Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
First Claim
Patent Images
1. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety at the C-11 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 j 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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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-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-estratrienes. Therapeutic methods and pharmaceutical compositions are provided as well.
73 Citations
22 Claims
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1. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-11 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 j 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. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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2. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-11 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 independently hydrogen, lower alkyl, or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring; 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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3. A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety
at the C-11 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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4. A compound having the structure of formula (II)
wherein: -
R is selected from the group consisting of C and N, and, when R is C, is in either the E or Z configuration;
r1 and r2 are optional double bonds;
X 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 substituted with one or more substituents selected from the group consisting of hydroxyl, oxo, alkoxy, amino, alkyl-substituted amino, halogeno, aryl, heteroaryl and heterocycloalkyl,X′
is hydrogen or 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, optionally substituted as for X, orX and X′
are linked to form a heterocycle containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
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;
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;
R4 is hydrogen or lower alkyl;
R5 is selected from the group consisting of hydrogen, lower alkoxy, halogen, cyano, —
CH2CH═
CH2, —
CHO, —
NR14 R15 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═
CH2, —
NR16R17 and —
(CH2)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;
R9 is hydrogen or alkyl, with the proviso that when R is N, R9 is not present;
R10 is methyl or ethyl; and
R19 and R20 are independently selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, and halogen, or R19 and R20 together form ═
O,or a pharmaceutically acceptable salt or ester thereof. - View Dependent Claims (5, 6)
wherein: j is an integer in the range of 1 to 5 inclusive;
p is an integer in the range of 0 to 6 inclusive; and
R29 and R30 are independently hydrogen, lower alkyl or halogenated lower alkyl, or are linked together to form a heterocycloalkyl ring; 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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6. The compound of claim 5, having the structure of formula (IIb)
wherein R29 and R30 are lower alkyl or 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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7. 3-Hydroxy-11E-[2′
- -(2″
-N,N-dimethylaminoethoxy-ethylidene)-1,3,5(10)-17-estrone.
- -(2″
Specification