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US 2008/0176884 A1Published application
7,8-Saturated-4,5-Epoxy-Morphinanium Analogs
AssigneeProgenics Pharmaceuticals, Inc.
InventorsJulio Perez, Amy Qi Han, Yakov Rotshteyn
Life of this patent
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Abstract
Novel 7,8-saturated-4,5-epoxy-morphinanium analogs are disclosed. Pharmaceutical compositions containing the 7,8-saturated-4,5-epoxy-morphinanium analogs and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as modulators of opioid receptors.
Claims32
Compounds having the formula I(e):
- or a pharmaceutically acceptable salt form, polymorph, or prodrug thereof, wherein:
- R1 and R2 are independently H, OH, OR29, halide, silyl;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R1 and R2 are combined to form a C3-C6 carbocycle fused ring, a benzo fused ring,
- or a 5-6 membered heteroaryl fused ring;
- R3 is H, silyl, CO2R19, SO2R19, B(OR19)2;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R5 is H, OH, OR29,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R6 is H, ═O, N(CH3)2, ═(R19)(R19′), =(hetero cycle substituted with 0-3R20), ═(C3-C7 cycle substituted with 0-3R20) or any cyclic ring;
- R7 is H, OH, OR29,
- (C1-C20) alkyl substituted with 0-3 R19;
- (C2-C20) alkenyl substituted with 0-3 R19;
- (C2-C20) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R6 and R7 are combined to form an O-fused ring, a C3-C6 carbocycle fused ring, a benzo fused ring, 5-, 6- or a 5-6 membered aryl with 0-3 R20, or a heteroaryl fused ring;
- R8 is H, OH, OR29, hetero cycle with 0-3R20, alkylaryl with 0-3R20, arylalkyl with 0-3 R20,
- wherein, X is bond, ═O, O, S, N(R29), SO—SO2, SO2N(R29), CON(R29), N(R29)CON(R29′), N(R29)C(═NR29′)N(R29″), COO,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R14 is H, OH, halide, hetero cycle with 0-3R20, alkylaryl with 0-3R20, arylalkyl with 0-3 R20,
- wherein, X is bond, ═O, O, S, N(R29), SO, SO2, SO2N(R29), CON(R29), N(R29)CON(R29′), N(R29)C(═NR29′)N(R29″), COO,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- aryloxy, acyloxy,
- or combined with R18 to form an O-fused ring, or a C3-C6 carbocycle fused ring, or if R6=a cyclic ring, or forms a cyclic ring with R7, may be further be an alkoxy or aryloxy;
- wherein if R6 is ═O, R14 is not:
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- R17 is heterocycle with 0-3R20, alkylaryl with 0-3R20, arylalkyl with 0-3 R20,
- wherein, X is bond, ═O, O, S, N(R29), SO, SO2, SO2N(R29), CON(R29), N(R29)CON(R29′), N(R29)C(═NR29′)N(R29″), COO,
- (C4-C20) alkyl substituted with 0-3 R25;
- (C4-C20) alkenyl substituted with 0-3 R25;
- (C4-C20) alkynyl substituted with 0-3 R25;
- (C3-C10) cycloalkyl substituted with 0-3R26;
- (C3-C10) carbocycle substituted with 0-3R26;
- aryl substituted with 0-3R26;
- R18 is (C1-C3) alkyl substituted with 0-3 R27;
- (C2-C4) alkenyl substituted with 0-3 R27;
- (C2-C4) alkynyl substituted with 0-3 R27;
- R19 is at each occurrence is independently selected from:
- H, aryl substituted with 0-3R20, C1-C6 alkyl, CF3, OR24, Cl, F, Br, I, ═O, CN, NO2, NR22R23;
- C3-C10 carbocycle substituted with 0-3 R21;
- aryl substituted with 0-3 R21;
- or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R21;
- R20 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, acetyl, OR25, XR25,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, CF3, acetyl, OR25, XR25.
