Notice of Entitlement

PZOO/OOl : Section 29 AUSTRALIA

Patents Act 1990

NOTICE OF ENTITLEMENT

We Jenapharm GmbH of Otto-Schott-Strasse 15, 07745 Jena, Germany, the Applicant in respect of Application No. 29741/95 state the following:

ft• · · · ft0 1. Jenapharm GmbH is the Nominated Person in respect of the application. • · · 0 • ••ftft 2, The actual inventors of the invention, the subject of the application, are Sifgrid ft• · » ft ft β · SCHWARZ, Walter ELGER, Hans-Joachim SIEMANN, Gudrun REDDERSEN ft ft 3 ft · ft and Birgitt SCHNEIDER • • ft ftft • ft 9 ft ft • • <ί·ft 3 The Nominated Person is entitled to the grant of a patent in respect of the application because the said Nominated Person derived title to the invention from ft ft ft the actual inventors by virtue of assignment contract. • ft · eftft ft • ft··ft * • ft ft ftft 4 The Nominated Person is entitled to claim priority from the application listed in the • ft ft ft ftft ft declaration under Article 8 of the PCT because the Nominated Person is the ft ft ftft applicant in respect of the application listed in the declaration under Article 8 of the ft ft PCT, and because the application was the first application made in a Convention country in respect of the invention. ft » ft ftftft ft ft ft ft ·ft

______.______7 October, 1998

A member of the firm of DAVIES COLLISON CAVE for and on behalf of the applicant

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AU9529741

(12) PATENT ABRIDGMENT (11) Document No. AU-B-29741/95 (19) AUSTRALIAN PATENT OFFICE (10) Acceptance No. 699701

(54) Title ESTRA-1,3,5(10)-TRIENE DERIVATIVES, METHODS OF PREPARING SUCHCOMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM International Patent Classification(s) (51)6 CO7J 041/00 A61K 031/56 C07J 043/00 C07J 053/00 (21) Application No.: 29741/95 (22) Application Date : 03.07.95 (87) PCT Publication Number: WO96/05216 (30) Priority Data (31) Number (32) Date (33) Country 4429397 09.08.94 DE GERMANY (43) Publication Date : 07.03.96 (44) Publication Date of Accepted Application : 10.12.98 (71) Applicant(s) JENAPHARM GMBH (72) Inventor(s) HANS-JOACHIM SIEMANN; SIGFRID SCHWARZ; WALTER ELGER; GUDRUN REDDERSEN; BIRGITT SCHNEIDER (74) Attorney or Agent DAVIES COLLISON CAVE , GPO Box 3876, SYDNEY NSW 2001 (57) Claim 1. Estra-l,3,5(lO)-trien derivatives of the general Formula I

II O wherein R is a RT^N group, withR1 and R2, independently of each other, represent a hydrogen atom, a CrC5-alkyl residue or, together with the N atom, a polymethylenimino residue with 4 to 6 C atoms or a morpholine residue,

R3 is a hydrogen atom or an alkyl group with 1-5 C atoms,

R4 is a hydrogen atom, a hydroxy group, an esterified hydroxy group, a haloalkyl group with 1-5 C atoms or an alkoxy group with 1-5 C atoms, era·

(11) AU-B-29741/95 -2- (10)699701 R3 and R6 are a hydrogen atom each or, together, stand for a methylene group,

R7, R8 and R9, independently of each other, stand for a hydrogen atom or a hydroxy group,

and ring B may contain one or two double bonds or

R8 is an alkinyl residue with up to 5 carbon atoms with the proviso that R1 and R2 are hydrogen atoms, or at least one of the residues R3, R4, R3, Rfi or R7 is not hydrogen and R1 and R3 have a different meaning from each other , or

R8 and R9 together may represent an oxygen atom with the proviso that at least one of the residues R3, R4, R3, R6 or R7 is different from hydrogen, or

R3 and R8 may represent a vinylene or ethylene group.

4, Pharmaceutical compositions containing an estra-1,3,5(10)-trien derivative according to Claim 1 or 2 which may be combined with pharmaceutically safe adjuvants and carriers. OPI DATE 07/03/96 APPLN. ID 29741/95 AOJP DATE 26/04/96 PCT NUMBER PCT/DE95/00877 AU9529741

(51) Internationale Patentklassifikation 6 ; (11) Internationale VeroiTentlichungsnununer: WO 96/05216 C07J 41/00, A61K 31/56, C07J 53/00, Al (43) Internationales 43/00 Veroffentlichungsdatum: 22. Februar 1996 (22.02.96)

(74) Anwalt: WABLAT, Wolfgang; Potsdamer Chaussee 48, D- (21) Internationales Aktenzeichen: PCT/DE95/00877 14129 Berlin (DE). (22) Internationales Anmeldedatum: 3. Juli 1995 (03.07.95)

(81) Bestimmungsstaaten: AU, BG, BR, BY, CA, CN, CZ, FI, HU, (30) Prioritatsdaten: JP, KP, KR, KZ, LK, LV, MN, NO. NZ. PL, RO, RU, SK, P 44 29 397.6 9. August 1994 (09.08.94) DE UA, US, UZ, VN, europfiisches Patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).

(71) Anmelder (fiir alle Bestimmungsstaaten ausser US): JE- NAPHARM GMBH [DE/DE]; Otto-Schott-Strasse 15, VerSfTentlicht D-07745 Jena (DE). Mit internationalem Recherchenbericht.

(71) Anmelder (nur fiir US): SIEMANN, Christei (Erbin des verstoibenen Erfinders) [DE/DE]; Fritz-Ritter-Strasse 6, D- 07747 Jena (DE).

(72) Erflnder: SIEMANN, Hans-Joachim (verstorben). I 8 (72) Erfinder; und (75) Erflnder/Anmelder (nur fiir US): SCHWARZ, Sigfrid [DE/DE]; Ottogerd-Mtihlmann-Strasse 17, D-07743 Jena 1 (DE). ELGER, Walter [DE/DE]; SchorlemeraUee 12b, D-14195 Berlin (DE). REDDERSEN, Gudrun [DE/DE]; HUgelstrasse 25, D-07749 Jena (DE). SCHNEIDER, Birgitt , [DE/DE]; Damaschkeweg 19, D-07745 Jena (DE).

(54) Title: ESTRA-1,3,5(10)-TRIENE DERIVATIVES, METHODS OF PREPARING SUCH COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

(54) Bezeichnung: ESTRA-1,3,5( 10)-TRIEN-DERIVATE, VERFAHREN ZU IHRER HERSTELLUNG UND DIESE VERBINDUNGEN ‘ ENTHALTENDE PHARMAZEUT1SCHE ZUSAMMENSETZUNGEN

(57) Abstract

The invention concerns novel estra-1,3,5(10)-triene amidosulphamates with an R-SO2-O- group in the 3-position, R being an R*R2N- group in which R* and R2, independently of each other, are a hydrogen atom, an alkyl group with 1 to 5 C-atoms or, together with the N-atom, a polymethyleneimino group with 4 to 6 C-atoms or a motpholino group. The compounds described are suitable for use in hormonal contraception and in climacteric hormone-replacement therapy (HRT), as well as in the treatment of gynaecological and andrological conditions. The compounds described thus only have a low hepatic oestrogenicity, Also described are methods of preparing the compounds described, plus the preparation of pharmaceutical compositions containing them.

(57) Zusammenfaaeung

Die Erfindung betrifft neue Estra-1,3,5(10)-trien-Amidosulfamate, welche an der 3-Position eine R-SCh-O-Gruppe tragen, wobei R cine R'R2N-Gnippe 1st, worin R* und R2 unabhingig voneinander ein Wasserstoffatora, einen Alkylrest mit 1-5 C-Atomen oder zusammen mit dem N-Atom einen Polymethylenimlnorest mit 4 bis 6 C-Atomen oder einen Morpholinorcst bedeuten. Die erfindungsgemaflen Verbindungen sind zur hormonalen Kontrazeption und in der klimakterischen Hormon-Replacement-Therapie (HRT) sowie zur Behandlung gyndkologischer und andrologischer Krankheitsbilder geeignet. Daher weisen die erfindungsgemaflen Verbindungen nur eine geringe hepatische Estrogenitat auf. Femer werdcn Verfahren zur Hentellung der erfindungsgemaflen Verbindungen beschrieben, sowie zur Herstellung pharmazeutischer ’ Zusammensetzungen.

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Estra-1, 3, 5(10)-Trien Derivatives, Processes for their Preparation and Pharmaceutical Compositions containing these Compounds I

Description

This invention relates to new estra-1, 3, 5(10)-trien sulfamates.

I 10 Estrogens play a major role in hormonal contraception and climacteric hormone replacement therapy (HRT) as well as in the treatment of gynecological (e.g. £ I mammary carcinoma) and andrological (e.g. prostate carcinoma) diseases.

Ϊ; In HRT and for contraception, estrogens are predominantly used in combination 15 with a gestagen, e.g, levonorgestrel, desogestrel, gestodene, drospirorenone, norethisterone, cyproterone acetate, chlormadinone acetate and dienogest.

For contraception, estrogens are required for reliable suppression of follicular maturation and ovulation. They will also substitute for widely suppressed 20 endogenic, ovarian secretion of estradiol. Such substitution is essential to maintenance of an artificial menstruation cycle and other functions of sexual organs, which would not be satisfactorily achievable by a gestagen alone.

Endogenic estrogens also have important central nervous and metabolic functions I 25 in the female organism.

Normal estrogen levels make a crucial contribution to individual comfort and wellbeing (L. Zichella; Clinical Management of the Menopausal Woman; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 15-22). Their presence, 3 0 through various mechanisms, may help in preventing development of cardiovascular diseases, for example, by generating "favourable" lipoprotein patterns in the blood (G. Samsioe; Hormone Replacement Therapy and Cardiovascular Disease; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 0 23-29), inhibition of lipid incorporation into vascular walls (T.B. Clarkson; 35 Experimental Effects of Progesterone versus Progestins on Arterial Wall; Gynecol, Endocrinol., 6: Suppl. 1 [1992], 15), reduction of blood pressure through

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? O f 2 5 ; favourable action on vascular tonus (R.A. Lobo; Estrogen and Cardiovascular i Disease; Ann, New York Acad. Sciences, 592 [1990], 286-294), reduction of j perfusion resistance in important vascular regions, attenuation of contractile stimuli } * on vascular muscle (C. Jiang et al.; Acute effect of 178-estradiol on rabbit j 5 coronary artery contractile responses to endothelin-1; Am. J. Physiol., 263 [1992], ; " H271-H275). The inner vascular walls, under the impact of estrogens, release j factors (prostacyclins) which counteract to the buildup of blood clots.

