DE2218016A1 - Preparation for contraception - Google Patents

Description

dr. y <: ν "ι -c ^ a waiter beil" ^ioui °

: ■■: - :. woLFF

^: 'April 13, 1972

FΠΛ! -I - ';' -.:. "'- T · λ. · Λ /.·\ΑΙN-HÖCHST

Our no. 17 756

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 avoids the use of progestogens and menstrual and intermenstrual bleeding limited to a small extent.

It is known to have progestogens and estrogens by themselves or can be used in combination to regulate fertility. Various preparations are currently being used in particular three main preparations with the following "compositions" are used.

Combination preparations containing an estrogen and a progestagen and generally administered from the fifth day of a menstrual cycle to 20 or 21 days.

209846/1187

Preparations administered in sequence, for which one estrogen from the fifth day of the cycle and then an estrogen-progestagen combination is administered. It numerous variants of this preparation have been proposed.

Continuously administered progestogen supplements (or mini-pills) where a progestogen is administered daily will.

The combination and sequential preparations, while inhibiting conception with great effectiveness, do not represent the ideal form of one Contraceptives as in some cases they increase menstrual bleeding and sometimes they decrease cause intermenstrual bleeding (spotting).

The progestagen preparations administered continuously contain such a low dose of progestogen that the majority of the recipients do not inhibit ovulation and ovulation and cycle continued essentially as if no progestagen had been administered. It is however, it is known that the ingestion of the continuously administered progestogen supplements is considerably high of intermenstrual bleeding and extensive bleeding accompanies iat, so this type of contraception and birth control is severely limited.

209846/1 187

221801a

Proposals have been made to reduce the intermenstrual Reduce blood loss and extensive bleeding with continuous use of progestogen preparations. For example, it has been suggested to add estrogen to the progestogen for the last few days of each cycle.

Roy, Greenblatt, Mahesh and Jungck describe in "Fertility Sterility", Vol. 14, pages 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 in functional Uterine bleeding, however, found that none of the 11 ovulated women had clomiphene of different lengths in doses of 50 to 200 mg per day who received the Ovulation was suppressed.

It has now been found that clomiphene, especially cis-clomiphene, as well as certain other estrogen antagonists mentioned in the present case are among those according to the invention Conditions with an estrogen as described below allow to be administered to a high degree to achieve contraception and at the same time to reduce merfibrous bleeding and intermenstrual bleeding reduce to a minimum. In a world threatened by a population explosion, this statement is which paves the way to new and better contraception opens, of the utmost importance.

209846/1187

This novel combination according to the invention can be administered in various ways. For example, can the anti-estrogen agents and the estrogen continuously every day or intermenstrual or as a single pharmaceutical unit can be administered, eliminating the need for a labeled monthly package not applicable. The estrogen antagonists and the estrogen can also be administered together on a single day or on several selected days per cycle or month. The estrogen antagonists and the estrogen can also be administered sequentially each day; for example, the estrogen antagonist may be used during part or part of the time or during be taken for the entire first two thirds of the menstrual cycle, i.e. from the 5th to the 20th day of the cycle, and the estrogen is taken for part or part of the time or for the entire last third of the menstrual cycle, i.e. from the 20th to the 28th day. The estrogen, for example, can also be used during a part or part-time or .wälifend the entire first third of the menstrual cycle, i.e. from the 2nd to the 10th day, and the anti-estrogen agent be taken during part or all of the last two-thirds of the menstrual cycle. The anti-estrogen agent and the estrogen can also be administered alternately; for example, the estrogen can be used throughout the menstrual cycle or during part or part of the time of the cycle, i.e. from the 2nd to 10th and 20th to 28th day, with one or more days between

2 0 9 8 A 6/1 1 8 7

the non-steroidal agent is administered on the 10th and 25th day. It is also possible to have a marked monthly supply to use with or without placebos.

The subject of the invention is thus a new contraceptive, the one estrogen together with certain, the estrogen counteracting. Contains funds. The exact one Mechanism of action of the combination of anti-estrogen agents and estrogen is not known.

