Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators
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Abstract
The present invention is directed to novel heteroatom containing tetracyclic derivatives, pharmaceutical compositions containing them, their use in the treatment and/or prevention of disorders mediated by one or more estrogen receptors and processes for their preparation. The compounds of the invention are useful in the treatment and/or prevention of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.
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Citations
26 Claims
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1. A compound of formula (I)
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15)
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2. A compound as in claim 1 wherein
- - - - represents a single bond or a double bond,X is selected from the group consisting of O and S; -
Y is selected from the group consisting of CRARB, CRARB(CH2)1-2, CRARBC(O), CH2C(O)CH2, C(O) and CH2CRARBCH2; provided that when X is S, then Y is selected from the group consisting of CRARB, CRARB(CH2)1-2, CH2C(O)CH2 and CH2CRARBCH2; wherein each RA and RB is independently selected from hydrogen, hydroxy, lower alkyl or lower alkoxy;
provided that both RA and RB are not hydroxy;Z is selected from the group consisting of O and S; R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, —
C(O)-aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl);
wherein the lower alkyl, aryl, aralkyl, heteroaryl or heteroaryl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(lower alkyl), NO2, CN, CO2H, RC, —
SO2—
NRDRE, —
NRDRE, NRD—
SO2—
RF, -(alkyl)0-4-C(O)NRDRE, —
C(O)O-(lower alkyl)-NRDRE, —
C(O)—
NH-(lower alkyl)-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-RF, -(alkyl)0-4-NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF, —
O-(lower alkyl)-OSi(lower alkyl)3, —
O-(lower alkyl)-ORD or —
O-(lower alkyl)-formyl;wherein RC is selected from the group consisting of lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(lower alkyl);
wherein the aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(alkyl), NO2, CN, CO2H, —
SO2—
NRDRE, NRDRE, NRD—
SO2—
RF, -(alkyl)0-4-C(O)—
NRDRE, -(alkyl)0-4NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE or -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF;wherein Q is selected from the group consisting of O, S, NH, N(lower alkyl) and —
CH═
CH—
;wherein RD and RE are each independently selected from the group consisting of hydrogen and lower alkyl;
alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl;
wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, oxo, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;wherein RF is selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(lower alkyl);
wherein the aryl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;R2 is selected from the group consisting of hydroxy, lower alkyl, lower alkenyl, aryl, —
C(O)-aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl);
wherein the alkyl, aryl, aralkyl, heteroaryl or heteroaryl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(lower alkyl), NO2, CN, CO2H, RC, —
ORC, —
SO2—
NRDRE, —
NRDRE, -(alkyl)0-4—
C(O)NRDRE, —
C(O)O-(lower alkyl)-NRDRE, —
C(O)—
NH-(lower alkyl)-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-NRDRE, —
C(O)—
(N containing heterocycloalkyl, bound throughthe N atom)-RF, (alkyl)0-4-NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF, —
O-(lower alkyl)-OSi(lower alkyl)3, —
O-(lower alkyl)-ORD or —
O-(lower alkyl)-formyl;alternatively, R1 and R2 are taken together with the carbon atom to which they are bound to form C(O); provided that when R1 and R2 are taken together with the carbon atom to which they are bound to form C(O) and X is selected from the group consisting of O and S, then Y is selected from the group consisting of CRARB, CRARB(CH2)1-2, CRARBC(O), CH2C(O)CH2 and CH2CRARBCH2; n is an integer selected from 0 to 2; each R3 is independently selected from the group consisting of halogen, hydroxy, RC, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano, —
OC(O)RG, —
OC(O)ORG, —
OC(O)N(RG)2, —
OSi(RG)3, —
ORG, —
O-(alkyl)1-4-C(O)RG and —
O-(alkyl)1-4-C(O)ORG;wherein each RG is independently selected from hydrogen, alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one;
wherein the alkyl, aryl or aralkyl group is optionally substituted with one to two substituents independently selected from lower alkyl, halogenated lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano, —
OC(O)-(lower alkyl) or —
C(O)O-(lower alkyl);alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group;
wherein the heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;m is an integer selected from 0 to 2; each R4 is independently selected from the group consisting of halogen, hydroxy, RC, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano, —
OC(O)RG, —
OC(O)ORG, —
OC(O)N(RG)2, —
OSi(RG)3, —
ORG, —
O-(alkyl)1-4-C(O)RG and —
O-(alkyl)1-4-C(O)ORG;provided that when - - - - is a single bond, X is O, Y is CH(lower alkyl), Z is O, R1 is hydrogen and R2 is lower alkyl, then at least one of n or m is an integer selected from 1 to 4;provided further that when - - - - is a single bond, X is O, Y is CH(lower alkyl), Z is O, R1 is hydrogen, R2 is alkyl, n is 1 and m is 1, then R3 and R4 are other than methoxy or ethoxy;provided further that when - - - - is a double bond, X is O, Y is CH2, Z is O, R1 and R2 are taken together with the carbon atom to which they are bound to form C(O), n is 0 and m is 2, then each R4 is not hydroxy or alkoxy;provided further that when - - - - is a double bond, X is O;
Y is CH2;
Z is O;
R1 and R2 are taken together with the carbon atom to which they are bound to form C(O);
n is 0 or 2;
R3 is methoxy and m is 1 or 2;
then R4 is other than hydroxy or methoxy;or a pharmaceutically acceptable salt thereof.
