DE2149281A1 - Preparation for contraception - Google Patents

Description

LAWYERS Oct. 11, 1Q71

DR. JUR. DIPL-CHEM. WALTER BEIL
ALFRED HOEPPENER
DR. J ⁴ JR. DiPL-CHEM. H.-J. WOLFP
DR. JUS. HANS CHR. AX

FRANKFURTAM MAIN-HIGH?

Our no.17.379

Richardson-Merrell, Inc. New York, N.Y., V.St.A.

Preparation for contraception.

The invention relates to a novel preparation for achieving better contraception, whose Administration of intermenstrual uterine bleeding or extensive bleeding restricted to a minimum.

It is known; that progestin and estrogen steroids, alone or in combination, to regulate fertility can be used. Currently will be different preparations, especially three main preparations with the following Compositions used:

Combination drugs that contain an estrogen and a progestagen and generally administered from the fifth day of a menstrual cycle to 20 or 21 days will.

Preparations administered in sequence, for which an estrogen from the fifth day of the cycle and then

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an estrogen-progestagen combination is administered. Numerous variants of this preparation have been proposed.

Continuously administered progestogen preparations (or mini-pills) in which progestogen is administered daily will.

The combination and those administered in sequence

^ richer preparations are highly effective ovulatory inhibitors, However, it is not the ideal form of contraception as it affects the normal physiological ovules - ' inhibit the process.

The continuously administered progestogen preparations contain such a low dose of a progestogen steroid, that in the majority of recipients there is no inhibition of ovulation and ovulation and cycle im essentially as if no progestagen had been administered. However, it is known that the ingestion of The last mentioned preparations are quite common from intermenstrual uterine bleeding and extensive bleeding so that this type of contraception and birth control is severely limited.

Various suggestions have been made to reduce intermenstrual bleeding and extensive bleeding when continuously taking progestogen supplements to reduce. For example, it has been suggested to add progestogen to the last few days of each cycle Adding estrogen. '

Roy, Greenblatt, Mahesh and Jungck describe in

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"Fertility Sterility", Vol. 14 "Page" 575-95 (1963) the prolonged administration of racemic clomiphene citrate Women who lack ovulation to induce ovulation and of racemic clomiphene citrate alone or with estrogenic and progestatic compounds for functional ones Uterine bleeding, however, found that none of the 11 women with ovulation who have different lengths of cloudphen in. had received doses of 50 to EOO mg per day » the ovulation was suppressed In contrast, clomiphene and, in particular, cis-clomiphene and other agents mentioned above prevent use conception and at the same time reduce uterine blood " do gen.

Namely, it was found. d & L · - the addition of an anti-estrogenic agent, as described below, to a progestogen indicated below leads to a reduction in intermenstrual sub-bleeding or extensive bleeding without significantly reducing the contraceptive effect statement that opens the way to new and better contraception is of the utmost importance. In the present case, contraception is understood to mean the prevention of conception or fertilization by insemination.

. · The novel combination according to the invention can be based on be administered in various ways. For example, the drug counteracting agent and the pro-stare be administered continuously or intermenstrually as a pharmaceutical unit, so that the

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There is no need for marked monthly maintenance. The estrogen counteracting agent and the progestagen can also be administered one after the other a part or during part or when any of "ge" be taken entire MenstruationsEyklus. the estrone gen counteracting means and the progestogen W can also be administered alternately "Further, it is mSglieh, a labeled month pack .with qThe without Plaoe" b.os to use .

