AU611160B2

AU611160B2 - Combined use of an antigestagen and a progesterone synthesis inhibitor of the trilostane and epostane type

Info

Publication number: AU611160B2
Application number: AU17750/88A
Authority: AU
Inventors: Sybille Dr. Beier; Krysztof Dr. Chwalisz; Walter Dr. Elger; Marianne Fahnrich; Syed Hamiduddin Dr. Hasan; Beate Kosub; Gordon Oliver Dr. Potts
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1987-06-16
Filing date: 1988-06-16
Publication date: 1991-06-06
Anticipated expiration: 2008-06-16
Also published as: AU1775088A; ES2059556T3; ATE94391T1; EP0296097A2; DE3884067D1; JP2716461B2; DK327288A; DE3720420A1; IE63453B1; EP0296097A3; IE881804L; ZA884315B; DK327288D0; CA1318251C; PH25728A; JPS63316725A; EP0296097B1; IL86731A0; IL86731A

Abstract

The medicine contains a progesterone synthesis inhibitor (ProH) of the trilostane or epostane type and an antigestagen (AG) and is used for inducing labour at term in humans and animals and for terminating normal or pathological pregnancy. The combination according to the invention is also suitable for treating hormone-dependent tumours, endometriosis and dysmenorrhoea.

Description

P.162967/SLC/MBS/3425T.2 611160

AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: I is document coLntan's tihe amendments allowed under Section 83 by the Supervising Examiner on ad is correct for printing C Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventors: Address for Service: SCHERING AKTIENGESELLSCHAFT Fur Besucher, Berlin-Wedding, MullerstraBe 170-178, D-1000 Berlin, Germany Dr Walter Elger; Dr Sybille Beier; Beate Kosub; Marianne Fahnrich; Dr Krzysztof Chwalidz; Dr Syed Hamidduddin Hasan; Dr Gordon Oliver ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

Complete Specification for the invention entitled "COMBINED USE OF AN ANTIGESTAGEN AND A PROGESTERONE SYNTHESIS INHIBITOR OF THE TRILOSTANE AND EPOSTANE TYPE".

The following statement is a full description of this invention including the best method of performing it known to me:- 1 REPRINT OF RECEIPT S1000368 ASC 49 110 COMBINED USE OF AN ANTIGESTAGEN AND A PROGESTERONE SYNTHESIS INHIBITOR OF THE TRILOSTANE AND EPOSTANE TYPE This invention relates to a pharmaceutical agent, which comprises a progesterone synthesis inhibitor (Prol) of the type of trilostane and epostane, and an antigestagen (AG).

It is sometimes necessary, in order to avert dangers to the mother and/or child, to induce labor artificially or terminate pregnancy prematurely. Surgical techniques and pharmacological methods are available for this purpose.

One possible pharmacological method is the vaginal or intramuscular administration of prostaglandins, which, in the case of termination of pregnancy, is carried out in the first or second trimester of pregnancy (Contraception 1983, Vol.

27, 51-60 and Int. J. Gynaecol. Obstet. 1982, Vol. 20, 383- 386).

The advantage of prostaglandin use is the possibility of employing it over a long period of the pregnancy.

Disadvantages of prostaglandins which should be mentioned are acute side effects such as pain and nausea. In addition, in the case of the termination of pregnancy in advanced phases of pregnancy, the success rate does not exceed 90%, even with prolonged duration of prostaglandin treatment.

4 Another possibility for terminating pregnancy comprises administration of an antigestagen (Med. et Hyg. 1982, Vol.

2087-2093). Antigestagens are better tolerated than are prostaglandins, but are less effective, and have a longer latency period and greater individual variability of the onset of action compared with prostaglandins. In addition, it has been observed clinically that they have a tendency to cause hemorrhages, which can be severe.

