US 2001/0056099 A1Published application

Method of reducing morbidity and the risk of mortality

OwnerWesley W. Day, Andrew G. Lee +1inventors

InventorsWesley W. Day, Andrew G. Lee, David D. Thompson

Life of this patent

Estimating the term…

Abstract

This invention relates to methods, pharmaceutical compositions and kits useful in reducing cardiovascular morbidity and the risk of mortality in men and post-menopausal women and morbidity and the risk of mortality in post-menopausal women from the combined reduction of breast cancer, osteoporosis and cardiovascular disease by the administration of estrogen agonists/antagonists. 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.

Claims25

Dependent claims

A method of reducing morbidity and/or the risk of mortality comprising:

administering to a subject in need thereof, an effective amount of a compound of formula
14
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)
15
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
16
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
17
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
(j)
18
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 (CI-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 C1-8 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, quaternary ammonium salt, or a prodrug thereof.

91 more elements

A kit for use by a consumer to reduce cardiovascular morbidity and/or the risk of mortality in a subject and/or reduce morbidity and/or the risk of mortality in post-menopausal women due to the combined effects of reduced cardiovascular disease, reduced breast cancer and reduced osteoporosis, said kit comprising:

a) a pharmaceutical composition comprising a compound of formula (I):
21
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) —NR7R6;
(b)
22
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
Z1 and G in combination may be
23
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
24
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
(j)
25
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 R3 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 a prodrug thereof and a pharmaceutically acceptable vehicle, carrier or diluent;
and
b) instructions describing a method of using the pharmaceutical composition to reduce the risk of morbidity and/or the risk of mortality.

94 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/757,817Filed 10 Jan 2001
Priority: 12 Jan 2000
Published: 27 Dec 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

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,…
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/138
Having aromatic rings , e.g. ketamine, nortriptyline: aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol

Family

Application60/175,663Us provisional application · filed 12 Jan 2000
US 2001/0056099 A1This patent

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

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Abstract

A method of reducing morbidity and/or the risk of mortality comprising:

administering to a subject in need thereof, an effective amount of a compound of formula
14
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)
15
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
16
Z1 and G in combination may be
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
17
(g) —CR2(OH)—;
(h) —CONR2—;
(i) —NR2CO—;
(j)
18
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 (CI-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 C1-8 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, quaternary ammonium salt, or a prodrug thereof.

91 more elements

Facts

Application

09/757,817Filed 10 Jan 2001

Priority

12 Jan 2000

Published

27 Dec 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

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,…
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/138
Having aromatic rings , e.g. ketamine, nortriptyline: aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
A61K 31/404
Condensed with carbocyclic rings, e.g. carbazole: indoles, e.g. pindolol