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- or
- NR22R23 may be a heterocyclic ring selected from the group piperidinyl, homopiperidinyl, thiomorpholinyl, piperizinyl, and morpholinyl;
- R22, at each occurrence, is independently selected from H, C1-C6 alkyl, C6-C10 aryl, hetero aryl, hetero cycle, alkylaryl, arylalkyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R23, at each occurrence, is independently selected from:
- H, (C1-C6) alkyl, C6-C10 aryl, hetero aryl, hetero cycle, alkylaryl, haloalkyl, and arylalkyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- wherein R22 and R23 may further be combined to form 5-, 6-, 5-6-membered cycle with 0-3R20;
- R24, at each occurrence, is independently selected from H, phenyl, benzyl, (C1-C6) alkyl, haloalkyl and (C2-C6) alkoxyalkyl;
- R25, at each occurrence, is independently selected from:
- H, C1-C6 alkyl, haloalkyl, OR24, ═O, CN, NO2, NR27R28;
- C3-C10 carbocycle substituted with 0-3 R27;
- aryl substituted with 0-3 R27;
- or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R27;
- R26, at each occurrence, is independently selected from:
- H, (C1-C6)alkyl, benzyl, phenyl, phenethyl, (C1-C6 alkyl)-C(═O)—;
- R27, at each occurrence, is independently selected from:
- —OH, —OR28, C1-C6 alkyl, C1-C4 alkoxy;
- R28, at each occurrence, is independently selected from:
- C1-C6 alkyl;
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(—O)2—;
- and
- R29 is at each occurrence is independently selected from:
- H, C1-C6 alkyl, CF3, acyl(C1-C6)alkyl;
- acylaryl substituted with 0-3 R21;
- C3-C10 carbocycle substituted with 0-3 R21;
- aralkyl substituted with 0-3 R21;
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R21;
- or aryl substituted with 0-3R20;
- and
- X− is an anion
109 more elements
Compounds having the formula I:
- or a pharmaceutically acceptable salt form, polymorph, or prodrug thereof, wherein:
- R17 and R18 are selected alternatively with respect to one another from (a) or (b):
- (a) unsubstituted or non-halogen substituted:
- C4-C20 (cycloalkyl)alkyl or (cycloalkenyl)alkyl, (cycloheteryl)alkyl, (cycloaryl)alkyl;
- C4-C10 (cycloalkyl)alkyl or (cycloalkenyl)alkyl, (cycloheteryl)alkyl, (cycloaryl)alkyl
- (b) substituted or unsubstituted linear or branched C1-C3 alkyl, C2-C3 alkenyl, or C3 alkynyl;
- wherein if (b) is selected as methyl, and R6 below is selected as ═O, (a) is not unsubstituted (cyclopropyl)methyl;
- R6 is O, ═CH2, —N(CH3)2, or any cyclic ring, or forms a cyclic ring with R7;
- R7 and R8 are H or alkyl;
- R14 is OH, halide, amido, amino, or forms a cyclic ring with R18, and if R6=a cyclic ring, or forms a cyclic ring with R7, may further be an alkoxy or aryloxy, and if R6 is not ═O, R14 may be alkoxy or aryloxy;
- R1 and R2 are independently H, halide, alkoxy, alkyl, or aryl
- R3 is H, C1-C4 alkyl, or C1-C3 acyl, -silyl
- R5 is H, OH, alkyl, alkoxy, or aryloxy;
- and
- X− is an anion.