The subject of the discovery is thus a new one Contraceptive that contains a progestogen with an anti-estrogen agent contains “How In the case of other contraceptives, the exact mechanism of action of the combination of the anti-estrogen agent and the Prague conference is not known »

In carrying out the invention displaceable dene estrogen .entgegenwirkende agents can be used "ψ For example, 2 ~ ^ ~ p -. (£ _chloro-l:, 2" diphenyl- 'vinyl) "phenoxy_7-triethylamine (clomiphene) ,. cis-Glomiphen Isomeres, 2 - / "p- (p- Methoxy- cl -phenyl-phenylphenethyl) -phenoxy-7-triethylamine, 1- {2 - /" jp- (qc- ^ p-Methoxyphenyl J ^ -ß-nit ro styryl) -phenoxy. ^ - ethyl} -pyrrolidine _}; 2- / ~ p- (1, a-Diphenyl-1-putenyl) -phenoxy ^ 7-NjN-dimethylethylamine, 2- ^ p- (1,2- Diphenyl-1-tiutenyl) -phenoxy_7 -N ₅ II-diirethyliithylamine-Äntiestrogenes Isomeres, '2- / ^; p- (b-liethoxy «2-phenylinden-3-yl) -phenQxy__7-triäthyiämin',"'l - ^^ ^ / ^ P "''"

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(3 »4-Piiiydro-6-methoxy-2-pheiiyl-1-naph" bhyl) -phenoxy _7- ■ ethyl} -pyrrolidine, dl-13-ethyl-gona-1,3,5 (10) -triene- 3jl ^ <*, 17ß-triol and compounds of the structural type below are used, in particular also / c <- (p-hydroxyphenyl) - & - (cyclohexylidene) _7-p-cresol diacetate, / ~ oc - (p-hydroxyphenyl ) - ex. - (2-methylcyclohexylidene) __ Z-pcresol diacetate and 2f-, if * - (cyclohexylidenemethylene) -diphenol:

where E = H or COCH ₃ , R ¹ = H or CH ₃ .

The estrogen preferably used according to the invention counteracting agent "is cis-clomiphene; the isomer of Clomiphene has no progestagenic effect and is through the "physico-chemical characteristics given below identified. Pharmaceutically usable salts of the abovementioned basic estrogens counteract the effects Means, e.g. citrates, dihydro citrates, lialeate, HydroChloride, Acetate, Nitrate, Sulphate or Phosphate can also be used.

. Progestagens that can be contained in oral preparations according to the invention include:. . _: .

Chlormadinon ö-Chlor - ^ - hydroxy-pregna-

4,6-diene-3,2O-dione J.

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16-methylene chloromadinone

Me ges -trolsec et at ; Melenges-krolacetat-

IToräthindron (Foräthisteron) Nor & thindrone acetate norgestrel

Norgestrel acetate chingestanol

Chingestanol acetate Chingestron

Gestovis

Medroxyprogesterone Acetate Ethylene Diacetate

3-De soxyno räthindron (Lynstrenol)

Noräthylnodrel 6-Chlor-Lö-msthylen-17-hydroxy-pregna-4,6-diene-3,20-dione ;

17 ot hydroxy-6-ethyl-pregna-4,6-diene-3 »20-dione acetate ;

17 α -hydroxy-δ-methyl-1-omethylene-pregna-4,6-diene-3,20-dione acetate;

17-hydroxy-l9-nor-17 u -pregn-

l> Xthyl-17-hydroxy-l8 ^ 19-dinor-17 iX-progn-i-'r-ein-ZO-in-3-on »" - ■ - "

3- (cyclopentyloxy) -19-nor ^ ·, ._- 17di -pregna-3 * 5-dien-2Q-yn'-17-ol; · ■■ · ■

3- (cyclopeiityloxy) -pregna-3, dien-20-clion j

3- (cyclopentyloxy) -17Qihydroxy-pregna-3,5-dien-20-one acetate;

17-Hydroxy-o o (-methylpre gn-4 en-3 »20-dione acetate;

19-nör-17 o (. -Pg
3β, 17-diol diacetate;