Various antiestrogenic agents can be used in the practice of the invention. So can for example 2-up- (2-chloro-1,2-diphenylvinyl) -phenoxy J-triethylamine (Clomiphene), cis-Clomiphene isomer, 2-IJ3- (p-Methoxy-ft-phenylphenethyl) -phenoxy 3-triethylamine, 1- {2- {£ - (* - Qj-Methoxyphenyl 3-ß-nitrostyryl) -phenoxy J-ethyl} -pyrrolidine , 2- Ij) - (1,2-diphenyl- 1-buteny 1) -phenoxy 3-N, N-dimethy 1-ethylamine, 2-fe- (1,2-diphenyl-l-butenyl) -phenoxy> Ν, Ν-αί-methylamine ^ antiestrogen isomer, 2-i £ - (6-methoxy-2-phenylinden-3-yl) -phenoxy 3-triethylamine, 1- {2- ί £ - (3,4-dihydro -6-methoxy-2-phenyl-1-naphthyl) -phenoxy-3-ethyl} -pyrroliden, dl-13-ethyl-gona-l, 3,5 (10) -triene-2-l6et, 17ßtriol and compounds of the following structure type, in particular also [«- (£ -hydroxyphenyl) - <* - (cyclohexylidert 3-p_-cresoldia1icetat, [et- (p-hydroxyphenyl) -et- (2-methylcyclohexylidene) 3-cresol diacetate and 4,4 '- (cyclohexylidenemethylene) diphenol be used:

2 0 9 8 4 ß / 1 1 8 7

C =

where R = H or COCH

= H or CH.

The one preferably used according to the invention, the estrogen counteracting agent is cis-clomiphene, the isomer of Clomiphene, which has no progestagenic activity and by the physico-chemical indicated below Characteristics is identified. Pharmaceutically acceptable salts of the aforementioned non-steroids basic agents, e.g. citrates such as dihydrocitrate, maleates, hydrochlorides, acetates, nitrates.,. Sulfates or phosphates can also be used.

Among the estrogenic, tolerable esters and salts that Can be used in the oral preparations of the invention include:

Mestranol, 3-methoxy-19-nor-17 cc-pregna-1,3,5 (10) -trien-20-yn-17-ol

2098A6 / 1 187

Quinestrol, 3- (cyclopentyloxy) -19-nor-17-a-pregna-1,3,5 (10) -trien-20-yn-17-ol

Ethynyl estradiol, 17 a-ethynyl-1,3,5 (10) -estratriene-3,17ß-

Methallenostril, ß-Ethy1-6-methoxy-α, α-dimethy1-2-naphthalene propionic acid,

Stilböstrol, α, OrDiethylstilbenediol

Dienestrol, 4, M '- (diethylidene ethylene) diphenol Hexös trol, H, ι "" - (1,2-diethylethylene) diphenol Chlorotrianise, chlorotris- (p-methoxypheny1) -ethylene Conjugated estrogens, United States Pharmacopoeia.

These and other compounds that can be used for depot injections include estradiol cyclopentyl propionate, estradiol valerate, polyestradiol phosphate, as well as other esters of estradiol or other estrogens. at appropriate choice of dosage will replace any of the estrogen antagonists mentioned above Substances cis-clomiphene citrate and any of the foregoing estrogen, the xthinyl estradiol used in Examples 1 and 2, achieving correspondingly more useful Compositions.

The administration can take place in various forms, e.g. in the form of tablets, capsules, liquids and the like., which contain the active ingredients and the corresponding pharmaceutical carriers and extenders. For oral too Administering compositions, the active ingredients are first brought into powder form and then into granules, tablets or capsules processed, or first dissolved or suspended in a suitable liquid carrier, and then encapsulated in soft gelatin. It can also use

2098 AG / 1187

Injectable compositions having a depot effect are prepared according to appropriate carriers. Besides, that can do the estrogen counteracting agents together with an estrogen using pharmaceutically acceptable implants or intrauterine or intravaginal insoles are used, for example bodies in which the active ingredients are included or incorporated into polymeric materials, e.g., silastic material. It is known to use lower daily doses for administration in implants or inserts than in oral administration in tablets.