12 more elements
Compounds having the formula I(a):
- or a pharmaceutically acceptable salt form or prodrug thereof, wherein:
- R1 and R2 are independently H, OH, OR29, halide, silyl;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R1 and R2 are combined to form a C3-C6 carbocycle fused ring, a benzo fused ring,
- or a 5-6 membered heteroaryl fused ring;
- R3 is H, silyl;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R5 is H, OH, OR29,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R6 is H, ═O, N(CH3)2, or any cyclic ring;
- R7 is H, OH, OR29,
- (C1-C20) alkyl substituted with 0-3 R19;
- (C2-C20) alkenyl substituted with 0-3 R19;
- (C2-C20) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R6 and R7 are combined to form an O-fused ring, a C3-C6 carbocycle fused ring, a benzo fused ring, or a 5-6 membered heteroaryl fused ring;
- R8 is H, OH, OR29
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R14 is H, OH, halide,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- aryloxy, acyloxy,
- or combined with R18 to form an O-fused ring, or a C3-C6 carbocycle fused ring, or if R6=a cyclic ring, or forms a cyclic ring with R7, may be further be an alkoxy or aryloxy;
- wherein if R6 is ═O, R14 is not:
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- R17 is (C4-C20) alkyl substituted with 0-3 R25;
- (C4-C20) alkenyl substituted with 0-3 R25;
- (C4-C20) alkynyl substituted with 0-3 R25;
- (C3-C10) cycloalkyl substituted with 0-3R26;
- (C3-C10) carbocycle substituted with 0-3R26;
- aryl substituted with 0-3R26;
- R18 is (C1-C3) alkyl substituted with 0-3 R27;
- (C2-C4) alkenyl substituted with 0-3 R27;
- (C2-C4) alkynyl substituted with 0-3 R21;
- R19 is at each occurrence is independently selected from:
- H, C1-C6 alkyl, CF3, OR24, Cl, F, Br, I, ═O, CN, NO2, NR22R23;
- C3-C10 carbocycle substituted with 0-3 R21;
- aryl substituted with 0-3 R21;
- or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R21;
- R20 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- or
- NR22R23 may be a heterocyclic ring selected from the group piperidinyl, homopiperidinyl, thiomorpholinyl, piperizinyl, and morpholinyl;
- R22, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R23, at each occurrence, is independently selected from:
- H, (C1-C6) alkyl, benzyl, phenethyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R24, at each occurrence, is independently selected from H, phenyl, benzyl, (C1-C6) alkyl, and (C2-C6) alkoxyalkyl;
- R25, at each occurrence, is independently selected from:
- H, C1-C6 alkyl, OR24, ═O, CN, NO2, NR2, R28;
- C3-C10 carbocycle substituted with 0-3 R27;
- aryl substituted with 0-3 R27;
- or
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R27;
- R26, at each occurrence, is independently selected from:
- H, (C1-C6)alkyl, benzyl, phenyl, phenethyl, (C1-C6 alkyl)-C(═O)—;
- R27, at each occurrence, is independently selected from:
- —OH, —OR28, C1-C6 alkyl, C1-C4 alkoxy;
- R28, at each occurrence, is independently selected from:
- C1-C6 alkyl;
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R29 is at each occurrence is independently selected from:
- H, C1-C6 alkyl, CF3, acyl(C1-C6)alkyl;
- acylaryl substituted with 0-3 R21;
- C3-C10 carbocycle substituted with 0-3 R21;
- aralkyl substituted with 0-3 R21;
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R21;
- or aryl substituted with 0-3R20;
- and
- X− is an anion.
