[19]
`
`[11]
`
`4,310,523
`
`United States Patent
`Neumann
`[45] Jan. 12, 1982
`
`
`
`[54] COMBINED ANTIESTROGENS AND
`ANTIGONADOTROPICALLY EFFECTIVE
`ANTIANDROGENS FOR THE
`PROPI-IYLAXIS AND THERAPY OF
`I-IYPERPLASIA OF THE PROSTATE
`
`[75]
`
`Inventor:
`
`[73] Assignee:
`
`Frietlntund Neunlann, Berlin, Fed.
`Rep. of Germany
`
`Sellering Akliengesellschnft, Berlin
`and Bergkarnen, Fed. Rep. of
`Gennany
`
`[21] Appl. No.: 195,812
`
`[22] Filed:
`
`Oct. 1|], 1980
`
`Related U.S. Application Data
`
`Continuation-in-part of Ser. No. 28,745, Apr. 10, 1979.
`abandoned.
`
`Foreign Application Priority Data
`
`[63]
`
`[30]
`
`Apr. 17, 1978 [DE]
`
`Fed. Rep. of Germany ..... .. 2817157
`
`[51]
`Int. Cl.3 .................... .. ACIIN 45/00; A61K 31/56
`
`[52] U.S. C1. .............................................. .. 424/240
`[53] Field of Search ........... .. 260/397.5, 3914, 397.46;
`424/233, 230
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`260/397.4
`.... .. 424/243
`.................... .. 424/242
`
`2/1963 Ringold et al.
`3,076,323
`l/1969 Neri
`3,423,501‘
`4,055,641 I0/I91’? Benson eta].
`
`OTHER PUBLICATIONS
`
`Chem. Abstracts (1978), vol. 89, Par. 1978043.
`
`Primary Exomirter—E1bert L. Roberts
`Attorney, Agent, or F£rm—-Mi1le11 & White
`
`[57]
`
`ABSTRACT
`
`A pharmaceutical composition comprising an anti-
`estrogen and an antigonadotropically effective anti-
`androgen, e.g.,
`in a weight ratio of anti~estrc-gen to
`anti-androgen of essentially 2:1 to 1:10 is effective for
`the prophylaxis and therapy of prostate hyperplasia.
`Suitable anti-estrogens include, for example, tamoxifen.
`Antigonadotropically active anti-androgens preferably
`are steroids having anti-androgenic and progestational
`properties, e.g., cyproterone acetate.
`'
`
`16 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 1
`
`

`
`I
`
`4,310,523
`
`COMBINED ANTIESTROGENS AND
`ANTIGONADOTROPICALLY EFFECTIVE
`ANTIANDROGENS FOR THE PROPI-IYLAXIS
`AND THERAPY OF I-IYPERPLASIA OF THE
`PROSTATE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of applica-
`tion Ser. No. 028.745, filed Apr. 10, 1979 now aban-
`doned.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to a new combination of
`drugs for the prophylaxis and therapy of prostate hy-
`perplasia.
`Prostate hyperplasia is a benign enlargement of the
`prostate beginning from the so-called “inner" prostate.
`The attendant complaints are due primarily to the resul-
`tant obstructions of the urethra. Voiding is made diffi-
`cult and retention of urine residue occurs. Without
`surgical interference, uremia can ensue.
`I-leretofore, it has hardly been possible to medicinally
`treat this disease, occurring with great frequency in
`older men. The phyto-preparations tested for this pur-
`pose, e.g.,
`,6-sitosterol, mixtures of various plant ex-
`tracts, and combinations of plant extracts with the neu-
`tropic spasmolytic azoniaspirochloride have proved
`ineffective as determined by a one-year study. Although
`the patients in this study experienced an improvement in
`miction symptoms, under therapy, an involution of the
`hyperplastic prostate was not achieved.
`Hormones have likewise been utilized in the treat-
`ment of prostate hyperplasia. Among these compounds,
`the depot progestogen gestonorone caproate deserves
`particular mention. As compared to the phyto-prepara-
`tions, 3 better effect is obtained with gestonorone capto-
`ate. The miction period, prolonged prior to treatment, is
`markedly shortened, and the maximum llow value (flow
`of urine per unit time) is improved. A marked reduction
`of the size of the adenoma, however, also cannot be
`achieved with this compound.
`In U.S. Pat. No. 3,423,507, a treatment of prostate
`hypertrophy is described. It involves use of the proge-
`stationally and anti-androgenically effective esters of
`6-ch|oro-1'l'-hydroxy-lo.,2o-methylenepregna-4,6-
`diene-3,20-dione (cyproterone esters). However, it was
`found that even under this treatment there is only a
`partial retrogression of hyperplasia. '
`In prostate hyperplasia, the fibromuscular proportion
`of the prostate (interstitium) proliferates primarily. A
`possible cause for this, inter alia,
`is a shift in the es-
`trogen/androgen ratio in favor of the estrogens. It has
`been Found in various investigations that, in older men,
`the serum testosterone concentrations are reduced; at
`the same time, the proportion of SHBG (sex honnone
`binding globuline, specific transport protein for ste-
`roids) increases, so that the biological availability of
`androgens is even further reduced.