17-Hydroxy-19-nor-17 ei -pregn 4-en-20-in j

17-hydroxy-l9-no.r-17ot "-pregn 5 (NG) _{-en-20-yn-3-one",: -:.}

These and other compounds that may be used for depot injections include 17 <* -hydroxyprogesterone caproate, 16 α, 17 et -diliydroxyprogesterone -

acetophenide and esters of Megestrol, Helengestrol, Nof-

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ethindron

If the dosage is selected accordingly, each of the above counteracting estrogen replaces :; & $ © $ © € ... cis-clomiphene citrate, and each of the foregoing progestogens the Chingestanolacetat in BGispi.eI, e.noIkXSn.d vS un * ·: ter generating corresponding "useful compositions ^1"

The administration may be in various FoI ⁴ Bi © r ^ ·; ..; ■. FolgGii, p.3, in the form of tablets, capsules, th and the like which contain the active and the sponding pharmaceutical carrier and extenders enthä2 "*. ^"c: -. ten For oral compositions are dio V / irkstoffe in powder form first brought and then processed to · 'granules, tablets or capsules, Ss can be prepared with a depot effect further comprising respective carriers injectable compositions in addition, the östrogeii counteracting. Means can be used together with a progestagen using pharmaceutically suitable implants and intrauterine or intravaginal inserts, for example bodies in which the active ingredients are enclosed or incorporated into polymeric materials, e.g. silastic material Doses per day for administration in grafts or polymeric inserts are required as by oral administration chung in tablets.

Suitably, the östragen counteracting compound is usually at least a few days dc-s Men struationszo / klus from 10 to Z ^l j. Day and the progestogen normally at least on a few days of the menstrual cycle "from the 5th to the .28th day in order to achieve a high degree of contraception and a low intermen-

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as well as achieve a low extensive Blur * tuns, the combination can be, but also inter-Bienstruell been used orally Türlich or continuously nit or without Un.-interruption throughout the menstrual cycle: struelle Ljterusblutuni '.

Is eis =? Cloial'pheiizltrat used., So are the different ibe ^ - vorzu .'-- th 2; u3ai.i :: isn.etzunge33. and un, Tefä; liren intersected ^ liciieii posierun ^ sborcichQ aur oral Vorabreichunf; per "ag y / ie ί

Pro "-" esX _a:: ven - 0.5 Cis-Cloffliphen ϊΛΓ- - 0.5 sitrate, mg vhlormadinon 0.1 -r ■ 0.7 5.0 0.5-50 Ϊ6 = -i ie thy le hlo r maaiiion QA - • 0.7 5.0 U lie ges trolac et at 0.1 - • 0.7 - 0.5 JI , Heiengestrol acetate 0.1 « • -0.6 0.7 .1! iloräthindron (iiorathiiic t ere η) 0.05 - 0.5 11 iiOrgestrel 0.005 -0.075 11 iiorat hindronac ο tat 0.05 - 0.5 H ₊ ior "estrolaeetat 0.005-0.075 11 Quinrostanol 0.05 it Ghlngcstaiiolaee asked .0.05 M. -jliin ^ estroü 0.5 - H Gectoyis 0.5 * M. jit hindioldiac e tat 0.05 it De GOjxr / iiQ r ät hinr ". R ο ρ U

: iei Yein '/ enclunf: vgii Chirjrostaiiolacetat als Prο .restar ·;: · 3η; 3ind the un / ^ eräliren Dure-hGC: linittsdosiorun "slr.li
tioiioii i5.ro '! a: to? oral administration ζ “.Β. -how

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UGtrogen ent-S e ge nv / ende link

mg

cis-Cloriipheiidihydrositrat 0.5 - 50

Chlorophyllodihydrocitrate θ '- 200

Z-Γ ρ- (p-methoxy-Λ-phenylphenethyl) -phenoxy J? Triethylamine hydrochloride ~ 10 - 1000

1- { Z-Γ ο- (οι -Γ £ -Kothoxy-

phenylj ^ i-nitro styryl) -phon-

oxy _ / - 'dt Iiyl "V -nyrrοlidinnono -

citrate 1 - 100

2- ^ io- (1,2-diphenyl-l-butonyl) -

: y 7-H "" - dinethyluthylaoin 1 - 100

ChIn-

stanol

acetate

LIC

0.05 - 0.5 ti

Z-Γ - (1,2-Diphenyl-l-but onyl) - -ph enoxy_ / --T, H- dime thylä t hy 1 anin - Anti-estrocsTi isomer 1 - 100

