1. An intake manifold section for installing in an intake system of an internal combustion engine, comprising:
a tube body including an inlet opening, an outlet opening and a fresh air path section running from the inlet opening to the outlet opening,
an air mass sensor fastened to the tube body and protruding into the fresh air path section,
a bypass channel disposed on the tube body and bypassing the fresh air path section connected to a blow-by gas path at an inlet side.
2. The intake manifold section according to claim 1,
wherein the bypass channel is formed integrally on the tube body.
3. The intake manifold section according to claim 1,
wherein the inlet opening of the tube body is connected to an outlet of an inlet component of the intake system on the inlet side,
further wherein the outlet opening of the tube body is connected to an inlet of an outlet component of the intake system on an outlet side,
and further wherein the bypass channel opens on the outlet side into the outlet component on the outlet side.
4. The intake manifold section according to claim 3,
wherein the tube body has an outlet connection on the outlet side, the outlet connection including the outlet opening and being configured to be connected to the outlet component of the intake system on the outlet side,
and further wherein the bypass channel includes an outlet section.
5. The intake manifold section according to claim 4,
wherein the outlet connection has an inner skin with a round internal cross-section laterally delimiting the outlet opening, and an outer skin with a round external cross-section surrounding the inner skin.
6. The intake manifold section according to claim 1,
wherein the bypass channel projects over the outlet opening on the outlet side.
7. The intake manifold section according to claim 1,
wherein the bypass channel has a connection piece on the inlet side capable of being connected to a gas line outlet of a blow-by gas line guiding the blow-by gas path.
8. The intake manifold section according to claim 7,
wherein the outlet of the blow-by gas line is arranged on an inlet component of the intake system on the inlet side,
and further wherein the outlet of the blow-by gas line is formed integrally on the inlet component on the inflow inlet side.
9. The intake manifold section according to claim 1,
wherein the air mass sensor has a housing and is at least one of glued and welded to the tube body,
and further wherein at least one of the tube body and the housing is produced from plastic.
10. The intake manifold section according to claim 1,
wherein the intake manifold section is a pre-mounted unit configured to be installed with a calibrated air mass sensor into the intake system.
11. An intake system for the fresh air supply of an internal combustion engine, comprising: at least one intake manifold section.
having a tube body, an air mass sensor and a bypass channel, wherein the tube body includes an inlet opening, an outlet opening and a fresh air path section running from the inlet opening to the outlet opening,
further wherein the air mass sensor is fastened to the tube body and protrudes into the fresh air path section,
and further wherein the bypass channel is disposed on the tube body and bypassing the fresh air path section connected to a blow-by gas path at an inlet side.
12. The intake manifold section according to claim 11, wherein the bypass channel is formed integrally on the tube body.
13. The intake manifold section according to claim 11, wherein the inlet opening of the tube body is connected to an outlet of an inlet component of the intake system on the inlet side, further wherein the outlet opening of the tube body is connected to an inlet of an outlet component of the intake system on an outlet side, and further wherein the bypass channel opens on the outlet side into the outlet component on the outlet side.
14. The intake manifold section according to claims 13, wherein the tube body has an outlet connection on the outlet side, the outlet connection including the outlet opening and being configured to be connected to the outlet component of the intake system on the outlet side, and further wherein the bypass channel includes an outlet section.
15. The intake manifold section according to claim 14, wherein the outlet connection has an inner skin with a round internal cross-section laterally delimiting the outlet opening, and an outer skin with a round external cross-section surrounding the inner skin.
16. The intake manifold section according to claim 11,wherein the bypass channel projects over the outlet opening on the outlet side.
17. The intake manifold section according to claim 11, wherein the bypass channel has a connection piece on the inlet side capable of being connected to a gas line outlet of a blow-by gas line guiding the blow-by gas path.
18. The intake manifold section according to claim 17, wherein the outlet of the blow-by gas line is arranged on an inlet component of the intake system on the inlet side, and wherein the outlet of the blow-by gas line is formed integrally on the inlet component on the inlet side.
19. The intake manifold section according to claim 11, wherein the air mass sensor has a housing and is at least one of glued and welded to the tube body, and wherein at least one of the tube body and the housing is produced from plastic.