When administered for longer than one day per month or menstrual cycle, the estrogen antagonist will suitably at least some Days of the menstrual cycle from the 10th to the 20th day and an estrogen administered at least on some days of the menstrual cycle before the 12th and / or after the 16th day, to produce a high level of contraception with minimal merger bleeding and low intermenstrual bleeding.

As used above, the various preferred compositions and approximate average dosage ranges are for oral administration per day as follows:

2 0 9 8 A S / 1 1 8 7

estrogen cis-clomiphene citrate mg mg Mestranol 0.01-0.5 1-50 Ethinyl estradiol 0.01-0.5 ti Quinestrol 0.01-0.5 It Metal estril 1.5-30.0 Il Stilbostrol 0.1-15.0 ti Dienestrol 0.1-15.0 It HexöBtrol 0.1-15.0 It Chlorine trianise 12-288
«Mm. f \ C Λ Γ \ Γ \ ti
Il

When using ethinyl estradiol as an estrogen, the approximate average daily dosage ranges suitable for oral administration, e.g. as follows:

estrogen-ethinyl estradiol antagonist

mg mg

cis-Clomiphendihydro-

citrate 1-50 0.01-0.5

Clomiphendihydro-

citrate 10 - 200 "

2- Cp-methoxy-o-phenylphenethyl) phenoxy I-triethylamine hydrochloride 10 - 1000 "

1 £ 2- [p- (Ot- ip-methoxy-

phenyl 3-ß-nitrostyryl) -

phenoxy 3-ethyl ^ pyrrolidine

monocitrate 1 - 100 "

2098A6 / 1187

- Io -

2-ip- (1,2-diphenyl-lbutenyl) -phenoxy} -N, N-dimeliylethylamine

2- Ip- (1,2-dipheny 1-1-butenyl) phenoxy j-N, N-dimethylethylamine anti-estrogen isomer

2- [p- (6-methoxy-2-phenylinden-3-yl) phenoxy I-triethylamine hydrochloride

1- {2- Ip- (3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl) phenoxy j-ethyl ^ pyrrolidene hydrochloride

[ar (p-hydroxypheny 1) - cc- (cyclohexylidene)> p-cresol diacetate

^, ^ '- (Cyclohexylidenemethylene) -diphenol

dl-13-ethyl-gona-1,3,5 (10) triene-3, 16ce-17β-triol

estrogen antagonist

mg

1 - 100

1 - 100

2 - 200

2 - 200

100 100 100

Ethiny! Estradiol

mg

0.01-0.5

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

) _O N CH ₀ CH ₀ O

209846/1 1

It is evident to the person skilled in the art that the clomiphene, I, is present as a mixture of the cis and trans isomers. These Mixtures have been separated by various researchers (see e.g. British Patent 1,099,093, F.P. Palopoli et al., J. Med. Chem., Vol. 10, p. 84 (1967) and A. Richardson Jr. and H.D. Benson, 153rd National Meeting American Chemical Society, Miami Beach, Fla., April 1967, excerpt M4), but opinions differ regarding the designation of the cis and trans configuration of the isomers. In the present case it is assumed that this isomer has the cis configuration, although it is referred to in the British patent as the tans isomer is, in the present case means ice-clomiphene isomer the isomer with the following physicochemical characteristics:

Ultraviolet absorption spectra - The citrate salt shows peaks in methanol at 239 πιμ (e 22000) and 296 ΐημ (e 11400), while in 0.1N HCl the absorption is 238 ΐημ ( ^e 2o500) and 294 mp (€ Io200). Infrared absorption spectra The citrate wast in KBr aromatic CH bands at 693 cm (shoulder: 69Ο cm), 752 cm "(shoulder: 746 cm and

—1 —1

756 cm) and 837 cm.

The base has peaks, more clearly defined, at 693 * cm " ¹ (doublet), 747, 758 cm" ¹ (doublet) and 836 cm " ¹ .