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3. A compound as in claim 1 wherein
- - - - represents a single bond or a double bond,X is selected from the group consisting of CRARB and C(O); -
Y is selected from the group consisting of O and S; provided that when Y is S, then X is selected from the group consisting of CRARB; wherein each RA and RB is independently selected from hydrogen, hydroxy, lower alkyl or lower alkoxy;
provided that both RA and RB are not hydroxy;Z is selected from the group consisting of O and S; R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, —
C(O)-aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl);
wherein the lower alkyl, aryl, aralkyl, heteroaryl or heteroaryl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(lower alkyl), NO2, CN, CO2H, RC, —
SO2—
NRDRE, —
NRDRE, NRD—
SO2—
RF, -(alkyl)0-4-C(O)NRDRE, —
C(O)O-(lower alkyl)-NRDRE, —
C(O)—
NH-(lower alkyl)-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-RF, -(alkyl)0-4-NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF, —
O-(lower alkyl)-OSi(lower alkyl)3, —
O-(lower alkyl)-ORD or —
O-(lower alkyl)-formyl;wherein RC is selected from the group consisting of lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(lower alkyl);
wherein the aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(alkyl), NO2, CN, CO2H, —
SO2—
NRDRE, NRDRE, NRD—
SO2—
RF, -(alkyl)0-4—
C(O)—
NRDRE, -(alkyl)0-4-NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE or -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF;wherein Q is selected from the group consisting of O, S, NH, N(lower alkyl) and —
CH═
CH—
;wherein RD and RE are each independently selected from the group consisting of hydrogen and lower alkyl;
alternatively RD and RE are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered ring selected from the group consisting of heteroaryl or heterocycloalkyl;
wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, oxo, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;wherein RF is selected from the group consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(lower alkyl);
wherein the aryl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;R2 is selected from the group consisting of hydroxy, lower alkyl, lower alkenyl, aryl, —
C(O)-aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl);
wherein the lower alkyl, aryl, aralkyl, heteroaryl or heteroaryl-(lower alkyl) group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, —
SH, —
S(lower alkyl), NO2, CN, CO2H, RC, —
ORC, —
SO2—
NRDRE, —
NRDRE, -(alkyl)0-4-C(O)NRDRE, —
C(O)O-(lower alkyl)-NRDRE, —
C(O)—
NH-(lower alkyl)-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-NRDRE, —
C(O)—
(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-RF, -(alkyl)0-4-NRD—
C(O)—
RF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-NRDRE, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
ORF, -(alkyl)0-4-(Q)0-1-(alkyl)0-4-C(O)—
NRDRE, -(alkyl)0-4-C(O)-(alkyl)0-4-C(O)—
ORF, —
O-(lower alkyl)-OSi(lower alkyl)3, —
O-(lower alkyl)-ORD or —
O-(lower alkyl)-formyl;alternatively, R1 and R2 are taken together with the carbon atom to which they are bound to form C(O); provided that when R1 and R2 are taken together with the carbon atom to which they are bound to form C(O) and Y is selected from the group consisting of O and S, then X is selected from the group consisting of CRARB; n is an integer selected from 0 to 2; each R3 is independently selected from the group consisting of halogen, hydroxy, RC, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano, —
OC(O)RG, —
OC(O)ORG, —
OC(O)N(RG)2, —
OSi(RG)3, —
ORG, —
O-(alkyl)1-4-C(O)RG and —
O-(alkyl)1-4-C(O)ORG;wherein each RG is independently selected from hydrogen, lower alkyl, aryl, aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one;