20. The intake manifold section according to claim 11, wherein the intake manifold section is a pre-mounted unit configured to be installed with a calibrated air mass sensor into the intake system.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A method of treating andropause in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
2. The method of claim 1 wherein the estrogen agonistantagonist is a compound of formula I
37
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;
38
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
39
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
40
(g) CR (OH);
(h) CONR2;
(i) NR2CO;
41
(k) CC;
R is hydrogen or C1-C6 alkyl;
R 2and R 3are independently
(a) hydrogen; or
(b) C1-C4 alkyl;
R 4 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, 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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
3. The method of claim 1 wherein the estrogen agonistantagonist is a compound of formula (IA)
42
wherein G is
43
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
4. The method of claim 1 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
5. The method of claim 4 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
6. A method of treating gynecomastia in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
7. The method of claim 6 wherein the estrogen agonist I antagonist is a compound of formula I
44
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;
45
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
46
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
47
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
48
(k) CC;
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, 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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
8. The method of claim 6 wherein the estrogen agonistantagonist is a compound of formula (IA)
49
wherein G is
50
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
9. The method of claim 6 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
10. The method of claim 9 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
11. A method of treating lipid disorders in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
12. The method of claim 11 wherein the estrogen agonistantagonist is a compound of formula I
51
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;
52
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
53
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
54
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
55
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
13. The method of claim 11 wherein the estrogen agonistantagonist is a compound of formula (IA)
56
wherein G is
57
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
14. The method of claim 11 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
15. The method of claim 14 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
16. A method of treating cardiovascular disease in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
17. The method of claim 16 wherein the estrogen agonistantagonist is a compound of formula I
58
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;
59
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
60
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
61
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
62
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
18. The method of claim 16 wherein the estrogen agonist I antagonist is a compound of formula (IA)
63
wherein G is
64
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
19. The method of claim 16 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
20. The method of claim 19 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
21. A method of treating atherosclerosis in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonist I antagonist and testosterone.
22. The method of claim 21 wherein the estrogen agonist I antagonist is a compound of formula I
65
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;
66
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
67
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
68
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
69
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
23. The method of claim 21 wherein the estrogen agonistantagonist is a compound of formula (IA)
70
wherein G is
71
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
24. The method of claim 21 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
25. The method of claim 24 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
26. A method of maintaining or improving vascular reactivity in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
27. The method of claim 26 wherein the estrogen agonistantagonist is a compound of formula I
72
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;
73
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
74
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
75
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
76
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
28. The method of claim 26 wherein the estrogen agonistantagonist is a compound of formula (IA)
77
wherein G is
78
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
29. The method of claim 26 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
30. The method of claim 29 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
31. A method of increasing libido in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
32. The method of claim 31 wherein the estrogen agonistantagonist is a compound of formula I
79
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;
80
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
81
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
82
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
83
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
33. The method of claim 31 wherein the estrogen agonistantagonist is a compound of formula (IA)
84
wherein G is
85
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
34. The method of claim 31 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
35. The method of claim 34 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
36. A method of treating hypogonadism in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
37. The method of claim 36 wherein the estrogen agonistantagonist is a compound of formula I
86
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;
87
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
88
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
89
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
90
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
38. The method of claim 36 wherein the estrogen agonistantagonist is a compound of formula (IA)
91
wherein G is
92
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
39. The method of claim 36 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
40. The method of claim 39 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
41. A method of treating benign prostatic hyperplasia in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
42. The method of claim 41 wherein the estrogen agonistantagonist is a compound of formula I
93
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;
94
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
95
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
96
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
97
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
43. The method of claim 41 wherein the estrogen agonistantagonist is a compound of formula (IA)
98
wherein G is
99
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
44. The method of claim 41 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
45. The method of claim 44 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
46. A method of treating osteoporosis in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of an estrogen agonistantagonist and testosterone.
47. The method of claim 46 wherein the estrogen agonistantagonist is a compound of formula I
100
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;
101
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
102
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
103
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
104
(k) CC;
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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
48. The method of claim 46 wherein the estrogen agonistantagonist is a compound of formula (IA)
105
wherein G is
106
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
49. The method of claim 46 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
50. The method of claim 49 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
51. A method of treating andropause, gynecomastia, lipid disorders, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or increasing libido, or maintaining or improving vascular reactivity in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of testosterone and an estrogen agonistantagonist that is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-4-(2-piperidin-1-yl-ethoxy)-benzyl-naphthalen-2-ol, 4-2-(2-aza-bicyclo2.2.1hept-2-yl)-ethoxy-phenyl-6-hydroxy-2-(4-hydroxy-phenyl)-benzobthiophen-3-yl-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
52. A method of treating andropause, gynecomastia, lipid disorders, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or increasing libido, or maintaining or improving vascular reactivity in a male patient, the method comprising administering to a male patient in need thereof a therapeutically effective amount of testosterone and an estrogen agonistantagonist that is selected from a compound of formulas V or VI:
107
wherein:
R1B is selected from H, OH, OC(O)C1-C12 alkyl (straight chain or branched), OC1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, OC(O)C1-C12 (straight chain or branched), OC1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety:
108
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, OH, CF3, or OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2 R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2 H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4) alkyl;
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof;
a compound, TSE-424, of formula Va below:
109
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof; or a compound of formula III or formula IV below:
110
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
53. A kit for treating andropause, gynecomastia, lipid disorders, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or increasing libido, or maintaining or improving vascular reactivity in a male patient, the kit comprising:
a) one or more pharmaceutical compositions comprising an estrogen agonistantagonist and testosterone; and
b) instructions for administering the pharmaceutical composition to treat andropause, gynecomastia, lipid disorders, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or increase libido, or maintain or improve vascular reactivity in a male patient.
