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Home , Gestonorone caproate

United States Patent (19) 11) 4,310,523 Neumann 45) Jan. 12, 1982

54 COMBINED AND (56) References Cited ANTIGONALDOTROPCALLY EFFECTIVE FOR THE U.S. PATENT DOCUMENTS PROPHYLAXIS AND THERAPY OF 3,076,823 2/1963 Ringold et al...... 260/397.4 HYPERPLASA OF THE 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 and an antigonadotropically effective anti , 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- include, for example, . Apr. 17, 1978 DE Fed. Rep. of Germany ...... 287157 Antigonadotropically active anti- preferably 51 Int. Cl...... A01N 45/00; A61K 31/56 are having anti-androgenic and progestational 52 U.S. Cl...... 424/240 properties, e.g., . 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 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 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 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 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 =bis(p-acetoxyphenyl)cyclohexylideneme the same time, the proportion of SHBG (sex 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 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 , 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. . 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, , 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 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. tested are administered subcutaneously. The compound These compounds are fully conventional and are is dissolved in a medium consisting of benzylbenzoate/- 10 described, for example, in the following references: castor oil (1:10). On the twelfth day, the animals are compounds of Formula I, for example, in U.S. Pat. Nos. autopsied. The progestational transformation of the 3,234,093; 3,076,823; 3,549,671; 3,789,087 and in British endometrium is rated by the McPhail scale (1 = no ef Pat. Nos. 890,315; 1,005,495; 1,049,026 and 1,172,086; fect; 4=complete transformation of the endometrium). and compounds of Formula II, for example, in U.S. Pat. There is determined the minimum amount (Threshold 15 No. 3,492,338, the disclosures of all of which are incor Dose) of the tested compounds sufficient to achieve an porated by reference herein. adequate positive effect (McPhail= 1.5). Typical compounds of general Formula I include the Suitable anti-androgens having an antigonadotropic 17-esters of, for example: acitivty per this invention include preferably steroids 6-chloro-17-hydroxy-la,2a-methylenepregna-4,6- having anti-androgenic and progestrational properties 20 diene-3,20-dione, and having the following Formula I or II: 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione,