Although the conjoint use of prostaglandins and antigestagens (EP 84730108.2) has uncontestable advantages over administration of the individual active substances alone (especially reduction in the amount of each active 2 substance), it does not, for example, solve the problems which generally occur when prostaglandins are used: undesired side effects, such as gastrointestinal effects or uterine pain, the necessity for inpatient treatment, the storage and shelf-life of the pharmaceutical, owing to a lack of stability, being limited and/or elaborate, the impossibility of the most user-friendly administration form, namely oral, and thus the impossibility of combining the two active substances in a tablet, pill or coated tablet.

It has also been suggested to use the combination of prostaglandins, glucocorticoids and antigestagens for the induction of labor or for termination of pregnancy. The antigestagens can be either receptor competitive progesterone antagonists or compounds which antagonize the effect of gestagens by a different route, e.g, the derivatives of trilostane of U.S. patent 4,160,027. (See U.S. S.N. 790,020, filed October 22, 1985; DOS 3438994.6, filed October 22 1984).

Another possibility which. has been suggested for premature termination of pregnancy is treatment with progesterone synthesis inhibitors such as epostane derivatives (also US Patent 4,160,027). However, it has been found that it is impossible to induce abortion in guinea pigs in advanced prognancy even with doses high enough to cause a marked reduction in the serum progesterone level. In early human pregnancy, the success rate even with the maximum epostane doses is not 100%. Once again, clinical treatment is successful only in combination with prostaglandins, but very large amounts of active substances (30 mg of PGE 2 5 X 600 mg of epostane) are necessary for this. In addition to this disadvantage, the method is subject to the problems associated with the use of prostaglandins which have been discussed above.

Pharmaceutical compositions for post-coital fertility control, which contain a competitive progesterone antagonist (antigestagen) as well as a progesterone and estrogen synthesis blocker are already generically described in US patent 4,670,426. Typical representatives of the competitive 3 A progesterone antagonists to be used are fluocinolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17-acetate with acetone and 17B-hydroxy-11B,(4dimethylaminophenyl-l)-17o<-prop-l-ynyl-estra-4,9-dien-3-one and equivalent derivatives. The stated dosages for these compounds is between 20 and 100 mg per person per day. As examples for the progesterone and estrogen synthesis blocker there are cited aminogluthetimide, 2o<-cyano-4,4,1l'<trimethyl-5-androst-5-ene-17B-ol-3-one, 20,25diazacholesterol, and compounds with equivalent activity.

Doses of 300 to 1000 mg are stated. The use of the agent according to US patent 4,670,426 has to take place as early as possible within the first week after sexual intercourse over a period of 3 days; the treatment should best be continued 2 to 6 days. Prevention of nidation and thus of a pregnancy is caused by the synergistic effect in the combined use of the two components of the composition, and with a success rate on the order of 90% or more.

More recently the use of antigestagens in the field of tumor therapy, especially for treatment of mastocarcinoma, has also been discussed. A first phase II study with the already mentioned 17B-hydroxy-113-(4-dimethylaminophenyl)- 17o-prop-l-ynyl-estra-4,9-dien-3-one on postmenopausal or ovariectomy endocrine-therapy-resistant patients with metastasizing mastocarcinoma is reported by Maudelonde et al in Hormonal Manipulation of Cancer, eds. J.G.M. Klijn, R.

S Paridaens and J. A. Folkens in Raven Press, p.55 (1987).

SUMMARY OF THE INVENTION This invention provides agents which do not have the abovementioned disadvantages, are additionally highly effective, where possible more effective than the known agents, and have fewer side effects than the latter.

This invention has found that the use of a combination of progesterone synthesis inhibitors of the trilostane and epostane type(s) and antigestagens (competitive progesterone antagonists), i.e. of substances which both act on the principle of inhibition of the action of progesterone, (and 4 1_ each of which is, by itself, only incompletely effective or entirely ineffective, even at high dosages), is surprisingly completely effective even with a dramatic reduction in these doses.