Z-Γ P- (o-Metlioxy-2-phenylindene-

5-yl) -phonoxyJ7-triäthylar.iin-

hydrochiorid 2 - 200

1- {2 - / "p- (3,4-Dih: / dro-6-methoxy-2-phenyl-1-naphthyl) -phenoxy 7-ethyl-pyrrolidene hydrochloride. 2-200

/ ~ Ot - (p-hydroxyphenyl) - α -

tcycloSexyliden) _7p-cresol-di-

acetate "2-200

£ a - (p-Hydroxyphenyl) - oc - (2-methylcyclohexylidene) _7-p-crecoldiacctate ~

^ i, h '- (Cyclohcxylidennethylene) uiphcnol

rii-13-ethyl-rona-l, 3.5 (10) -

il

1 - 100

2 - 200 1 - .100

_v changed according to input an-rcn α _{; Ώ} .1 JLiAl 1 ".

• v 1

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The preferred anti-estrogen compound, the cis-clomiphene isomer, has the following structure :

It is evident to the person skilled in the art that aas Clomiphon, 1, is present as a mixture of the cis and trans isoner3n. These mixtures were separated by various researchers (see, for example, British patent specification 1 099 09.5; FP Faiopoli et al., J. Hed. Chem., Vol. 10, S. Qk (1967) and Ao Fd. Char ds ο η jr. And HD Benson, 153 i.'ationalos gripping the American, Chemical Society, Miami Beach, 1 ' ¹ Ia., April 1967, excerpt Hk), but there are different views as to the designations of the ice and. trans configuration of the isomers. Is present in _c ^r venonmen, .that this isomer has the cis configuration, although it is referred to in British Patent Specification than the trans isomers. In the present case, the cis- clomiphene isomer means the isomer with the following physical-chemical characteristics:

Ultraviolet absorption spectra - The citrate salt shows maxima in methanol at 239 κ jul (£ .22000) and 29ΰ Ri ^ t

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- ii -

( t 11 / + 00), while in 0.11s HCl the absorption reads "at 258 η ^. (c 200) and 29" η α (£ 10200). Infrared absor "- tioiiGspelitren - DaG citrate is aromatic in KDr

C-li-3anden at G93 ceT ¹ {shoulder; 690 cm " ¹ ), 752 cnf ¹

—1 —1 ■ —1

(Shoulder: 7-iC era and 756 cn) and o> 7 cm on *

Dis ^ aac ν / ciot Haxlina, more clearly defined, bsi o93, ^ Jo cm " ¹ <iX3uLlGt),? I47, 758 cn" ¹ (doublet) and ü5b era "on. Das kornraa ^ no virjcli-e iiesoiaansspeuztrura (CI) Cl ₂₎ dor IJacc ^·:; .ct v ic ίο Oblivious .'7GkGnIi

'JheriGchG on g pal— advance; "sir; ί 1 ·) sclieraa

7, Ιό

SIIfGLET

Mon. II

TKIPLET S. k QUARTET 2 TRIPLET 2 TBIPLET 2 DOlBLET ⁺ 2 DOUBLET ⁺ S. MULTIPLE

CHy of (Cpilulpii-Cxi _o of (CUH, -) ₂ ii-'JIi ₂ of> XJ-CH ₂ -CiX ₂ O CH ₀ of -CHpO-

Aroiraten ortho - su ba-, they hen iither

Arouiaten jneta- zu ba-! 3: i.ther

tuiertein. ^ trust- to ether φ

Aroraaton with nlehtsuüct.i 'tuiertein φ r; e; u ~ zu bacl * · F, eli G m l'lttoer jzi

B ₂ scheme at 6.52 :, 0.02.

jji "Doli: ioi: i-jntrae.ssu2iicen - In jieaazol at the ISaGe has a Jjisol-moiaeiit iron for measuring

fie—

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In contrast, the compound referred to herein as trans-clomiphene has the following physicochemical Characteristics:

Ultraviolet absorption spectra - The citrate salt shows maxima in methanol at 229 m u ( t 20400) and 292 mjH. Ct 12700), while in 0.1N HCl the absorptions are roughly 224 (i 19600) and 287 nu ^ (£ 11400).

