Enzymatic resolution of selective estrogen receptor modulators

Details Enzymatic resolution of selective estrogen receptor modulators Enzymatic resolution of selective estrogen receptor modulators

2001-05-07

2004-12-07

Tate, Christopher R. (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

C514S266400, C514S256000, C514S252170, C514S235500, C514S234500, C514S233500, C514S228200, C544S060000

Reexamination Certificate

active

06828134

ABSTRACT:

BACKGROUND OF THE INVENTION
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.
The value of naturally occurring estrogens and synthetic compounds demonstrating “estrogenic” activity has been in their medical and therapeutic uses. A traditional listing of the therapeutic applications for estrogens alone or in combination with other active agents includes: oral contraception; relief for the symptoms of menopause; prevention of threatened or habitual abortion; relief of dysmenorrhea; relief of dysfunctional uterine bleeding; an aid in ovarian development; treatment of acne; diminution of excessive growth of body hair in women (hirsutism); the prevention of cardiovascular disease; treatment of osteoporosis; treatment of prostatic carcinoma; and suppression of post-partum lactation [Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1421-1423]. Accordingly, there has been increasing interest in finding newly synthesized compounds and new uses for previously known compounds which are demonstrably estrogenic, this is, able to mimic the action of estrogen in estrogen responsive tissue.
From the viewpoint of pharmacologists interested in developing new drugs useful for the treatment of human diseases and specific pathological conditions, it is most important to procure compounds with some demonstrable estrogen-like function but which are devoid of proliferative side-effects. Exemplifying this latter view, osteoporosis, a disease in which bone becomes increasingly more fragile, is greatly ameliorated by the use of fully active estrogens; however, due to the recognized increased risk of uterine cancer in patients chronically treated with active estrogens, it is not clinically advisable to treat osteoporosis in intact women with fully active estrogens for prolonged periods. Accordingly, estrogen agonists are the primary interest and focus.
Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. These cost the nation over $10 billion. Hip fractures are the most serious, with 5%-20% of patients dying within one year, and over 50% of survivors being incapacitated.
The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. Worldwide fracture incidence is forecast to increase three-fold over the next 60 years, and one study estimates that there will be 4.5 million hip fractures worldwide in 2050.
Women are at greater risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake.
Estrogen is the agent of choice in preventing osteoporosis or post menopausal bone loss in women; it is the only treatment which unequivocally reduces fractures. However, estrogen stimulates the uterus and is associated with an increased risk of endometrial cancer. Although the risk of endometrial cancer is thought to be reduced by a concurrent use of a progestogen, there is still concern about possible increased risk of breast cancer with the use of estrogen.
SUMMARY OF THE INVENTION
The present invention relates to a process (Process A) for preparing a compound of the formula
wherein:
A is selected from CH
2
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 R
4
;
(b) naphthyl, optionally substituted with 1-3 substituents independently selected from R
4
;
(c) C
3
-C
8
cycloalkyl, optionally substituted with 1-2 substituents independently selected from R
4
;
(d) C
3
-C
8
cycloalkynyl, optionally substituted with 1-2 substituents independently selected from R
4
;
(e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from R
4
;
(f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR
2
— and —S(O)
n
— optionally substituted with 1-3 substituents independently selected from R
4
; 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—, —NR
2
—, NR
2
— and —S(O)
n
—, optionally substituted with 1-3 substituents independently selected from R
4
;
Z
1
is
(a) —(CH
2
)
p
W(CH
2
)
q
—;
(b) —O(CH
2
)
p
CR
5
R
6
—;
(c) —O(CH
2
)
p
W(CH
2
)
q
;
(d) —OCHR
2
CHR
3
; or
(e) —SCHR
2
CHR
3
—;
G is
(a) —NR
7
R
8
;
(b)
 wherein n is 0, 1 or 2; m is 1, 2 or 3; Z
2
is —NH—, —O—, —S—, or —CH
2
—; 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 R
4
; 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 R
4
;
Z
1
and G in combination may be
W is
(a) —CH
2
—;
(b) —CH═CH—;
(c) —O—;
(d) —NR
2
—;
(e) —S(O)
n
—;
(f)
(g) —CR
2
(OH)—;
(h) —CONR
2
—;
(i) —NR
2
CO—;
(j)
(k) —C≡C—;
R is hydrogen or C
1
-C
6
alkyl;
R
2
and R
3
are independently
(a) hydrogen; or
(b) C
1
-C
4
alkyl;
R
4
is
(a) hydrogen;
(b) halogen;
(c) C
1
-C
6
alkyl;
(d) C
1
-C
4
alkoxy;
(e) C
1
-C
4
acyloxy;
(f) C
1
-C
4
alkylthio;
(g) C
1
-C
4
alkylsulfinyl;
(h) C
1
-C
4
alkylsulfonyl;
(i) hydroxy (C
1
-C
4
)alkyl;
(j) aryl (C
1
-C
4
)alkyl;
(k) —CO
2
H;
(l) —CN;
(m) —CONHOR;
(n) —SO
2
NHR;
(o) —NH
2
;
(p) C
1
-C
4
alkylamino;
(q) C
1
-C
4
dialkylamino;
(r) —NHSO
2
R;
(s) —NO
2
;
(t) -aryl; or
(u) —OH.
R
5
and R
6
are independently C
1
-C
8
alkyl or together form a C
3
-C
10
carbocyclic ring;
R
7
and R
8
are independently
(a) phenyl;
(b) a C
3
-C
10
carbocyclic ring, saturated or unsaturated;
(c) a C
3
-C
10
heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
(d) H;
(e) C
1
-C
6
alkyl; or
(f) form a 3 to 8 membered nitrogen containing ring with R
5
or R
6
;
R
7
and R
8
in either linear or ring form may optionally be substituted with up to three substituents independently selected from C
1
-C
6
alkyl, halogen, alkoxy, hydroxy and carboxy;
a ring formed by R
7
and R
8
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
wherein R
1
is (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)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.
The terms “GC-4, PS30, AY30, PGE, AK, N, L-10, AP-12, FAP-15, R-10, G, MAP10 and SAM II” are names of lipase enzymes used in this invention and sold by Amano Chemical Co., 1157 North Main Street, Lombard, Ill. 60148.
The terms “lipase from
Pseudomonas fluorescens,
lipase from
Candida cylindracea,
lipase from
Mucor miehei,
lipase from Wheat germ, lipase from
Rhizopus arrhizus,
lipase from
Mucor javanicus,
lipase from
Pseudomonas cepacia,
lipase from
Cadia lipolytica
and lipase from
Penicillium roqueforfti”
are names of lipase enzymes used in this invention and sold by Fluka Chemical Co., 1001 West St. Paul Avenue, Milwaukee, Wis. 53233.
The terms “lipopr

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