`In the conventional laboratory animal species, only
`older dogs experience spontaneous prostate hyperplasia
`comparable to the changes caused in males by prostate
`hyperplasia. Also in the dog, there is a proliferation
`primarily of the fibromuscular portion of the prostate. It
`is also possible to cause the aspects of the disease in
`younger dogs by treatment with an estrogen or an es-
`trogen/androgen mixture. Our own experiments have
`
`5
`
`10
`
`15
`
`20
`
`25
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`shown that the additional treatment with anti-androgen
`(cyproterone acetate) leads to total atrophy of the gland
`parenchyma, but that the proliferation of the inter-
`stitium is not affected.
`
`In autoradiographic studies on human prostate hyper-
`plasia tissue, it has furthermore been shown that only
`the gland epithelium (parenchyma) is a target organ for
`androgens, rather than the interstitium. Additionally, it
`was discovered that fibroblast cultures from human
`
`prostata hyperplasia tissue arornatize testosterone about
`seven to nine times more strongly to estrogens than
`fibroblast cultures derived from healthy prostata tissue.
`
`SUMMARY OF THE INVENTION
`
`Accordingly, it is an object of this invention to pro-
`vide a method and an agent for" the human male which
`is effective to produce an involution of the epithelial as .
`well as the fibromuscular portion of the prostate,
`whereby an increased secretion of androgens is also to
`be avoided.
`It is an object of this invention to provide a method
`and an agent for the prophylaxis and treatment of pros-
`tate hyperplasia.
`Upon further study of the specification and appended
`claims, further objects and advantages of this invention
`will become apparent to those skilled in the art.
`These objects have been attained by the present in-
`vention by providing an agent. and a method of use
`thereof, comprising an anti-estrogen and an anti-andro-
`gen having an antigonadotropic effect, in a weight ratio
`of anti-estrogen to anti-androgen of essentially 2:1 to
`1:10, preferably 2:1 to 1:2.
`
`DETAILED DISCUSSION
`
`Suitable anti-estrogens for use in accordance with this
`invention include all conventional anti-estrogens, both
`steroidal and non-steroidal. Examples of suitable non-
`steroidal anti-estrogens include:
`'
`tamoxifen = (Z)-2-[p-(1.2-diphenyb 1-butenyl)-phenom
`y]-N,N-dimethylethylamine,
`nafogtidine = l-(2-[4-(6-methoxy—2-phenyl-3,4-dihydro-
`l—naphthyl) phenoxy]-ethyl)-pyrrolidine, hydrochlo-
`ride,
`MER25 = l-[p-(2-diethylaminoethoxy)-phenyl]-2-(p-
`methoxyphenyl}l-phenylethanol,
`TACE=tri-(p-anisolyl)-chloroethylene.
`clomiphene = 1-Ip-(,3-diethylaminoethoxy)phenyl]-1,2-
`diphenylchloroethylene,
`cyclofenil = bis{p-acetoxyphenyl)cyclohexylideneme-
`thane, and
`C1-628 = 1-(2-(p-[ct-Ifp-methoxyphenyl)-B-nitrostyryl]-
`phenoxy}-ethyl)-pyrrolidine.
`Examples of suitable steroidal anti-estrogens include:
`RU-161 17 = l la-methoxy-17a.-ethynyl-1,3,5(l0)-estra-
`triene—3,l'}'B-diol, and
`168-ethylestradiol = 16,8-ethyl- l ,3,5( l0-estratriene-
`3,173-diol.
`The structures of the non-steroidal anti-estrogens are
`as follows:
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 2
`
`

`
`3
`
`4,310,523
`
`-
`
`,
`
`.
`
`.
`
`Ci
`' C
`
`\
`
`Cl
`
`4
`-continued
`
`-
`'
`N—(C.H2l2-0
`
`I
`
`_.
`
`.
`
`_
`
`5
`
`10
`
`15
`
`'
`
`20
`
`25
`
`30
`
`35
`
`Nafoxidim:
`
`The structures of the steroidal antiestrogens are as
`follows:
`'
`
`.RU-1fi[l'.-'
`
`.
`
`__
`I 16,8-erhylestradiol
`
`.
`
`-
`
`C2H5\
`/
`
`CZH5
`
`N(CH1)g—0
`
`'
`
`Clomiphene
`
`N . (CH1}1—O
`
`CH3
`
`\
`/
`
`CH3
`
`Tamoxifen
`
`_
`
`c=c\
` / 2
`
`C H
`
`5
`
`.
