KR20010031801A - Anti-estrogen plus progestin containing oral contraceptives - Google Patents

Abstract

The present invention provides a contraceptive method comprising administering a combination of non-uterine aromatic antiestrogens and progestin for 28 days every 28 day menstrual cycle to women of childbearing age.

Description

Anti-estrogen plus progestin containing oral contraceptives

The present invention relates to oral regimen contraception containing non-uterine anti-estrogen (ie tissue selective estrogen) and progestin.

Many oral contraceptives consist of a combination of progestin and estrogen that is administered continuously for 21 days during each 28-day cycle, followed by no medication for 7 days or placebo for 7 days. The most important aspects of successful oral contraceptive products are effective contraception, good cycle control (prevention of spots and bleeding and formation of hemostasis) and minimal side effects. Combinations of oral contraceptives typically act by inhibition of gonadotropin. In addition, the progestin component exhibits contraceptive efficacy primarily through the inhibition of ovulation, and other peripheral effects include changes in the cervical mucosa (increasing difficulty in introducing sperm into the uterus) and changes in the endometrium (reducing the likelihood of transplantation). It is included). The estrogen component is important to enhance the ovulation effect of progestin and also to maintain cycle control.

Some examples of progestin-only contraceptives are known. For example, products containing noethine drone (350 μg) or levonorgestrel (75 μg) are useful, but there are some problems that limit the ultimate water solubility. The first problem is that the currently available oral progestin only contraceptives are administered at doses that do not completely inhibit ovulation, resulting in higher pregnancy rates than the currently available oral contraceptive formulations. Nevertheless, pregnancy rates (typically less than 3 per 100 women per year) are good, mainly due to changes in the cervical mucosa and moderate changes in the endometrium. The second problem with these agents is that there is a very high rate of abnormal or unexpected bleeding in women using them. The lack of predictable menstruation due to irregular development and bleeding of the uterine gland (endometrium) is a common phenomenon in progestin-only contraceptives for injectable and implantable. Less than 80% of women using either form of progestin-only contraceptive have been reported to develop this side effect.

British patent specification 1326528 describes an estrogen antagonist (preferably cis-clomiphene) for use with progestin for use as a contraceptive. The estrogen antagonists described in British Patent 1326528 are uterine oriented [Kumar, A. India. J. Biosc. 20 (5): 665 (1995)], whereas the antiestrogens of the present invention do not.

The present invention provides a contraceptive method for women of childbearing age, comprising continuously administering a combination of non-uterine aromatic antiestrogens and progestin during the 28-day menstrual cycle. Non-uterine oriented antiestrogens are commonly defined as agents that do not form clinically important uterine mucosal proliferation. More particularly, the present invention provides a female of childbearing age with a contraceptive effective amount of a combination of non-uterine anti-estrogens of Formulas (I) and (II) or a pharmaceutically acceptable salt thereof and progestin for 28 consecutive days per menstrual cycle. Provide a method of contraception.

In the above formula,

R ₁ is H, OH, alkoxycarbonyl or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen or mono- or 1 to 12 carbon atoms; Poly-fluoroalkoxy,

R ₂ is H, OH, alkoxycarbonyl or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen, mono- or 1 to 12 carbon atoms Poly-fluoroalkoxy, cyano, alkyl of 1 to 6 carbon atoms, or trifluoromethyl, provided that when R ₁ is H, R ₂ is not OH,

R ₃ and R ₄ are each independently H, OH, alkoxycarbonyl or aralkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen and 1 carbon atom. To mono- or poly-fluoroalkoxy, or cyano, to 12,

X is H, alkyl of 1 to 6 carbon atoms, cyano, nitro, trifluoromethyl or halogen,

n is 2 or 3,

Y is a saturated, partially saturated or unsaturated 5-7 membered heterocycle containing nitrogen, which is from the group consisting of -O-, -NH-, alkylamine having 1 to 6 carbon atoms, -N <and S (O) _m Optionally contain a selected second heteroatom,

m is 0-2.

When either of R ₁ to R ₄ is aralkoxycarbonyl or aralkoxy, the aryl group is preferably benzyl. When either of R ₁ to R ₄ is cycloalkyloxy, the cycloalkyl group is preferably cyclopentyl. When either of R ₁ to R ₄ is alkoxy, the alkyl group is preferably straight or branched methyl, ethyl, propyl or butyl. n is preferably 2.

