6 alkyl or A and B combine to form ═O;
• or R50 and R60 combine to form a ring
• where the CH2 groups are independently and optionally substituted;
• and
• R13 is nitro;
• J is one of S, SO or SO2;
• J′ is one of O, S, SO or SO2;
• Q is one of C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl;
• G is one of C-attached hetero-C5-10-aryl, optionally substituted C6-10 aryl, a quaternary ammonium salt of a nitrogen containing hetero-C5-10-aryl group or a quarternary salt of an amino substituted C6-10 aryl group;
• T is C-attached hetero-C5-10-aryl or a quaternary ammonium salt of a nitrogen containing hetero-C5-10-aryl group;
• E is optionally substituted C6-10 aryl or a quaternary ammonium salt of an amino substituted C6-10 aryl group;
• L is one of amino, amido, cyano, thiocyano, azido, nitro, hydroxy, halo, carboxyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkanoyloxy, hydrogen, sulfate, thiosulfate, sulfonate, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl or mercapto. and stereoisomers thereof.