US 2001/0041718 A1Published application

Compositions and methods for treating conditions responsive to estrogen

AssigneePfizer Inc.

InventorsDavid D. Thompson, Andrew G. Lee, Wesely W. Day, Robert L. Rosati

Life of this patent

Estimating the term…

Abstract

This invention relates to methods, pharmaceutical compositions and kits useful in treating conditions responsive to estrogen by the administration of estrogen agonists/antagonists. Conditions responsive to the compositions and methods include rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts. The compositions are comprised of an estrogen agonist/antagonist and a pharmaceutically acceptable vehicle, carrier or diluent. The compositions and methods of treatment are effective while substantially reducing the concomitant liability of adverse effects associated with estrogen administration.

Claims31

Dependent claims

A method of treating a condition responsive to estrogen comprising:

administering to a human in need thereof, an effective amount of a compound of formula (I):
15
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
z1 is
(a) —(CH2)p W(CH2)q—;
(b) —O(CH2)p CR5R6—;
(c) —O(CH2)pW(CH2)q—;
(d) —OCHR2CHR3—;
or
(e) —SCHR2CHR3—;
G is
(a) —NR7R8;
(b)
16
wherein n is 0, 1 or 2;
m is 1, 2 or 3;
Z2 is —NH—, —O—, —S—, or —CH2—;
optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4;
or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
or
17
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
18
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
(j)
19
or
(k) —C≡C—;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen;
or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) —CO2H;
(I)—CN;
(m) —CONHOR;
(n) —SO2NHR;
(o) —NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) —NHSO2R;
(s) —NO2;
(t) -aryl;
or
(u) —OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C1-C6 alkyl;
or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2or 3;
or an optical or geometric isomer thereof;
or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.

92 more elements

A kit for use by a consumer to treat rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles or cataracts, said kit comprising:

a) a pharmaceutical composition comprising a compound of formula (I):
22
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
Z1 is
(a) —(CH2)p W(CH2)q—;
(b) —O(CH2)p CR5R6—;
(c) —O(CH2)pW(CH2)q—;
(d) —OCHR2CHR3—;
or
(e) —SCHR2CHR3—;
G is
(a) —NR7R8;
(b)
23
wherein n is 0, 1 or 2;
m is 1, 2 or 3;
Z2 is —NH—, —O—, —S—, or —CH2—;
optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected fromR4;or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
or
24
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
25
(f)
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2Co—;
26
(j)
(k) —C≡C—;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen;
or
(b) C1-C4 alkyl;
R4is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) —CO2H;
(l)—CN;
(m) —CONHOR;
(n) —SO2NHR;
(o) —NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) —NHSO2R;
(s) —NO2;
(t) -aryl;
or
(u) —OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C1-C6 alkyl;
or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof;
or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester or quaternary ammonium salt or prodrug thereof and a pharmaceutically acceptable vehicle, carrier or diluent;
and
b) instructions describing a method of using the pharmaceutical composition to treat rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles or cataracts.

92 more elements

A topical formulation for the reduction of skin wrinkles comprising:

a compound of formula (I):
29
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
Z, is
(a) —(CH2)p W(CH2)q—;
(b) —O(CH2)p CR5R6—;
(c) —O(CH2)pW(CH2)q—;
(d) —OCHR2CHR3—;
or
(e) —SCHR2CHR3;
G is
(a) —NR7R8;
30
(b)
wherein n is 0, 1 or 2;
m is 1, 2 or 3;
Z2 is —NH—, —O—, —S—, or —CH2—;
optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4;
or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
or
31
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
32
(f)
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
33
(j) or
(k) —C≡C—;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen;
or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) —CO2H;
(l) —CN;
(m) —CONHOR;
(n) —SO2NHR;
(o) —NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) —NHSO2R;
(s) —NO2;
(t) -aryl;
or
(u) —OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C1-C6 alkyl;
or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
or an optical or geometric isomer thereof;
or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester or quaternary ammonium salt or prodrug thereof and a pharmaceutically or cosmetically acceptable topical vehicle.

91 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/758,778Filed 11 Jan 2001
Priority: 12 Jan 2000
Published: 15 Nov 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 8/4913
With one nitrogen as the only hetero atom: having five membered rings, e.g. pyrrolidone carboxylic acid
A61K 31/138
Having aromatic rings , e.g. ketamine, nortriptyline: aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…

Family

Application60/175,752Us provisional application · filed 12 Jan 2000
US 6,632,834 B2Related patent
US 2001/0041718 A1This patent

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

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Abstract

A method of treating a condition responsive to estrogen comprising:

administering to a human in need thereof, an effective amount of a compound of formula (I):
15
wherein:
A is selected from CH2 and NR;
B, D and E are independently selected from CH and N;
Y is
(a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
(c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
(d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
or
(g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
z1 is
(a) —(CH2)p W(CH2)q—;
(b) —O(CH2)p CR5R6—;
(c) —O(CH2)pW(CH2)q—;
(d) —OCHR2CHR3—;
or
(e) —SCHR2CHR3—;
G is
(a) —NR7R8;
(b)
16
wherein n is 0, 1 or 2;
m is 1, 2 or 3;
Z2 is —NH—, —O—, —S—, or —CH2—;
optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4;
or
(c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
or
17
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
18
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
(j)
19
or
(k) —C≡C—;
R is hydrogen or C1-C6 alkyl;
R2 and R3 are independently
(a) hydrogen;
or
(b) C1-C4 alkyl;
R4 is
(a) hydrogen;
(b) halogen;
(c) C1-C6 alkyl;
(d) C1-C4 alkoxy;
(e) C1-C4 acyloxy;
(f) C1-C4 alkylthio;
(g) C1-C4 alkylsulfinyl;
(h) C1-C4 alkylsulfonyl;
(i) hydroxy (C1-C4)alkyl;
(j) aryl (C1-C4)alkyl;
(k) —CO2H;
(I)—CN;
(m) —CONHOR;
(n) —SO2NHR;
(o) —NH2;
(p) C1-C4 alkylamino;
(q) C1-C4 dialkylamino;
(r) —NHSO2R;
(s) —NO2;
(t) -aryl;
or
(u) —OH;
R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
R7 and R8 are independently
(a) phenyl;
(b) a C3-C10 carbocyclic ring, saturated or unsaturated;
(c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C1-C6 alkyl;
or
(f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
e is 0, 1 or 2;
m is 1, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2or 3;
or an optical or geometric isomer thereof;
or a nontoxic pharmacologically acceptable acid addition salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.

92 more elements

Facts

Application

09/758,778Filed 11 Jan 2001

Priority

12 Jan 2000

Published

15 Nov 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol
A61K 8/4913
With one nitrogen as the only hetero atom: having five membered rings, e.g. pyrrolidone carboxylic acid
A61K 31/138
Having aromatic rings , e.g. ketamine, nortriptyline: aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…