Estrogens are additionally indispensable to women for preservation of the bone 10 structure. Their loss may cause osseous degradation (osteoporosis) (C. Christiansen; Prevention and Treatment of Osteoporosis with Hormone Replacement Therapy; Int. J. of Fertil. and Menop. Studies, 38, Suppl. 1 [1993], 45-54). These latter "central nervous" and "metabolic" effects of estrogens are major aspects in HRT, 15 Notwithstanding the numerous appreciable aspects of estrogen therapy, there still are certain unresolved problems which impose limitations on the therapeutic use of estrogens or may entail undesirable effects.

20 The bioavailability of natural estrogens (estradiol, estrone, estrone sulphate, esters of estradiol, estriol) tends to be minimised after oral application (K.B. Lokind et al.; Oral bioavailability of 17B-estradiol and various ester prodrugs in the rat; Int. ί J. Pharmaceutics, 76 [1991], 177-182), That minimised amount is of high individual variability, and a dosage of general validity, consequently,cannot be 25 recommended. The use of natural estrogens (estradiol) for hormonal contraception has been negatively assessed because of these pharmacokinetic restrictions (W. Kuhnz et al.; Pharmacokinetics of Estradiol, Free and Total Estrone in Young Women, following Single Intravenous and Oral Administration of 17fi-Estradiol; Arzneimittel-Forschung /Drug Res., 43(11), 9 [1993], 966-973). Rapid elimination 30 of substances from blood is another problem. Estrogen substitution in HRT must repeatedly be readjusted to the individual recipient. Efforts so far have failed to develop estradiol prodrugs for improved oral bioavailability (K.B. Lokind et at; see above), Synthetic estrogens, too, are accompanied by serious drawbacks. Ethinyl estradiol 35 (EE) is the most important synthetically modified estrogenic steroid. It is an estrogen that plays a predominant role in oral hormonal contraception. Apart from h 7 «β»****’

EE, mestranol is used in few cases, a "prodrug" which is metabolised to EE in the organism (J.W. Goldzieher; Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications; Am. J. Obstet. Gynecol,, 163 [1990], 318-322). EE, when orally applied (to a human recipient), 5 is much better in bioavaiiability than the aforementioned natural estrogens, although its oral bioavaiiability may drastically decline, depending on the individual recipient. Goldzieher, in the context of pharmacodynamics, stressed the negative consequences implied in the variability of the area under the curve (AUC) as well as variability of half-life and time passing until maximum blood levels were 10 reached. The highest AUC recorded from his study, 0-24 hours from application, amounted to 2121 pg x h/ml. The lowest AUC was 284 pg x h/ml. A similar scatter of AUC, around the factor 6 to 7, was described by Hiimpel et al, (M. Hiimpel et al.; Comparison of Serum Ethinyl Estradiol, Sex Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two 15 Low-Dose Combined Oral Contraceptives; Horm. Res., 33 [1990], 35-39).

The route taken by orally applied active substances, following absorption, is from the intestinal lumen via liver into the organism. This fact is of particular relevance 20 to estrogenic substances, as the liver is a success organ for estrogens, and their oral administration thus may lead to strong intrahepatic estrogenic effects. Secretional activities regulated by estrogens in the human liver include synthesis of transport proteins, CBG, SHBG and TBG, angiotensinogen, various factors that play a major physiological role in blood coagulation, and lipoproteins. 25 If, however, natural estrogens are fed to the female organism by bypassing passage through the liver, say, by transdermal application, the above liver functions will not be affected and will stay unchanged (U, Larsson-Cohn et al.; Some biochemical consequences of post-menopausal hormone replacement treatment; in: 30 The Controversial Climacteric, Ed,: P.A. van Keep et al.; MTP Press Ltd. [1982]). Oral administration of therapeutically equivalent doses of natural estrogens leads to unambiguous response by various hepatic parameters: rise of SHBG, CBG, angiotensin, HDL (high-density lipoproteins) (J.C, Stevenson et al.; Oral versus Transdermal Hormone Replacement Therapy; Int. J. of Fertil. and 35 Menop. Studies, 38 Suppl. 1 [1993], 30-35). Hepatic estrogen effects resulting from equine estrogen mixtures (socalled conjugated estrogens) were clearly found \

4 i to be more strongly pronounced than those attributable to natural estrogens (C.A. Mashchak et al.; Comparison of pharmacodynamic properties of various estrogen formulations; Am. J. Obstet. Gynecol., 144 [1982] 511-518). Even stronger hepatic estrogenicity may be attributed to ethinyl-estradiol and DES. Related to 5 antigonadotropic properties, the estrogenic effectiveness of EE in the liver is eight to ten times as high as that of orally administered natural estrogens. Hence, there is a highly unfavourable dissociation of properties (B, von Schoultz et al.; Estrogen Therapy and Liver Function - Metabolic Effects of Oral and Parenteral Administration; The Prostate, 14 [1989], 389-395). 10 The following observation shows that undesirable hepatic estrogen effects cannot be avoided by dose reduction of EE in contraceptives. Reduction from 30 pg to 20 pg EE, either dose in combination with 150 pg of the same gestagen, did not result in reduction, after three months, of considerably increased angiotensin levels and 15 gave, at best, marginally reduced values after six months (A. Basdevant et al.; ί Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 meg to 20 meg in oral contraceptives containing desogestrel; Contraception, 48 [1993], 193-204).

)' 2 0 Fatal thromboembolic complications are known to be a real problem in the context of high-dosage estrogen therapy of men for prostate carcinoma (B. von Schoultz et at; loc.cit.),

The strategy of oral hormonal contraception is determined in a somewhat subdued 2 5 manner by potential side-effects of EE in the liver.

Given the need for contraceptive effectiveness together with preservation of regular menstruation, on the one hand, and the high potential of side-effects, on the other, the difficulty of controlling desired EE blood levels means a severe problem 3 0 comparable to a tightrope walking exercise. A considerable percentage of women may not be in a position of using oral contraceptives because their theshold of acceptance is exceeded by menstrual abnormalities or estrogen-related side-effects.

The risk of cardiovascular diseases, even with fatal outcome, clearly tends to 3 5 grow in response to hormonal contraceptives (V. Wynn; Oral contraceptives and coronary diseases; J. Reprod, Med., 36, Suppl, 3 [1991], 219-225). Some of the

jntl-2O.DOC s

risk factors depend on age (J.I. Mann; Oral contraceptives and myocardial infarction in young women; Pharmacol. Steroid. Contracept. Drugs, Eds.: S. Garrattini and H.W. Berendes, Raven Press, New York [1977], 289-296). Several health authorities, therefore, have warned against the use of hormonal 5 contraceptives by women beyond the age of 35 years. The risk of contracting a cardiovascular disease is even greater for smoking female users of hormonal contraceptives beyond 35 (F.A. Leidenberger; Klinische Endokrinologie fiir Frauenarzte; 382-383; J.I. Mann, loc.cit.). The risk of fatal cardiovascular diseases in users of oral contraceptives was found 10 to be five to six times higher than in control populations (F.A. Leidenberger; loc.cit,). These data provide evidence to the effect that there are sizeable sub groups of sexually mature women to whom conventional hormonal contraceptives can be applied only with an unjustifiably high risk or must not be applied at all.

15 Latest research suggests that the above problems should be attributed to the , § estrogen component of hormonal contraceptives rather than to the gestagen 1 : component (Skouby et al.; J. Obstet. Gynecol. [1990], 1535-1537). At a "consensus meeting", the conclusion was drawn that the real risk of fatal myocardial infarction did not depend on the length of use. These findings seemed 20 to confirm that fatal clotting was not attributable to chronic damage to arterial walls in the heart (arteriosclerosis) but to acute effects upon hemostatic functions in 1 the liver (R.A, Lobo; loc.cit.). Hence, reduction of estrogen effects on the liver appears to be a way to eliminate the above risks of hormonal contraception and the associated restrictions on applicability. 25 The risks described in the context of EE are explicitly ruled out for natural estrogens, i.e. estrogens of hepatic estrogenicity lower than that of EE (R.A. Lobo; loc.cit.). Individual adaptation of dosage is generally required for HRT, using natural 3 0 hormones on the basis of latest technology. Treatment, in this context, has proved to be accompanied by major uncertainties relating to the risk of overdosage or underdosage.

FR-2 133 484, GB-1 317 373, DD-114 806, DE-1 949 095, DD-201 143, DD-207 35 447, GB-1 398 026 and FR-2 429 797 as well as Schwarz et at, Pharmazie 30 (1975) 17-21, Stolzner et al., Pharmazie 30, (1975) 52-53 and Schwarz et al. Z.

JB46823,DOC 6

Chem, (1970) 229-300 describe estra-l,3,5(10)-trien derivatives which carry an sulfamate residue at the OH-group in the 3-position.

WO-94/01450 and FP-0 430 386 describe 14,17-bridged 16-hydroxy estratrienes. 5 No compounds carrying an sulfamate residue in the 3-position are disclosed.

Howarth et al. in J. Med. Chem. (1994) 37, 219-221 describe estron sulphamates and their therapeutical capabilities.

