Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
First Claim
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1. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety at the C-17 position of the estratriene nucleus, wherein:
- j is an integer in the range of 0 to 5 inclusive;
p is an integer in the range of 0 to 6;
R29 and R30 are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R29 and R30 are not both hydrogen; and
L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen.
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Abstract
Novel anti-estrogenic compounds are provided which are useful to treat a variety of disorders, particularly estrogen-dependent disorders. Preferred compounds have a 1,3,5(10)-estratriene nucleus, and are substituted at the C-17 or C-11 position with a molecular moiety which renders the compounds effective to competitively block the binding of estrogen to its receptor. Particularly preferred compounds are 17-desoxy-1,3,5(10)-estratrienes. Therapeutic methods and pharmaceutical compositions are provided as well.
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Citations
21 Claims
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1. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
p is an integer in the range of 0 to 6;
R29 and R30 are selected from the group consisting of hydrogen, lower alkyl, and halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring, with the proviso that R29 and R30 are not both hydrogen; and
L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereof, and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen. - View Dependent Claims (7, 8, 9, 10, 11, 12, 13, 14, 20)
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2. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
p is an integer in the range of 0 to 6;
R29 and R30 are lower alkyl or are linked together to form a heterocycloalkyl ring; and
Q1, Q2, Q3 and Q4 are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.
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3. A compound having the formula (Ia)
wherein: -
j is an integer in the range of 0 to 5 inclusive;
p is an integer in the range of 0 to 6 inclusive;
when r2 is present, R1 is CR11R12, wherein R11 and R12 are hydrogen or lower alkyl, and when r2 is absent, R1 is hydrogen, alkyl or halogen;
R2 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, aryl, alkaryl, —
ONO2, —
OR13 and —
SR13 wherein R13 is alkyl, acyl or aryl;
R3 is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, aryl, alkaryl, cyano, —
OR13 and —
SR13 wherein R13 is alkyl, acyl, or aryl;
as defined previously; R4 is hydrogen or lower alkyl;
R5 is selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, —
CH2CH═
CH2, —
CHO, —
NR14R15 and —
(CH2)NR14R15 wherein R14 and R15 may be the same or different and are either hydrogen or alkyl, or together form a five- or six-membered cycloalkyl group optionally containing an additional nitrogen heteroatom;
R6 is selected from the group consisting of hydrogen, alkyl, acyl, —
C(O)-aryl, —
C(O)-alkyl and —
SO2NH2;
R7 is selected from the group consisting of hydrogen, halogen, —
NO2, —
CHO, —
CH2CH═
CH3, —
NR16R17 and —
(CH3)NR16R17 wherein R16 and R17 may be the same or different and are either hydrogen, alkyl or acetyl;
R8 is selected from the group consisting of hydrogen, hydroxyl, —
OR18 and —
SR18 wherein R18 is lower alkyl, lower acyl or aryl;
R10 is methyl or ethyl;
R29 and R30 are selected from the group consisting of hydrogen, lower alkyl and halogenated lower alkyl, or are linked together to form a five- or six-membered heterocycloalkyl ring, with the proviso that when R3 is hydrogen, then R29 and R30 are not both hydrogen; and
L is a five- or six-membered cyclic moiety that may or may not be aromatic, optionally containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and combinations thereon and optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halogenated alkyl, alkenyl, and alkoxy, carboxyl, hydroxy, amino, nitro, cyano, and halogen, or a pharmaceutically acceptable salt or ester thereof. - View Dependent Claims (4)
wherein R29 and R30 are lower alkyl or are linked together to form a five- or six-membered heterocycloalkyl ring, and Q1, Q2, Q3 and Q4 are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, alkoxy, alkyl, halogen, amino, and alkyl-substituted amino.
