AU693628B2

AU693628B2 - Use of 3,4-diphenylchromans

Info

Publication number: AU693628B2
Application number: AU43293/96A
Authority: AU
Inventors: Martin William Edwards; Birgitte Hjort Guldhammer; Ved Prakash Kamboj; Niels Korsgaard; Virender Mohan Labroo; James Robertson Piggott; Suprabhat Ray; Michael Shalmi
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1995-01-13
Filing date: 1996-01-10
Publication date: 1998-07-02
Anticipated expiration: 2016-01-10
Also published as: IL116746A0; WO1996021444A1; NO973243L; HUP9877967A2; EP0804190A1; MX9705219A; CA2208861A1; JPH10511962A; CN1168096A; HUP9702244A3; CZ212297A3; AU4329396A; NO973243D0

Description

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for the treatment or prophylaxis gynaecological disorders

FIELD OF THIS INVENTION

The present invention relates to the use of compounds of the general formula I for the treatment of patients suffering from gynaecological disorders, especially endometriosis, dysfunctional bleedings, endometrial cancer, polycystic ovarian syndrome and anovulatoric bleeding and prophylaxis hereof. Furthermore, this invention also relates to the use of compounds of the general formula I for the induction of endometrial thinning e.g. prior to surgery on the uterus. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.

BACKGROUND OF THIS INVENTION

A number of endocrine disorders in the breast and the reproductive organs in women is associated with an disturbed stimulation with oestrogen on the involved tissues.

Endometriosis is a disorder characterised by an occurrence of endometrial tissue outside the uterine cavity. This tissue is sensitive to the cyclic estradiol stimulation which occurs during the normal menstrual cycle. The symptoms include dysmenorrhoea, dyspareunia, infertility, abdominal pains, obstipation and mechanical ileus. The current treatment of endometriosis is surgery or a medical suppression of ovarian function by continuous or cyclic treatment by a combination of oestrogen and gestagen or gestagen alone or a suppression with a synthetic gestagen- like derivative of testosterone. Surgery is expensive and only suitable when the endometriosis is localized. Oestrogen/gestagen in different combinations is associated with bleeding disorders whereas danazol treatment is expensive and associated with side-effects such as meno- pausal syndrome and virilization.

One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of endometriosis.

Dysmenorrhoea in ovulatory cycles and dysfunctional uterine bleeding in anovulatory cycles are disorders which are characterised by transient disruptions of the synchronous hypothalamic-pituitary-ovarian patterns necessary for the regular ovulatory cycles. Dysfunctional uterine bleeding can also result from either a sudden withdrawal of oestrogen or as a breakthrough bleeding after prolonged oestrogen stimulation. In common the pathogenesis of these disorders therefore include abnormal endometrial oestrogen stimulation. Currently the treatment of these disorders involves different regimens of oestrogen oral contraceptives which can be associated with other forms of bleeding disorders and menopausal-like syndrome.

A further object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of dysfunctional bleedings.

An object of the present invention is also to provide compounds which can effectively be used in the treatment or prophylaxis of anovulatoric bleeding. Surgical techniques such as endometrial ablation and resection are being increasingly used in women with dysfunctional uterine bleeding as an alternative to hysterectomy. This allows women to be treated as day patients, and reduces the convalescence period from six weeks to two- or three days. Dysfunctional uterine bleeding is estimated to affect 20% of women during their reproductive years. Prethinning of the endometrium creates optimal surgical conditions by reducing fluid absorption, a potentially serious condition in ablative surgery. For the time being only danazol, which is expensive and associated with side- effects such as menopausal symptoms and virilization has been licensed for this indication.

Thus, another object of the present invention is to provide compounds which can effectively be used for endometrial thinning e.g. prior to surgery on the uterus.

Endometrial cancer is the most common gynaecologic malignancy in the United States, and its incidence is rising. Some patients are at high risk of developing endometrial carcinoma and include the obese, diabetic, hypertensive and infertile; those with failure of ovulation and dysfunctional bleeding; longstanding oestrogen users; and those with severe degree of endometrial hyperplasia. The common denominator for many of these risk factors is excess oestrogenic stimulation. Besides different possibilities for the treatment of the different underlying risk factors no treatment exists which can reduce development of carcinomas at the level of the endometrium.