10 Kalvoda et al., Helvetica Chimica Acta (1967) 50, 281-288, Uberoi et al., Steroids (1985) 45, 325-340, Peters et al„ J. Med. Chem. (1989) 32, 1642-1652, Bhavnani et al., Steroids (1991), 201-210 and Chemical Abstracts, Vol. 91, page 97, No, 204845 t (1979) describe estra-1,3,5(10)-trien-derivatives which carry an ether substitution at the 3-OH-group. Together with these compounds pharmacological 15 effects are desribed. j

This invention, consequently, has been made for the purpose of providing estra-1, 3, 5(10)-trien derivatives which do not exhibit the above detrimental characteristics and side-effects. 20 This purpose is met, according to the invention, by providing estra- 1, 3, 5(10)-trien derivatives in conformity with the general Formula I i

25 O

Where R is an R^R^N group, in which Rl and R^, independent of each other, represent a hydrogen atom, a C1-C5 alkyl residue or, together with the N atom, a 3 0 pplymethylene-imino residue with 4 to 6 C atoms or a morpholine residue, with R^ being a hydrogen atom or an alkyl group with 1-5 C atoms,

JB46S23.DOC 'Ίΐΐ'ΐιίοΒΙΜ

P:\WPDOCS\GRS\628383.CLM -7/10/98

-7-

with R4 being a hydrogen atom, a hydroxy group, an esterified hydroxy group, a haloalkyl group with 1-5 C atoms or an alkoxy group with 1-5 C atoms R5 and R6 being a hydrogen atom each or, together, being a methylene group, 5 R7, Rs and R9, independent of each other, representing a hydrogen atom or a hydroxy group, and ring B containing one or two double bonds or R8 is an alkinyl residue with up to 5 carbon atoms with the proviso that R1 and R2 are

hydrogen atoms, or at least one of the residues R3, R4, R5, R6 or R7 is not hydrogen and R1 »··· and R3 have a different meaning from each other, or ’··* 10 R8 and R9 together may represent an oxygen atom with the proviso that at least one of the residues R3, R4, Rs, R6 or R7 is different from hydrogen, or «'* * ♦» R5 and R8 may represent a vinylene or ethylene group. « ·

The estra-l,3,5(10)-trien derivatives, according to this invention, which carry an R-S02-0 15 grouping at the C atom 3 and in which R plays the role described above may contain additional double bonds between C atoms 6 and 7, 7 and 8, 8 and 9, 9 and 11,8 and 14, 14 and 15 and/or 15 and 16. • ~ Ur

• 4 9 ♦ 9 ♦ 4 i^waai MW

i The estra-1, 3, 5(10)-trien derivatives, according to this invention, which carry an S R-SO2-O grouping at the C atom 3 and in which R plays the role described above may contain oxo-goups at C atoms 6, 7, 11, 15, 16 and/or 17, 5 The estra-1, 3, 5(10)-trient derivatives, according to this invention, which carry an ; R-SO2-O grouping at the C atom 3 and in which R plays the role described above ί may carry additional hydroxy groups at C atoms 6, 7, 9, 11, 14, 16 and/or 17, and f these hydroxy groups may be esterified or etherified. j 10 Such esterification will be through common derivatives of physiologically

ί ^-compatible inorganic or organic acids. These may be phosphoric acid, sulphuric = acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, ; citric acid, salicylic acid, valeric acid, adipic acid and benzoic acid. More applicable acids may be seen, for example, from "Fortschritte der * I 15 Arzneimittelforschung", Vol. 10, pp, 224-225, Birkhauser Verlag, Basel and 5 Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol, 66, pp. 1-5 (1977). Etherification is achieved by means of common derivatives of aliphatic alcohols ■ . i With up to six carbon atoms.

; 20 The estra-1, 3, 5(10)-trien derivatives, according to this invention, which carry an ! R-SO2-O grouping at the C atom 3 and in which R plays the role described above 5 may be substituted at C atoms 6, 7, 11, 14, 15, 16 and/or 17 by alkyl residues, i alkylidene residues, alkenyl residues and alkinyl residues with up to five carbon j atoms, and these residues, in turn, may be substituted in the same manner by alkyl, ; 25 alkylidene, alkenyl or alkinyl residues or halogen. ί ί The estra-1, 3, 5(10)-trien derivatives, according to this invention, which carry an I R-SO2-O grouping at the C atom 3 and in which R plays the role described above P may be substituted by alkylene residues or alkenylene residues with up to three ! 30 carbon atoms between C atoms 14 and 15 or 14 and 17, j 3-sulfamate-estra-l,3,5(10)-trien derivatives, according to this invention which j carry an R-SO2-O grouping at the C atom 3 and in which R plays the role I described above, for example, may be as follows: 35

JB46823.DOC X

17B-hydroxy-14a,15a-methylene-estra-l,3,5(10)-trien-3-yl N,N- dimethylsulfamate, 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10)-trien-3-yl N,N diethylsulfamate, 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10)-trien-3-yl pyrrolidinosulphonate, 5 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10)-trien-3-yl morpholinosulphonate, 17B-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-trien-3-yl N- methylsulfamate, ί 17 B-hydroxy-14a, 15a-methy lene-estra-1,3,5 (10)-tr ien-3-y 1 sulfamate, 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10), 7-tetraene-3-yl N,N- 10 dimethylsulfamate, 17B-hydroxy-14a, 15a-methylene-estra-l,3,5(lQ), 6,8-pentaene-3-yl N,N- dieilylsulfamate, 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10), 8-tetraene-3-yl N,N- dimethylsulfamate, 15 llB-chloromethoxy-17B-hydroxy-estra-l,3,5(10)-trien-3-yl N,N-dimethylsulfamate, i 17B-hydroxy-14a,15a-vinylene-estra-l,3,5(10)-trien-3-yl N,N-diethylsulfamate, 1 14a,17a-ethylene-17B-hydroxy-estra-l,3,5(10)-trien-3-yl pyrrolidinosulphonate, 16a,17B-dihydroxy-14a,17a-ethylene-estra-l,3,5(10)-trien-3-yl N,N- diethylsulfamate, 20 17B-hydroxy-7a-methyl-estra-l,3,5(10)-trien-3,llB-diyl 3-N,N-dimethylsulfamate- 11-nitrate, 17B-hydroxy-llB-methoxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl N,N- dimethylsulfamate, 17B-hydroxy-19-nor-17a-pregrt-l,3,5(10)-trien-20-in-3-yl-sulfamate, 25 17B-hydroxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl N-methylsulfamate, 17B-hydroxy-estra-l,3,5(10),7-tetraene-3-yl N,N-diethylsulfamate, 17B-hydroxy-estra-l,3,5(10), 6, 8-pentaene-3-yl N,N- dimethylsulfamate, 17a-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-8-tetraene-3-yl sulfamate, 3 0 llB-methoxy-17-oxo-estra-l,3,5(10)-trien-3-yl sulfamate, 17B-hydroxy-estra-l,3,5(10)-trien-3-yl N-methylsulfamate, 17B-hydroxy-estra-l,3,5(10)-trien-3-yl sulfamate^ 17B-hydroxy-estra-l,3,5(10), 6,8-pentaene-3-yl sulfamate, I7a-hydroxy-estra-l, 3,5(10)-trien-3-y 1 sulfamate, 35 estra-l,3,5(10)-trien-3, 17B-diyi 3-sulfamate, 17-pentanoate, estra-l,3,5(10)-trien-3, 17B-diyl 3,17-sulfamate, t

JK46823.DOC 16α, 17 β-dihydroxy-estra-l, 3,5(10)-trien-3-y 1 Ν, N-diethy lsulfamate, l6a,17B-dihydroxy-estra-l,3,5(10)-trien-3-yl Ν,Ν-dimethylsulfamate, 16α, 17B-dihydroxy-estra-l,3,5(10)-trien-3-yl morpholinosulphonate, 16α. 17B-dihydroxy-estra-l,3,5(10)-trien-3-yl N-methylsulfamate, 16α, 17B-dihydroxy-estra-l,3,5(10)-trien-3-yl sulfamate, 1 ΙΒ-chloromethoxy- 17B-hydroxy-estra-1,3,5(10)-trien-3-yl sulfamate, 17B-hydroxy-14a, 17a-vinylene-estra-l ,3,5(10)-trien-3-yl sulfamate, 14a, 17a-ethylene-17B-hydroxy-estra-l,3,5(10)-trien-3-yl N- methylsulfamate 16a, 17B-dihydroxy-14a, 17a-ethylene-estra-l,3,5(10)-trien-3-yl sulfamate, 17B-hydroxy-7a-methyl-estra-l,3,5(10)-trien-3, 1 ΙΒ-diyl 3-sulfamate-ll-nitrate, 17B-hydroxy-llB-methoxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl sulfamate.

Particular preference is given also to estra-l,3,5(10)-trien derivatives of the general Formula I, with R^ and R^ standing for hydroxy groups.

Particular preference is given to estra-l,3,5(10)-trien derivatives of the general Formula I, with R^ and R^ together representing an ethylene or methylene group.

The following estra-1,3,5(10) derivatives, according to this invention, are particularly preferred: 17B-hydroxy-l4a,15a-methylene-estra-l,3,5(10)-trien-3-yl N,N-diethylsulfamate, 16a,17B-dihydroxy-estra-l,3,5(10)-trien-3-yl Ν,Ν-dimethylsulfamate, 17B-hydroxy-14a,15a-methylene-estra-l,3,5(10)-trien-3-yl Ν,Ν-dimethylsulfamate and 16a,17B-dihydroxy-estra-l,3,5(10)-trien-3-yl N,N-diethylsulfamate.

This invention is, furthermore, related to a process for the production of estra- l,3,5(10)-trien derivatives according to the invention and which is characterised by conversion of an estra-1,3,5(10)-trien derivative of the general formula (I) with the meaning indicated above, with the condition that an OH-group is present at the 3- position, in a generally known way with an appropriately substituted amidosulphonyl chloride of the general formula R-SO2-C1, in which R has the meaning indicated above by esterification of the 3-OH group of the estra-1,3,5(10)- trien derivative. 11

Conversion is generally carried out in a two-phase system in the presence of a quarternary ammonium salt which acts as phase transfer catalyst. Conversion temperatures are between room temperature and 100 °C. Common two-phase systems are used as solvents, such as chloroform-water, dichloromethane-water, 5 toluene-water etc.

Another subject of this invention is relating to pharmaceutical compositions which contain estra-l,3,5(10)-trien derivatives of the general Formula I as active substance, with these compositions possibly containing adjuvants and carriers as 10 may be required.

The pharmaceutical compositions, according to this invention, may additionally contain one or more of the aforementioned gestagens, such as levonorgestrel, desogestrel, gestodene, drospirorenone, norethisterone, cyproterone acetate, ; 15 chlormadinone acetate or dienogest. j

The pharmaceutical compositions, according to this invention, may as well be provided in the form of multi-stage or combination products.

20 The combination product for contraception, for example, consists of a first stage which may be a combination of several components, namely a biogenic estrogen, a synthetic estrogen, a gestagen and/or an estra-l,3,5(10)-trien derivative, according to this invention, and one or several additional stages which may consist of a ii pharmaceutically safe placebo or a biogenic or synthetic gestagen or a biogenic or 25 synthetic estrogen or an estra-l,3,5(10)-trien derivative, according to this invention, or a combination of several components, namely a biogenic estrogen, a synthetic estrogen, a gestagen, an estra-l,3,5(10)-trien derivative, according to this invention, or a combination of synthetic estrogens or an estra-l,3,5(10)-trien derivative, according to this invention, and a gestagen.

30 The biogenic estrogen, for example, possesses a component of the group of estradiol, estrone, estrane, estriol and other biogenic estrogens or at least one compound which rapidly makes one of the aforementioned estrogen components split off immediately after taking.