Infrared absorption spectra - The citrate shows in KBr aro-

- 1 - 1 - 1

matic C-H bands at 696 cm, 942 cm and 840 cm The last band was assigned to the two neighboring hydrogen absorptions, the others to five causing neighboring hydrogen atoms.

The base has these maxima at 693 cm ~ (shoulder: 696 cm, .746 cm and 836 cm " ¹ .

Nuclear Magnetic Resonance Spectrum - The Nuclear Magnetic The resonance spectrum (CDCl ^) of the base is characterized as follows

draws: Splitting
management
schoma Uo. H CH ₇ , from Assignment meta - to basic Chemical
Miscellaneous
exercise ( b ) TRIPLET 3 CHp of (C ₂ Iy ₂ N- 1.04 QUARTET ' 4th CHp from ' (C ₂ H ^) ₂ N- 2.64 TRIPLET 2 CH ₂ of ■ > H-CII ₂ -CH ₂ O 2.88 TRIPLET 2 Aromatics -CH ₂ O 4.06 DOUBLET ⁺ 2 ortho - to basic 6.9O ⁺ seem ether DOUBLET ⁺ 2 Aromatics
ether 7.5'O ⁺

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Chemical splitting

Differential

exercise (>.) schema Ho. H assignment ^

7.02 SINGLET 5 aromatics with unsubstituted φ according to basic ether φ

approx. 7.2 MULTIPLE 5 aromatics with unsubstituted φ ice to basic ether φ

⁺ A ₂ B ₂ scheme at 6.90, ■ 7.36 S>.

Dipole Moment Measurement - The base measured in benzene at room temperature has a dipole moment of 2.108 + O, OO8D.

Example 1:

The following is an example of the composition of a Tablet indicated:.

For granulation PrQ ₁ tablet

(a) Chinestanol acetate. 0.3

(b) cis-clomiphene citrate 10.0 mg

(c) 3 % strength sucrose, 67.5 mg

(d) Lactose '109.2 mg

(e) corn starch 105.0 mg

(f) Pregelatinized Starch 25.0 mg

As a lubricant

(g) Magnesium stearate 3.0 mg

(h) corn starch to give 320.0 mg

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A mixture of the previously sieved and finely pulverized ingredients' (a) to (f) is mixed with deionized passer granulated and passed through a No. 2 wet sieve. The granules are dried at 49 ° C. and passed through a sieve. given to reduce the particle size. Then the components (g) and (h) are added as lubricants and the amount of corn starch is chosen so that a weight of 320 mg per tablet is achieved. This will make the tablet shaped that one in each case 320 mg of the mixture using punches and dies with a diameter of 9.53 ram compressed.

Example 2:

For example, a capsule has the following composition:

(a.) Chinestanol acetate 0.3 mg.

(b) cis-clomiphene citrate 10.0 mg

(c) lactose 172, Λ mg

(d) Terra alba 21.5 Big

(e) Magnesium stearate 4.3 rag

(f) corn starch. 21.5

The ingredients (a) to Cf) are passed through a No. sieve, mixed well in a suitable mixer and with a net falling weight of 230 rag per. Capsule placed in hard gelatin capsule # k . ¹ ■ - ■ - "'

Example J> \ -

A preparation of 10 mg of cis-clomiphene dihydrocitrate

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and 0.3 ng of clilormadinone is given in a capsule orally daily on women, either continuously or for at least 5 days during the month or during the non-menstrual periods, to use a high level of contraception and to achieve low intermenstrual uterine bleeding and low extensive bleeding.