wherein the lower alkyl, aryl or aralkyl group is optionally substituted with one to two substituents independently selected from lower alkyl, halogenated lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano, —
OC(O)-(lower alkyl) or —
C(O)O-(lower alkyl);alternatively two RG groups are taken together with the nitrogen atom to which they are bound to form a heterocycloalkyl group;
wherein the heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro or cyano;m is an integer selected from 0 to 2; each R4 is independently selected from the group consisting of halogen, hydroxy, RC, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano, —
OC(O)RG, —
OC(O)ORG, —
OC(O)N(RG)2, —
OSi(RG)3, —
ORG, —
O-(alkyl)1-4-C(O)RG and —
O-(alkyl)1-4-C(O)ORG;provided that when - - - - is a double bond, X is CH2, Y is O, Z is O and R1 and R2 are taken together with the carbon atom to which they are bound to form C(O), then at least one of n or m is an integer selected from 1 to 2;provided further that when - - - - is a double bond, X is CH2;
Y is O;
Z is O;
R1 and R2 are taken together with the carbon atom to which they are bound to form C(O), and m is 2 then R4 is other than methoxy;or a pharmaceutically acceptable salt thereof.
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4. A compound as in claim 2 wherein
- - - - represents a double bond,X is O; -
Y is selected from the group consisting of —
CH2—
, —
CH2CH2—
, —
CH2CH2CH2—
, —
CH(lower alkoxy)-, —
CH(OH)—
, —
CH2CH(OH)CH2—
, —
CH(lower alkyl)-, —
CH2C(O)— and
—
CH2C(O)CH2—
;Z is O; R1 is selected from the group consisting of hydrogen and lower alkyl; R2 is selected from the group consisting of hydroxy, lower alkenyl, carboxy-lower alkyl, hydroxy-lower alkyl, aryl, 4-(1-N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom)-alkoxy)-phenyl, 4-(di(lower alkyl)amino-alkoxy)-phenyl, 4-(di(lower alkyl)amino)-phenyl, 4-aralkyloxy-phenyl, lower alkoxy-carbonyl-lower alkyl, 4-(lower alkoxy-lower alkoxy)-phenyl, di(lower alkyl)amino-(lower alkoxy)-carbonyl-(lower alkyl), (N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-(lower alkoxy)-carbonyl-(lower alkyl), (N containing heterocyloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-(lower alkyl)-amino-carbonyl-(lower alkyl), (N containing heteroaryl)-(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-C(O)-(lower alkyl), (halo-substituted aryl)-(N containing heterocycloalkyl (wherein said N containing heterocycloalkyl is bound through the N atom))-carbonyl-(lower alkyl), 4-((N containing heterocycloalkyl)-(lower alkoxy))-phenyl-carbonyl, 2-hydroxy-2-(4-N containing heterocycloalkyl-lower alkoxy)-phenyl)-ethyl, 4-(tri(lower alkyl)silyloxy-(lower alkoxy)-phenyl, 4-(hydroxy-lower alkoxy)-phenyl, 4-(formyl-lower alkoxy)-phenyl, 4-(carboxy-lower alkoxy)-phenyl, 4-(lower alkoxy-carbonyl-lower alkoxy)-phenyl, 4-(piperidinyl-2,6-dione-lower alkoxy)-phenyl, 4-(pyrrolidinyl-2,5-dione-(lower alkyl)-phenyl, R*-4-(pyrrolidinyl-2,5-dione-(lower alkoxy)-phenyl and S*-4-(pyrrolidinyl-2,5-dione-(lower alkoxy)-phenyl; alternatively R1 and R2 are taken together with the carbon atom to which they are bound to form C(O); n is an integer from 0 to 1; R3 is selected from the group consisting of halogen, hydroxy, lower alkoxy, tri(lower alkyl)-silyloxy, —
OC(O)-(lower alkyl), —
OC(O)-C(phenyl)-OC(O)-(lower alkyl), —
OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one) and —
OC(O)—
C(CH3)(CF3)-phenyl;m is is an integer from 0 to 1; R4 is selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, tri(lower alkyl)-silyloxy, —
OC(O)-(lower alkyl), —
OC(O)—
CH(phenyl)-OC(O)-(lower alkyl), —
OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one) and —
OC(O)—
C(CH3)(CF3)-phenyl;provided further that when - - - - is a double bond;
X is O;
Y is CH2;
Z is O;
R1 and R2 are taken together with the carbon atom to which they are bound to form C(O);
n is 0;
R3 is methoxy and m is 1;
then R4 is other than hydroxy or methoxy;or a pharmaceutically acceptable salt thereof.