Progesterone synthesis inhibitors (Prol) of the trilostane and epostane type and antigestagens (AG) can be administered conjointly for inducing labor at term, in humans and animals and for terminating normal or pathological pregnancies therein. Further, the combination according to the invention of progesterone synthesis inhibitors and antigestagen is suitable for treatment of endometriosis, dysmenorrhea and hormone-dependent tumors, for example, carcinoma of the breast and durosarcoma.

A 100% effectiveness is absolutely necessary for the use of these compounds for terminating pregnancy or inducing labor, since an embryotoxic action of the involved compounds can never be ruled out with certainty, in practice co In the treatment of hormone-dependent tumors, this invention proves superior to the sole use of antigestagen.

o 20 Brief Description of the Drawing o VaiJous other objects, features and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in connection with the accompanying drawings, in which like reference characters designate the same or similar parts throughout the several views, and wherein: Fig. 1 shows a comparison of the effect of an antigestagen (RU-486) alone, a prostaglandin synthesis inhibitor (epostane) alone, and the combination together in inducing abortion in pregnant guinea pigs.

dpc day post coitus /d s.c. per day subcutaneously /d p.o. per day by mouth Progesterone synthesis inhibitors of the type of trilostane or epostane and antigestagens are used for all these purposes in one dose unit or separately, simultaneously 5 L, and/or sequentially, in a ratio by weight which is pre 4 rably 1:40 to 60:1, preferably 1:30 to 30:1. The treatment with progesterone synthesis inhibitors and antigestagens per this invention is, as a rule, carried out for 1 to 4, preferably 1 to 2 days. It is possible and preferred for progesterone synthesis inhibitor and antigestagen to be administered combined in one dose unit.

Suitable antigestagens include all compounds which have a strong affinity for the gestagen receptor (progesterone receptor) and, moreover, have no important intrinsic gestagenic activity. Non-limiting examples of suitable competitive progesterone antagonists include the following steroids: 11-l[(4-N,N-dimethylamino)-phenyl]-173-hydroxy-17mpropynyl-4,9(10)-estradien-3-one (RU-486), 11l3-[(4-N,N-dimethylamino)-phenyl]-17B-hydroxy-18methyl-7c-propynyl-4,9(10)-estradien-3-one, and 11B-(4-N,N-dimethylamino)-phenyll-17aB-hydroxy-17apropynyl-D-homo-4,9(10)16-estratrien-3-one (European Patent Application 82,400,025.1 Publication No, 0,057,115); and furthermore 113-p-methoxyphenyl-78-hydroxy-17a-ethynyl-4,9(10)estradien-3-one (Steroids 37 (1981) 361-382) and 11-[(4-N,N-dimethylamino)-phenyl)-17-hydroxy-178-(3hydroxypropyl)-13a-methyl-4, 9-gonadien-3-one (European Patent No. 0129 499 corresponding to U.S. Ser. No. 621308).

The foregoing listing is exemplary only. Many other antigestagens can be used, as disclosed in Fertility and Sterility 40, 253 (1982), Steroids 37, 361-382 (1981) and !o I R -A 6S 'sec

S

<,ro Zk iis 44 EP0057115.

The amounts of antigestagens used according to the present invention are thereby below the amounts otherwise customary for termination of pregnancy (and, nevertheless often insufficient 5 for a 100% success rate). In general 5 to 200 mg of 113-[(4-N,N-dimethylamino)-phenyl]-17<-hydroxy-17B-propynyl-4,9- (10)-estradien-3-one per day (and per dosis unit), or a biologically equivalent amount of another antigestagen, is sufficient. These bioavailably equivalent amounts can be LO determined routinely and conventionally, by performing differential potency studies using fully routine pharmacological protocols, as disclosed in Fertility and Sterility 40, 253 (1982), Steroids 37, 361 (1981).

