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Illlllllllllllllllllllilllllllllllllllllllllllllllllllllllll IlllllllllllllllllllllIllllllllllllllllllllllllllllllllllllllllllllllllllll US005189212A United States Patent [191' [11] Patent Number: 5,189,212 Ruenitz [45] Date of Patent: Feb. 23, 1993 [54] TRIARYLETHYLENE CARBOXYLIC ACIDS Ruenitz, P. C., et al., Drug Metabolism and Disposition. WITH ESTROGENIC ACTIVITY 13, 5, (1985). Katzenellenbogen, J., et al., Journal of Labelled Com [75] Inventor: Peter C. Ruenitz, Clarke City, Ga. pounds and Radiopharmaceuticals, vol. XVIII, No. 6 [73] Assignee: University of Georgia Research (1980). - Foundation, Inc., Athens, Ga. (List continued on next page.) [21] Appl. No.: 579,398 Primary Examiner-Jose G. Dees Assistant Examiner-Keith MacMillan [22] Filed: Sep. 7, 1990 Attorney, Agent. or Firm-Kilpatrick 8L Cody [51] Int. Cl.5 .................... .. C07C 59/40; C07C 69/76; A01N 37/10 [57] ABSTRACT [52] U.S. Cl. .................................. .. 562/468; 562/491; 'Nonsteroidal estrogenic triarylethylene carboxylic 562/584; 560/57; 560/101 acids of the formula [58] Field of Search .............. .. 562/468, 491; 514/532, . 514/569, 570; 560/57, 101; 569/584 [56] References Cited U.S. PATENT DOCUMENTS 2,914,563 11/1959 Allen ................................. .. 562/584 W1? Q 4,729,999 3/1988 Young ............................... .. 514/569 4,851,433 7/1989 Kraus. OTHER PUBLICATIONS Jarman et al., Journal of Chem Res. Synop. (4), pp. X 116-117, 1985. Johnson, David W., “Synthesis of Haptens Related to wherein R is (CH2),,,O or (CH2),,, where m is an integer (Z)— and (E)-Clomiphene”, Aust. J. Chem., vol. 33, pp. from 1 to 4 and n is an integer from 0 to 4, X is hydrogen 461-464 (1980). or hydroxyl, Y is methyl, ethyl, chlorine, or bromine, Jannen et al., J. Chem. Research (M), 1985, 1342-1388 and wherein the RCOOH and X moieties are either supporting micro?che for J. Chem. Research(S), 1985, meta or para to the phenyl ethylene linkage. Examples 116-117. of active compounds include 4-hydroxytamoxifen acid, McCague, R., J. Chem. Research (S), 58 (1986). 3-hydroxytamoxifen acid, A-[l-(p-hydroxyphenyD-Z Ruenitz, P. C., et al., J. Med. Chem, 25, 1056-1060 pheny1-l-butenyl1benzoic acid and 4-[1-(p-hydroxy (1982). phenyl)-2-phenyl-1-butenyl]phenylacetic acid.‘ Compo Coe, P. L. et al., J. Chem. Soc. Perkin Trans. I, 475 sitions containing these triarylethylene carboxylic acids (1986). can be administered to patients to alleviate medical Johnson, M. D., et al., Anti-Ostrogens and M CF-7 Cells, conditions associated with a de?ciency of estrogen, The MacMillan Press Ltd., 1989. including osteoporosis, premenstrual syndrome, vaso Stevenson, D., et al., J. Pharm. & Biamed. Analysis, 6, motor symptoms associated with menopause, atrophic 1065-1068, (1988). vaginitis, Kraurosis vulvae, female hypogonadism, pri Armstrong, R. D., et al., Journal of Chromatography, ' mary ovarian failure, excessive hair growth and pros 414, 192-196 (1987). tatic cancer. Adam, H. K., et al., Biochem. Pharmacology. 27, 145-147, (1979). 29 Claims, 3 Drawing Sheets 5,189,212 Page 2 OTHER PUBLICATIONS Lien, E. A., et al., Cancer Research, 48, 2304-2308 McCague, R., et al., J. Med. Chem, 31, 1285-1290 (1988). (1988). Kemp, J. V., et al., Biochemical Pharmacology, 32 (13), McCague, R., et al., J. Med. Chem, 32, 2527-2533 2045-2052 (1983). (1989). Fromson, J. M., et al., Xenabiotica, 3 (11), 711-714 Foster, A. B., et al., J. Med. Chem, 28, 1491-1497 (1973). (1985). Fromson, J. M., _et al., Xenobiotica, 3 (11) 693-709 Reidy, G. F., et al., Biochemical Pharmacology, 38 (1), (1973). 195-199 (1989). Jordan, V. C., et al., Cancer Research, 43, 1446-1450 Kikuta, C., et al., J. Pharmaceutical & Biomedical Analy (1983). ' . sis, 7, 329-337 (1989). Simberg, N. H., et al., J. Steroid Biochem, 36 (3), Bain, R., et al., Biochem Pharmacology, 32(2), 373 197-202 (1990). (1983). Sipila, H., et al., J. Steroid Biochem, 36 (3) 211-215 Soininen, K., et al., J. Int. Med. Res. 14, 162 (1986). (1990). Parr, I. B., et al., Biochemical Pharmacology, 36(9), Hasan, S. A., et al., Analytical Letters, 23(2), 327-334 1513-1519 (1987). (1990). US. Patent Feb. 23, 1993 Sheet 1 of 3 5,189,212 c=c\ Q CH2CH3 F/GURE 7 x . ‘COMPOUND 0 R x TAMOXIFEN ACID OCH2CO2H - H 4-HYDRQXY TAMOXIFEN OCHZCOZH OH ACID TAMOXIFEN O'CH2CH2N(CH3)2 H 4-HYDROXYTAMOXIFEN 0CH2CH2N(CH3)2 OH F/GURE Z % SPECIFIC BINDING 100 < —=— 4-HTA 80- —Q- ESTRADIOL -e- TA 60 4o 20 o1 llllnlll l?llnn lfilllnl llllll? 