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The synthetic estrogen, according to this invention, possesses at least one component of the group of ethinyl estradiol, mestranol and other synthetic estrogens or at least one compound which rapidly makes one of the aforementioned estrogen components split off immediately after taking. 5 The gestagen, according to this invention, possesses at least one component of the group of levonorgestrel, desogestrel, progesterone, norethisterone acetate, chlormadinone acetate, gestodene, cyproterone acetate and other natural and/or synthetic gestagens or at least one compound which rapidly makes one of the 10 aforementioned gestagen components split off immediately after taking.

Another subject of this invention is relating to ways of providing pharmaceutical compositions which may be used for hormonal contraception, climacteric hormone substitution therapy and treatment for gynecological and andrological diseases, 15 such as mammary carcinoma and prostate carcinoma.

Another subject of this invention is relating to pharmaceutical compositions in the form of tablets, tablets for controlled release, coated tablets, pills, capsules, film tablets and film tablets for controlled release. 20 The pharmaceuticals are manufactured in generally known and established processes in conformity with desired modes of application and in appropriate dosage, using common solid or liquid carriers or diluents and common pharmaceutical adjuvants. Preference is given to formulations for oral application. 25 Such formulations may be tablets, film tablets, coated tablets, capsules, pills, powder or depot preparations.

Appropriate tablets, for example, may be obtained be intermixing of the active substance with known adjuvants, such as inert diluents like dextrose, sugar, 30 sorbitol, mannitol, polyvinylpyrrolidone, blasting agents like corn starch or alginic acid, bonding agents like starch or gelatin, lubricants like magnesium stearate or talc and/or agents by which to achieve a depot effect, such as car boxy lpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may as well be made up of several layers.

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Coated tablets can be made, accordingly, by coating cores made in analogy to tablets, using common coating agents, such as polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coat may consist of several layers, and the adjuvants mentioned in the context of tablets may be used.

5 Capsules with active substances in them, for example, may be manufactured by intermixing the active substance with an inert carrier, such as lactose or sorbitol, and encapsulating it in gelatin capsules.

10 However, in view of the severe drawbacks of conventional estrogen derivatives used for medical purposes, an urgent demand has come up for compounds without those drawbacks.

The compounds, according to this invention, were surprisingly found to be 15 superior to EE with regard to estrogenic efficacy, accompanied by maximum genital estrogen effects in the uterus and hepatic estrogenicity not stronger than that of estradiol, the natural estrogen. This constellation, as provided by the compounds according to this invention, will bring about substantial improvement in therapeutic properties, as compared to natural and synthetic estrogens.

20 Contraceptives containing the estra-l,3,5(10)-trien derivatives, according to this invention, are likely to enable total redefinition of restrictions on the use of hormonal contraception, since they are less effective or not effective at all on the hemostatic system.

25 Contraceptives containing the estra-l,3,5(10)-trien derivatives, according to this invention, on account of their dramatically reduced estrogen effects, may be applied in doses high enough for cycle control better than that achievable by means of conventional EE,contraceptives.

30 The use of EE in hormone substitution therapy at present is strictly rejected because of the side-effects involved. The risks implied in non-natural (biogenic) estrogens have ceased to exist with the advent of the estra-l,3,5(10)-trien derivatives according to this invention. Different from the natural estrogens which 35 are predominant in hormone substitution therapy today, an advantage is provided by significantly superior controllability, as oral bioavailability is clearly defined

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and is no longer burdened with the major individual variability of biogenic estrogens.

Evidence was provided to hepatic estrogenicity in ovariectomised rats: The adult 5 female experimental animals (breeder: HSD/WIN-.WU) were ovariectomised (Day 14). Treatment with one daily oral application of test substances was started two weeks after ovariectomy.

All animals were assigned to groups by randomised approach. The experiment was 10 a block design. All animals were weighed twice, prior to and at the end of the experiment.

Start and end of treatment were defined as Day 1 (=dl) or Day 7 (=d7). The animals were sacrificed on Day 8. Several organs (uterus, adrenal glands, 15 liver) were removed and weighed and were passed on in deep-frozen condition (-196 °C) for further investigation.

Blood was taken from the retrobulbar plexus prior to treatment (dO) as well as on (d4) and (d8), with the animals etherized. The serum thus obtained was used to 20 determine IGFμ angiotensin I, cholesterol and HDL cholesterol.

Methods of determination: IGFi - RIA bioMerieux Co.; Angiotensin - modified RIA for renin activity - Sorin Co,; 25 Cholesterol/HDL - enzymatic tests, photometry, reagents supplied from Dr. Bruno Lange GmbH.

The results obtained from the assays are given in Table 1.

30 Orally applied estra-l,3,5(10)-trien derivatives, according to this invention, for uterine efficacy, are equivalent or superior to ethinyl estradiol (EE). Also, effects on parameters of hepatic estrogenicity are absent or are significantly lower than those of comparable doses of ethinyl estradiol (EE).

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The blood levels of estra-1,3,5(10)-trien derivatives, according to this invention, are much higher than those of the comparable substances, estradiol (E2), ethinyl estradiol (EE) and estriol (E3).

Table 1: Oral estrogen effects Impact on sexual function and hepatic parameters

Substance Dosage/d Uterus Total HDL Angioten Blood pg/animal weight cholest. choiest. sin I level p.o. (mg) (mg/dl (mg/dl (ng/mg (pg/ml plasma) plasma) plasma) (serum)

Estradiol 10 182 84.3 54.1 344.6 19.2 (E2) Ethinyl 10 353 41.9 24.3 639.6 28.9 estradiol (EE) Estriol 10 302 70.9 42.7 495.9 8.815 (E3) J 983 10 349 75.5 48.3 413.2 33.2 J 989 10 183 95.8 52.5 412.9 42.875 J 982 10 193 83.3 50.8 421.5 46.4 J 984 10 246 89.6 47.8 405.3 75.8

The invention is explained by the following examples.

Example 1: General manufacturing specifications for N,N-disubstituted 3-sulfamates of estra-1,3,5(10)-trien derivatives.

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The estra-1,3,5(10)-trient derivative earmarked for esterification, amidosulfonylchloride, alkali hydroxide or alkaline-earth hydroxide as well as quarternary ammonium salt as phase transfer catalyst are added under vigorous agitation to a mixture of an appropriate organic solvent and water. Agitation is 5 continued until full completion of esterification is signalled by analytical evidence (thin-layer chromatography), with working temperatures between 50 °C and 100 °C being permissible, as shortening of reaction time may be desired. The two phases then are separated from each other. The aqueous phase is re-extracted, and the unified organic extracts are consecutively washed in diluted hydrochloric acid, 10 saturated sodium hydrogencarbonate solution and water. The extract then is dried over anhydrous sodium sulphate and is evaporated under reduced pressure for dryness. The residue is recrystallised from an appropriate solvent.

Example 2 (= J 983): 15 Preparation of 17B-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-trien-3-yl N ,N-diethylsulfamate

2 g of 14a, 15a-methylene-estra-l,3,5(10)-trien-3, 17B-diol are suspended in 30 ml of toluene, 4 ml of water, 0.32 g of benzyltriethylammonium chloride, 20 2.94 ml of Ν,Ν-diethylamidosulphonyl chloride and 2.1 ml of 40% sodium hydroxide solution and are agitated and heated for two hours to an intrinsic temperature of 80 °C.

Cooling to room temperature is followed by processing as described in Example 1. 25 The crude product thus obtained is chromatographed to silica gel (particle size: 0.063 to 0.2 mm). The title compound is obtained, following elution in chloroform / ethyl acetate 9:1 and recrystallisation from methanol. Melting point: 68-73 °C; iH-NMR: 0.26 (m, CH2), 0.99 (s, 18-H), 3.38 (q, 7.2 Hz, CH3-CH2-N), 3.55 (dd, Σ16 Hz), 7.31 (d, 8.8 Hz, 1-H) ppm 30 (CDCI3).

Example 3 (= J 989): Preparation of 16a, 17B-dihydroxy-estra-l,3,5(10)-trien-3-yl N,N- dimethylsulfamate 35 if

120 ml of water, 1.58 g of benzyltriethylammonium chloride, 7.44 ml of N,N- dimethylamidosulphonyl chloride and 4 ml of 40% sodium hydroxide solution are agitated and added at a temperature of 80 °C to a solution of 2 g of estriol in 800 ml of toluene. Heating is continued to 80 °C. The pH value 10 of the reactive solution is maintained in the course of that process by addition of 40% sodium hydroxide solution. Completion of reaction of all initial compounds is followed by cooling to room temperature and by work-up as described in Example 1. The residue thus obtained is recrystallised from acetone/n-hexane to give the title compound. 10 Melting point: 180-181 °C; iH-NMR: 0.67 (s, 18-H), 2.89 (s, CH3-N), 3.32 (m, 17-H), 3.84 (m, 16-H), 4.64, 4.71 (d each, 4.9 Hz, OH each), 7.34 (d, 8.8 Hz, 1-H) ppm (D6-DMSO).

15 Example 4 (= J 982): Preparation of 17B-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-trien-3-yl N,N- dimethylsulfamate

Reaction is performed, as described in Example 1, in a mixture of 30 ml of 20 dichloromethane and 6.6 ml of water, between 1 g of 14a, 15a-methylene-estra- l,3,5(10)-trien, 3,17p-diol, 2.4 g of sodium hydroxide, 0.24 g of triethylbenzylammonium chloride and 3.6 ml of N,N-dimethylamidosulphonyl chloride. The title compound is obtained, following work-up, chromatographic purification and recrystallisation of the reaction product from acetone. 25 Melting point: 193-196 °C; iH-NMR: 0.255 (m, CH2), 0.99 (s, 18-H), 2.98 (s, CH3-N), 3.55 (dd, Σ16 Hz, 17-H), 7.32 (d, 8.6 Hz, 1-H) ppm (CDC13).

Example 5 (= J 984): Preparation of 16a, 17B-dihydroxy-eslra-l ,3,5(10)-trien-3-yl N,N-diethylsulfamate 30 Reaction is performed, as described in Example 1, in a mixture of 800 ml of toluene and 128 mi of water, between 2 g of estriol, 5.2 g of sodium hydroxide, 1.72 g of triethylbenzylammonium chloride and 9.75 ml of N,N~ diethylamidosulphonyl chloride. The title compound is obtained, following work 35 up, chromatographic purification and recrystallisation from acetone. Melting point: 121-124 °C; iH-NMR: 0.67 (s, 18-H), 1.11 (t, 7.1 Hz,

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CH3-CH2-N), 3.33 (q, 7.1 Hz, CH3-CH2-N), 3.83 (m, 16-H), 4.65, 4.72 (all d, 4 Hz, 3.5 Hz, 16-OH, 17-OH), 7.33 (d, 8.4 Hz, 1-H) ppm (D6-DMS0).

