US 2008/0167360 A1Published application

Cycloalkylidene Compounds as Selective Estrogen Receptor Modulators

AssigneeSmithKline Beecham Corporation

InventorsJing Fang, Dennis Heyer, Subba Reddy Katamreddy, Kenneth William Batchelor, Richard Dana Caldwell

Life of this patent

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Abstract

The present invention relates to compounds of formula (I) with a variety of therapeutic uses, more particularly the substituted cyclic alkylidene compounds are useful for selective estrogen receptor modulation.

Claims17

Dependent claims

A compound of formula (I):

including salts, solvates, and pharmacologically functional derivatives thereof wherein
R1 is H or F;
R2 and R4 each independently are selected from H, OH, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, or cyano;
R3 is —(Y)z—R8;
z is 0 or 1;
Y is —C≡C— or —CRe═CRf—;
each R5 is H;
or
both R5s together combine to form a bridging alkylene chain —CH2)m—, where m is 2, 3, or 4, when each R6 and each R7 is H and X is —(CH2)m-2—;
each of R6 and R7 are selected from H or alkyl;
or
when X is —(CH2)m—, both R6s are H, and both R7s together combine to form a bridging alkylene chain —(CH2)m—, where each m is the same and is as defined;
or
when X is —(CH2)m—, both R7s are H, and both R6s together combine to form a bridging alkylene chain —(CH2)m—, where each m is the same and is as defined;
when z is 0, then R8 is alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocyclyl, heterocyclyl substituted with one or more alkyl, cyano, —O(CH2)tCN, —CO2H, —(CH2)tCO2H, —O(CH2)tCO2H, —(CH2)tOH, —O(CH2)tOH, —O(CH2)tO(CH2)tOH, —C(O)NRaRb, —O(CH2)tC(O)NRaRb;
—NRaSO2Rd, or —NRaC(O)Rc;
when z is 1, then R8 is, —CO2H, —(CH2)tCO2H, —(CH2)tOH, —C(O)NRaRb, or —PO3HRa;
each t independently is 1 to 8;
X is —(CH2)n— where n is 0, 1, 2, or 3, —C(Rh)2—, —O—, —S(O)p where p is 0, 1, or 2, —C(Rg)2OC(Rg)2—, or —C(CH2)v— where v is 2 to 7 and forms a spirocycle with the depicted ring that contains X;
Ra is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rb is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rc is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rd is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
or
Ra and Rb, Ra and Rc, or Ra and Rd may combine with the atoms to which they are bound to form an optionally substituted heterocyclyl;
and
Re and Rf each are independently selected from H, alkyl, halogen, and haloalkyl;
Rg is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rh is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
wherein each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

27 more elements

A compound selected from:

(2E)-3-{4-[Cycloheptylidene(phenyl)methyl]phenyl}prop-2-enoic acid;
(2E)-3-{4-[Cycloheptylidene(phenyl)methyl]phenyl}prop-2-enamide;
2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethanol;
2-{[2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;
({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;
4-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene) methyl]phenyl}oxy) butanoic acid;
({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene) methyl]phenyl}oxy)acetonitrile;
2-({4-[(4-Fluorophenyl) (3,3,5,5-tetramethylcyclohexylidene) methyl]phenyl}oxy)ethanol;
(2E)-3-{4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid;
4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic acid;
3,5-Dimethyl-4-{4-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}isoxazole;
1-Methyl-4-{4-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1H-pyrazole;
4-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-3,5-dimethylisoxazole;
3-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}furan;
2-{[2-({4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;
2-{4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}furan;
4-{4-[(4-fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-1-methyl-1H-pyrazole;
4-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-1-butanol;
2-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetamide;
({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;
2-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethanol;
({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetonitrile;
4-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic acid;
4-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)-1-butanol;
5-[({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)methyl]-1H-tetrazole;
2-{[2-({2-Methyl-5-[phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;
4-({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)butanoic acid;
({4-[Phenyl(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}oxy)acetic acid;
(2E)-3{-4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoic acid;
(2E)-3-{4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic acid;
(2E)-3-{4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoic acid;
4-{4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}butanoic acid;
4-{4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}butanoic acid;
2-({4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethanol;
2-({4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethanol;
2-{[2-({4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;
2-{(2-({4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}oxy)ethyl]oxy}ethanol;
4-[(4-Fluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoic acid;
4-[Phenyl(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]benzoic acid;
and
4-[(4-Fluorophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]benzoic acid, including salts, solvates, and pharmacologically functional derivatives thereof.

38 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/915,436Filed 24 May 2006
Priority: 25 May 2005
Published: 10 Jul 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification63 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…

Family

Application60/684,433Us provisional application · filed 25 May 2005
US 7,723,393 B2Related patent
US 2008/0167360 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

including salts, solvates, and pharmacologically functional derivatives thereof wherein
R1 is H or F;
R2 and R4 each independently are selected from H, OH, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, or cyano;
R3 is —(Y)z—R8;
z is 0 or 1;
Y is —C≡C— or —CRe═CRf—;
each R5 is H;
or
both R5s together combine to form a bridging alkylene chain —CH2)m—, where m is 2, 3, or 4, when each R6 and each R7 is H and X is —(CH2)m-2—;
each of R6 and R7 are selected from H or alkyl;
or
when X is —(CH2)m—, both R6s are H, and both R7s together combine to form a bridging alkylene chain —(CH2)m—, where each m is the same and is as defined;
or
when X is —(CH2)m—, both R7s are H, and both R6s together combine to form a bridging alkylene chain —(CH2)m—, where each m is the same and is as defined;
when z is 0, then R8 is alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocyclyl, heterocyclyl substituted with one or more alkyl, cyano, —O(CH2)tCN, —CO2H, —(CH2)tCO2H, —O(CH2)tCO2H, —(CH2)tOH, —O(CH2)tOH, —O(CH2)tO(CH2)tOH, —C(O)NRaRb, —O(CH2)tC(O)NRaRb;
—NRaSO2Rd, or —NRaC(O)Rc;
when z is 1, then R8 is, —CO2H, —(CH2)tCO2H, —(CH2)tOH, —C(O)NRaRb, or —PO3HRa;
each t independently is 1 to 8;
X is —(CH2)n— where n is 0, 1, 2, or 3, —C(Rh)2—, —O—, —S(O)p where p is 0, 1, or 2, —C(Rg)2OC(Rg)2—, or —C(CH2)v— where v is 2 to 7 and forms a spirocycle with the depicted ring that contains X;
Ra is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rb is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rc is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rd is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
or
Ra and Rb, Ra and Rc, or Ra and Rd may combine with the atoms to which they are bound to form an optionally substituted heterocyclyl;
and
Re and Rf each are independently selected from H, alkyl, halogen, and haloalkyl;
Rg is H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
Rh is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, or heterocyclyl;
wherein each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted.

27 more elements

Facts

Application

11/915,436Filed 24 May 2006

Priority

25 May 2005

Published

10 Jul 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification63 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…