10 100 1000 10000 CONCENTRATION (nM) . US. Patent Feb. 23, 1993 Sheet 2 of 3 5,189,212 140 F/GURE 3 120 - 100" J 80- +4-HTA O —-l-TAM O: E 60 O U °\° 40: \_ 2O O I l I l l l' l l - 1 1O CONCENTRATION (uM) 120 ' +[4-HTA] _J O I |_ Z O O °\° O I llllllll I Tlllllll IIIIIHI 0.01 0.1 1 1o [DRUG ,u M] . US. Patent Feb. 23, 1993 Sheet 3 of 3 5,189,212 700 F/GURE 5 600 500 a:a’ 400 ‘. Qg 300 LL 0 200 °\° 100 t O l l l I l l 1 l 0 -13 -12 -11 -10 -9 -e -7 '6 -5 L06 CONCENTRATION, M F/GUFPE 6 .5 4-HTA .L 4... ‘P O ._ 3_ T: X E _ o 2 TA 1 - glyOH - 0.0 0.25 0.5 0.75 1.0 5,189,212 1 2 Hydroxy tamoxifen (4-HT) is a major metabolite. Acid TRIARYLETHYLENE CARBOXYLIC ACIDS WITH metabolites of TAMfhowever, have not been detected. ESTROGENIC ACTIVITY Studies based on receptor competitive binding have shown that the basic and neutral metabolites of TAM The U.S. Government has certain rights in this inven generally possess estrogen receptor affinities and anties tion by virtue of grants from the National Institutes of trogenic activities that equal or exceed those of TAM Health. itself. In addition, studies have demonstrated that these This invention relates to triarylethylene carboxylic metabolites localize with TAM in tumors of patients on acids with estrogenic activity and their method of use. TAM therapy. Clomiphene (2-[4-(2-chloro-l,2-diphenylethenyl) BACKGROUND OF THE INVENTION‘ phenoxy]4N,N-diethylethanamine) is a pharmaceutical Steroidal hormones are organic molecules that are compound closely structurally related to tamoxifen. synthesized in the body in an organ or gland and then The preparation of clomiphene is described in U.S. Pat. carried through the blood to induce activity at a remote No. 2,914,563. Clomiphene is a nonsteroidal antiestro location. Steroidal hormones contain a perhydrocyclo gen that is prescribed to induce ovulation in infertile pentanophenanthrene moiety. Estrogens are an impor women with physiological indications of normal estro tant class of steroidal hormones that stimulate the devel gen levels. In the hypothalamus, clomiphene antago opment and maintenance of fundamental sexual charac nizes estradiol-mediated feedback inhibition of gonado teristics in humans. The principal naturally occurring trophin-releasing hormone secretion. Tamoxifen has estrogen in humans is estradiol, that plays a pivotal role also been administered to initiate ovulation in anovula in the regulation and maintenance of the androgen/es tory women, and is favored therapeutically over clomi trogen balance. Estrogens have also been found useful phene for this purpose because it has a lower incidence in the treatment of certain medical conditions and dis of side effects. eases. For example, estradiol, a steroid hormone pro U.S. Pat. No. 4,894,373 to Young describes the use of duced by the ovary, is useful in the treatment of osteo 25 clomiphene, tamoxifen, nafoxidene, and other antiestro porosis, premenstrual syndrome, vasomotor symptoms genic compounds in the treatment of menopause and associated with menopause, atrophic vaginitis, Krauro osteoporosis. sis vulvae, female hypogonadism, primary ovarian fail Toremifene (2-[4-(2»chloromethyl-1,2-diphenyle ure, excessive hair growth and prostatic cancer. Estro 30 thenyl)phenoxy]—N,N-diethylethanamine), is a triphen gens are also used in combination with another female ylethylene compound structurally related to tamoxifen sex hormone, progesterone, to promote gonadotropin that has antineoplastic activity Hasan, Analyt. Letters suppression and to act as an oral contraceptive. 23(2), 327-334 (1990), reported that toremifene is me Diethylstilbestrol, conjugated estrogens, and ethinyl tabolized in vivo to a number of compounds, including estradiol have been used as steroidal estrogen substi two metabolites in which the diethylethanamine side tutes for pharmaceutical administration. However, ad chain is replaced with oxyacetic acid and the methyl ministration of steroidal hormone substitutes have been ester of oxyacetic acid. No biological activities have associated with a number of side effects, including myo been reported for these metabolites. cardial infarction, thromboembolism, cerebrovascular While several nonsteroidal antiestrogenic compounds disease, and endometrial carcinoma. In fact, while es have been developed, very few nonsteroidal estrogenic trogens and estrogen substitutes are currently the only compounds have been identi?ed. There is strong need known effective treatment for osteoporosis, their use is for nonsteroidal estrogenic compounds for use in estro severely limited due to side effects of long term steroi gen replacement therapy, and speci?cally menopause dal treatment. Further, no new estrogen substitutes therapy. It has been estimated that one-fourth of all have been marketed in the last twenty years, perhaps women seek medical adviceor treatment for this condi due to certain severe side effects, including devastating tion. Nonsteroidal estrogenic compounds are also birth defects, that were found associated with adminis needed for osteoporosis therapy, in the prevention of tration of diethylstilbestrol. uterine bleeding, failure of ovarian development at the In light of problems associated with steroidal ther age of puberty, prevention of excessive growth of body apy, a signi?cant amount of research has been carried 50 hair, and for oral contraceptives.
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