103 more elements
Compounds having the formula I(b):
- or a pharmaceutically acceptable salt form, polymorph, or prodrug thereof, wherein:
- R1 and R2 are independently H, OH, OR29, halide, silyl;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R1 and R2 are combined to form a C3-C6 carbocycle fused ring, a benzo fused ring,
- or a 5-6 membered heteroaryl fused ring;
- R3 is H, silyl;
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R5 is H, OH, OR29,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R6 is H, ═O,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- amine, amide, sulfonamide, ester, heterocycle, cyclic carbohydride, aryl;
- R7 is H, OH, OR29,
- (C1-C20) alkyl substituted with 0-3 R19;
- (C2-C20) alkenyl substituted with 0-3 R19;
- (C2-C20) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- or R6 and R7 are combined to form an O-fused ring, a C3-C6 carbocycle fused ring, a benzo fused ring, or a 5-6 membered heteroaryl fused ring;
- R8 is H, OH, OR29
- (C1-C8) alkyl substituted with 0-3R19,
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- R14 is H, OH,
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- aryl substituted with 0-3R20;
- aryloxy, acyloxy,
- or R14 is combined with R18 to form an O-fused ring, or a C3-C6 carbocycle fused ring;
- wherein if R6=O, R14 is not
- (C1-C8) alkyl substituted with 0-3 R19;
- (C2-C8) alkenyl substituted with 0-3 R19;
- (C2-C8) alkynyl substituted with 0-3 R19;
- (C3-C10) cycloalkyl substituted with 0-3R20;
- (C3-C10) carbocycle substituted with 0-3R20;
- R17 is (C4-C10) alkyl substituted with 0-3R25;
- (C4-C10) alkenyl substituted with 0-3R25;
- (C4-C10) alkynyl substituted with 0-3R25;
- (C3-C10) cycloalkyl substituted with 0-3R26;
- (C3-C10) carbocycle substituted with 0-3R26;
- aryl substituted with 0-3R26;
- R18 is (C1-C3) alkyl substituted with 0-3R27;
- (C2-C4) alkenyl substituted with 0-3R27;
- (C2-C4) alkynyl substituted with 0-3R27;
- R19 is at each occurrence is independently selected from:
- H, C1-C6 alkyl, CF3, OR24, Cl, F, Br, I, ═O, CN, NO2, NR22R23;
- C3-C10 carbocycle substituted with 0-3R21;
- aryl substituted with 0-3R21;
- or
- a 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R21;
- R20 at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- R21, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR22R23, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- or
- NR22R23 may be a heterocyclic ring selected from the group piperidinyl, homopiperidinyl, thiomorpholinyl, piperizinyl, and morpholinyl;
- R22, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R23, at each occurrence, is independently selected from:
- H, (C1-C6) alkyl, benzyl, phenethyl,
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R24, at each occurrence, is independently selected from H, phenyl, benzyl, (C1-C6) alkyl, and (C2-C6) alkoxyalkyl;
- R25, at each occurrence, is independently selected from:
- H, C1-C6 alkyl, OR24, ═O, CN, NO2, NR27R28;
- C3-C10 carbocycle substituted with 0-3R27;
- aryl substituted with 0-3R27;
- or
- a 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, wherein said 5 to 10 membered heterocycle is substituted with 0-3R27;
- R26, at each occurrence, is independently selected from:
- H, (C1-C6)alkyl, benzyl, phenyl, phenethyl, (C1-C6 alkyl)-C(═O)—;
- R27, at each occurrence, is independently selected from:
- —OH, —OR28, C1-C6 alkyl, C1-C4 alkoxy;
- R28, at each occurrence, is independently selected from:
- C1-C6 alkyl;
- (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- and
- R29 is at each occurrence is independently selected from:
- H, C1-C6 alkyl, CF3, acyl(C1-C6)alkyl;
- acylaryl substituted with 0-3R21;
- C3-C10 carbocycle substituted with 0-3R21;
- aralkyl substituted with 0-3R21;
- 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3R21;
- or aryl substituted with 0-3R20;
- and
- X− is an anion.
111 more elements
A composition comprising at least one compound, polymorph, or salt thereof, selected from the group consisting of:
- 17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-methylenemorphinanium;
- 17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-17-methyl-3-propyloxy-6-oxomorphinanium;
- 17-Allyl-17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-6-oxomorphinanium;
- 17-cyclobutylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium;
- 17-cyclopentylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-methylenemorphinanium;
- 17-(3,3′-dimethylallyl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium;
- 17-(3′-phenylbut-2′-ynyl)-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium;
- 17-(2′,2′-Difluorocyclopropyl)methyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium;
- 17-cyclopropylmethyl-4,5α-epoxy-3-benzyloxy-14-hydroxy-17-methyl-6α-methoxy-morphinanium;
- and
- 17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6β-hydroxy-8-propoxy-morphinanium;
- 17-(2′-Methylcyclopropyl)methyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6α-methoxy morphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methyl-6β-methoxy morphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3-methoxy-14-hydroxy-17-methyl-6-methylenemorphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-17-methylmorphinanium;
- 3-Acetyl-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-17-methylmorphinanium;
- 17-[(2′-tetrahydrofuryl)methyl]-4,5α-epoxy-3,14-dihydroxy-17-methyl-6-oxo-morphinaninium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-17-methyl-14-(3′-phenylpropyloxy)morphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-17-methyl-14-propyloxy morphinanium;
- 17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-17-methyl-14-methoxy-morphinanium;
- 17-methyl-4,5α-epoxy-3-hydroxy-(17,14-N,O-ethylene-6-oxo-morphinanium;
- and
- 17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-(17,14-N,O-ethylene)-6-oxo-morphinanium.