6-chloro-17-hydroxypregna-1,4,6-triene-3,20-dione, (I) 6-chloro-38,17-dihydroxy-la,2a-methylenpregna-4,6- dien-20-one, 25 6-chloro-38-methoxy-17-hydroxy-1a,2a-methylene pregna-4,6-dien-20-one, 6-fluoro-17-hydroxy-la,2a-methylenepregna-4,6-diene 3,20-dione, 30 17-hydroxy-1a,2a-methylenepregna-4,6-diene-3,20 dione and 4,6-dichloro-17-hydroxy-la,2a-methylenepregna-4,6- diene-3,20-dione. Preferred compounds of general Formula I include wherein 35 6-chloro-17-hydroxy-1a,2a-methylenepregna-4,6- R1 and R2 are hydrogen or together form an addi diene-3,20-dione acetate (cyproterone acetate) and tional carbon-to-carbon bond or methylene; 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione ace R3 is a conventional acyl residue in accordance with tate ( acetate). conventional steroid chemistry; Typical compounds of general Formula II include, Y is oxygen or the grouping (H, OR4) wherein R4 is 40 for example: hydrogen, acyl as defined above, or alkyl; 6-chloro-17ag-acetoxy-17aa-methyl-la,2O-methylene X1 is hydrogen or chlorine; and D-homo-4,6-androstadiene-3,17-dione and X2 is hydrogen, fluorine, chlorine or alkyl; or 6-chloro-17a-acetoxy-1713-methyl-1a,2a-methylene-D- homo-4,6-androstadiene-3,17a-dione. A (II) 45 Anti-androgens having antigonadotropic effect which are not of Formula I or II, but which are equiva R5 17,al 17 lent to those which do have these formulae are included R6 within the scope of this invention. The anti-estrogens can be administered for this inven tion approximately in the same dosages at which the o? 50 commercial anti-estrogens are employed, i.e., in daily X dosages of about 5-100 mg, e.g., for tamoxifen. Simi larly, the antigonadotropically active anti-androgens wherein - can be administered in amounts of about 5-100 mg per R5 and R6 are hydrogen or together are methylene; 55 day. - X is hydrogen, fluorine or chlorine; and The particular dosage for a given patient will vary A-B is according to conventional factors and according to the particular combination of compounds employed. For R7-O CH3 g O CH3 O-R8 example, the dosages mentioned herein are typical for N / N - 60 all named compounds but are especially suitable for the C17a C17 or C7 C17 combination of cyproterone acetate and tamoxifen. Corresponding dosages for any other combination of wherein R7 and R8 are a conventional acyl residue as suitable ingredients can be conventionally and routinely defined above for Formula I. determined by simple experiments to determine the Suitable acyl residues mentioned above include all 65 dosages which produce anti-androgenic and anti-estro such residues of the acids conventionally used in steroid genic effects, respectively, which are equivalent to chemistry for the esterification of secondary and ter those produced by cyproterone acetate and tamoxifen tiary hydroxy groups. Preferred such acyl groups are at the mentioned dosages, e.g., using fully conventional 4,310,523 10 pharmaceutical protocols, such as those mentioned -continued herein. The anti-estrogen and anti-androgen can be adminis Composition of a Tablet: tered in a combined unitary form. They can also be 225.0 mg. total weight of the tablet which is produced in the administered separately in two different forms of ad- 5 usual way in a tablet press. ministration in analogy to the separate conventional administration of each of the ingredients for conven- Optionally, it is also possible to process cyproterone tional purposes. acetate and tamoxifen with respectively one-half of the The active agents can be processed into the custom- aforementioned additives separately, and press a two ary forms of application for mammals, e.g., humans, 10 layer tablet. E.gents the customary additives, in vehicles galenic and/or pharmacy flavor in amelioratingaccordance EXAMPLE 2 with conventional methods. For oral application, which is preferred, suitable particularly are tablets, dragees, Composition of a Tablet: capsules, pills, suspensions O . Typical unit 15 10.0 mg. 6-chloro-17-hydroxy-lo,2a-methylenepregna-4,6- dosages of each ingredient are: anti-estrogen 5-50 mg, diene-3,20-dione acetate (cyproterone acetate) e.g., of tamoxifen; and anti-androgen 5-50 mg, e.g., of 10.0 mg. (Z)-2-p-(1,2-diphenyl-1-butenyl)-phenoxy-N,N- cyproterone acetate; with greater or lesser amounts dimethylethylamine (tamoxifen) being possible depending on the relative efficacy of a : R oriarch particular compound and the dosage desired for partic- 20 2.5 R poly-N-vinylpyrrolidone 25 ular regimens. 2.0 mg. "Aerosil' Suitable for parenteral, especially intramuscular ad- 0.5 mg. magnesium stearate ministration are oily solutions, e.g., sesame oil solutions 225.0 mg. total weight of the tablet which is produced in the or castor oil solutions. Typical unit dosages are: anti- usual way in a tablet press. estrogen 10-100 mg; and anti-androgen 10-100 mg, 25 greater or lesser, amounts being possible as described Optionally, cyproterone acetate and tamoxifen can also above. To increase solubility, it is also possible to add be pressed, with respectively one-half of the above solubilizers, for example, benzyl benzoate or benzyl recited additives, separately into a two-layer tablet. alcohol. Without further elaboration, it is believed that one 30 EXAMPLE 3 skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The Composition of an Oily following preferred specific embodiments are, there- 500.0 mg,in cyproterone acetate fore, to be construed as merely illustrative, and not 50.0 mg. tamoxifen limitative of the remainder of the disclosure in any way 35 353.4 mg. castor oil whatsoever. In the following examples, all temperatures 618.6 mg. benzyl benzoate are set forth uncorrected in degrees Celsius; unless oth- 1072.0 mg. A 1 ml. erwise indicated, all parts and percentages are by weight. The solution is filled into an ampoule. Cyproterone EXAMPLE 1 40 acetate and tamoxifen C3 also be filled separately into two chambers, with respectively one-half of the above mentioned additives. Composition of a Tablet: The preceding examples can be repeated with similar 20.0 mg. 6-chloro-17-hydroxy-1a:2a-methylenepregna-4,6- success by substituting the generically and specifically diene-3,20-dione acetate (cyproterone acetate) 45 described reactants and/or operating conditions of this 200 mg. (Z)-2-[p-(1,2-diphenyl-1-butenyl)-phenoxy-N,N- invention for those used in the preceding examples. 120.5 mg. stylethylamine (tamoxifen) From the foregoing description, one skilled in the art 59.5 mg. corn starch can easily ascertain the essential characteristics of this 2.5 mg. poly-N-vinylpyrrolidone 25 invention, and without departing from the spirit and 20 mg. "Aerosi!" m 50 scope thereof, can make various changes and modifica 0.5 mg. magnesium stearate tions of the invention to adapt it to various usages and conditions. TABLE 1 Antiestrogenic Effect of Ru-16117 and Tamoxifen on the Estradiol-stimulated Weight of Infantile Mice (Mode of Administration: Subcutaneous - Number of Animals per Group: Eight) Ru-16117, Tamoxifen and Estradiol are dissolved in a medium consisting of benzylbenzoate/castor oil (1:10) Ru-67 Tamoxifen %. Inhibition %. Inhibition Dose over 3 Days Uterus Weight Decrease of Uterus Weight Uterus Weight Decrease of Uterus Weight (ug/Animal/Day) (mg) in Comparison to (mg) in Comparison to - 0.03 ug Average Value - Single Estradiol Average Value E Single Estradiol Estradiol/Animal/Day Standard Deviation Administration Standard Deviation Administration 0.3 600 + 2.4 8 www. m 3 49.8 - 1.6 27 57.5 - 2, 1. 30. 34.32.3 58 43.3 3.1 40 100 ww. 39.7 - 3. 46 300 ama 34. 4.3 58 Single Administration of 0.03 ug Estradiol 63.9 6.2