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5. A compound as in claim 4 wherein
Y is selected from the group consisting of — - CH2—
, —
CH2CH2—
, —
CH2CH2CH2—
, —
CH(OCH3)—
, —
CH(OH)—
, —
CH2CH(OH)CH2—
, —
CH(CH(CH3)2)—
, —
CH2C(O)— and
—
CH2C(O)CH2—
;R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydroxy, allyl, carboxymethyl, hydroxy-ethyl, 3-hydroxy-n-propyl, phenyl, 4-(1-piperidinyl-ethoxy)-phenyl, S*-4-(piperidinyl-ethoxy)-phenyl, R*-4-(piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepanyl-ethoxy)-phenyl, R*-4-(1-azepanyl-ethoxy)-phenyl, S*-4-(1-azepanyl-ethoxy)-phenyl, 4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl, R*-4-(dimethylamino-ethoxy)-phenyl, S*-4-(dimethylamino-ethoxy)-phenyl, 4-(diisopropylamino-ethoxy)-phenyl, R*-4-(diisopropylamino-ethoxy)-phenyl, S*-4-(diisopropylamino-ethoxy)-phenyl, 4-(dimethylamino)-phenyl, 4-benzyloxy-phenyl, 4-(1-piperidinyl-n-propoxy)-phenyl, 4-(t-butyl-dimethyl-silyloxy-ethoxy)-phenyl, 4-(methoxy-ethoxy)-phenyl, methoxy-carbonyl-methyl, isopropoxy-carbonyl-methyl, dimethylamino-ethoxy-carbonyl-methyl, piperidinyl-ethoxy-carbonyl-methyl, pyrrolidinyl-ethoxy-carbonyl-methyl, morpholinyl-ethoxy-carbonyl-methyl, dimethylamino-n-propoxy-carbonyl-methyl, morpholinyl-ethyl-amino-carbonyl-methyl, morpholinyl-n-propyl-amino-carbonyl-methyl, pyrrolidinyl-ethyl-amino-carbonyl-methyl, 4-(2-pyridyl)-piperazinyl-carbonyl-methyl, 4-(4-fluorophenyl)-piperazinyl carboxy-methyl, 4-(piperidinyl-ethoxy)-phenyl-carbonyl, 2-hydroxy-2-(4-(piperidinyl-ethoxy)-phenyl)-ethyl, 4-(2-hydroxy-ethoxy)-phenyl, R*-4-(2-hydroxy-ethoxy)-phenyl, S*-4-(hydroxy-ethoxy)-phenyl, 4-(3-hydroxy-n-propoxy)-phenyl, R*-4-(3-hyd roxy-n-propoxy)-phenyl, S*-4-(3-hydroxy-n-propoxy)-phenyl, 4-(formyl-methoxy)-phenyl, 4-(carboxy-methoxy)-phenyl, 4-carboxy-ethoxy)-phenyl, 4-(methoxy-carbonyl-methoxy)-phenyl, 4-(methoxy-carbonyl-ethoxy)-phenyl, R*-4-(piperidinyl-2,6-dione-ethoxy)-phenyl, R*-4-(pyrrolidinyl-2,5-dione-ethoxy)-phenyl, S*-4-(pyrrolidinyl-2,5-dione-ethoxy)-phenyl, R*-4-(pyrrolidinyl-2,5-dione-n-propoxy)-phenyl and S*-4-(pyrrolidinyl-2,5-dione-n-propoxy)-phenyl; alternatively R1 and R2 are taken together with the carbon atom to which they are bound to form C(O); R3 is selected from the group consisting of fluoro, hydroxy, methoxy, t-butyl-dimethyl-silyloxy, —
OC(O)-methyl, —
OC(O)-t-butyl, —
OC(O)—
CH(phenyl)-OC(O)CH3, —
OC(O)-(1,7,7-trimethyl-2-oxabicyclo[.2.1]heptan-3-one), and —
OC(O)—
C(CH3)(CF3)-phenyl;R4 is selected from the group consisting of fluoro, hydroxy, methyl, methoxy, t-butyl-dimethyl-silyloxy, —
OC(O)-methyl, —
OC(O)-t-butyl, —
OC(O)—
CH(phenyl)-OC(O)CH3, —
OC(O)-(1,7,7-trimethyl-2-oxabicyclo[.2.1]heptan-3-one) and —
OC(O)—
C(CH3)(CF3)-phenyl;provided further that when - - - - is a double bond;
X is O;
Y is CH2;
Z is O;
R1 and R2 are taken together with the carbon atom to which they are bound to form C(O);
n is 0;
R3 is methoxy and m is 1;
then R4 is other than hydroxy or methoxy;or a pharmaceutically acceptable salt thereof.