`
`”"“"”2'°®\
`
`lC=C
`\N02
`
`I
`
`CH3O
`
`CL628 '
`
`_
`
`I
`
`
`
`C=C\
`
`-
`
`CH3O
`
`Cl
`
`TACE
`
`__
`
`'
`CH3.-_~0_0
`
`-
`
`=c
`
`CH3CO . o
`
`_
`
`-.
`
`Cydorenil
`
`C1H5\
`
`C2-Hs/
`
`-
`N - fCH2)2 . 0
`
`'
`
` /
`
`MER—25
`
`-
`
`_
`
`_
`
`.
`
`-
`
`-
`
`.
`
`:
`
`_
`
`__
`
`_
`
`_
`
`_
`
`'
`
`.
`
`'
`
`OH
`I
`C—C{1
`H
`
`OCH;
`
`_
`
`I
`
`,
`
`.
`
`'
`
`40
`
`As can be seen, antiestrogens equivalent to the exam-
`
`ples listed above ingeneral includesubstituteddipheny-
`
`lalkanes (non-steroidal) and substituted estradiols (ste-
`roidal). All such antiestrogens meeting the requirements
`45 set forth herein are, of course, within the scope of this
`invention.
`_
`_
`'
`The steroidalcompounds are discussed, respectively,
`in Azadian-Boulanger et al, Eur. J. Med. Chem. 1978,
`13(4), 313-9 or Raynaud et ai, J. Steroid. Biochen'li.,
`1975, 6, 6l5—«22, and Takikawa, Chem. Pharm. Bul .,
`so 1977, 25(3) 501-3, the_ disclosures of which are incorpo-
`rated by reference herein. All of the exemplary anties-
`trogens - mentioned above are discussed in Nishino,
`Gyniikologe 12, 199-211 (1979), whose disclosure is
`55 also entirely incorporated by reference herein.
`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-
`tially the same spectrum of hormonal activity as tamox-
`59 ifen. More particularly, since.al|-known anti-estrogens
`also display estrogenous effects (depending on the dos-
`age, duration of administration, host species,
`target
`organ, etc.), the anti-estrogens of the invention should
`
`have a ratio of anti-estrogenic activity to estrogenic
`
`55 activity‘ which is about the same as or larger than that of
`tamoxifen. A description of the activity spectrum of
`tamoxifen is contained in, e.g., Drugs I6:l—24' (1978). all
`of whose disclosure is incorporated by reference herein.
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 3
`
`

`
`4,310,523
`
`5
`For purposes of this application, the terms “essen-
`tially the same spectrum of (honnonal) activity“ refers
`to the situation wherein two agents are effective for
`essentially the same purpose, i.e., possess essentially the
`same activities, but not necessarily with the same degree
`of effectiveness.
`
`The relevant activity spectra and activities, e.g., es-
`trogenic, antiestrogenic, endrogenic, gestagenic (see
`below), etc., can be determined by any of the conven-
`tional pharmaceutical protocols available for such pur-
`poses. Which particular ones are employed is not criti-
`cal as long as both comparison agents are tested under
`the same conditions.
`For example, estrogenous/antiestrogenous activities
`can be determined by the conventional sialic acid test
`and by determination of uteral and vaginal weight
`changes in mice and rats. See, for example. the men-
`tioned Nishino reference, especially Tables 1 and 2 and
`FIG. 2, along with the accompanying disclosure. These
`tests can be conducted as follows (see also, U.S. Pat.
`No. 3,95l,959, whose disclosure is incorporated by
`reference herein):
`Female NMRI-strain mice weighing about 30 g are
`ovariectomized. Starting with the 10th day after castra-
`tion, the animals receive the substance to be tested once
`daily for 3 days. The daily dose is dissolved in 0.] ml of
`castor oil containing a small amount of benzyl benzoate.
`The solution to be tested is administered subcutaneously
`to 6 animals per each dose. On the fourth day after the
`treatments, the animals are sacrificed by decapitation
`and exsanguinated. Vagina and uterus are immediately
`excised and weighed into a test tube for hydrolysis. The
`determination of the sialic acid is conducted according
`to Svennerholm/Biochem. Biophys. Acta 24 (1957)
`604/. The increase in the vagina and uterus organ
`weights in dependence on the dose, as well as the reduc-
`tion on the sialic acid content are determined. Therefore
`is derived the relative effective strength of the com-
`pound to be tested compared to the standard, estradiol.
`As parameters of the estrogenic activity, the sialic acid
`concentration and the uterus and vagina organ weights
`are employed. Data obtained are subjected to regression
`analysis to test the regression and linearity of the dose-
`responsive curve.