54. The kit of claim 53 wherein the estrogen agonistantagonist is a compound of formula I
111
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;
112
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
113
W is
(a) CH2;
(b) CHCH;
(c) O;
(d) NR2;
(e) S(O)n;
114
(g) CR2(OH);
(h) CONR2;
(i) NR2CO;
115
(k) CC;
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, 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 pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.
55. The kit of claim 53 wherein the estrogen agonistantagonist is a compound of formula (IA)
116
wherein G is
117
R4 is H, OH, F, or Cl; and B and E are independently selected from CH and N or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
56. The kit of claim 53 wherein the estrogen agonistantagonist is ()-cis-6-phenyl-5-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-5,6,7,8-tetrahydro-naphthalene-2-ol or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt, or a prodrug thereof.
57. The kit of claim 56 wherein the estrogen agonistantagonist is in the form of a D-tartrate salt.
58. The kit of claim 53 that includes an additional compound that is useful for treating andropause, gynecomastia, lipid disorders, cardiovascular disease, atherosclerosis, hypogonadism, benign prostatic hyperplasia, or osteoporosis, or increasing libido, or maintaining or improving vascular reactivity in a male patient.
59. A kit of claim 53 wherein the estrogen agonistantagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-4-(2-piperidin-1-yl-ethoxy)-benzyl-naphthalen-2-ol, 4-2-(2-aza-bicyclo2.2.1hept-2-yl)-ethoxy-phenyl-6-hydroxy-2-(4-hydroxy-phenyl)-benzobthiophen-3-yl-methanone, EM-652, EM-800, GW 5638, GW 7604, and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
60. A kit of claim 53 wherein the estrogen agonistantagonist is selected from a compound of formulas V or VI:
118
wherein:
R1B is selected from H, OH, OC(O)C1-C12 alkyl (straight chain or branched), OC1-C12 alkyl (straight chain or branched or cyclic), or halogens or C1-C4 halogenated ethers;
R2B, R3B, R4B, R5B, and R6B are independently selected from H, OH, OC(O)C1-C12 (straight chain or branched), OC1-C12 (straight chain or branched or cyclic), halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl (straight chain or branched), or trifluoromethyl;
XA is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, and halogen;
s is 2 or 3;
YA is the moiety:
119
wherein:
a) R7B and R8B are independently selected from the group of H, C1-C6 alkyl, or phenyl optionally substituted by CN, C1-C6 alkyl (straight chain or branched), C1-C6 alkoxy (straight chain or branched), halogen, OH, CF3, or OCF3; or
b) R7B and R8B are concatenated to form a five-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
c) R7B and R8B are concatenated to form a six-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
d) R7B and R8B are concatenated to form a seven-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2 R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
e) R7B and R8B are concatenated to form an eight-membered saturated heterocycle containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2H, CN, CONHR1B, NH2, NH(C1-C4 alkyl), N(C1-C4alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4)alkyl; or
f) R7B and R8B are concatenated to form a saturated bicyclic heterocycle containing from 6-12 carbon atoms either bridged or fused and containing one nitrogen heteroatom, the heterocycle being optionally substituted with 1-3 substituents independently selected from the group consisting of hydrogen, hydroxyl, halo, C1-C4 alkyl, trihalomethyl, C1-C4 alkoxy, trihalomethoxy, C1-C4 acyloxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, hydroxy (C1-C4)alkyl, CO2 H, CN, CONHR1B,
NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NHSO2R1B, NHCOR1B, NO2, or phenyl optionally substituted with 1-3 (C1-C4) alkyl; or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof; a compound, TSE-424, of formula Va below:
120
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof; or a compound of formula III or formula IV below:
121
or an optical or geometric isomer thereof; or a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt or prodrug thereof.