Nuclear Magnetic Resonance Spectrum - THE N.M.R. Spectrum (CDCl-) the base is labeled as follows:

2 0 9 8 4.6 / 1 1 8 7

Chemical
Miscellaneous
exercise (δ) Aufspal
tion
scheme No.H CH, from Assignment 0.99 TRIPLET 3 CHp of (C ₂ H ₅ J ₂ N- 2.53 QUARTET 4th CH ₂ of (C ₂ H ₅ J ₂ N- 2.73 TRIPLET 2 CH ₂ of 5N-CH ₂ -CH ₂ O 3.84 TRIPLET 2 Aromatics -CH ₂ O- 6.52 ⁺ DOUBLET ⁺ 2 ether ortho to basic Aromatics
ether 6.82 ⁺ DOUBLET ⁺ 2 Aromatics
ated 0
Ether 0 meta- to basic 7.18 MULTIPLE 5 Aromatics
ated 0
ether with unsubstituted
trans to basic: 7.35 SINGLET 5 with unsubstituted
gem- to basic

⁺ A ₂ B ₂ scheme at 6.52, 6.82 6.

Dipole Moment Measurements - Measured in benzene at room temperature, the base has a dipole moment of 2.860 ± 0.008 D.

In contrast, the present has as trans-clomiphene designated compound has the following physico-chemical characteristics:

Ultraviolet absorption spectra - the citrate salt shows peaks in methanol at 229 πιμ (e 20400) and 292 mp (c 12700), while in 0.1N HCl the absorptions at 224 mp (e 196ΟΟ) and 287 mp (e 11400).

209846/1 187

Infrared Absorption Spectra - The citrate shows aromatic CH bands in KBr at 696 cm, 742 cm " ¹ and 840 cm" ¹ . The last band has been assigned to the two adjacent hydrogen absorptions, while the others are absorptions caused by 5 adjacent hydrogen atoms.

- 1 - 1

The base has these peaks at 693 cm (shoulder: 696 cm),

- 1 - 1

746 cm and 836 cm.

Nuclear Magnetic Resonance Spectrum - The nuclear magnetic resonance spectrum (CDCl,) of the base is characterized as follows:

Chemical
Miscellaneous
exercise (δ) Aufspal
management
scheme No. H Assignment 1.04 TRIPLET 3 CH, of (C ₃ H ₅ ) ₂ N- 2.64 QUARTET 4th CH ₀ of (C ₀ H-) _O N- 2.88 TRIPLET 2 CH ₂ of ^ N-CH ₂ -CH ₂ O 4.06 TRIPLET 2 CH ₂ of -CH ₂ -O- 6.9O ⁺ DOUBLET ⁺ 2 Aromatics ortho to basic
ether 7.36 ⁺ DOUBLET ⁺ 2 Aromatics meta- to basic
Ether 7.02 SINGLET 5 Aromatics with non-substituted
ated 0 gem- to basic
Ether 0 approx. 7.2 MULTIPLE 5 Aromatics with rich substance

ated 0 ice to basic Ether 0

^f A ₂ B ₂ -fJ scheme at 6.90, 7 »36

2098A6 / 1187

2218015

Dipole moment measurement - The base measured in benzene at room temperature has a dipole moment of 2.108 ί 0.008 D.

example 1

Below is the composition of an example Tablet indicated:

For granulation per tablet

(a) fithinyl estradiol 0.1 mg

(b) cis-clomiphene citrate 10.0 mg

(c) 3 % strength sucrose, 67.5 mg

(d) lactose 109.4 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

A mixture of the previously sieved and finely pulverized ingredients (a) to (f) was granulated with deionized water and passed through a moist Mr. 2 sieve. Dan granules were dried at '19 ⁰ C and by a i »tob Mr. 12, where, in order to reduce the TnL Lohengröße. Then the ingredients (g) and (h) were added as lubricants and the amount of corn flour was chosen so that a weight of 320 mg per tablet was achieved. The pill

2098/1 6/1187

was shaped by adding 320 mg each of the mixture Now compressed using punches and dies with a diameter of 9.53.