`Furthermore,
`the level of antiestrogenous activity
`can be ascertained by measuring one or more of the
`following non-limiting listing of effects of the agent, all
`of which reflect an interference with the usual effects of
`estrogens: the estrogen-induced proliferation and homi-
`fication of the vaginal epithelium of rats and mice are
`prevented; the estrogen-induced hypophysis hypertro-
`phy in rats is inhibited; the uterotropic effect of effec-
`tive estrogens is inhibited, for instance,
`the estrogen-
`stimulated uterus growth in rodents is inhibited;
`the
`estrogenous effect in the sialic acid test is eliminated
`(the estrogen-determined decrease in sialic acid concen-
`tration in the vagina of mice is eliminated); the estrogen-
`stirnulated prolactin release in rats is inhibited; etc.
`For example, antiestrogenic activity can be demon-
`strated by an agent's effect on the uterus growth test for
`estradiol as follows:
`
`Daily for 3 days 0.03 ,u.g of estradiol and measured
`dosages of the antiestrogen to be tested are simulta-
`neously applied to castrated or infantile mice subcutane-
`ously. The animals are killed on the fourth day, and the
`uteri are removed and weighed without contents (See
`Table I). The same test is carried out on castrated or
`infantile rats using 0.1 _ug of estradiol.
`
`[0
`
`i5
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`It is especially to_be noted that the structures of the
`antiestrogens of this invention are not derived from
`those of compounds which possess an androgenic or
`gestagenic activity. Accordingly, they do not possess
`androgenic or gestagenic side-effects. The antiestrogens
`of this invention are believed to act by displacing estro-
`gens from the active centers (receptors) in the host; on
`the other hand, for example, compounds possessing
`some level of antiestrogenic activity and also andro-
`genic or gestagenic activity function via other signifi-
`cantly different mechanisms, e.g., by removal of andro-
`gen which gives results categorizable as antiestrogenic.
`One example of compounds having possible antiestro-
`genic effects which are not included within the scope of
`this invention are- those disclosed in U.S. Pat. No.
`4,055,641 to Benson et al which are primarily anabolic
`androgens. For example, the compound preferred by
`Benson et al, 3,I7-dioxoandrost-4-ene-19-al {Column 3,
`lines 6'.r'—68) was tested in the vaginal swab test-of the
`castrated rat after subcutaneous application in a dosage
`of 1 mg. Hornification of the vaginal epitelium took
`place, demonstrating that 3,l7-dioxo-androst-4-ene-
`19-al displays a strongly estrogenous effect. In addition,
`the compounds of Benson et al were tested on intact
`(not castrated) male animals or probands. These estrog-
`enous substances acted on the prostate by removal of
`androgen, not by displacing estrogen as for the antics-
`trogens used in this invention. The difference between
`the antiestrogens acting through an antagonism to estro-
`gen receptors,
`i.e.,
`those used in this invention, and
`those which are primariy androgenic or gestogenic in
`activity with some simultaneous antiestrogenic effect is
`also discussed in Nishino, supra.
`The lack of androgenous activity can be ascertained,
`e.g., by the levator ani/seminal vesicle test on rats and
`the lack of gestagenous activity, e.g., by the Clauberg
`test on rabbits. These tests are conducted as follows (see
`also, U.S. Pat. No. 3,994,937, whose disclosure is incor-
`porated by reference herein):
`
`ANABOLIC AND‘ ANDROGENIC ACTIVITY
`
`Six male rats weighing 90-100 g are castrated. Seven
`days after castration, subcutaneous injections are ad-
`ministered to each animal during a period of fourteen
`days. The total number of injections is twelve and each
`injection involves 0.3-0.1 mg, respectively. On the day
`after the last application, the animals are autopsied and
`the weights of the seminal vesicle, the prostate gland
`and the levator ani muscle are determined. The weights
`of the organs are calculated relative to 100 g of body
`weight.
`From the weights of the organs, the average weight is
`determined for the six test animals as a function of each
`particular close.
`-
`Employing this test, which is conducted in a slightly
`modified conventional manner [Hershbergen L. G.;
`Shipley, E.; Meyer, R. K.; Proc. Soc. Exp. Biol. (N.Y.)
`33 (I953) 175]
`the following data are obtained. The
`anabolic activity is evidenced by the levator ani weight;
`and the adrogenic activity is evidenced both by the
`seminal vesicle weight and the prostate gland weight.
`The highest values of organ weights which are ob-
`tainable by administration of the highest acceptable
`doses of the strongest known anabolic substance and of
`the -strongest known androgenic substance,
`respec-
`tively, are about 70 mg musculas levator ani per I00 g
`body weight, and about 450 mg seminal vesicle per 100
`g body weight.