- CH2—
-
6. A compound as in claim 5 wherein
Y is selected from the group consisting of — - CH2—
, —
CH2CH2—
, —
CH2CH2CH2—
, —
CH(OCH3)— and
—
CH(OH)—
;R2 is selected from the group consisting of phenyl, 4-(1-piperidinyl-ethoxy)-phenyl, R*-4(piperidinyl-ethoxy)-phenyl, S*-4-(piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepanyl-ethoxy)-phenyl, R*-4-(azepanyl-ethoxy)-ohenyl, S*-4-(1-azepanyl-ethoxy)-phenyl, 4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl, R*-4-(dimethylamino-ethoxy)-phenyl, S*-4-(dimethylamino-ethoxy)-phenyl, R*-4-(diisopropylamino-ethoxy)-phenyl, S*-4-(diisopropylamino-ethoxy)-phenyl, 4-(dimethylamino)-phenyl, 4-(3-hydroxy-n-propoxy)-phenyl; alternatively R1 and R2 are taken together with the carbon atom to which they are bound to form C(O); R3 is selected from the group consisting of hydroxy, methoxy and —
OC(O)-t-butyl;R4 is selected from the group consisting of fluoro, hydroxy, methoxy and —
OC(O)-t-butyl;provided further that when - - - - is a double bond;
X is O;
Y is CH2;
Z is O;
R1 and R2 are taken together with the carbon atom to which they are bound to form C(O);
n is 0;
R3 is methoxy and m is 1;
then R4 is other than hydroxy or methoxy;or a pharmaceutically acceptable salt thereof.
- CH2—
-
7. A compound as in claim 6 wherein
Y is selected from the group consisting of — - CH2—
, —
CH2CH2—
, —
CH2CH2CH2— and
—
CH(OH)—
;R2 is selected from the group consisting of phenyl, 4-(1-piperidinyl-ethoxy)-phenyl, R*-4-(piperidinyl-ethoxy)-phenyl, S*-4-(piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepanyl-ethoxy)-phenyl, R*-4-(azepanyl-ethoxy)-phenyl, S*-4-(1-azepanyl-ethoxy)-phenyl, 4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl, R*-4-(dimethylamino-ethoxy)-phenyl, S*-4-(dimethylamino-ethoxy)-phenyl, R*-4-(diisopropylamino-ethoxy)-phenyl, S*-4-(diisopropylamino-ethoxy)-phenyl, 4-(dimethylamino)-phenyl, 4-(3-hydroxy-n-propoxy)-phenyl; or a pharmaceutically acceptable salt thereof.
- CH2—
-
8. A compound as in claim 7 wherein
R1 is selected from the group consisting of hydrogen and methyl; -
R2 is selected from the group consisting of phenyl, 4-(1-piperidinyl-ethoxy)-phenyl, R*-4-(piperidinyl-ethoxy)-phenyl, S*-4-(piperidinyl-ethoxy)-phenyl), 4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepanyl-ethoxy)-phenyl, R*-4-(1-azepanyl-ethoxy)-phenyl, S*-4-(azepanyl-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl, R*-4-(dimethylamino-ethoxy)-phenyl, S*-4-(dimethylamino-ethoxy)-phenyl, R*-4-(diisopropylamino-ethoxy)-phenyl, S*-4-(diisopropylamino-ethoxy)-phenyl, 4-(dimethylamino)-phenyl, 4-(3-hydroxy-n-propoxy)-phenyl; R3 is selected from the group consisting of hydroxy and —
OC(O)-t-butyl;or a pharmaceutically acceptable salt thereof.