Example 2

A capsule has the following composition, for example

(a) Ethinyl estradiol 0.1 mg

(b) cis-clomiphene citrate 10.0 mg

(c) lactose 172.6 mg

(d) Terra alba 21.5 mg

(e) Magnesium stearate 1.3 mg

(f) corn starch 21.5 mg

Ingredients (a) to (f) were passed through a No. sieve, mixed well in a suitable mixer and placed in a No. ¹ I hard gelatin capsule with a net fill weight of 230 mg per capsule.

Example 3

A preparation of 10 mg of cis-clomiphene citrate and 0.1 mg of ethinyl estradiol was administered orally daily in a capsule Women either continuously or for at least 5 days a month or during the periods when there is no menstruation is done, given a high level of contraception with minimal and low menstrual bleeding Occurrence of intermenstrual bleeding.

2 0 9 B / 6/1 1 8 7

Example 4

A preparation of IO mg of cis-clomiphene citrate and 2 ¹ I mg chlorotrianisene was administered as in Example 3 to a high degree of contraception with minimal menstrual bleeding and low occurrence to achieve inter-menstrual bleeding.

Example 5

A preparation of 10 mg of cis-clomiphene citrate and 0.1 mg of mestranol, which was administered as in Example 3, caused a high level of contraception with minimal Menstrual bleeding and low intermenstrual bleeding.

209 Ρ- Α 6/1187

Claims (1)

Claims 1.Preparation for contraception, containing essentially an agent that counteracts estrogen, namely 1 - 50 mg cis-clomiphene, 10 - 200 mg clomiphene, 10 - 1000 mg 2-fp- (p-methoxy-ct-phenylphenethyl) -phenoxy ihtriethylamine, 1.0-100 mg l- {2- ίρ- (α- ίρ-methoxyphenyl 3-ß-nitrostyryl) -phenoxy 3-ethyl) -pyrrolidine, 1.0-100 mg 2-Cp- (1,2-diphenyl -1-butenyl) -phenoxy 3-N, N-dimethylethylamine, 1.0 100 mg 2-Ip- (1,2-diphenyl-l-butenyl) -phenoxy> N, N-dimethylethylamine antiestrogen isomer, 2 - 200 mg of 2-lp- (6-methoxy-2-phenylinden-3-yl) -phenoxy J-triethylamine, 2.0-200 mg of 1- [2- [p- (3, * l-dihydro-6-methoxy -2-phenyl-l-naphthyl) -phenoxy 3-ethyl ^ -pyrroliden, 2.0 - 200 mg [a- (p-hydroxyphenyl) -a- (cyclohexylidene) 3-p-cresol diacetate, 1.0 - 100 mg [c- (p-hydroxypheny 1) - cc- (2-methyIcyclohexy liden) Jp-cresol diacetate, 2.0 - 200 mg 4, lJ ^! - (Cyclohexylidenemethylene) diphenol, 1.0 100 mg dl-13-ethyl-gona-l, 3.5 (10) -triene-3, 16a, 17ß-triol or pharmaceutically acceptable salts of the basic compounds, and estrogen. 2. Preparation according to claim 1, characterized in that the estrogen counteracting agent is cis-clomiphene citrate is. 3. Preparation according to claim 1, characterized in that the estrogen 0.01-0.5 mg mestranol, 0.01-0.5 mg ethinyl estradiol, 0.01-0.5 mg quinestrol, 1.5-30.0 mg methallenostril, 0.1-15.0 mg stilboestrol, 0.1-15.0 mg dienoestrol, 0.1 - 15.0 mg hexoestrol, 12 - 288 mg chlorotrianise or 0.6 - 10.0 mg conjugated estrogen qind. 2098 4 6/1187 ¹ I. Preparation according to claim 3> characterized in that the estrogen counteracting agent is cis-clomiphene citrate. 5. Preparation according to claim ^, characterized in that the estrogen counteracting agent about 5 to 20 mg of cis-clomiphene citrate is. For
Richardson-Merrell Ine (Dr. H.J. Wolff) Lawyer 209 ίΠ 6/1187