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 4
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 4
`
`

`
`7
`
`PROGESTATIONAL ACTIVITY
`
`4,310,523
`
`8
`derived from aliphatic carboxylic acids of 1-8 carbon
`atoms, e.g., acetic acid, propionic acid, butyric acid,
`valeric acid, isovaleric acid, caproic acid, enanthic acid.
`etc. The esters of acetic acid (acetyl residues) are espe-
`cially preferred. The many other conventional acyl
`groups are equivalents. Alkyl
`includes lower alkyl
`groups of 1-5 carbon atoms, the methyl group being
`preferred.
`These compounds are fully conventional and are
`described, for example,
`in the following references:
`compounds of Formula I, for example, in U.S. Pat. Nos.
`3,234,093; 3,0':'6,823; 3,549,671; 3,739,087 and in British
`Pat. Nos. 890,315; 1,005,495; 1,049,026 and 1,172,086;
`and compounds of Formula II, for example, in U.S. Pat.
`No. 3,492,338, the disclosures of all of which are incor-
`porated by reference herein.
`Typical compounds of general Formula I include the
`1?-esters of, for example:
`6—chloro-l?-hydroxy-1ct,2o.-methylenepregna-4,6-
`diene-3,20—dione,
`6-chloro-17-hydroxypregna-4,6-diene-3,20-dione,
`6-chloro-l7-hydroxypregna-1,4,6-triene-3,20-dione,
`6-chloro-3.f, l 'l'-dihydroxy- 1a,2a-methylenpregna-4,6-
`dien-20~one,
`6-chI0ro-3.§—methoxy-1'l'-hydroxy-1o:,2ct-methylene-
`pregna-4,6-dien-20—one,
`6-lluoro-1 7-hydroxy- I a,2o:-meth y1enepregna-4,6—diene-
`3,20-dione,
`17-h yd roxy- 1 ct,2ct-methylenepregna-4,6-diene-3,20-
`dione and
`
`4,6~dichloro-1'l'-hydroxy-la,2o:-methylenepregna-4,6-
`diene-3,20-dione.
`Preferred compounds of general Formula I include
`6-chloro- 1 7-hydroxy-1o;,2ct-methylenepregna-4,6-
`diene-3,20-dione acetate (cyproterone acetate) and
`6-chloro- 1 7-hydroxypregna-4,6-diene-3,20-dione
`ace-
`tate (chlormadinone acetate).
`Typical compounds of general Formula II include,
`for example:
`6-chloro-1Ta,8-acetoxy-1Tact-methyl—1a,2ot-methylene-
`D-homo-4,6-androstadiene-3,17-dione and
`6-ch1oro-1?r1-acetoxy-1'lB—methyl-la.,2ct-methylene-D-
`homo-4,6—androstadiene-3,17a-dione.
`effect
`Anti-androgens
`having
`antigonadotropic
`which are not of Formula I or II, but which are equiva-
`lent to those which do have these formulae are included
`within the scope of this invention.
`The anti-estrogens can be administered for this inven-
`tion approximately in the same dosages at which the
`commercial anti-estrogens are employed,
`i.e.,
`in daily
`dosages of about 5-100 mg, e.g., for tamoxifen. Simi-
`larly,
`the antigonadotropically active anti-androgens
`can be administered in amounts of about 5-100 mg per
`day.
`The particular dosage for a given patient will vary
`according to conventional factors and according to the
`particular combination of compounds employed. For
`example, the dosages mentioned herein are typical for
`all named compounds but are especially suitable for the
`combination of cyproterone acetate and tamoxifen.
`Corresponding dosages for any other combination of
`suitable ingredients can be conventionally and routinely
`determined by simple experiments to determine the
`dosages which produce anti-androgenic and anti-estro-
`genie effects, respectively, which are equivalent
`to
`those produced by cyproterone acetate and tamoxifen
`at the mentioned dosages, e.g., using fully conventional
`
`The progestational activity can be determined by the
`Clauberg test on infantile spayed rabbits weighing 800
`to 1000 grams. A daily dose of 5 ug of estradiol dis-
`solved in I ml of sesame oil is subcutaneously adminis-
`tered over a period of six days. From the seventh to the
`eleventh day, measured dosages of the compound to be
`tested are administered subcutaneously. The compound
`is dissolved in a medium consisting of benzylbenzoate/—
`castor oil (1:10). On the twelfth day, the animals are
`autopsied. The progestational
`transformation of the
`endometrium is rated by the McPhail scale (1 =no ef-
`fect; 4=complete transformation of the endometrium).
`There is determined the minimum amount (Threshold
`Dose) of the tested compounds sufficient to achieve an
`adequate positive effect (McPhail= 1.5).
