United States Patent (19) 11) 4,310,523 Neumann 45) Jan
Total Page：16
File Type：pdf, Size：1020Kb
United States Patent (19) 11) 4,310,523 Neumann 45) Jan. 12, 1982 54 COMBINED ANTIESTROGENS AND (56) References Cited ANTIGONALDOTROPCALLY EFFECTIVE ANTIANDROGENS FOR THE U.S. PATENT DOCUMENTS PROPHYLAXIS AND THERAPY OF 3,076,823 2/1963 Ringold et al. .................. 260/397.4 HYPERPLASA OF THE PROSTATE 3,423,507 1/1969 Neri................. ... 424/243 4,055,641 10/1977 Benson et al. ...................... 424/242 (75) Inventor: Friedmund Neumann, Berlin, Fed. Rep. of Germany OTHER PUBLICATIONS (73) Assignee: Schering Aktiengesellschaft, Berlin Chem. Abstracts (1978), vol. 89, Par. 197804g. and Bergkamen, Fed. Rep. of Germany Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Millen & White 21 Appl. No.: 195,812 22 Filed: Oct. 10, 1980 57 ABSTRACT A pharmaceutical composition comprising an anti Related U.S. Application Data estrogen and an antigonadotropically effective anti androgen, e.g., in a weight ratio of anti-estrogen to 63) Continuation-in-part of Ser. No. 28,745, Apr. 10, 1979, anti-androgen of essentially 2:1 to 1:10 is effective for abandoned. the prophylaxis and therapy of prostate hyperplasia. 30 Foreign Application Priority Data Suitable anti-estrogens include, for example, tamoxifen. Apr. 17, 1978 DE Fed. Rep. of Germany ....... 287157 Antigonadotropically active anti-androgens preferably 51 Int. Cl. ...................... A01N 45/00; A61K 31/56 are steroids having anti-androgenic and progestational 52 U.S. Cl. .................................................... 424/240 properties, e.g., cyproterone acetate. 58) Field of Search ............. 260/397.5, 397.4, 397.46; 424/238, 230 16 Claims, No Drawings 4,310,523 1. 2 shown that the additional treatment with anti-androgen COMBINED ANTIESTROGENS AND (cyproterone acetate) leads to total atrophy of the gland ANTIGONALDOTROPCALLY EFFECTIVE ANTANDROGENS FOR THE PROPHYLAXIS parenchyma, but that the proliferation of the inter AND THERAPY OF HYPERPLASA OF THE 5 stitium is not affected. PROSTATE In autoradiographic studies on human prostate hyper plasia tissue, it has furthermore been shown that only CROSS-REFERENCE TO RELATED the gland epithelium (parenchyma) is a target organ for APPLICATIONS androgens, rather than the interstitium. Additionally, it This application is a continuation-in-part of applica 10 was discovered that fibroblast cultures from human tion Ser. No. 028,745, filed Apr. 10, 1979 now aban prostata hyperplasia tissue aromatize testosterone about doned. seven to nine times more strongly to estrogens than BACKGROUND OF THE INVENTION fibroblast cultures derived from healthy prostata tissue. The present invention relates to a new combination of 15 drugs for the prophylaxis and therapy of prostate hy SUMMARY OF THE INVENTION perplasia. Accordingly, it is an object of this invention to pro Prostate hyperplasia is a benign enlargement of the vide a method and an agent for the human male which prostate beginning from the so-called "inner' prostate. is effective to produce an involution of the epithelial as . The attendant complaints are due primarily to the resul 20 tant obstructions of the urethra. Voiding is made diffi well as the fibromuscular portion of the prostate, cult and retention of urine residue occurs. Without whereby an increased secretion of androgens is also to surgical interference, uremia can ensue. be avoided. Heretofore, it has hardly been possible to medicinally It is an object of this invention to provide a method treat this disease, occurring with great frequency in 25 and an agent for the prophylaxis and treatment of pros older men. The phyto-preparations tested for this pur tate hyperplasia. pose, e.g., g-sitosterol, mixtures of various plant ex tracts, and combinations of plant extracts with the neu Upon further study of the specification and appended tropic spasmolytic azoniaspirochloride have proved claims, further objects and advantages of this invention ineffective as determined by a one-year study. Although 30 will become apparent to those skilled in the art. the patients in this study experienced an improvement in These objects have been attained by the present in miction symptoms, under therapy, an involution of the vention by providing an agent, and a method of use hyperplastic prostate was not achieved. thereof, comprising an anti-estrogen and an anti-andro Hormones have likewise been utilized in the treat ment of prostate hyperplasia. Among these compounds, 35 gen having an antigonadotropic effect, in a weight ratio the depot progestogen gestonorone caproate deserves of anti-estrogen to anti-androgen of essentially 2:1 to particular mention. As compared to the phyto-prepara 1:10, preferably 2:1 to 1:2. tions, a better effect is obtained with gestonorone capro ate. The miction period, prolonged prior to treatment, is DETAILED DISCUSSION markedly shortened, and the maximum flow value (flow 40 Suitable anti-estrogens for use in accordance