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5. A chemical compound selected from the group consisting of:
- (E)-3-hydroxy-21-(2′
-hydroxylethylamino)-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[3′
-(N,N-dimethylamino)-propylamino]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-{2-[2″
-(N,N-dimethylamino)ethoxy]-ethoxy}-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[3′
-(N,N-dimethylamino)propoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(N,N-dimethylamino)-ethanethio]-19-norpregna-1,3,5(10),17(20-tetraene, (E)-3-hydroxy-21-[2′
-(pyrrolidinyl)ethoxy]-19-norpregna-1,3,5(10), 17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(morpholinyl)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(piperazinyl)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
-methyl-21-[2′
-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-2-methoxy-21-[2′
-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
-methyl-21-[2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(N,N-dimethylamino)-2-propoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (Z)-3-hydroxy-21-[2′
-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-(N-methyl-3-(R,S)-pyrrolidinoxy)-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[N-methyl-2(S)-pyrrolidinylmethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (K)-3-hydroxy-2-N,N-dimethylaminomethyl-21-[2′
-(N′
,N′
-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
-methyl-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (K)-3-hydroxy-7α
-methyl-21-{2′
-[2″
-(N,N-dimethylamino)-ethoxy]ethoxy}-19-norpregna-1,3,5(10),17(20)-tetraene, (E)- and (Z)-3-hydroxy-7α
-methyl-21-[2′
-(pyrrolidinyl)methoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
- and 7β
-ethyl-21-[2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (Z)-3-tetrahydropyranyloxy-20-methyl-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-tetrahydropyranyloxy-20-methyl-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (Z)-3-hydroxy-20-methyl-21-]2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-20-methyl-21-[2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, and 21-(2′
-N,N-dimethylaminoethoxy)-[17(20)E]-19-norpregna-1,3,5(10),18(20)-tetraene-3-O-sulfamate.
- (E)-3-hydroxy-21-(2′
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6. A chemical compound selected from the group consisting of:
- (E)-3-hydroxy-21-[2′
-(N,N-dimethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
-methyl-21-[2′
-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-2-methoxy-21-[2′
-(N,N-dimethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, the citrate of (E)-3-hydroxy-7α
-methyl-21-[2′
-(N,N-diethylamino)ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
-methyl-21-{2′
-[2″
-(N,N-dimethylamino)-ethoxy]ethoxy}-19-norpregna-1,3,5(10),17(20)-tetraene, (E)- and (Z)-3-hydroxy-7α
-methyl-21-[2′
-(pyrrolidinyl)methoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, (E)-3-hydroxy-7α
- and 7β
-ethyl-21-[2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene, and (E)-3-hydroxy-20-methyl-21-[2′
-(N,N-diethylamino)-ethoxy]-19-norpregna-1,3,5(10),17(20)-tetraene.
- (E)-3-hydroxy-21-[2′
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15. A method for lowering serum cholesterol in the body of a mammalian individual, comprising administering to the individual an effective serum cholesterol lowering amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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16. A method for inhibiting a pulmonary hypertensive disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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17. A method for inhibiting skin atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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18. A method for inhibiting vaginal atrophy, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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19. A method for inhibiting an estrogen-dependent CNS disorder, comprising prophylactically administering to a postmenopausal female individual an effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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21. A method for inhibiting a CNS disorder in a postmenopausal human female, comprising administering to the individual a therapeutically effective amount of a 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-17 position of the estratriene nucleus, wherein: -
j is an integer in the range of 0 to 5 inclusive;
R21 is hydrocarbyl including at least one oxygen atom, sulfur atom, and/or nitrogen atom in the form of an —
O—
, —
S—
, —
NH—
or —
N(alkyl)-linkage, and optionally including additional substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl; and
R22 is hydrogen or alkyl, or, when m is 0, R21 and R22 may be linked to form a five-or six-membered cyclic moiety which may or may not be aromatic, containing 0 to 3 heteroatoms selected from the group consisting of N, O and S, and substituted with 0 to 4 substituents selected from the group consisting of alkyl, alkenyl, alkynyl and alkoxy.
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Specification