`Suitable anti-androgens having an antigonadotropic
`acitivty per this invention include preferably steroids
`having anti-androgenic and progestrational properties
`and having the following Formula I or II:
`
`5
`
`10
`
`15
`
`20
`
`‘EH:
`C=°
`
`R2
`
`
`
`Y¢
`
`(1)
`
`25
`
`30
`
`35
`
`wherein
`R1 and R2 are hydrogen or together form an addi-
`tional carbon-to-carbon bond or methylene;
`R3 is a conventional acyl residue in accordance with
`conventional steroid chemistry;
`Y is oxygen or the grouping (H, OR4) wherein R4 is 40
`hydrogen, acyl as defined above, or alkyl;
`X1 is hydrogen or chlorine; and
`X2 is hydrogen, fluorine, chlorine or alltyl; or
`
`A
`
`[Ta
`
`Hi} 11
`
`(11) 45
`
`R5
`'
`
`R5__
`
`Ofi
`
`X
`
`wherein
`
`50
`
`'
`
`55
`
`R5 and R5 are hydrogen or together are methylene;
`X is hydrogen, fluorine or chlorine; and
`A-B is
`
`R'.‘_O
`
`ICH3 ' El)
`Cna
`Cu or
`
`CH3
`
`0
`u
`Cm
`
`\ /’
`Cl?
`
`0‘R“
`
`wherein R7 and R3 are a conventional acyl residue as
`defined above for Formula 1.
`Suitable acyl residues mentioned above include all 65
`such residues ofthe acids conventionally used in steroid
`chemistry for the esterification of secondary and ter-
`tiary hydroxy groups. Preferred such acyl groups are
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 5
`
`

`
`4,310,523
`
`9
`pharmaceutical protocols, such as those mentioned
`herein.
`The anti-estrogen and anti-androgen can be adminis-
`tered in a combined unitary form. They can also be
`administered separately in two different forms of ad-
`ministration in analogy to the separate conventional
`administration of each of the ingredients for conven-
`tional purposes.
`The active agents can be processed into the custom-
`ary forms of application for mammals, e.g., humans,
`using the additives, vehicles arid/or flavor ameliorating
`agents customary in galenic pharmacy in accordance
`with conventional methods. For oral application, which
`is preferred, suitable particularly are tablets, dragees,
`capsules, pills, suspensions or solutions. Typical unit
`dosages of each ingredient are: anti-estrogen 5-50 mg.
`e.g., of tamoxifen; and anti-androgen 5-50 mg, e.g., of
`cyproterone acetate; with greater or lesser amounts
`being possible depending on the relative efficacy of a
`particular compound and the dosage desired for partic-
`ular regimens.
`Suitable for parenteral, especially intramuscular ad-
`ministration are oily solutions, e.g., sesame oil solutions
`or castor oil solutions. Typical unit dosages are: anti-
`estrogen 10-100 mg; and anti-androgen 10-100 mg,
`greateror lesser amounts being possible as described
`above. To increase solubility, it is also possible to add
`solubilizers, for example, benzyl benzoate or benzyl
`alcohol.
`Without further elaboration, it is believed that one
`skilled in the art can, using the preceding description,
`utilize the present invention to its fullest extent. The
`following preferred specific embodiments are,
`there-
`fore, to be construed as merely illustrative, and not
`limitative of the remainder of the disclosure in any way
`whatsoever. In the following examples, all temperatures
`are set forth uncorrected in degrees Celsius; unless oth-
`envise indicated, all parts and percentages are by
`weight.
`
`5
`
`I0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4-0
`
`10
`-continued
`
`225.0 mg.
`
`Composition of a Tablet:
`total weight of the tablet which is produced in the
`usual way in a tablet press.
`
`is also possible to process cyproterone
`it
`Optionally,
`acetate and tamoxifen with respectively one-half of the
`aforementioned additives separately, and press a two-
`layer tablet.
`
`EXAMPLE 2
`
`Composition of a Tablet:
`[00 mg. 6-ehloro- I7-hyd roxy- la.2a-ntethylenepregna-4,6
`diene-3.20-dione acetate (cyproterone acetate)
`l0.0 mg. {Z}-2-[p-(l,2-dipheny|- l-l:Iuteny|}-pItenoxy]-N,N-
`dimethylethylamine (tamoxifen)
`lactose
`[3115 mg.
`69.5 mg. corn starch
`2.5 mg. poly-N-vinylpyrrolidone 25
`2.0 mg. "Aerosil"
`0.5 mg. magnesium stearate
`225.0 mg.
`total weight of the tablet which is produced in the
`usual way in a tablet press.
`
`Optionally, cyproterone acetate and tamoxifen can also
`be pressed, with respectively one-half of the above-
`recited additives, separately into a two-layer tablet.
`
`EXAMPLE. 3
`
`Composition of an Oily Solution
`50.0 mg. cyproterone acetate
`50.0 mg.
`tamoxifen
`353.4 mg. castor oil
`618.6 mg. benzyl benzoate
`I0'l'2.0 mg. él ml.