with this of urine per unit time) is improved. A marked reduction invention include all conventional anti-estrogens, both of the size of the adenoma, however, also cannot be achieved with this compound. steroidal and non-steroidal. Examples of suitable non In U.S. Pat. No. 3,423,507, a treatment of prostate steroidal anti-estrogens include: hypertrophy is described. It involves use of the proge 45 tamoxifen = (Z)-2-p-(1,2-diphenyl-1-butenyl)-phenox stationally and anti-androgenically effective esters of y-N,N-dimethylethylamine, 6-chloro-17-hydroxy-la,2a-methylenepregna-4,6- nafoxidine=1-(2-4-(6-methoxy-2-phenyl-3,4-dihydro diene-3,20-dione (cyproterone esters). However, it was 1-naphthyl) phenoxy-ethyl)-pyrrolidine, hydrochlo found that even under this treatment there is only a partial retrogression of hyperplasia. 50 ride, In prostate hyperplasia, the fibromuscular proportion MER25 = 1-p-(2-diethylaminoethoxy)-phenyl)-2-(p- of the prostate (interstitium) proliferates primarily. A methoxyphenyl)-1-phenylethanol, possible cause for this, inter alia, is a shift in the es TACE=tri-(p-anisolyl)-chloroethylene, trogen/androgen ratio in favor of the estrogens. It has clomiphene= 1-p-(3-diethylaminoethoxy)phenyl-1,2- been found in various investigations that, in older men, 55 diphenylchloroethylene, the serum testosterone concentrations are reduced; at cyclofenil =bis(p-acetoxyphenyl)cyclohexylideneme the same time, the proportion of SHBG (sex hormone binding globuline, specific transport protein, for ste thane, and roids) increases, so that the biological availability of CI-628 = 1-(2-(p-a-(p-methoxyphenyl)-f3-nitrostyryl androgens is even further reduced. 60 phenoxy)-ethyl)-pyrrolidine. In the conventional laboratory animal species, only Examples of suitable steroidal anti-estrogens include: older dogs experience spontaneous prostate hyperplasia RU-16117 = 1 la-methoxy-17a-ethynyl-1,3,5(10)-estra comparable to the changes caused in males by prostate triene-3,1713-diol, and hyperplasia. Also in the dog, there is a proliferation 16,3-ethylestradiol = 166-ethyl-1,3,5(10-estratriene primarily of the fibromuscular portion of the prostate. It 65 is also possible to cause the aspects of the disease in 3,1713-diol. younger dogs by treatment with an estrogen or an es The structures of the non-steroidal anti-estrogens are trogen/androgen mixture. Our own experiments have as follows: 4,310,523 3 4. -continued C2H5 YCH 2)-)-O / C2H5 CEC V Cl Clomiphene OCH3 CH3 N Nafoxidine N. (CH3)2- 15 The structures of the steroidal antiestrogens are as CH3 c=c V follows: C2H5 RU-161 17 20 Tamoxifen 25 N-(CH2)2-O HO CEC . V NO2 30 CH3O C1-628 35 V - . 40 As can be seen, antiestrogens equivalent to the exam C ples listed above in general include substituted dipheny CH3O lalkanes (non-steroidal) and substituted estradiols (ste roidal). All such antiestrogens meeting the requirements set forth herein are, of course, within the scope of this TACE 45 invention. The steroidal compounds are discussed, respectively, in Azadian-Boulanger et al, Eur. J. Med. Chem. 1978, CH3CO. O. 13(4), 313-9 or Raynaud et ai, J. Steroid. Biochem., 1975, 6, 615-22, and Takikawa, Chem. Pharm. Bull, 50 1977, 25(3) 501-3, the disclosures of which are incorpo rated by reference herein. All of the exemplary anties CH3CO. O. trogens. mentioned above are discussed in Nishino, Gynakologe 12, 199-211 (1979), whose disclosure is 55 also entirely incorporated by reference herein. Cyclofenil In general, those anti-estrogens which have a spec trum of activity essentially the same as that of tamoxifen are employable in this invention, most notably, essen C2H5 tially the same spectrum of hormonal activity as tamox YN/ (CH2)22. o (pH OCH 3 60 ifen. More particularly, since, all known anti-estrogens C2H - also display estrogenous effects (depending on the dos arts C-CH V age, duration of administration, host species, target H organ, etc.), the anti-estrogens of the invention should have a ratio of anti-estrogenic activity to estrogenic 65 activity which is about the same as or larger than that of tamoxifen. A description of the activity spectrum of MER-2S . tamoxifen is contained in, e.g., Drugs 16:1-24 (1978), all of whose disclosure is incorporated by reference herein. 4,310,523 7 8 derived from aliphatic carboxylic acids of 1-8 carbon PROGESTATIONAL ACTIVITY atoms, e.g., acetic acid, propionic acid, butyric acid, The progestational activity can be determined by the valeric acid, isovaleric acid, caproic acid, enanthic acid, Clauberg test on infantile spayed rabbits weighing 800 etc. The esters of acetic acid (acetyl residues) are espe to 1000 grams. A daily dose of 5 ug of estradiol dis- 5 cially preferred. The many other conventional acyl solved in 1 ml of sesame oil is subcutaneously adminis groups are equivalents. Alkyl includes lower alkyl tered over a period of six days. From the seventh to the groups of 1-5 carbon atoms, the methyl group being eleventh day, measured dosages of the compound to be preferred.