Preferred compounds are those in which R ₁ is selected from H, OH, alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, benzyloxy, cycloalkyloxy or halogen having 3 to 12 carbon atoms, and R ₂ , R ₃ and R ₄ are independently H, OH or a carbon number of 2 to 12, alkoxycarbonyl, alkoxy of 1 to 12 carbon atoms, benzyloxy, cycloalkyloxy of 3 to 12 carbon atoms, halogen, cyano, C ₁ -C ₆ alkyl or tree to Romethyl, preferably trifluoromethyl, provided that when R ₁ is H, R ₂ is OH and X is H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl or Is selected from halogen and Y is Phosphorus compound.

The preparation of the antiestrogens of Formulas (I) and (II) is described in EP 802 183, published October 22, 1997, which is incorporated herein by reference.

Particularly preferred preferred antiestrogens of formulas (I) and (II) are shown in the table below.

Particularly preferred antiestrogens of formula (I) or (II) are the compounds of examples 31 and 32 in the table above. The antiestrogens of Formula I or II are preferably administered in the same daily dose of 0.1-150 mg of the compound of Example 32.

Preferred progestins are levonorgestrel, norgestrel, desozestrel, 3-ketodezogestrel, noethynedrone, zestoden, noethysterone acetate, norzestemate, osaterone, cyproterone acetate, tri Including but not limited to mezestone, dienozest and drospirenone. Progestin is more preferably levonorgestrel. When levonorgestrel is used as progestin, the daily dose of levonorgestrel is preferably 30 to 150 µg, more preferably 50 to 110 µg, most preferably 75 to 100 µg. The table below shows the preferred dosages of representative progestins of the present invention.

Preferred Daily Dose Range of Progestin

Progestin Dosage

Levonorgestrel 30 to 150 µg

Nordestrel 60 to 300 µg

Desozetrrel 45 to 225 μg

3-ketodesozetrrel 45-225 μg

100 μg to 1 mg of noethine drone

100 mg to 1 mg of noreosterone acetate

Gestoden 20 to 115 µg

Norzestimate 75 to 500 μg

Osarteron 100 ㎍ to 2.5 mg

Trimeston stone 30-1500 µg

Dienozest 500µg to 3.75mg

Drospirenone 500㎍ ~ 3.75mg

Cyproterone Acetate 450µg to 2.5mg

The present invention also provides other non-uterine anti-estrogens (and preferred daily doses) such as raloxifene (1 to 600 mg), droroxifene (1 to 600) for 28 days per 28 day menstrual cycle to provide contraception. Mg), idoxipine (1 to 600 mg), napoxidine (0.5 to 600 mg), toremifene, TAT-59 (0.1 to 600 mg), levomeloxyphene (0.5 to 600 mg), LY-353381 (1 to 600 mg), CP-336156, MDL-103323, EM-800 and ICI-182,780 (0.1 to 150 mg) and a combination of progestin.

The present invention also includes other progestins and non-uterine oriented antiestrogens that would be apparent to those skilled in the art.

The antiestrogens plus progestin regimen is preferably administered continuously during the 28-day menstrual cycle according to the monophasic type of regimen. In a single phase regimen, the same dose of each antiestrogens and progestin is administered daily during the administration period. 28-day continuous administration of the antiestrogens plus progestin combination will eliminate hemostasis associated with other discontinuous oral regimen contraception and eliminate irregular bleeding (prevention and spots) associated with oral regimen contraception alone.

When the compound of Example 32 and levonorgestrel are administered according to a 28-day single phase regimen, the following dosages are preferred and regimen A is most preferred.

hygiene Example 32 Levonor estrel A 2mg 90 µg B 3mg 75 µg C 5mg 100 µg

Antiestrogen plus progestin contraceptives of the present invention may also be administered for 28 days of each menstrual cycle according to a step regimen (ie, double, triple, quadruple, etc.). In this regimen, the same dose of combination is administered daily at specific periods and each period is administered at different dosages in either progressive or continuous periods. In a conventional quadruple regimen, each period can be up to seven days. The regimen may be a quadruple ascending regimen which increases the dose of antiestrogens plus progestin from stages I to II and from stages II to III, then the dose during the fourth phase is typically lower than the first phase. Those skilled in the art are known that the present invention includes regimens with the highest dose of either the first or second phase. Other variations include changing the dose of antiestrogens in four periods, where the dose of stage III is usually the highest and the dose of stage IV is the lowest, while maintaining a constant dose of progestin for all four periods. Alternatively, the dose of antiestrogens can remain constant for four periods, while the dose of progestin varies from period to period.