Progesterone synthesis inhibitors which can be used according to the invention include all inhibitors of the 33o hydroxysteroid dehydrogenase enzyme system which reduce the blood progesterone level and are of the type of trilostane (4a,5-epoxy-3,17B-dihydroxy-5a-androst-2-ene-2-carbonitrile) and/or epostane 4 a,5-epoxy-3,173-dihydroxy-43,17ac-dimethyl- 5-androst-2-ene-2-carbonitrile).

By compounds of the trilostane and/or epostane type, there are included, among others, 5-androstanes having the structural features: 2-cyano 4 a, 5a-epoxy, and 17B-hydroxy or-alkanoyloxy (1-6 C atoms). See USP 4,160,027. In an especially preferred subgenus, there are included such which include, instead of a 3-one feature, the structural unit 2-ene-3-hydroxy. In addition, all of such compounds can have substituents, those defined in USP n

U

ao i s 14^E VSt.

7 4,160,027.

I The amounts of these progesterone synthesis inhibitors which are used are also far below the amounts otherwise customary for the mentioned indications. When epostane is used as the progesterone synthesis inhibitor, as a rule a total of 5-600 mg, preferably 30-300 mg, will suffice. One dose unit I contains about 5-300 mg of epostane or a biologically equivalent amount of another such progesterone synthesis iinhibitor. These bioavailably equivalent amounts can be S 10 determined routinely and conventionally, by performing differential potency studies using fully routine i pharmacological protocols, as disclosed in AM.J.Obstet.

iGynecol., Suppl., 1987, 157, 1065-74. The activity of the claimed combination in treating hormone-dependent tumors can be determined according to already known methods, as disclosed in the mentioned reference to Maudelone et al.

The amounts of antigestagen and progesterone synthesis inhibitor can vary from 1:20 to 20:1 when treating a hormone-dependent tumor or treating endometriosis (daily dosage 0 '2 unit 10 to 200 mg of each) or from 1:30 to 30:1 when treating dysmenorrhea (daily dosage unit 10 to 300 mg of each). In A every case the upper limit of the dosage depends of the constitution of the respective patient and of the intended duration of the respective treatment.

The antigestagens and progesterone synthesis in inhibitors can be administered, locally, topically, enterally or parenterally. For the preferred oral administration it is possible to use in particular, tablets, coated tablets, 8 1445E capsules, pills, suspensions or solutions, which can be prepared in the customary manner using the additives and vehicles customary in pharmacy. See for example, the several references mentioned above. Preparations suitable for local or topical administration include, vaginal suppositories or transdermal systems such as skin plasters.

According to the present invention for terminating pregnancy or inducing labor the combination is administered in every case after nidation, preferably in the second or third S trimester of pregnancy, in the case of inducing labour shortly before or on the term of labor. The compounds can be S administered in any sequence, preferably simultaneously, in the on. case of sequential administration the second may be administered at any time after the first so long as it becomes bioavailable in the patient at the same time as an effective a dose of the first is still bioavailable. For example, the Prol can be administered within one or two days after AG.

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, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Example 1 Composition of a tablet containing 11B-[(4-N,N-dimethyl-amino)-phenyl]-17B-hydroxy-17a-propynyl-4, 9(10)-estradien-3-one for oral administration.

