US 2004/0176415 A1Published application

Enzymatic resolution of selective estrogen receptor modulators

AssigneePfizer Inc.

InventorKevin K. Liu

Life of this patent

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Abstract

The present invention relates to a process for preparing 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen-2-ol compounds useful as an estrogen agonist.

Claims40

Dependent claims

A process for preparing a compound of the formula:

42
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 cycloalkynyl, 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—, 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)
43
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;
Z1 and G in combination may be
44
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
45
(g) —CR2(OH)—;
(h) —CONR2;
(i) —NR2CO—;
(j)
46
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) C—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;
and optical and geometric isomers thereof;
comprising selectively deacetylating a compound of the formula
47
wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo, in the presence of a hydrolytic enzyme and an aqueous buffer solution.

92 more elements

A process for preparing a compound of the formula:

50
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 cycloalkynyl, 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—, 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)
51
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;
Z1 and G in combination may be
52
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(e) —S(O)n—;
(f)
53
(g)
(h) —CONR2—;
(i) —NR2CO—;
(j)
54
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;
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;
and optical and geometric isomers thereof;
comprising enzymatically resolving of a compound of the formula
55
wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo in the presence of a lipase and an aqueous buffer solution;
and (b) reacting the compound of formula IV so formed
56
wherein R1 is as defined above, with a base in the presence of a polar protic solvent.

94 more elements

A process for preparing a compound of the formula:

60
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 cycloalkynyl, 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—, 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)
61
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;
Z1 and G in combination may be
62
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2;
(e) —S(O)n—;
(f)
63
(g) —CR2(OH)—;
(h) —CONR2;
(i) —NR2CO—;
(j)
64
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;
(l) 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;
and optical and geometric isomers thereof;
comprising enzymatically resolving of a compound of the formula
65
in the presence of a lipase and an acetylating agent, and (b) reacting the compound of formula IV so formed
66
wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo, with a base in the presence of a polar protic solvent.

94 more elements

A process for preparing a compound of the formula:

70
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 cycloalkynyl, 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—, 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)
71
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;
Z1 and G in combination may be
72
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2;
(e) —S(O)n—;
(f)
73
(g) —CR2(0H)—;
(h) —CONR2;
(i) —NR2CO—;
(j)
74
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, 2 or 3;
n is 0, 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3;
and optical and geometric isomers thereof;
comprising enzymatically resolving of a compound of the formula
75
wherein R is (C1-C6)alkyl, in the presence of lipase,

92 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/791,462Filed 2 Mar 2004
Priority: 8 May 2000
Published: 9 Sep 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C12P 17/165
Containing two or more hetero rings: heterorings having nitrogen atoms as the only ring heteroatoms
A61P 5/24
Drugs for disorders of the endocrine system: of the sex hormones
A61P 19/10
For bone diseases, e.g. rachitism, Paget's disease: for osteoporosis
C12P 17/10
Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms: nitrogen as only ring hetero atom

Family

Application60/202,418Us provisional application · filed 8 May 2000
Application09/850,545Division · filed 7 May 2001
Application10/791,462Division · filed 2 Mar 2004
US 2002/0049219 A1Published application
US 6,828,134 B2Related patent
US 7,351,567 B2Related patent
US 2004/0176415 A1This patent

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

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Abstract

The present invention relates to a process for preparing 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen-2-ol compounds useful as an estrogen agonist.

A process for preparing a compound of the formula:

42
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 cycloalkynyl, 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—, 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)
43
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;
Z1 and G in combination may be
44
W is
(a) —CH2—;
(b) —CH═CH—;
(c) —O—;
(d) —NR2—;
(e) —S(O)n—;
(f)
45
(g) —CR2(OH)—;
(h) —CONR2;
(i) —NR2CO—;
(j)
46
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) C—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;
and optical and geometric isomers thereof;
comprising selectively deacetylating a compound of the formula
47
wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo, in the presence of a hydrolytic enzyme and an aqueous buffer solution.

92 more elements

Facts

Application

10/791,462Filed 2 Mar 2004

Priority

8 May 2000

Published

9 Sep 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C12P 17/165
Containing two or more hetero rings: heterorings having nitrogen atoms as the only ring heteroatoms
A61P 5/24
Drugs for disorders of the endocrine system: of the sex hormones
A61P 19/10
For bone diseases, e.g. rachitism, Paget's disease: for osteoporosis
C12P 17/10
Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms: nitrogen as only ring hetero atom

Family

Application60/202,418Us provisional application · filed 8 May 2000

Application09/850,545Division · filed 7 May 2001

Application10/791,462Division · filed 2 Mar 2004

US 2002/0049219 A1Published application

US 6,828,134 B2Related patent

US 7,351,567 B2Related patent

US 2004/0176415 A1This patent

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