US 6,281,205 B1 · Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use

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.

Claims16

Dependent claims

A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein:
m is an integer in the range of 1 to 6;
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.

3 more elements

A compound having the structure of formula (IIIa)

wherein:
m is an integer in the range of 1 to 6 inclusive;
n is 0 or 1;
p is an integer in the range of 0 to 6 inclusive;
r2 is an optional double bond, and 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 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═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;
R10 is methyl or ethyl;
R23 is hydrogen or lower alkyl;
and
R24 and R25 are both hydrogen or are both methylene bound to each other through a single covalent bond,
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, alkyl-substituted amino, nitro, cyano, and halogen.

16 more elements

Dependencies are inferred from the claim text.

Facts

Application

09/220,408Filed 24 Dec 1998 · continuation in part

Priority

24 Dec 1997

Granted

28 Aug 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07J 41/00
Normal steroids containing one or more nitrogen atoms not belonging to a
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 5/32
Of the sex hormones: antioestrogens
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives

Abstract

Claims16

Dependent claims

A 17-desoxy-1,3,5(10)-estratriene containing the molecular moiety

at the C-17 position of the estratriene nucleus, wherein:
m is an integer in the range of 1 to 6;
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.

3 more elements

A compound having the structure of formula (IIIa)

wherein:
m is an integer in the range of 1 to 6 inclusive;
n is 0 or 1;
p is an integer in the range of 0 to 6 inclusive;
r2 is an optional double bond, and 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 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═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;
R10 is methyl or ethyl;
R23 is hydrogen or lower alkyl;
and
R24 and R25 are both hydrogen or are both methylene bound to each other through a single covalent bond,
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, alkyl-substituted amino, nitro, cyano, and halogen.

16 more elements

Dependencies are inferred from the claim text.

Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use

Life of this patent

Abstract

Claims16

Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use

Life of this patent

Abstract

Claims16