| Enzymatic resolution of selective estrogen receptor modulators -> Monitor Keywords |
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Enzymatic resolution of selective estrogen receptor modulatorsRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Micro-organism, Tissue Cell Culture Or Enzyme Using Process To Synthesize A Desired Chemical Compound Or Composition, Preparing Heterocyclic Carbon Compound Having Only O, N, S, Se, Or Te As Ring Hetero Atoms, Nitrogen As Only Ring Hetero AtomEnzymatic resolution of selective estrogen receptor modulators description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070249025, Enzymatic resolution of selective estrogen receptor modulators. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This non-provisional application is based upon and claims priority from provisional patent application No. 60/202,418, filed May 8, 2000. BACKGROUND OF THE INVENTION [0002] 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. [0003] 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. [0004] 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. [0005] 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. [0006] 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. [0007] 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. [0008] 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 [0009] The present invention relates to a process (Process A) for preparing a compound of the formula wherein: [0010] A is selected from CH.sub.2 and NR; [0011] B, D and E are independently selected from CH and N; [0012] Y is [0013] (a) phenyl, optionally substituted with 1-3 substituents independently selected from R.sup.4; [0014] (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R.sup.4; [0015] (c) C.sub.3-C.sub.8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R.sup.4; [0016] (d) C.sub.3-C.sub.8 cycloalkynyl, optionally substituted with 1-2 substituents independently selected from R.sup.4; [0017] (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of --O--, --NR.sup.2-- and --S(O).sub.n--, optionally substituted with 1-3 substituents independently selected from R.sup.4; [0018] (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of --O--, --NR.sup.2-- and --S(O).sub.n-- optionally substituted with 1-3 substituents independently selected from R.sup.4; or [0019] (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.sup.2--, NR.sup.2--and --S(O).sub.n--, optionally substituted with 1-3 substituents independently selected from R.sup.4; [0020] Z.sup.1 is [0021] (a) --(CH.sub.2).sub.pW(CH.sub.2).sub.q--; [0022] (b) --O(CH.sub.2).sub.pCR.sup.5R.sup.5--; [0023] (c) --O(CH.sub.2).sub.pW(CH.sub.2).sub.q; [0024] (d) --OCHR.sup.2CHR.sup.3--; or [0025] (e) --SCHR.sup.2CHR.sup.3--; [0026] G is [0027] (a) --NR.sup.7R.sup.8; [0028] (b) [0029] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z.sup.2 is --NH--, --O--, --S--, or --CH.sub.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.sup.4; or [0030] (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.sup.4; [0031] Z.sup.1 and G in combination may be [0032] W is [0033] (a) --CH.sub.2--; [0034] (b) --CH.dbd.CH--; [0035] (c) --O--; [0036] (d) --NR.sup.2--; [0037] (e) --S(O).sub.n--; [0038] (f) [0039] (g) --CR.sup.2(OH)--; [0040] (h) --CONR.sup.2--; [0041] (i) --NR.sup.2CO--; [0042] (j) [0043] (k) --C.ident.C--; [0044] R is hydrogen or C.sub.1-C.sub.6 alkyl; [0045] R.sup.2 and R.sup.3 are independently [0046] (a) hydrogen; or [0047] (b) C.sub.1-C.sub.4 alkyl; [0048] R.sup.4 is [0049] (a) hydrogen; [0050] (b) halogen; [0051] (c) C.sub.1-C.sub.6 alkyl; [0052] (d) C.sub.1-C.sub.4 alkoxy; [0053] (e) C.sub.1-C.sub.4 acyloxy; [0054] (f) C.sub.1-C.sub.4 alkylthio; [0055] (g) C.sub.1-C.sub.4 alkylsulfinyl; [0056] (h) C.sub.1-C.sub.4 alkylsulfonyl; [0057] (i) hydroxy (C.sub.1-C.sub.4)alkyl; [0058] (j) aryl (C.sub.1-C.sub.4)alkyl; [0059] (k) --CO.sub.2H; [0060] (l) --CN; [0061] (m) --CONHOR; [0062] (n) --SO.sub.2NHR; [0063] (o) --NH.sub.2; [0064] (p) C.sub.1-C.sub.4 alkylamino; [0065] (q) C.sub.1-C.sub.4 dialkylamino; [0066] (r) --NHSO.sub.2R; [0067] (s) --NO.sub.2; [0068] (t) -aryl; or [0069] (u) --OH. [0070] R.sup.5 