Example /{.;

A preparation of 10 mg of cis-clomiphene dihydrocitrate and 0.3 mg megestrol acetate is administered as in Example 3, a high degree of contraception and a low intermenstrual uterine bleeding as well as low to achieve extensive bleeding.

Example 5:

jjine preparation of 10 mg cis-clomiphene citrate and 0.3 "-V-; Iielengesterolacetat is administered as in Example 3 and causes high levels of contraception and low intermenstrual uterine bleeding as well little widespread bleeding.

Example 6:

A preparation of 10 mg of cis-clomiphene citrate and. 0.5 Vi-: Chingestaiiol acetate is administered orally in tablet form to women daily, either continuously or during the .. periods when menstruation does not occur.

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a high degree of contraception 'and a ge rings intermenotral uterine bleeding as well as slight extensive Cause bleeding.

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Claims (1)

ι? Claims; 1 »Preparation for contraceptionY characterized in that it consists essentially of one; Estrogen-counteracting agents, namely 0.5-50 mg cis-clomiphene, 2.0 to 200 mg clomiphene, 10 to 1000 mg 2- / "p- (p-MeUhOXy-oc" .phenylphenethyl) -phenoxy_ _> 7 "'triethylamine , 1.0 to 100 ag 1-7 2 - / "p- (a .- /" p-rMethQxyphenyl J-ß'-nitrostyryl) -phenoxy_7-ethyl] -pyrrolidine, 1.0-100 mg 2- / ""p- (1,2-Di-phenyl-1-butenyl) -phonoxy J ^ -Ii, ίΤ-dimethylethylamine, 1.0-100 mg 2 - /" p- {1,2-3Diphöi | yl-l -butenyl) -phenoxy 7'N, iT * iäimethyläthylamin-Antiestrogen-Isomerem, 2.0 to 200 mg 2 - ^ "" p- (6-methoxy ^ -phenylinden-J-yl) -phenoxy ^ 7 "tr Hi t hylamin, 2.0 to 200 mg of l- {2 - / * p (3 i | --DihydrQ-6-mQthoxy-2 "ph © _{nyl-lnaphthyl?)} -phenoxyJ7-ethyl ^ -pyrrgllden, £, Q up to 200 mg £ 'cc -ip-hydroxyphenyl) - oc - »{GyclQliexyliden ^ Jp-cresol * - diaeetat, 1.0 to 100 mg . £ ~' ol - (p-Hydroxyphenyl) - oi * {2-methyloyclohexylidenJ ^ ^ P- ^ GSoldiaeetat, 2.0 to 200 mg 4 ₁ ^ ⁱ - '(Gyclohexylidenmethyle.n) "diphenolj ₍ 1.0 to 100 mg dl-13-Ätliyl-gona-l, 3j5 (10) -' trien- 3 _r 16 oc, l? Ss-triol or the equivalent weight of a pharmaze a useful salt of the basic compounds and a progestagen, 2 »Preparation according to claim 1 _} dadup ^ h marked that the estrogen counteracting agent is phen ^ itrate * 3 »Prepared according to | .sprueh 1, thereby net that the Progoebugon from 0.1 to Q ,? mg ghloriiiadindn, received on J "_4i ... J: J_ Jfa {H 0 μ, 209815/1672 2U9281 0.1 to 0.7 mc megestrol acetate, 0.1 to 0.6 mg heloiigestrolacetate 0.05 to 0.5 ßg norathindrone and its acetate, 0.005 to 0.075 ng of iforgestrel and its acetate, 0.05 to 0.5 Hig Chingestanol and its acetate, 0.1 to 0.7 rag Desoxyiiorätliindroii or 0.05 to 0.5 ng of ethindiol diacetate consists. A preparation according to claim 3, characterized in that the estrogen counteracting agent is cis-glomiphene citrate, preferably in an amount of about 1 to 20 mg. For: Richardson-Merrell, Ine, Lawyer ι Ι BATH ORIGINAL