At the time of administration, the combination of antiestrogens plus progestin contraceptives is preferably administered in a single dosage form, ie tablets or pills, each unit providing a full daily dose. It is also desirable to mix progestin and antiestrogens together in the same dosage unit. Such dosage units can be prepared by conventional methods known to those skilled in the art. In each dosage unit, the contraceptive active progestins and estrogens are combined with excipients, vehicles, pharmaceutically acceptable carriers and colorants.

The present invention also provides a contraceptive kit suitable for daily oral administration comprising a total of 28 individual dosage units. In such kits, each dosage unit consists of a combination of a daily dose of progestin equal to the progesterone activity for 30-150 μg levonorgestrel and a daily dose of antiestrogens equal to 0.5-25 mg of the compound of Example 32. . The daily dose may preferably be arranged in a foam pack or a dial pack tablet dispenser. Particularly preferred dosages of the dosage units of progestin and antiestrogens and the respective combinations referred to specifically are described above.

Claims (18)

A contraceptive method comprising administering to a female of childbearing age a contraceptive effective amount of a combination of an anti-estrogen or a pharmaceutically acceptable salt thereof and progestin of formula (I) or (II) for 28 consecutive menstrual cycles. Formula I Formula II In the above formula, R ₁ is H, OH, alkoxycarbonyl or aralkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy, halogen having 3 to 12 carbon atoms, or mono- having 1 to 12 carbon atoms. Or poly-fluoroalkoxy, R ₂ is H, OH, alkoxycarbonyl or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen, mono- or 1 to 12 carbon atoms Poly-fluoroalkoxy, cyano, alkyl of 1 to 6 carbon atoms, or trifluoromethyl, provided that when R ₁ is H, R ₂ is not OH, R ₃ and R ₄ are each independently H, OH, alkoxycarbonyl or aralkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen and 1 carbon atom. To mono- or poly-fluoroalkoxy, or cyano, to 12, X is H, alkyl of 1 to 6 carbon atoms, cyano, nitro, trifluoromethyl or halogen, n is 2 or 3, Y is a saturated, partially saturated or unsaturated 5-7 membered heterocycle containing nitrogen, which is from the group consisting of -O-, -NH-, alkylamine having 1 to 6 carbon atoms, -N <and S (O) _m Optionally contain a selected second heteroatom, m is 0-2. The compound of claim 1 wherein Y is How to be. The compound of claim 1, wherein R ₁ is selected from H, OH, alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, benzyloxy, cycloalkyloxy having 3 to 12 carbon atoms, or halogen, and R ₂ , R ₃ and R ₄ are independently H, OH or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, benzyloxy, cycloalkyloxy having 3 to 12 carbon atoms, halogen, cyano, C ₁ -C ₆ alkyl Or trihalomethyl, preferably trifluoromethyl, provided that when R ₁ is H, R ₂ is not OH and X is H, C ₁ -C ₆ alkyl, cyano, nitro, trifluoro Romethyl or halogen, and Y is How to be. The method of claim 1, wherein the progestin is levonorgestrel, norgestrel, desozestrel, 3-ketodezogestrel, noethetrone, zestodene, noestosterone acetate, norgestistate, osateron, cysteine The method is selected from the group consisting of proteron acetate, trimeston, dienozest and drospirenone. The method of claim 4, wherein the progestin is levonorgestrel. The method according to any one of claims 1 to 5, wherein the antiestrogens a) 5-benzyloxy-2- (4-ethoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or drug Academically acceptable salts thereof b) 5-benzyloxy-2-phenyl-3-methyl-1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -1 H-indole or a pharmaceutically acceptable salt thereof, c) 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or drug Academically acceptable salts thereof d) 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -1 H-indole or pharmaceutical Salts thereof, which are allowed as e) 5-benzyloxy-2- (4-fluoro-phenyl) -3-methyl-1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -1 H-indole or pharmaceutical Salts thereof, which are allowed as f) 5-benzyloxy-2- (4-fluoro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or drug Academically acceptable salts thereof g) 5-benzyloxy-2- (4-chloro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or pharmaceutical Salts thereof, which are allowed as h) 5-benzyloxy-2- [3,4-methylenedioxy-phenyl] -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H- Indole or pharmaceutically acceptable salts thereof, i) 5-benzyloxy-2- [4-isopropoxy-phenyl] -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or Pharmaceutically acceptable