-
-
9. A compound as in claim 5 wherein the compound of formula (I) is selected from the group consisting of
8-(2,2-dimethyl-propionyloxy)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester 2,2-dimethyl propionic acid; -
8-(2,2-dimethyl-propionyloxy)-5R-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester 2,2-dimethyl propionic acid; 8-(2,2-dimethyl-propionyloxy)-5S-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester 2,2-dimethyl propionic acid; 8-fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromenen-2-ol; 8-(2,2,-dimethyl-propionyloxy)-5-hydroxy-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-yl ester 2,2,-dimethyl-propionic acid; 5-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydrochromeno[4,3-c]chromene-2,8-diol; 5R*-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydrochromeno[4,3-c]chromene-2,8-diol; 5S*-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydrochromeno[4,3-c]chromene-2,8-diol; 2,2-Dimethyl propionic acid, 8-hydroxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester; 2,2-Dimethyl propionic acid, 8-hydroxy-11-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,11-dihydro-chromeno[4,3-c]chromen-2-yl ester; 5-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5S*-(−
)-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol;5R*-(+)-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5-[4-(2-Dimethylamino-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5R*-(+)-[4-(2-Dimethylamino-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5S*-(−
)-[4-(2-Dimethylamino-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol;5-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5R*-(+)-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol; 5S*-(−
)-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-8-fluoro-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol;2-Methoxy-5S*-(−
)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-8-ol;8-Methoxy-5S*-(−
)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ol;and pharmaceutically acceptable salt thereof.
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11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.
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12. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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13. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
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14. A method of treating a disorder mediated by an estrogen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1, wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.
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15. A method of treating a disorder mediated by an estrogen receptor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim 11, wherein the disorder mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.
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2. A compound as in claim 1 wherein
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10. A compound of formula (I)
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16. A process for the preparation of a compound of formula (DX)
- View Dependent Claims (18)
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18. A compound prepared according to the process of claim 16.
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18. A compound prepared according to the process of claim 16.
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17. A process for the preparation of a compound of formula (DXI)
- View Dependent Claims (19)
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19. A compound prepared according to the process of claim 17.
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19. A compound prepared according to the process of claim 17.
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20. A compound having the formula:
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21. A compound having the formula:
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22. A compound having the formula:
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23. A compound having the formula:
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24. A compound having the formula:
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25. A compound having the formula:
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26. A compound having the formula:
Specification
- Resources
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Current AssigneeOrtho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
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Original AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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InventorsJain, Nareshkumar F., Xu, Jiayi, Kanojia, Ramesh M., Ng, Raymond, Sui, Zhihua
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Primary Examiner(s)COLEMAN, BRENDA LIBBY
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Application NumberUS10/307,735Publication NumberTime in Patent Office1,898 DaysField of Search514/63, 514/217.03, 514/232.8, 514/321, 514/422, 514/431, 514/432, 514/450, 514/453, 540/596, 544/69, 544/148, 546/14, 546/197, 548/406, 548/526, 549/4, 549/12, 549/24, 549/25, 549/214, 549/268, 549/276, 549/277, 549/354, 549/384US Class Current514/217.03CPC Class CodesA61P 13/08 of the prostateA61P 15/00 Drugs for genital or sexual...A61P 15/16 Masculine contraceptivesA61P 15/18 Feminine contraceptivesA61P 19/02 for joint disorders, e.g. a...A61P 19/10 for osteoporosisA61P 25/00 Drugs for disorders of the ...A61P 25/28 for treating neurodegenerat...A61P 3/06 AntihyperlipidemicsA61P 35/00 Antineoplastic agentsA61P 43/00 Drugs for specific purposes...A61P 5/30 OestrogensA61P 9/00 Drugs for disorders of the ...C07D 493/04 Ortho-condensed systems