5 Example 6: General manufacturing specifications for N-monosubstituted and N-unsubstituted 3- sulfamates of estra-l,3,5(10)-trien derivatives. A base (triethylamine or 2,6-di-tert. butyl-4-methylpyridine) and monosubstituted or N-unsubstituted amidosulphonyl chloride are agitated and added one by one to a solution of estra-l,3,5(10)-trien 10 derivative in an appropriate solvent (dichloromethane, pyridine or dimethyl formamide). The reaction temperature should not exceed + 20 °C. Complete conversion of the parent material is recordable by means of thin-layer chromatography, after one to three hours. For processing, the reactive solution is washed in diluted aqueous hydrochloric acid, saturated aqueous sodium 15 hydrogencarbonate solution and water and is dried above anhydrous sodium sulphate and is evaporated to dryness in a rotary vacuum evaporator. The residue is purified over silica gel and/or by recrystallisation by means of column chromatography.

20 Example 7 (= J 1044): Preparation of 14a, 15a-methylene estradiol 3-(N-methyl)sulfamate

Reaction is performed, as described in Example 6, in a solution of pyridine (12.7 ml) and 2,6-di-tert. butyl-4-methylpyridine (5.1 g), between methylene 25 estrone (1.17 g) and (N-methyl)amidosulphonyl chloride (1 ml). The crude product, following work-up, is purified by column chromatography (chloroform / ethyl acetate 9/1) and is recrystallised from acetone/n-hexane to give 14a, 15a- methylene estrone-(N-methyl)sulfamate. Argon shielding, exclusion of moisture and agitation are the conditions under 30 which a borane solution (25 ml), prepared from sodium boron hydride (1 g) and boron trifluoride-diethylether complex (3.5 ml) fei tetrahydroiurane (44 ml), are added in portions, at 0 °C to + 5 °C, to a solution of 14a, 15a-methylene estrone - (N-methyl)sulfamate (809.5 mg) in tetrahydroiurane (15 ml). The reactive solution is allowed to stand for 20 hours at 0 °C to +5 °C, before it is dripped 35 into iced water. The title

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compound is obtained, following work-up, column chromatography (chloroform / ethyl acetate 9/1) and recrystallisation from acetone.

Melting point: 192-193.5 °C; iH-NMR: 0.20 (m, ΟΗ2), 0.2555 (m, CH2), 0.89 5 (s, H-18), 2.71 (d, 3.8 Hz, CH3-NH), 3.43 (m, H-17), 4.43 (d, 5.3 Hz, OH), 7.39 (d, 8.5 Hz, H-l), 8.12 (m, NH) ppm (Dg-DMSO).

Example 8 (= J 1011): Preparation of estrone - (N-methyl)sulfamate 10 Reaction is performed, as described in Example 6, of estrone (3 g) in a solution of dichloromethane (1200 ml) and triethylamine (28.2 ml) with N-methylamido- sulphonyl chloride (3 ml). The crude product, following work-up, is recrystallised from acetone/n-hexane to give the title compound. 15 Melting point: 192.5-196.5 °C; iH-NMR: 0.91 (s, H-18), 2,95 (d, 5.1 Hz, CH3-NH), 4.58 (m, NH), 7.30 (d, 8.2 Hz, H-l) ppm (CDC13).

Example 9 (= J 1012): ; Preparation of estradiol - (N-methyl)sulfamate 20 ; Estrone - (N-methyl)sulfamate (1 g) is reduced with sodium boron hydride (624.2 ί mg) in a mixture of tetrahydrofurane (20 ml) and methanol (20 ml). The crude \ product, following work-up, is recrystallised from acetone/n-hexane to give the

I title compound, j 25 Melting point: 194 - 198.5 °C; iH-NMR: 0.78 (s, H-18), 2.94 (d, 5.2 Hz, ϊ CH3-NH), 4.53 (m, NH), 3.73 (dd, Σ16.9 Hz, H-17), 7,,30 (d, 8.4 Hz, H-l) ppm (CDC13).

Example 10 (= J 1036): «•aS 3 0 Preparation of 17a-ethinyl estradiol-3-(N-methyl)-sulfamate. Reaction is induced, as described in Example 6, of 17a-ethinyl estradiol- 17-trimethylsilylether (1 g) in a solution of dichloromethane (25 ml) and 2,6-di- tert. butyl-4-methylpyridine (3.3 g) with (N-methyl)amidosulphonyl chloride (0.72 ml). The reactive solution is processed by agitation for five hours in aqueous 1:1 35 diluted hydrochloric acid unto complete cleavage of the silylether, whereafter the

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crude product is purified by column chromatography (toluene/chloroform/methanol 80/15/5) and is recrystallised from acetone/n-hexane to give the title compound.

Melting point: 156-162.5 °C; iH-NMR: 0.88 (s, H-18), 2.61 (s, =CH), 2.94 (d, 5 5.2 Hz, CH3-NH), 4.53 (m, NH), 7.31 (d, 8.8 Hz, H-l) ppm (CDCI3).

Example 11 (= J 994): Preparation of estrone-sulfamate. Estrone (1 g) is dissolved in dimethylformamide (20 ml). Amidosulphonyl chloride 10 (2.14 g) is then added to that solution. Agitation for six hours is followed by precipitation in water, and the product is recrystallised from ethyl acetate to obtain the title compound. Melting point: 199 - 202 °C; iH-NMR: 0.83 (s, H-18), 7.35 (d, 8.7 Hz, H-l), 7.9 (s, NH2) ppm (Dg-DMSO). 15 Example 12 (= J 995): Preparation of estradiol-3-sulfamate Estrone-sulfamate (1.4 g) is reduced with sodium boron hydride (960 mg) in a solution of tetrahydrofurane (28 ml) and methanol (28 ml). Work-up is followed by 20 recrystallisation of the crude product from acetone to give the title compound. Melting point: 211 - 213 °C; iH-NMR: 0.67 (s, H-18), 3.53 (t, d 7.9 Hz, 4.7 Hz, H-17), 4.55 (d, 4.8 Hz, OH), 7.34 (d, 8.6 Hz, H-l), 7.90 (s, NH2) ppm (Dg-DMSO).

25 Example 13 (= J 1018) Preparation of 14a, 15a-methylene estradiol-3-sulfamate Reaction is performed, as described in Example 6, of 14a, 15a-methylene- estradiol-17-tert. butyldimethylsilylether (100 mg) in a solution of dichloromethane A (3 ml) and 2.6-di-tj?rt. butyl-4-methylpyridine (180 mg) with amidosulphonyl 30 chloride (145 mg). The crude product, following work-up, is purified by column chromatography (toluene/'acetone 4/1) and is recrystallised from acetone/n-hexane, i I so that 14a, 15a-methyier>e-17B-tert. butyl-dimethylsilyloxy-estra-l,3,5(10)-trien- 3-yl-sulfamate is obtained. i 14a, 15a-methylene-17B-ter1. butyl-dimethylsilyloxy-estra-l,3,5(10)-trien-3-yl- 35 sulfamate (2.2 g) is dissolve^) in tetrahydrofurane (100 ml). A mixture of acetic j ; acid/water/tetrahydrofurane ^/1./1 (220 ml) is added to that solution. The reactive

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solution is allowed to stand for seven days at room temperature before work-up, purification of the product by column chromatography (cyclohexane/ethyl acetate 3/2) and recrystallisation from acetone/n-hexane.

5 Melting point: 210 - 214 °C; iH-NMR: 0.20 (m, CH2), 0.26 (m, CH2), 0.89 (s, H-18), 3.4 (m, H-17), 4.41 (d, 5.2 Hz, OH) 7.39 (d, 8.8 Hz, H-l), 7.90 (s, NH2) ppm (Dg-DMSO).

Example 14 (— J 1028): 10 Preparation of 17a-ethinylestradiol-3-sulfemate Reaction is performed, as described in Example 6, of 17a-ethinylestradiol-17- trimethylsilylether (1.5 g) in a solution of dichloromethane (40 ml) and triethylamine (16 ml) with amidosulphonyl chloride (8 g). The crude product, following breakdown of the silylether group and work-up, is purified by column 15 chromatography (chloroform/ethyl acetate 7/3) and is recrystallised from acetone/n-hexane to give the title compound. Melting point: 209 - 211 °C; Ul-NMR: 0.76 (s, H-18), 3.35 (s, =CH), 5.35 (s, OH), 7.35 (d, 8.7 Hz, H-l), 7.89 (s, NH2) ppm (Dg-DMSO).

20 Example 15 (= J 1034); Preparation of estriol-3-sulfamate Reaction is performed, as described in Example 6, of estriol-16,17-bis-tert. butyldimethylsilylether (2 g) in a solution of dichloromethane (13 ml) and triethylamine (15.5 ml) with amidosulphonyl chloride (7.9 g). The crude product, following 25 work-up, is subjected to silylether cleavage, according to Example 13, whereafter the isolated substance is purified by column chromatography (chloroform/methanol/acetic acid 90/13/1) and is recrystallised from acetone/n- hexane to give the title compound. Melting point: 208 - 213 °C; hl-NMR: 0.67 (s, H-18), 3.30 (m, H-17), 3.84 (m, 30 H-16), 4.7 (m, OH), 7.32 (d, 8.4 Hz, H-l) ppm (Dg-DMSO).

Example 16 (= J 1040): Preparation of estriol-3-(N-methyl)sulfamate Reaction is performed, as described in Example 6, of estriol-16,17-bis-tert. butyl- 35 dimethylsilylether (1.7 g) in a solution of dichloromethane (51 ml) and 2,6-di-tert. butyl-4-methylpyridine (4.05 g) with (N-methyl)-amidosulphonyl chloride (0.87

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■ ml). The crude product, following work-up, is purified by column chromatography K (toluene/chloroform/methanol 80/15/5) and is subsequently subjected to silylether I cleavage, according to Example 13. The title compound was obtained from column I chromatography of the isolated substance (chloroform/ methanol/acetic acid 1 5 90/13/1) and recrystallisation from acetone/n-hexane. I Melting point: 199 - 202 °C; iH-NMR: 0.67 (s, H-18), 2.70 (s, NH-CH3), 3.30 I (m, H-17), 3,84 (m, H-16), 4.7 (m, OH), 7.33 (d, 8.7 Hz, H-l) ppm I (Dg-DMSO). f 10 Example 17 (= J 1050) Preparation of 17a-estradiol-3-sulfamate Reaction is performed, as described in Example 6, of 17a-estradiol-tert, butyldimethylsilylether (1.94 g) in a solution of dichloromethane (70 ml) and 2.6-di-tert. j 15 butyl-4-methylpyridine (3.6 g) with amidosulphonyl chloride (2.75 g). The crude I I product, following work-up, is purified by column chromatography I (toluene/acetone 4/1) and is recrystallised from acetone/n-hexane. The 17a-tert. i butyl-dimethylsilyloxy-estra-l,3,5(10)-trien~3-yl-sulfamate thus obtained is subjected to silylether cleavage according to Example 13. The title compound was 2 0 obtained from column chromatography of the isolated substance (toluene/ethyl Ii acetate/chloroform 6/3/1) and recrystallisation from acetone/n-hexane. ■ Melting point: 192 - 196 °C; iH-NMR: 0.62 (s, H-18), 3.59 (d, 5.5 Hz, H : 17), 7,36 (d, 8.8 Hz, H-l), 7.88 (s, NH2) ppm (Dg-DMSO).