21 more elements
Compounds having the formula I(c):
- or a pharmaceutically acceptable salt form, polymorph, or prodrug thereof,
- wherein:
- R17 and R18 are selected alternatively with respect to one another from (a) or (b):
- (a) unsubstituted or non-halogen substituted:
- C4-C20 (cycloalkyl)alkyl or (cycloalkenyl)alkyl, (cycloheteryl)alkyl, (cycloaryl)alkyl;
- C4-C10 (cycloalkyl)alkyl or (cycloalkenyl)alkyl, (cycloheteryl)alkyl, (cycloaryl)alkyl
- (b) substituted or unsubstituted linear or branched C1-C3 alkyl, C2-C3 alkenyl, or C3-alkynyl;
- wherein if (b) is selected as methyl and R6 below is selected ═O, (a) is not an unsubstituted (cyclopropyl)methyl;
- R6 is ═O, ═CH2, —N(CH3)2, or any cyclic ring, or forms a cyclic ring with R7;
- R7 and R8 are H, hydrocarbyl, cyclohydrocarbyl, alkoxy, amine, amide, hydroxy or substituted moieties thereof;
- R14 is H, OH, halide, N-alkyl, N-dialkyl, N-aryl, N-alkylaryl, N-cycloalkylalkyl, or forms a cyclic ring with R17 or R18;
- and if R6 is not —O, R14 may be alkoxy, aryloxy, or aryl-alkoxy;
- R1 and R2 are independently H, halide, alkoxy, alkyl, or aryl;
- R3 is H, C1-C4 alkyl, or C1-C3 acyl, -silyl;
- R5 is H, OH, alkyl, alkoxy, or aryloxy;
- and
- X− is an anion.
14 more elements
Compounds having the formula I(d):
- or a pharmaceutically acceptable salt form, polymorph, or prodrug thereof,
- wherein:
- R17 and R18 are a substituted or unsubstituted hydrocarbyl, when R6 is ═O at least one of which is not methyl when the other is unsubstituted cyclopropylmethyl;
- R6 is H, OH, OR25, ═O, ═CH2, —N-alkyl, N-dialkyl, acyloxy, alkoxy, alkyl, ═CR′R″ where R′ and R″ are independently H or C1-C10 alkyl, or any ring, or R6 forms a ring with R7;
- R7 and R8 are H or hydrocarbyl, cyclohydrocarbyl, alkoxy, amine, amide, hydroxy or substituted moieties thereof,
- R14 is H, OH, halide, N-alkyl, N-dialkyl, N-aryl, N-alkylaryl, N-cycloalkylalkyl, SR25, S(═O)R25, SO2R25, or forms a cyclic ring with R17 or R18;
- and if R6 is not ═O, R14 may be alkoxy, aryloxy, or aryl-alkoxy;
- R1 and R2 are independently H, halide, alkoxy, alkyl, or aryl;
- R3 is H, alkyl, C1-C3 acyl, silyl;
- R5 is H, OH, alkyl, alkoxy, or aryloxy;
- R25 is alkyl, aryl, arylalkyl;
- and
- X− is an anion.
10 more elements
A composition comprising at least one compound, polymorph, or salt thereof, selected from the group consisting of:
Dependencies are inferred from the claim text.