Another object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of endometrial cancer.

Polycystic ovaries are characterised by multiple follicular cysts or cystic follicles with varying degree of luteinization of the theca interna and different degrees of oestrogen overproduction. This will result in con¬ stant and prolonged endometrial oestrogen stimulation which causes infertility and increases the risk of different bleeding disorders and the risk of developing endometrial carcinoma. The treatment of polycystic ovaries is in general directed by a desire for pregnancy by the patient, and therapy constitutes either surgery or medical induction of ovulation. If this proves unsuccessful the patient can be treated with oral oestrogen contraceptives which, however can lead to different bleeding disorders and after prolonged treatment increase the risk of developing endometrial carcinoma.

Yet another object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of polycys- tic ovarian syndrome.

Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992). 444 - 450: Grubb. Curr Qpin

Obstet Gvnecol 3 (1991 ), 491 - 495; Sankaran et al., Contraception 9 (1974), 279 - 289; Indian Patent Specification No. 129187). Centchro¬ man has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781 - 783. Recently, centchroman as a racemate has been found potent as a cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al. _r J Min Bon Res 9 (1994), S 394).

U.S. patent 5,280,040 describes methods and pharmaceutical composi¬ tions for reducing bone loss using 3,4-diarylchromans and their pharma¬ ceutically acceptable salts. BRIEF DESCRIPTION OF THIS INVENTION

It has, surprisingly, been found that compounds of the general formula I as stated in claims 1-7 can be used in the treatment or prophylaxis of patients suffering from gynaecological disorders, especially endometriosis, dysfunctional bleedings, endometrial cancer, polycystic ovarian syndrome and anovulatoric bleeding. Furthermore, it has surpris¬ ingly been found that compounds of the general formula I as stated in claim 7 can be used for the induction of endometrial thinning.

DETAILED DESCRIPTION OF THIS INVENTION

The present invention is based in part on the discovery that a representa¬ tive 3,4-diarylchroman, centchroman (3,4-trans-2,2-dimethyl-3-phenyl-4- [p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychroman) is effective against endometriosis, dysfunctional bleeding, anovulatoric bleeding and polycystic ovarian syndrome, inter alia in rats. These animal models mimic the pre-menopausal condition and are generally recognized models of above mentioned indications. These data thus indicate that the 3,4- diarγlchromans are useful as therapeutic agents against endometriosis, dysfunctional bleeding, anovulatoric bleeding and polycystic ovarian syndrome in mammals, including primates such as humans.

The present invention is furthermore based in part on the discovery that a representative 3,4-diarylchroman, centchroman (3,4-trans-2,2- dimethyl-3-phenyl-4-[p-(beta-pyrrolidinoethoxy)phenyl]-7-methoxychro- man) is effective against endometrial cancer, inter alia in rats. These animal models mimic the peri-menopausal condition and are generally recognized models of endometrial cancer. These data thus indicate that the 3,4-diarylchromans are useful as therapeutic agents against endometrial cancer in mammals, including primates such as humans. Additionally, the present invention is based in part on the discovery that a representative 3,4-diarylchroman, centchroman is effective as an agent for thinning of the endometrium e.g. prior to surgery on the uterine tissues, inter alia in rats. These animal models mimic the pre-menopausal condition and are generally recognized models of endometrial hyperplasia. These data thus indicate that the 3,4-diarylchromans are useful as agents for the induction of thinning of the endometrium e.g. prior to surgery.

Within the present invention, compounds of formula I as stated in claim 1 -7 are used for the therein stated indications in a patient. Within for¬ mula I, R1 , R4 and R5 are individually hydrogen, halogen, trifluorome- thyl, lower alkyl, lower alkoxy or (tertiary amino)(lower alkoxy); and R2 and R3 are individually hydrogen or a lower alkyl. As used herein, the term "lower alkyl" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "lower alkoxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo and iodo. The tertiary amino radical may be a dialkylamine such as a dimethyl, diethyl, dipropyl, dibutyl or a polymethyleneimine, e.g. piperidine, pyrrolidine, N- methylpiperazine or morpholine. Preferred compounds include those in which R1 is lower alkoxy; R2 and R3 are lower alkyl, especially methyl; R4 is hydrogen; and R5 is (tertiary amino)(lower alkoxy) of the polyme¬ thyleneimine type. Within particularly preferred embodiments, R1 is in the 7-position and is lower alkoxy, particularly methoxy; each of R2 and R3 is methyl, R4 is hydrogen and R5 is in the 4-position and is a (tertiary aminoMlower alkoxy) radical such as pyrrolidinoethoxy. To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula I.