`
`The solution is tilled into an ampoule. Cyproterone
`acetate and tamoxifen can also be tilled separately into
`two chambers, with respectively one~half of the above-
`mentioned additives.
`The preceding examples can be repeated with similar
`success by substituting the generically and specifically
`described reactants and/or operating conditions of this
`invention for those used in the preceding examples.
`From the foregoing description, one skilled in the art
`can easily ascertain the essential characteristics of this
`invention, and without departing from the spirit and
`scope thereof, can make various changes and modifica-
`tions of the invention to adapt it to various usages and
`conditions.
`TABLE I
`
`EXAMPLE 1
`
`10.0 mg.
`
`Composition of a Tablet:
`20.0 mg. 6-chloro-17-hydroxy-la.,2t:t—melhylenepregna—4.6-
`dieue-3.20-dione acetate (cyproterone acetate)
`{Z}-2-[pv( l.1-diphenyl-l-butenyl)-phenoJty]-N,N-
`dimethylethylamlne (tamoxifen)
`lactose
`120.5 mg.
`corn starch
`59.5 mg.
`2.5 mg. poly-N-vinylpyrrolidone 25
`2.0 mg. "Aemil"
`0.5 mg. magnesium stearate
`
`45
`
`Antiestrogenic Effect of Ru-I61 IT and Tamoxifen on the Estradiol-stimulated Uterus Weight of Infantile Mice
`_
`(Mode of Administration: Subcutaneous - Number of Animals per Group: Eight)
`Ru-llil 1?. Tamoxifen and Estradiol are dissolved in a medium consisting of benzylbenzoate/Castor oil (I:l0)
`Rt!-16117
`Tamoxifen
`
`-
`
`% Inhibition
`‘ib Inhibition
`Decrease of Uterus Weight
`Uterus Weight
`Decrease of Uterus Weight
`Uterus Weight
`Dose over 3 Days
`in Comparison to
`(mg)
`in Comparison to
`{mg}
`{.t-Lg/Animalfflay)
`+ 0.03 pg
`Average Value 1
`Single Estradiol
`Average Value 1
`Single Estradiol
`
`Estradiolffitnimat/Day
`Standard Deviation
`Administration
`Standard Deviation
`Administration
`0.3
`60.0 2 1.4
`8
`-—
`—
`3
`49.8 i 1.6
`2'!
`515 : 2.]
`ll
`30 -
`34.3 i 2.3
`' 58
`43.3 i 3.]
`40
`ICK]
`—
`—-
`39.? t 3.1
`46
`3&3
`—
`—
`3-4.] : 4.3
`58
`Single Administration of
`0.03 pg Esttadiol
`
`63.9 1 6.1
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 6
`
`

`
`.11
`
`4,310,523
`
`TABLE 1—continued
`
`12
`
`Anliestrogenic Effect of Ru-lo] 1? and Tamoxifen on the Estradiol.-stimulated Uterus Weight of Infantile Mice
`I
`(Mode of .-‘tdminislralioni Subcutaneous — Number of Animals per Group: Eight)
`Ru—l6l 1?. Tamoxifen and Estradiol are dissolved in a medium consisting of bcnzylbenzoaleficaslor nil ( l:l0)
`once Daily over 3 Days
`Untreated Control
`
`II.8 1' L3
`
`As shown in Table I (above) Tamoxifen and Ru-I6] I? cause a sainiilarly pmnnunccd dosage-dependent decrease in uterus weight of Ihc eslradiol-stimulated uterus of
`infantile mice. Rn-loll? is somewhat more effective than Tamoxifen.
`
`What is claimed is:
`
`1. A pharmaceutical composition for the prophylaxis
`or treatment of prostate hyperplasia comprising an an-
`tiestrogen which is (Z)-2—[p-(l,2-diphenyI—1-butenyl)-
`phenoxy]-N,N-dimethylethylamine,
`l-(2-[4-(6-
`methoxy-2-phenyl-3,4-dihydro-l-naphthyl)-phenoxy]-
`ethyl)-pyrrolidone
`hydrochloride,
`l-[p-(2-die-
`thylaminoethoxy)-phenyl]-2-(p-methoxyphenyl}1-
`phenylethanol, tri-(p-anisolyl)-chloroethylene,
`l-[p-(B-
`diethylaminoethoxy)phenyl]-l,2-diphenylchloroethy-
`lene,
`bis(p-acetoxyphenyljcyclohexylidenemethane,
`1-[2-(p-[ct-(p-methoxyphenyl)-,8-nitrostyryl]-phenoxy)—
`ethyl]-pyrrolidine.
`or
`1 ia-methoxy- l‘i'a-.ethyny]-
`1,3,5(I0)-estratriene-3,lifi-diol, and a antigonadotropi-
`cally effective anti-androgen,
`in respective amounts
`such that the combination is effective for prophylaxis or_
`treatment of prostate hyperplasia.