9 1445E 10.0 mg of 1113-t(4-N,N-dimethylamino)-phenyl]-l7B-hydroxy- 17c(-propynyl-4 ,9(lO) -estradien-3 -one 140.5 mg of lactose 69.5 mg of corn starch 2.5 mg of polyvinylpyrrolidone mg of Aerosil mg of magnesium stearate 225.0 mg total weight EXAMPLE 2 Composition of a tablet containing 4DO-,5-epoxy-3,178-dihydroxy-43,17c<-dimethyl-57---androst-2-ene-2-carbonitrile (epostane) for oral administration mg of 4c,5 -epoxy- 3, 178-d ihydroxy- 4B,l 1--d imethyl androst-2-ene-2-carbonitrile 201 mg of lactose 139 mg of corn starch mg of polyvinylpyrrolidone mg of Aerosil 1.0 mg of magnesium stearate 380.0 mg total weight EXAMPLE 3 Composition of a tablet containing 4c>,5-epoxy-3,17Bdiyrx-c-nrs- ee2-abnirl (trilostane) for oral administration 20.0 mg of 4o<, 5-epoxy- 3, 17 3-dihydroxy-5c,-androst- 2-ene-2 carbonitrile 281.0 mg of lactose 139.0 mg of corn starch mg of polyvinylpyrrolidone mg of Aerosil mg of magnesium stearate 450.0 mg total weight 10 4 4I Pharmacological findings The model substances selected for experiments on pregnant guinea pigs were the progesterone synthesis inhibitor epostane and the antigestagen 11-[(4-N,N-dimethylamino -phenyl]-17B-hydroxy-1-l<-propyny1-4,9 (10)-estradien-3.one (RU 486). The dosages tested are shown in the figure.

Investigations on pregnant guinea pigs Test of the combination Description of the experiment Pregnant guinea pigs weighing about 800 g were entered in the experiment on day 42 of pregnancy (the 2nd day of vaginal opening in the mating period was regarded as the first day of pregnancy). Pregnancy was checked by palpation before the start of the experiment. The treatment with the selected test substances and the combination was effected by oral (epostane) or subcutaneous (RU 486) administration each day on days 43 and 44 of pregnancy. For this purpose, the antigestagen was dissolved in benzyl benzoate castor oil (mixing ratio 2 and the daily dose was injected s.c.

in a volume of 1.0 ml. The daily dose of epostane was suspended as microcrystals in Myrj(R)/ saline solution and administered divided into two equal doses in the morning and afternoon. Any expulsion of embryos was checked several times a day during and after the treatment. The animals were sacrificed on day 50 of pregnancy. The uteri were inspected, and the fetuses were examined.

Results The results of the experiments on the induction of abortion in pregnant guinea pigs on combined administration of antigestagens and progesterone synthesis inhibitors are shown ii: the figure.

Progesterone synthesis inhibitors At an oral dose of 30.0 mg/day, epostane was totally inactive in terms of an abortive effect (see Fig. 1).

11 L i

_I

Antiqestagens With the antigestagen RU 486 an existent pregnancy was terminated with 10 mg/d s.c. in 3 of 9 treated animals. The abortions took place after a latency period of 4 to 6 days after the start of treatment (see Fig. 1).

Antiqestacen/proqesterone synthesis inhibitor combination The combination of marginally effective antigestagen doses (10.0 mg of RU 486/d with an ineffective epostane does of 30 mg/d orally resulted in an abortion rate of 100% and a far more rapid occurrence of the abortions. The latency period was shortened to a maximum of 2 days (see Fig.

a ta 1) a, The preceding examples can be repeated with similar .e success by substituting the genericaly or specifically described reatants and/or operating conditions of this invention for those used in the preceding examples.

C From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this Sinvention, and without departing from the spirit and scope 20 thereof, can make various changes and modifications of the o* invention to adapt it to various usages and conditions.

a 12 12

Claims

1. A pharmaceutical composition which comprises a progesterone synthesis inhibitor of the trilostane or epostane type, and an antigestagen which has a strong affinity for the gestagen receptor and substantially no intrinsic gestagenic activity, and optionally a pharmaceutically acceptable carrier or excipient.

2. A pharmaceutical composition of claim 1 wherein the progesterone synthesis inhibitor is trilostane. .na 3. A pharmaceutical composition of claim 1 wherein the 0o progesterone synthesis inhibitor is epostane. So 4. A pharmaceutical composition of any one of claims 1 to 3, o wherein the progesterone synthesis inhibitor and the S antigestagen are in a ratio by weight of 1:40 to 60:1, respectively.