25... Example 18 (= J 1010): Preparation of 14a, 15a-methylene-estrone-sulfamate Reaction is performed, as described in Example 6, of 14a, 15a-methylene- estrone (765 mg) in a solution ol’dichloromethane (50 ml) and triethylamine (7.7 ml) with amidosulphonyl chloride (11.7 g). The crude protfeet, following work-up, 30 is purified by column chromatography (chloroform/ethyl acetate 9/1) and is recrystallised from acetone/n-hexane, so that the title compound is obtained. Melting point: 191 -195 °C; iH-NMR: -0.40 (m, CH2), 0.80 (m, CH2), 1.12 (s, H-18), 7.40 (d, 8 Hz, H-l), 7.93 (s, NH2) ppm (D6-DMSO).

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23 l· Example 19 (= J 1021) Preparation of 11 β-methoxyestrone-sulfamate Sodium hydride is added in portions (0.4 g, 80 %) to a solution of 11 β- methoxyestrone (2 g) in dimethylformamide (37 ml). On completion of evolution of hydrogen, amidosulphonyl chloride (6.2 g) is added, and the reactive mixture is agitated overnight at room temperature. It is then precipitated in water, and the I product is purified by column chromatography (chloroform/acetone 7/3). The title compound is obtained from recrystallisation from acetone/n-hexaue. Melting point: 191 -195 °C; ’HI-NMR: 0.99 (s, H-18), 3.20 (s, CH3O), 4.24 (m,

10 H-ll), 7.26 (d, 8.7 Hz, H-l), 7.93 (s, NH2) ppm (Dg-DMSO).

\ Example 20 (= J 1038) ! Preparation of estra-1,3,5(10)-trien-3, 17 B-diyl-3-sulfamate, j 17-pentanoate s 15 Reaction is performed, as described in Example 6, of estradiol-17-pentanoate (2 g), i dissolved in dimethylformamide (37 ml), with sodium hydride (336 mg, 80 %) and amidosulphonyl chloride (6.47 g). The title compound is obtained, following work ; up, column chromatography (chloroform/ethyl acetate 9/1) and recrystallisation ; from acetone/n-hexane. j 20 Melting point: 107 - 108 °C; iH-NMR: 0.78 (s, H-18), 0.87 (t, 7.3 Hz, CH3- i (CH2)3-CO), 2.29 (t, 7.2 Hz, C3H7-CH2-CO), 4.63 (dd, Σ15.5 Hz, H-17), 7.34 j (d, 8.4 Hz, H-l), 7.89 (s, NH2) ppm (Dg-DMSO).

Example 21 (= J 1051) ; 25 Preparation of 17a-hydroxy-14a, 15a-methylene-estra-l,3,5(10), 8-tetraene-3-yl- : suifamate ? Reaction is performed, as described in Example 6, of 14a, 15a-methylene-17a- i trimethylsilyloxy-estra-l,3,5(10)-trien-3-ol (100 mg) in a solution of ? dichloromethane (3 ml) and 2.6-di-tert. butyl-4-methylpyridine (180 mg) with 3 0 amidosulphonyl chloride (145 mg). The crude product, following cleavage of the silylether group and work-up, is purified by column chromatography (cyclohexane/ethyl acetate 3/2) and is recrystallised from acetone/n-hexane. j White foam; Fp 189-194°C, hl-NMR: 0.46 (m, CH2), 0.92 (s, H-18), 1.28 (m, I 35 CH2), 3.90 (d, Σ 6.0 Hz, H-17) ppm (CDCI3), 7.35 (d, 8.8 Hz, H-l), 7.88 ) (s, NH) ppm (Dg-DMSO).

JB46I23.DOC Example 22 (= J 992) Preparation of estrone - (N,N-dimethyl)sulfamate Estrone (1 g) together with dichloromethane (30 ml), water (3 ml), benzyltriethylammonium chloride (0.24 g), Ν,Ν-dimethylamidosulphonyl chloride (3.6 ml) and sodium hydroxide solution (40 %, 6 ml) is agitated at room temperature for two hours. This is followed by work-up, according to Example 1, and the product is recrystallised from ethyl acetate. Melting point: 192 - 194 °C; hl-NMR: 0.91 (s, H-18), 2.98 (s, N-CH3), 7.28 (d, 9.9 Hz, H-l) ppm (CDCI3).

Example 23 (= J 991) Preparation of estradiol-3-(N,N-dimethyl)sulfamate Reaction of estradiol (1 g) is performed, as described in Example 22. Work-up is followed by recrystallisation of the product from chloroform/methanol. Melting point: 204 - 208 °C; hl-NMR: 0.78 (s, H-18), 2.98 (s, N-CH3), 3.72 (dd, Σ16 Hz), 7.28 (d, 9.9 Hz, H-l) ppm (CDCI3).

Example 24 ( = J 1052) Preparation of 14a, 15a-methylene-estradiol-3-pyrrolidinosulphonate Reaction is performed, as described in Example 22, between 14a, 15a-methylene- estradiol (1.05 g) and dichloromethane (30 ml), water (3 ml), benzyltriethylammonium chloride (0.24 g), pyrrolidinosulphonyl chloride (4.5 ml) and sodium

hydroxide solution (40 %, 8 ml). The title compound is obtained, following work up, according to Example 1. Amorphous solid substance; ^H-NMR: 0.20 (m, CH2), 0.26 (m, CH2), 0.89 (s, H-18), 3.33 (m, -CH2-N-CH2-), 3.4 (m, H-17), 4.41 (d, 5.2 Hz, OH), 7.36 (d, 8.7 Hz, H-l) ppm (D6-DMSO).

Example 25 (= J 1053) Preparation of estriol-3-morphoIinosulphonate R^’ctim is performed, according to Example 3, of estriol (2 g) in a mixture of tt·'?·.300 ml) and water (120 ml) with morpholinosulphonyl chloride (9.2 ml), bt.\; urieihy laminonium chloride (1.58 g) and sodium hydroxide solution (40 %, 6.5 ml). The title compound is obtained, following work-up, according to Example iWerosBBBeiWSBHSSraesasssffisaasa

Melting point: 188 - 192 °C; iH-NMR: 0.67 (s, H-18), 3.28 - 3.36 (m, H-17, -CH2-N-CI12-), 3.65 - 3.68 (m, -CH2-O-CH2-), 4.7 (m, OH), 7.37 (d, 8.8 Hz, H-l) ppm (Dg-DMSO).

Example 26 (= J 1054) Preparation of equilenine-sulphamate Equilenine (1 g) is esterified with amidosulphonyl chloride in dimethylformamide solution, as described in Example 11, and is worked-up. Slightly yellowish resin; iH-NMR: 0.69 (s, H-18), 7.23, 756 (d, 8.4 Hz, d, 8.5 Hz, H-6 and H-7), 7.82 (d, 9.8 Hz, H-l), 7.9 (s, NH2) ppm (Dg-DMSO).

JE46823.DOC s

i P:\WPDOCS\GRS\M8383.CLM - 7/10/98

-26-

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. Estra-l,3,5(10)-trien derivatives of the general Formula I

II O 10 wherein (, • β · « R is a R‘R2N group,

9 9-9 9 tt 9 9 with R1 and R2, independently of each other, represent a hydrogen atom, a Cj-Cj-alkyl 4 • · 9 9 ί • · « • 9 · 9· residue or, together with the N atom, a polymethylenimino residue with 4 to 6 C atoms or a morpholine residue,

• · · 15 ·»·0 · O • · • 0 R3 is a hydrogen atom or an alkyl group with 1-5 C atoms, « · · 0

R4 is a hydrogen atom, a hydroxy group, an esterified hydroxy group, a haloalkyl group with 1-5 C atoms or an alkoxy group with 1-5 C atoms, 20 R5 and R6 are a hydrogen atom each or, together, stand for a methylene group,

-Z'

R7, R8 and R9, independently of each other, stand for a hydrogen atom or a hydroxy group, 25 and ring B may contain one or two double bonds or

R8 is an alkinyl residue with up to 5 carbon atoms with the proviso that R1 and R2 are hydrogen atoms, or at least one of the residues R3, R4, R5, R6 or R7 is not hydrogen and Rl and R3 have a different meaning from each other, or P:\WPDOCS\GRS\628383.CLM -7/10/98

-27-

R8 and R9 together may represent an oxygen atom with the proviso that at least one of

the residues R3, R4, R5, R6 or R7 is different from hydrogen, or

R5 and R8 may represent a vinylene or ethylene group.