`2. The composition of claim 1, "further comprising a
`pharmaceutically acceptable carrier.
`3. The composition of claim 1, wherein the weight
`ratio of anti-estrogen to anti-androgen is about 2:1—l: 10.
`4. The composition of claim 1, wherein the anti-estro'-
`gen is. (Z)-2-[p-(1,2-diphenyl-l-butenyl)-phenoxy]-N,N-
`diinethylethylamine,
`I-(2-[4-(6-methoxy-2-phenyl-3,¢
`dihydro-1-naphthyl)-phenoxy]-ethyl)-pyrrolidine
`hy-
`drochloride, or l-[p-(2-diethylaminoethoxy)-pheny|}-2-
`(p-methoxyphenyl}l-phenylethanol.
`5. The composition of claim 1 wherein '(Z)-2-[p-(l,2-
`diphenyl- l-butenyl)-phenoxy]-N,N-d_irnethylethyla- _.
`mine is theanti-estrogen.
`_
`'
`6. The composition of claim 1, wherein the anti-estro-
`gen is
`lla-methoxy-l')'o:-ethynyl-l,3,5(l0)-estratriene-
`3,173-diol.
`_
`._
`7." The composition of claim 1, wherein the an-
`tigonadotropically effective anti-androgen" is a com-
`pound of the formula
`‘
`
`
`
`wherein
`
`R1 and R2 are hydrogen or together form an addi-
`tional carbon-to-carbon bond or methylene;
`R3 is C1_s alkanoyl;
`'
`Y is oxygen or the grouping (H, OR4} wherein R4 is
`hydrogen, Ci_g alkanoyl or C[_5 alkyl;
`X1 is hydrogen or chlorine; and
`X2 is hydrogen, fluorine, chlorine or C1_5 alkyl; or
`
`10'
`
`I5
`
`20
`
`wherein
`
`lTa
`
`317
`
`25
`
`30
`
`35
`
`R5 and R5 are hydrogen or together are methylene;
`X is hydrogen, fluorine or chlorine, and
`A—B is
`
`117-0
`
`FH3 o
`\ /’ ..
`II_
`C|‘i'a
`C1‘:
`
`0
`II
`or Cm
`
`CH3
`
`\ /’Cl?
`
`0-1:“
`
`wherein. R7 and R3 are each C1_g alkanoyl.
`8.
`‘The composition of "claim 7, wherein the an-
`tigonadtropically effective anti-androgen is 6-chloro-
`1':'—_hy_drox y- 1 a,2a-methylenepregna-4,6-diene- 3,20-
`dione acetate.
`.
`9. The composition of claim 7, wherein the an-
`tigonadotropically effective anti-androgen_ is 6-chloro-
`I'.-'-hydroxypregna-4,6-diene-3,20-dione acetate.
`10. The composition of claim 4, wherein the an-
`tigonadotropically effective anti-androgen is 6-chloro-
`l'7-hydroxy-1ct,2a-methylenepregna-4,6-diene-3,20-
`dione acetate.
`-
`
`11. The composition of claim 4, wherein the an-
`tigonadotropieally effective anti-androgen is 6-chloro-
`l7-hydroxy;pregna-4,6-diene-3,20-dione acetate.
`12. The compound of claim 5, wherein the an-
`tigonadotropically effective anti-androgen is 6-chloro-
`l3'-hydroxy-1ct,2ct-methylenepregna-4,6-diene-3,20-
`dione acetate.
`
`45
`
`SO
`
`13. A pharmaceutical composition of claim 2, com-
`prising 5—50 mg of (Z)-2-[p-(l,2—diphenyl-l-butenyl)-
`phenoxy]-N,N-dimethylethylamine and 5-50 mg of
`6-chloro- l '.-'-h ydroxy- la,2o.- met hyIenepregna-4,6-
`diene-3,20-dione acetate, and the weight ratio of anti-
`. estrogen to anti-androgen is about 2:1 to 1:10.
`'14. A method for prophylaxis or treatment of prostate
`hyperplasia which comprises administering an amount
`of a composition of claim 1 effective for the prophylaxis
`"or treatment of prostate hyperplasia.
`15. A method for prophylaxis or treatment of prostate
`hyperplasia which comprises administering an amount
`.01‘ a composition of claim 3 effective for the prophylaxis
`'_ or treatment of prostate hyperplasia.
`16. The method-of claim 15, wherein the daily dosage
`of the anti-estrogen is 5-100 mg and the daily dosage of
`the anti-gonadotropically effective anti-androgen is
`S-100 mg.
`3
`i
`ll
`'3!
`1
`
`60
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 7
`
`MYLAN PHARMS. INC. EXHIBIT 1041 PAGE 7