salts thereof, j) 5-benzyloxy-2- (4-methyl-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or pharmaceutical Salts thereof, which are allowed as k) 5-benzyloxy-2- (3-benzyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole or drug Academically acceptable salts thereof l) 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -5-benzyloxy-2- (3-benzyloxy-phenyl) -3-methyl-1 H-indole or pharmaceutical Salts thereof, which are allowed as m) 5-benzyloxy-2- (4-benzyloxy-3-fluoro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl]- 1H-indole or a pharmaceutically acceptable salt thereof, n) 5-benzyloxy-2- (4-benzyloxy-3-fluoro-phenyl) -3-methyl-1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -1 H Indole or pharmaceutically acceptable salts thereof, o) 5-benzyloxy-2- (3-methoxy-phenyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -3-methyl-1 H-indole or pharmaceutical Salts thereof, which are allowed as p) 5-benzyloxy-3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2- (4-trifluoromethoxy-phenyl) -1H-indole Or a pharmaceutically acceptable salt thereof q) 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- {4-methyl-perrazin-1-yl) -ethoxy] -benzyl} -1 H-indole or pharmaceutical Salts thereof, which are allowed as r) 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -5-benzyloxy-2- (3-methoxy-phenyl) -3-methyl-1H-indole or pharmaceutical Salts thereof, which are allowed as s) 4- {3-methyl-1- [4- (2-pipepidin-1-yl-ethoxy) -benzyl] -1H-indole} hydrochloride, t) 4- {3-methyl-1- [4- (2-pipepidin-1-yl-ethoxy) -benzyl] -1H-indol-2-yl} -phenol hydrochloride, u) 3-methyl-2-phenyl-1- [4- (2-pipepidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride, v) 4- {5-methoxy-3-methyl-1- {4- [2- (piperidin-1-yl) -ethoxy] -benzyl} -1H-indol-2-yl} -phenol or Pharmaceutically acceptable salts thereof, w) 2- (4-methoxy-phenyl) -3-methyl-1- {4- [2- (piperidin-1-yl) -ethoxy] -benzyl} -1H-indol-5-ol or Pharmaceutically acceptable salts thereof, x) 5-methoxy-2- (4-methoxy-phenyl) -3-methyl-1- [4-piperidin-1-yl-ethoxy) -benzyl] -1H-indole hydrochloride, y) 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -5-methoxy-2- (4-methoxy-phenyl) -3-methyl-1H-indole hydrochloride, z) 2- (4-ethoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol or pharmaceutical Salts thereof, which are allowed as aa) 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-ethoxy-phenyl) -3-methyl-1 H-indol-5-ol or pharmaceutically Acceptable salts thereof, ab) 4- {5-fluoro-3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-2-yl} -phenol hydrochloride, ac) 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -3-methyl-2-phenyl-1H-indol-5-ol hydrochloride, ad) 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-pyrrolidin-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol or pharmaceutical Salts thereof, which are allowed as ae) 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol or pharmaceutical Salts thereof, which are allowed as af) 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol hydrochloride, ag) 2- (4-fluoro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol hydrochloride, ah) 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-fluoro-phenyl) -3-methyl-1 H-indol-5-ol or pharmaceutically Acceptable salts thereof, ai) 2- (3-methoxy-4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indole-5 -Ol hydrochloride, aj) 2-benzo [1,3] dioxol-5-yl-3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indole-5- All hydrochloride, ak) 2- (4-isopropoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride , al) 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-isopropoxy-phenyl) -3-methyl-1H-indol-5-ol hydrochloride, am) 2- (4-cyclopentyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol or a pharmaceutical Academically acceptable salts thereof an) 2- (4-chloro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride, ao) 2- (2,4-dimethoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol or Pharmaceutically acceptable salts thereof, ap) 2- (3-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol or pharmaceutical Salts thereof, which are allowed as aq) 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (3-hydroxy-phenyl) -3-methyl-1H-indol-5-ol or pharmaceutically Acceptable salts thereof, ar) 2- (3-fluoro-4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole-5 -Ols or pharmaceutically acceptable salts thereof, as) 2- (3-fluoro-4-hydroxy-phenyl) -3-methyl-1- [4- (azepane-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol or Pharmaceutically acceptable salts thereof, at) 2- (3-methoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol or pharmaceutical Salts thereof, which are allowed as au) 