2, Estra-l,3,5(10)trien derivatives according to Claim 1, namely

17P-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-trien-3-yl N,N-dimethylsulfamate,

17P-hydroxy-14a, 15a-methylene-estra-l ,3,5(10)-trien-3-yl N,N-diethylsulfamate,

17P-hydroxy-14a, 15a-methylene-estra-l ,3,5(10)-trien-3-yl pyrrolidinosulphonate,

10 17p-hydroxy-14a, 15a-methylene-estra-l,3,5(10)-trien-3-yl morpholinosulphonate, 17p~hydroxy-14

• • · ·a ·· 17P-hydroxy-14o, 15a-methylene-estra-1,3,5(10)-trien-3-yl sulfamate, ft ft ft« ft • ft · 17P-hydroxy-14a, 15a-methylene-estra-l,3,5(10), 7-tetraene-3-yl N,N-dimethyl- 'i

sulfamate, • • ft * ·· • ft · ft ftft 15 17P-hydroxy-14a, 15a-methylene-estra-l,3,5(10), 6,8-pentaene-3-yl N,N-diethyl- ft ft ft ft • ft ft ft ft ft sulfamate,

ft ft· ft 17P-hydroxy-14a, 15a-methylene-estra-l,3,5(10), 8-tetraene-3-yl N,N-dimethyl- ft ft ft ft «I ft sulfamate,

ft ft ft 17P-hydroxy-14a, 17a-vinylene-estra-l,3,5(10)-trien-3-yl N,N-dimethylsulfamate, ft ft ft ft 20 14a, 15a-ethylene-17P-hydroxy-estra-l ,3,5(10)-trien-3-yl pyrrolidinosulfamate, 16a, 17p-dihydroxy-14a, l7a-ethylene~estra-l,3,5(10)-trien-3-yl N,N-diethylsulfamate,

17P-hydroxy-7a-methyl-eStra-l,3,5(10)-trien-3, 1 ip-diyl 3-N,N-dimethylsulfamate-l 1-

nitrate,

17p-hydroxy-lip-methoxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl N,N-dimethyl-

25 sulfamate, (I 17p-hydroxy-19-nor-17a-pregn-l,3;5(10)-trien-20-in-3-yl sulfamate,

17P-hydroxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl N-methyl-sulfamate,

17P-hydroxy-estra-l,3,5(10), 7-tetraene-3-yl N,N-diethylsulfamate, 5 17P-hydroxy-estra-l,3,5(10), 6,8-pentaene-3-yl N,N dimethylsulfamate,

I P:\WPDOCS\GRM28383.CLM. 7/10/98 I

-28-

17a-hydroxy-14«, 15a-methylene-estra-l,3,5(10), 8-tetraene-3-yl sulfamate, 11 β-methoxy- 17-oxo-estra-1,3,5(10)-tr ien-3-y 1 sulfamate, 17P-hydroxy-estra-l,3,5(10)-trien-3-yl N-methylsulfamate, i 17P-hydroxy-estra-l ,3,5(10)-trien-3-yl sulfamate, 5 17P-hydroxy-3stra-1,3,5(10), 6,8-pentaene-3-yl sulfamate, 17a-hydroxy-estra-1,3,5(10)-trien-3-yl sulfamate 16a, 17P-dihydroxy-estra-l ,3,5(10)-trien-3-yl N,N-diethylsulfamate, 16a, 17P-dihydroxy-estra-l,3,5(10)-trien-3-yl N,N-dimethylsulfamate, « ft»····• · 16a, 17P-dihydroxy-estra-l ,3,5(10)-trien-3-yl morpholinosulphonate, *♦♦· 10 16a, 17P-dihydroxy-estra-l,3,5(10)-trien-3-yl N-methylsulfamate, • « « · • · • 6··« 16a, 17p-dihydroxy-estra-l,3,5(10)-trien-3-yl sulfamate, • • ••ft· · ft ft ·ft · 17P-hydroxy-l4a, 17a-vinylene-estra-l ,3,5(10)-trien-3-yl sulfamate, ft • ft ftftft ft • + ft· 14a, 17a-ethylene-17P-hydroxy-estra-l,3,5(10)-trien-3-yl N-methyl-sulfamate, 16a, 17P-dihydroxy-14a, 17a-ethylene-estra-l,3,5(10)-trien-3-yl sulfamate, • ft ft ft ft « ftft 15 17P-hydroxy-7a-methyl-estra-l,3,5(10)-trien-3, 1 Ιβ-diyl 3-sulfamate-ll-nitrate, • ftft ·ft » 17P-hydroxy-lip-methoxy-19-nor-17a-pregn-l,3,5(10)-trien-20-in-3-yl sulfamate. ft ft ft ft ft ft· ft ft ft ft 3. Process for preparation of the estra-l,3,5(10)-trien derivatives according to one of

0 « ft «ft ft Claims 1 or 2, characterised in that an estra-l,3,5(10)-trien derivative of the general ft ft ft ftft ft 20 formula (I) with the meaning indicated in claim 1, wherein an OH-group is present at the 3-position, is reacted in a fhanner known per se with an appropriately substituted amidosulphonyl chloride of the general formula R-SO2-C1, in which R has the meaning indicated in claim 1, forming an ester with the 3-OH group of the estra-l,3,5(10)-trien derivative.

V' ; - £

5 ΐ Λ ft «ο "ksSsiSSaL·'''^

P;\WPDOCS\GR$\628383.CLM · 7/10/98

-29-

4. Pharmaceutical compositions containing an estra-1,3,5(10)-trien derivative according to Claim 1 or 2 which may be combined with pharmaceutically safe adjuvants and carriers.

DATED this 6th day of October, 1998.

·♦·· 10 «· «· 0 9 e• · ··· • · · • • · « · ·· 9 • » ·β· Jenapharm GmbH By Its Patent Attorneys 15 DAVIES COLLISON CAVE 1» «9 ··· 0 • .9 · • 9990*: • *

0 ' *

• • ft· • «9«

W? i J 1 ; •hkssswss S?

Summary

This invention is relating to new estra-1,3,5(10)-trien-sulfamates carrying at the 3- 55 position an R-S02-0-group, with R being an R^R^N-group in which Rl and R2, independently of each other, represent a hydrogen atom, an alkyl residue with 1-5 C atoms or, together with the N atom, a polymethylene-imino residue with 4-6 C atoms or a moipholino residue.

1010 The compounds, according to this invention, are suitable for hormonal contraception and climacteric hormone replacement therapy (HRT) as well as for treatment of gynecological and andrological diseases. Hence, only low hepatic estrogenicity is exhibited by the compounds according to this invention.

Also described are processes for preparation of the compounds according to this invention and for preparation of pharmaceutical compositions. WWW

INTERNATIONAL SEARCH REPORT InU .onal Application No PCT/DE 95/00877 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 C07J41/00 A61K31/56 C07J53/00 C07J43/00

Accenting to International Patent Classification (IPC) or to both national clarsfication and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by daafication lymboii) IPC 6 CO7J Λ61Κ

Documentation Marched other than minimum documentation to the extent that such document! are included in the fields searched

Electronic data base consulted during the intemauonal March (name of data bate and, where practical, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, wiA indication, where appropnate, of Ae relevant pasuges Relevant to claim No.

X FR,A,Z 133 484 (VEB JENAPHARM) 1 December 1,3,4 1972 Y see page 2, line 14 - line 18; examples 1-4 21-23,25,27

X Z. CHEM. , 1,3,4 vol. 10, no. 8, 1970 pages 299-300, SCHWARZ S ET AL 'Steroids, XI. 17.alpha.-Ethyny1estradioi sulfamates' Y see the whole document 1-4

X GB.A.l 317 373 (VEB JENAPHARM) 16 May 1973 1,3,4 see examples 11-14,16

-/-.

Further documents are listed in the continuation of box C. |)(J Patent family members are listed in annex.

Speaal categories of cited documents. Islet document pubiidted alter the international filing dau ... .______or pnonty due and not in conflict with the application but A *”*"*"* j*"*/*1 , - an which it not ated to understand the principle or theory underlying the ceMMtTM to M oi pwvcuiw ratvtncc invention •E* eariwr document but pubhAed on or after the international ·χ· relevance; Ac claimed invention ruing date cannot be conadered novel or cannot be cantidered to "L" document which may throw doubts on priority daitnfi) or involve an inventive step when the document is taken alone h °f *n°°*r Ύ' *«"«n‘ «* relevance; Ae daimed invention ateaon or other tipeaai ream (teepeaned) eesrnot be eontdemd to involve en inventive etep when Ae *O* document refemng to an oral disclosure, uee, exhibition or document ii combined wiA one or more other such docu- otitar means menu, such combination being obvious to a person dulled ■p· doewnent pubtitiMd prior to Ae inumational filing dale but m the art. laMr titan Ae priority date claimed '** document member of Ae same patent family

Dale of Ae ecaml completion of Ae imsniMOMl natch Date nf mailing of Ae international March report

19 September 1995 2 6. tO. 95

Nmm anti mailing adtirsee of the ISA Authorised officer Euroman Patent Office, P.B. Silt Patentlaan 3 NL-ϋθ HV Rijewijk Td.(+31-70) 140-30«, Tx. 31 651 tponl, Fax: (+31*70) 340-301« Watchorn, P

Form FCT/ΙΙΑΛΙβ (Mart HMM) (July 1WJ) D*ae 1 of 4 INTERNATIONAL SEARCH REPORT Ink .onal Applicaton No PCT/DE 95/00877 (^Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropnate, of the relevant paauget Relevant to claim No.

X PHARMAZIE, 1,3,4 vol. 30, no. 1, 1975 BERLIN DE, pages 17-21, SCHWARZ S ET AL 'Steroids. 15. Sulfonyloxy derivatives of estrogens' Y see compounds 18-25, 28-32, 59-62, 1-4 80, 81 and 110-113

X PHARMAZIE, 1,3,4 vol. 30, no. 1, 1975 BERLIN DE, pages 52-53, STOELZNER W ET AL 'Dissociation of the antigonadotrophic and the contraceptive activities of certain estratriene derivatives' Y see the whole document 1-4

X DD.A.114 806 (S. SCHWARTZ) 20 August 1975 1,3,4 s Y see page 2, column 1, line 52 - line 59; 1-4 examples 2-4,6,9,10

X DE,A,19 49 095 (VEB JENAPHARM) 24 1,3,4 September 1970 Y see page 3, line 9 - line 18; examples 1-4 27-29

X DD,Z,201 143 (VEB JENAPHARM;GER. DEM. 1,3,4 REP.) 6 July 1983 Y see page 1, line 6-8; examples 3-5 1-4

X DD.A.207 447 (VEB JENAPHARM;GER. DEM. 1,3,4 REP.) 29 February 1984 Y see examples 1-5 1-4

X CHEMICAL ABSTRACTS, vol. 091, no. 25, 1,3,4 17 December 1979 Columbus, Ohio, US; abstract no. 204845, SHU H D ET AL 'Structure-activity relationships of estradiol derivatives' page 97; column 2; Y see abstract 1-4 & YAO HSUEH HSUEH PAO , vol. 14, no. 6, 1979 1ST MED. COLL. SHANGHAI;DEP. PHARMACOL.; SHANGHAI; PEOP. R. CHINA, pages 343-348,

. 1

•k

MUttll (mAUeuaUM »f it) (July 1M2) INTERNATIONAL SEARCH REPORT Ink onal Application No PCT/DE 95/00877

CXCononuanon) DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropnate, of the relevant passages Relevant to claim No.