It is preferred to use the compounds of formula I in the transconfigura- tion. These compounds may be used as racemic mixtures, or the isolated d- or I- enantiomers may be used. The trans-l-enantiomers are more preferred.

A particularly preferred compound for use within the present invention is centchroman having the formula IV as stated in claim 17.

Although only one enantiomer is shown, it will be understood that the formula IV is used herein to designate the transconfiguration of the 3- and 4-phenyl groups and that both the d- and l-enantiomers, as well as the racemic mixture, are included.

3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., Med Chem 19 (1976), 276 - 279, the contents of which are incorpo- rated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrange¬ ment is disclosed In U.S. Patent Specification No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer.

Within the present invention, 3,4-diarylchromans may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as fumaric acid, formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. The acid addition salts may be obtained as the direct products of com- pound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

3,4-diarylchromans and their salts are useful within human and veteri- nary medicine, for example, in the treatment of patients suffering from gynaecological disorders especially endometriosis, dysfunctional bleed¬ ings, endometrial cancer, polycystic ovarian syndrome and anovolatoric bleeding and furthermore for the induction of endometrial thinning. For use within the present invention, 3,4-diarylchromans and their pharma- ceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, supposi¬ tories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may formulate the com¬ pounds in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.

Oral administration is preferred. Thus, the active compound is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound is com- bined with a carrier and moulded into a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.

Pharmaceutical compositions are administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against gynaecolo¬ gical disorders especially endometriosis, dysfunctional bleedings, endo¬ metrial cancer, polycystic ovarian syndrome and anovolatoric bleeding or for induction of endometrial thinning. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.

The pharmaceutical compositions may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implanta¬ tion. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Controlled- release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 (1964), 1294 - 1297, 1984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,210,644, which are incorporated herein by reference.

The following examples are offered by way of illustration, not limitation.

Examples of preferred compounds are centchroman as a racemic mixture and as l-centchroman and d-centchroman. Furthermore, 3,4-trans-2,2- dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl]-7-hydroxychro- man is a preferred compound. The more preferred compound is isolated l-centchroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4-[p-(beta-pyrrolidino- ethoxy)phenyl]-7-methoxychroman).

Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as fumaric acid, formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, metha- nesulphonic acid and malonic acid.

The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protec¬ tion. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.

EXAMPLES Test 1 The competitive antiestrogenic action of centchroman has been demon¬ strated in uterine tissue from normal sexually mature Sprague-Dawley rats.

Twenty Sprague-Dawley sexually mature female rats (200-225 g) were obtained from Mollegaards breeding center, LI Skensved, Denmark. The rats were housed in metal hanging cages in groups of two and had ad libitum access to food and water for one week. Room temperature was maintained at 20° ± 1.5 ° with a minimum relative humidity of 40%. The photoperiod in the room was 12 hours light and 12 hours dark.

After the one week of acclimation period the rats were at random divided into five treatment groups of each 4 rats and daily oral treatment with the test compound was initiated. The test compound was given in five doses (0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 25 mg/kg/day or 75 mg/kg /day) for fourteen days. Following the dosing period the animals were weighed and sacrificed by asphyxiation with CO₂, the uterus was removed through a midline incision, and a wet uterine weight was determined after gently blotting on a towel.

Data shown in table I below shows comparative results among the treated rats. Treatment with centchroman in sexually mature rats with intact ovaries induce a significant hypoplasia of the uteri.

Table I.

Group Body weight Uterus weight Uterus/body

<g) (g) (mg/g)

0 mg/kg/day 182 0.49 2.71

5 mg/kg/day 159 0.18 1 .15

10 mg/kg/day 165 0.21 1 .25

25 mg/kg/day 153 0.20 1.30

75 mg/kg/day 135 0.18 1.32

From this observation it can be concluded that centchroman acts as an antagonist to the normal stimulating effect of oestrogen on the uterus. This was supported by the subsequent microscopy, which revealed an atrophic endometrium in these rats.