5. A pharmaceutical composition of any one of claims 1 4, o Swherein the progesterone synthesis inhibitor dose contains 5 to 600 mg of epostane, or such an amount of another progesterone synthesis inhibitor of the epostane or trilostane type that is biologically equivalent to 5 to 600 mg of epostane.

6. A pharmaceutical composition of any one of claims 1 to wherein the antigestagen does contains 5 to 200 mg of 11B-[(4- N,N-dimethylamino)-phenyl]-17B-hydroxy-17a-propynyl-4,9 (10)-estradien-3-one or a biologically equivalent amount cf another antigestagen.

7. A pharmaceutical composition of any one of claims 1 to wherein the antigestagen is llB-[( 4 -N,N-dimethylamino)-phenyl]-17B-hydroxy-17a-propynll-4,9 13 ASC 49 \i V 162967/GHG (10)-estradien-3-one and the progesterone synthesis inhibitor is trilostane or epostane.

8. A method of inducing labor, terminating pregnancy, treating a hormone-dependent tumor, treating endometriosis, or treating dysmenorrhea, in a subject comprising administering an effective amount of a composition of any one of claims 1 to 7 to said subject.

9. A method of claim 8 wherein said administration is for the purpose of inducing labor. A method of claim 8 wherein said administration is for the purpose of terminating a normal or pathological pregnancy.

11. A method of claim 8 wherein said administration is for the purpose of treating endometriosis or dysmenorrhea.

12. A method inducing labor, terminating pregnancy, treating a hormone-dependent tumor, treating endometriosis or treating dysmenorrhea in a subject, comprising administering to said subject an effective amount of a progesterone synthesis inhibitor of the trilostane or epostane type, and an effective amount of an antigestagen which has a strong affinity for the i gestagen receptor and substantially no intrinsic gestagenic activity, said progesterone synthesis inhibitor and said antigestagen being administered in the same or separate dosage Sunits.

13. A method of claim 12 wherein said administration is for the purpose of inducing labor.

14. A method of claim 12 wherein said administration is for the purpose of terminating a normal or pathological pregnancy. 14 7A 162967/GHG A method of claim 12 wherein said administration is for the purpose of treating endometriosis or dysmenorrhea.

16. A method of claim 12 wherein said progesterone synthesis inhibitor and antigestagen are administered separately and sequentially.

17. A method of claim 12 wherein said progesterone synthesis inhibitor and antigestagen are administered separately and simultaneously.

18. A method of claim 12 wherein said progesterone synthesis si eo inhibitor and antigestagen are administered in the same dose unit. uo 19. A method inducing labor, terminating pregnancy, treating 0 0 a hormone-dependent tumor, treating endometriosis or treating dysmenorrhea in a subject, comprising administering to saic subject an effective amount of a progesterone synthesis inhibitor, and an effective amount of an antigestagen which has 0 o a strong affinity for the gestagen receptor and substantially no intrinsic gestagenic activity, said progesterone synthesis inhibitor and said antigestagen being administered in the same or separate dosage units. A method of claim 19 wherein said administration is for the purpose of inducing labor.

21. A method of claim 19 wherein said administration is for the purpose of terminating a normal or pathological pregnancy.

22. A method of claim 19 wherein said administration is for the purpose of treating endometriosis or dysmenorrhea.

23. A method of claim 19 wherein said progesterone synthesis 15 Iijj I P

162967./GHG inhibitor and antigestagen are administered separately and sequentially. 24. A method of claim 19 wherein said progesterone synthesis inhibitor and antigestagen are administered separately and simultaneously. A pharmaceutical composition substantially as herein described with reference to any one of Examples 1 to 3. 26. A method of treating a subject by administering a progesterone synthesis inhibitor and an antigestagen, substantially as herein described with reference to the Combination Test Example. o u 0 C 0 0 0 DATED this 7th day of March, 1991. SCHERING AKTIENGESELLSCHAFT By Their Patent Attorneys ARTHUR S. CAVE CO. 16 L S NT