3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2- (4-trifluoro-methoxy-phenyl) -1H-indole-5- Ol or pharmaceutically acceptable salts thereof, av) 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-pyrrolidin-1-yl-ethoxy) -benzyl] -1 H-indol-5-ol hydrochloride, aw) 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride, ax) 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride, ay) 3-chloro-2- (4-hydroxy-2-methyl-phenyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole-5- Ol or pharmaceutically acceptable salts thereof, az) 2- (4-hydroxy-phenyl) -3-ethyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol hydrochloride, ba) 5-hydroxy-2- (4-hydroxy-phenyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1 H-indole-3-carbonitrile hydro Chloride, bb) 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -5-hydroxy-2- (4-hydroxy-phenyl) -1 H-indole-3-carbonitrile hydrochloride , bc) di of 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol hydrochloride Propionate, bd) di of 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol hydrochloride Pivalate, be) 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -1H-indol-5-ol or pharmaceutical And di-pivalate esters of salts thereof. The anti-estrogen according to any one of claims 1 to 6, wherein the anti-estrogen is 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl)- 3-methyl-1H-indol-5-ol or a pharmaceutically acceptable salt thereof. The process according to any one of claims 1 to 5, wherein the antiestrogens are 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl)-. The phosphorus method is 3-methyl-1H-indol-5-ol acetate. The method of claim 1, wherein the same dose of the antiestrogens and progestin combination is administered daily for 28 days. 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol acetate for women of childbearing age A contraceptive method comprising administering a daily dosage of 0.5-25 mg and 30-150 μg of levonorgestrel for 28 consecutive days at every 28-day menstrual cycle. The method of claim 10, wherein the same dose of the combination is administered daily for 28 days. A contraceptive method comprising administering a non-uterine aromatic antiestrogens and progestin combination to a woman of childbearing age for each 28 day menstrual cycle for 28 days. 13. The method of claim 12, wherein the progestin is levonorgestrel, norgestrel, desozestrel, 3-ketodezogestrel, noethetrone, zestodene, noestosterone acetate, norgestistate, osaterone, cy The method is selected from the group consisting of proteron acetate, trimeston, dienozest and drospirenone. The method of claim 13, wherein the antiestrogens are raloxifene, droroxifene, idoxipine, napoxidine, toremifene, TAT-59, levomeloxyphene, LY-353381, CP-336156, MDL-103323, EM-800 And ICI-182,780. The method of claim 14, wherein the same dose of antiestrogens and progestin combination is administered daily for 28 days. A contraceptive kit suitable for daily oral administration comprising 28 separate dosage units each containing a combination of non-uterine aromatic antiestrogens and progestin. 17. The method of claim 16, wherein the antiestrogens are compounds of Formula (I) or (II) or pharmaceutically acceptable salts thereof, and progestin is levonorgestrel, norgestrel, desozestrel, 3-ketodezogestrel, noethynedrone. , A kit selected from the group consisting of zestoden, noethysterone acetate, norgestimate, osaterone, cyproterone acetate, trimeston, dienozest and drospirenone. Formula I Formula II In the above formula, R ₁ is H, OH, alkoxycarbonyl or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen or mono- or 1 to 12 carbon atoms; Poly-fluoroalkoxy, R ₂ is H, OH, alkoxycarbonyl or alkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen, mono- or 1 to 12 carbon atoms Poly-fluoroalkoxy, cyano, alkyl of 1 to 6 carbon atoms, or trifluoromethyl, provided that when R ₁ is H, R ₂ is not OH, R ₃ and R ₄ are each independently H, OH, alkoxycarbonyl or aralkoxycarbonyl having 2 to 12 carbon atoms, alkoxy or aralkoxy having 1 to 12 carbon atoms, cycloalkyloxy having 3 to 12 carbon atoms, halogen and 1 carbon atom. Mono- or poly-fluoroalkoxy or cyano of 12 to 12, X is H, alkyl of 1 to 6 carbon atoms, cyano, nitro, trifluoromethyl or halogen, n is 2 or 3, Y is a saturated, partially saturated or unsaturated 5-7 membered heterocycle containing nitrogen, which is from the group consisting of -O-, -NH-, alkylamine having 1 to 6 carbon atoms, -N <and S (O) _m Optionally contain a selected second heteroatom, m is 0-2. 18. The method of claim 17, wherein the antiestrogens are 1- [4- (2-azpan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole- The kit is 5-ol acetate and progestin is levonorgestrel.