Claims

The use of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma¬ ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of gynaecological disorders.

2i The use according to claim 1 of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma¬ ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of endometriosis.

3^ The use according to claim 1 of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma- ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of dysfunctional bleedings.

v. The use according to claim 1 of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma¬ ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of endometrial cancer.

I _. The use according to claim 1 of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma- ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of polycystic ovarian syndrome.

i . The use according to claim 1 of compounds of the general formula I

wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma¬ ceutically acceptable carrier for the manufacture of a pharmaceutical composition for the treatment or prophylaxis of anovulatoric bleeding.

7i The use of compounds of the general formula I

(I) wherein R1 , R4 and R5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary aminoMlower alkoxy); and R2 and R3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharma- ceutically acceptable carrier for thinning of the endometrium.

8,. The use, according to any one of claims 1 -7, wherein R1 in the compound used is lower alkoxy, R2 and R3 are lower alkyl, R4 is hydro¬ gen and R5 is tertiary amino lower alkoxy.

S The use according to any one of claims 1 -8 wherein R1 is meth¬ oxy.

10. The use according to any one of claims 1 -9 wherein R2 is methyl.

1 1 . The use according to any one of claims 1 -10 wherein R3 is methyl.

12. The use according to any one of claims 1 -1 1 wherein R4 is hydrogen.

13. The use according to any one of claims 1 -12 wherein R5 is a group as stated in formula II below:

(ID 14. The use according to any one of claims 1 -13 wherein said com¬ pound is an isolated d- or l-enantiomer.

15. The use according to any one of claims 1-14 wherein said com¬ pound has the general formula III as stated below:

and the substituents are as defined in claim 1 above.

16. The use according to anyone of the preceding claims wherein said compound is an isolated l-enantiomer.

17. The use according to any one of claims 1 -15 wherein said com¬ pound is centchroman having the formula IV as stated below:

1 8. The use according to claim 1 7 wherein said compound is an isolated d- or l-enantiomer.

19. The use according to claim 1 7 wherein said compound is an isolated l-enantiomer.

20. The use according to any one of claims 1 -19 wherein said composition is in a form suitable for oral administration.

21 . The use according to any one of claims 1 -20 wherein said com¬ pound is administered as a dose in a range from about 0.001 to 75, preferably in a range from about 0.01 to 75, more preferably in the range from about 0.01 to 50 and especially in the range from about 0.1 to 25 mg/kg patient per day.

22. The use according to any one of claims 1 -21 wherein said composition is administered one or more times per day or week.

23. The use according to any one of claims 1 -21 wherein said composition is in the form of a dermal implant.

24. Method for treatment and prophylaxis of endometriosis compris¬ ing administering to a patient a clinically effective amount of a com- pound of above formula I stated to be used in any of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount suffi¬ cient to treat or prevent endometriosis.

25. Method for treatment and prophylaxis of dysfunctional bleedings comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any one of the preced¬ ing use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent dysfunctional bleedings.

26. Method for treatment and prophylaxis of endometrial cancer comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any one of the preced¬ ing use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent endometrial cancer.

27. Method for treatment and prophylaxis of polycystic ovarian syndrome comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any one of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent polycystic ovarian syndrome.

28. Method for treatment and prophylaxis of anovulatoric bleeding comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any one of the preced¬ ing use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent anovulatoric bleeding.

29. Method for endometrial thinning comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any of the preceding use claims or a pharmaceuti- cally acceptable salt thereof.

30. A method of treating or preventing endometriosis which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment. 31 . A method of treating or preventing dysfunctional bleedings which method comprises administering a clinically effective amount of com¬ pounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

32. A method of treating or preventing endometrial cancer which method comprises administering a clinically effective amount of com¬ pounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

33. A method of treating or preventing polycystic ovarian syndrome which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

34. A method of treating or preventing anovulatoric bleeding which method comprises administering a clinically effective amount of com¬ pounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

35. A method of endometrial thinning which method comprises administring a clinically effective amount of compounds and pharma¬ ceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

36. Any novel feature or combination of features described herein.