and R.sup.5 are independently C.sub.1-C.sub.8 alkyl or together form a C.sub.3-C.sub.10 carbocyclic ring; [0071] R.sup.7 and R.sup.8 are independently [0072] (a) phenyl; [0073] (b) a C.sub.3-C.sub.10 carbocyclic ring, saturated or unsaturated; [0074] (c) a C.sub.3-C.sub.10 heterocyclic ring containing up to two heteroatoms, selected from --O--, --N-- and --S--; [0075] (d) H; [0076] (e) C.sub.1-C.sub.6 alkyl; or [0077] (f) form a 3 to 8 membered nitrogen containing ring with R.sup.5 or R.sup.6; [0078] R.sup.7 and R.sup.8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C.sub.1-C.sub.6 alkyl, halogen, alkoxy, hydroxy and carboxy; [0079] a ring formed by R.sup.7 and R.sup.8 may be optionally fused to a phenyl ring; [0080] e is 0, 1 or 2; [0081] m is 1, 2 or 3; [0082] n is 0, 1 or 2; [0083] p is 0, 1, 2 or 3; [0084] q is 0, 1, 2 or 3; [0085] and optical and geometric isomers thereof; [0086] comprising selectively deacetylating a compound of the formula wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.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. [0087] 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. [0088] 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 roqueforti" are names of lipase enzymes used in this invention and sold by Fluka Chemical Co., 1001 West St. Paul Avenue, Milwaukee, Wis. 53233. [0089] The terms "lipoprotein lipase ca#70-6571-01, and lipoprotein lipase ca# 70-1481-01" are names of lipase enzymes used in this invention and sold by Genzyme Chemical Co., One Kendall Square, Cambridge, Mass. 02139. [0090] The terms "lipase from Candida cylindracea, lipase from Chromobacterium viscosum, lipase from Mucor miehei, lipase from Pancreatic, lipase from Pseudomonas fluorescens and lipase from Rhizopus niveus" are names of lipase enzymes used in this invention and sold by Recombinant Biocatalysis Chemical Co., 512 Elmwood Avenue, Sharon Hill, Pa. 19079. [0091] The term "PPL, type II" is a name of a lipase enzyme used in this invention and sold by Sigma Chemical Co., P. O. Box 14508, St. Louis, Mo. 63178. [0092] The term "Lip-300" " is a name of a lipase enzyme used in this invention and sold by TOYOBO Chemical Co., 1450 Broadway, New York, N.Y. 10018. [0093] The terms "immobilized, hog liver, esterase from Hog pancreas, esterase from Thernoanaerobium brockii, esterase from Bacillus sp and esterase from Mucor miehi" are names of esterase enzymes used in this invention and sold by Fluka Chemical Co., 1001 West St. Paul Avenue, Milwaukee, Wis. 53233. [0094] The terms "cholesterol esterase from Porcine pancreas, cholesterol esterase from Bovine pancreas, cholesterol esterase from Pseudonomas fluorescens, cholesterol esterase from Porcine liver, cholesterol esterase from Rabbit liver, cholinesterase, cholinesterase from Electric eel, cholinesterase, choloylglycine hydrolase and Porcine liver E-3128" are names of esterase enzymes used in this invention and sold by Sigma Chemical Co., P. O. Box 14508, St. Louis, Mo. 63178. [0095] The terms "cholesterin-esterase and cholesterin esterase from Pseudonomas fluorescens" are names of esterase enzymes used in this invention and sold by Boehringer Mannheim Chemical Co., 9115 Hague Road, Indianapolis, Ind. 46250. [0096] The terms "cat I-1256, dog I7379, eel I-1266, horse I9627, calf I7876, guinea pig I1631, mouse I8254, goat I2635, chicken I8001, sheep I0132, pigeon I8376, seal I7627, rattlesnake I9885, trout I5131, turtle I-0757, rat I1380, lungfish I7377, salmon I7502, eel (electrophorus electricus) I8380 and lemon shark I1130" are names of liver acetone powder enzymes used in this invention and sold by Sigma Chemical Co., P. O. Box 14508, St. Louis, Mo. 63178. [0097] The present invention further relates to Process A wherein the hydrolytic enzyme is lipase. [0098] The present invention further relates to Process A wherein the hydrolytic enzyme is esterase. [0099] The present invention further relates to Process A wherein the hydrolytic enzyme is liver acetone powder. Continue reading about Enzymatic resolution of selective estrogen receptor modulators... 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