X JOURNAL OF MEDICINAL CHEMISTRY, 1,3,4 vol. 37, no. 2, 21 January 1994 WASHINGTON US, pages 219-221, HOWARTH Ν M ET AL 'Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential* see page 219; examples 4-6

X GB,A,1 398 026 (VEB JENAPHARM;E. GER.) 18 1,3,4 June 1975 see claim 31; examples 2,4-6,18

Y FR.A.2 429 797 (JENAPHARM VEB) 25 January 1-4 1980 see page 1, line 21 - line 33; examples 2,4,7

Y ΕΡ,Α,Ο 430 386 (SCHERING AG) 5 June 1991 1-4 see the whole document

Y W0,A,94 01450 (SCHERING AG ) 20 January 1-4 1994 see the whole document

Y HELVETICA CHIMICA ACTA, 1-4 vol. 50, no. 1, 1967 BASEL CH, pages 281-288, J. KALVODA ET AL '7-a1pha-Methy1δ strogene' see page 282 - page 283; examples V,IX,XI,XV

Y STEROIDS, 1-4 vol. 45, no. 3-4, 1985 SAN FRANCISCO US, pages 325-340, N. UBEROI ET AL 'Structure Activity Reltionships of some Unique Estrogens Related to Estradiol Are Predicted by Fit into DNA* see page 325 - page 334

Y JOURNAL OF MEDICINAL CHEMISTRY, 1-4 vol. 32, no. 7, 1989 WASHINGTON US, pages 1642-1652, R. PETERS ET AL '17-Desoxy Estrogen Analogues* see page 1646; table II

• -/“

•

arrasania imntinuatiaa ·( mana mm) (Inly IMI) WWllWS

international search report tnh anal Application No PCT/DE 95/00877

; CXConUnuaUon) DOCUMENTS CONSIDERED TO BE RELEVANT

Category * I Citation of document, with mdtcauon, where appropriate, of the relevant passages Relevant to claim No.

STEROIDS: STRUCTURE, FUNCTION, AND 1-4 REGULATION, vol. 56, no. 4, 1991 MA US, pages 201-210, B. BHAVNANI ET AL 'Interaction of Ring-B Unsaturated Estrogens with Estrogen Receptors of Human Endometrium and Rat Uterus' see the whole document INTERNATIONAL SEARCH REPORT EnU onal Application No informanon on patent family mcmbcn PCT/DE 95/00877

Patent document Publication Patent family Publication cited in search report date member(s) date

FR-A-2133484 01-12-72 FR-A- 2036997 31-12-70 BE-A- 756922 16-03-71

GB-A-1317373 16-05-73 NONE

DD-A-114806 NONE

DE-A-1949095 24-09-70 ΑΤ-Λ,Β 314743 15-03-74 CH-A- 539028 31-08-73 SE-B- 368569 08-07-74

DD-Z-201143 NONE

DD-A-207447 NONE

GB-A-1398026 18-06-75 NONE

FR-A-2429797 25-01-80 BE-A- 877197 15-10-79 OE-A- 2911612 10-01-80 GB-A,B 2027030 13-02-80 JP-A- 55009071 22-01-80 NL-A- 7905020 03-01-80 SE-A- 7905658 29-12-79 SU-A- 1087525 23-04-84 US-A- 4231946 04-11-80

EP-A-0430386 05-06-91 DE-A- 3939893 06-06-91 DE-A- 3939894 06-06-91 OE-A- 4033871 23-04-92 AT-T- 122053 15-05-95 AU-B- 649239 19-05-94 AU-A- 6884191 26-06-91 CA-A- 2069880 30-05-91 WO-A- 9108219 13-06-91 DE-D- 59009011 08-06-95 HU-A- 67420 28-04-95 JP-T- 5503080 27-05-93 CN-A- 1052677 03-07-91

WO-A-9401450 20-01-94 DE-A- 4222316 05-01-94 1NTERNATIONALER RECHERCHENBER1CHT Inti onalea Aktcnzeichcn PCT/DE 95/00877

A.KLASSIFiZIERUNG DES ANMELDUNGSGEGENSTANDES IPK 6 C07J41/00 A61K31/56 C07J53/00 C07J43/00

Nach der internationalen Patenlklaoffikation (IPK) Oder nach der nabonalen Klacnfikabon und der IPK

B. RECHERCH1ERTE GEBIETE

Recherchierter Mindestprufnoff (Klassifikationsyitem und Klaatfikaeonssymbole) IPK 6 C07J A61K

Reeherchieite aber rucht zum Mindeitprilfstoff gehorende VeroffcnUichungen, soweit dicse unter die recherchierten Gcbiete fallen

Wkhrtnd der intemanonalen Recherche konsulberte elektronische Datenbank (Name der Datenbank und evtl. vcrwendetc Suchbegriffe)

C. ALS WESENTLICH ANGESEHENE UNTERLAGEN

Kate gone* Bczetchnung der Veroffentlichung, toweit erforderlich unter Angabe der in Betracht kommenden Teile Betr, Anspruch Nr.

X FR,A,2 133 484 (VEB JENAPHARM) l.Dezember 1.3.4 1972 Y siehe Seite 2, Zeile 14 - Zeile 18; 1-4 Beispiele 21-23,25,27

X Z. CHEM. , 1.3.4 Bd. 10, Nr. 8, 1970 Seiten 299-300, SCHWARZ S ET AL 'Steroids, XI. 17.alpha.-Ethynylestradiol sulfamates1 Y siehe das ganze Dokument 1-4

X GB,A,1 317 373 (VEB JENAPHARM) 16.Mai 1973 . 1,3,4 siehe Beispiele 11-14,16

, -/-- ’

I χί WciMrt Vcrdfltntiichungen and der Fortmung von FeldC zu I)( | Sich« Anhug PaUntfamilic ImhI entnehnwn ImJ ......

* Beaondera Kategonen von angegebenen VcroffenUichungen : *T* Spatere VeroffenUichung, die nach dem intemauonalen Anmddedanim .,. - .--.___ .ii.rmrmrn ti.At Trrhn.i. rtrf.nirrt oder dem Pnontatadatum vcrOffenUicht worden lit und nil der A Anmeidung mcht kollidiert, aondem nur zumVerriandm, dee der aber meht ait beaonder. tedcutaam anzuaehm tt Eriindungiugrondeliegenden Prinzips oder der ihr zugrundeltegendcn Έ' ilwraa Dokummt. daa jedoeh cm am Oder nach dem iMemaaanalcn Theone angegeben ist Anmddedanim verdffeiHlidit warden in ·χ· VeroffenUichung von bcsondmr Bedeutung; die beampruchte Erfindung *L* Vertffendiehung, die geeignet ist, eincn Prioritauanspruch zweildhaft er- kam allein aufpund dtcser Veroffcndichtmg neht ale neu Oder auf adMiwn au laasen, ndcr dureh die das VerofTeni iehungadatum einer eriindenscherl iligkcit beruhend hetmehtet werden andertn im Rethcschcnbencht gtnarmten VeroffenUicImng faclegt werden .γ. VeroffenUichung von bacmdertr Bedeutung; die beampruchte Erftnduni lodCTCke au. einem andercnbewnderenGnind angegeben nt(wie kannniehtal. auf erfmderischer Tabgkcit tarahend bemchtel ausgefuhrt) ___ werden, wenn die Veroffentlichung mis einer oder mehreren andertn Ό* VeidffenUtctMng, die etch auf cine mttndliehc Offenbantng, Y’croffentlichungen dieeer Kategone in Verbindung gebracht wd und cine Bemuzungi ante Auaddiung oder andert Maflnahmcn beaeht these Vertindung fur cinen Fachmainn nahtiiegcnd ist *P” VetdffeMliehiMig, die vor dem imaraabonalen Anmeldedatum, aber nach ·*· v«ner«*i.eiu.». λ. ,i_ih~. D.>Mr..iii. dem beanspnicnwi Pnoniaudtttim veroffenUicM worden i« * Ve^ffentlichung, die Mitglied denelben Patentfamilie lit

Datum dea AbKhluam der intemauonalen Recherche Abecndedatum del intemauonalen Reeherchenbenchu

19.September 1995 2 6 10. 95 Name und Peetanachrift der Internationale Rccherehcnbclwrde Bevollmachttgter Bedtemteter Europaiaches PatoMamt, P.B. 311 1 Patentlaan 2 NL · 3210 HV Rijswijk Tel, (+11-70) 340-2040, Tx. 31 ill epo nl. Fax (+31-70) 340-3014 Watchorn, P

Form,I,St PCT/ISA/210 (Watt3) (lull I M3) ■ v

INTERNATIONALE!* RECHERCHENBERICHT Ink onalei Aktenzeichen PCT/DE 95/00877

C.(Foruettung) ALS WESENTl.ICII ANGESEHENE UNTERLAOEN .

Kntegone* Bczeiehnung der VerolicnUichung, sowat erforderhch unter Angabc der in Betrachl kommenden Teile Betr. Anspruch Nr.

X PHARMAZIE, 1,3,4 Bd. 30, Nr. 1, 1975 BERLIN DE, Seiten 17-21, SCHWARZ S ET AL 'Steroids. 15. Sulfonyloxy derivatives of estrogens' Y siehe verbindungen 18-25, 28-32, 59-62, 1-4 80, 81 und 110-113

X PHARMAZIE, 1,3,4 Bd. 30, Nr. 1, 1975 BERLIN DE, Seiten 52-53 STOELZNER W ET AL 'Dissociation of the anti gonadotrophic and the contraceptive activities of certain estratriene derivatives' Y siehe das ganze Document 1-4

X DD,A,114 806 (S. SCHWARTZ) 20.August 1975 1,3,4 Y siehe Seite 2, Spalte 1, Zeile 52 - Zeile 1-4 59; Beispiele 2-4,6,9,10

X DE,A,19 49 095 (VEB JENAPHARM) 1,3,4 24.September 1970 Y siehe Seite 3, Zeile 9 - Zeile 18; 1-4 Beispiele 27-29

X DD,Z,201 143 (VEB JENAPHARM;GER. DEM. 1,3,4 REP.) 6.Juli 1983 Y siehe Seite 1, Zeile .6-8; Beispiele 3-5 1-4

X DD,A,207 447 (VEB JENAPHARMjGER. DEM. 1,3,4 REP.) 29.Februar 1984 Y siehe Beispiele 1-5 1-4

X CHEMICAL ABSTRACTS, vol. 091, no. 25, 1,3,4 17.Dezember 1979 Columbus, Ohio, US; abstract no. 204845, SHU H D ET AL 'Structure-activity relationships of estradiol derivatives* Seite 97; Spalte 2; Y siehe Zusammenfassung 1-4 & YAO HSUEH HSUEH PAO , Bd. 14, Nr. 6, 1979 1ST MED. COLL. SHANGHAI;DEP. PHARMACOL.; SHANGHAI; PEOP. R. CHINA, Seiten 343-348,

PermhlMt PCMSAfllO fFomcttuna von Blau 2) (JuU 19«) WBaew? W5

INTERNATIONALER RECHERCHENBERICHT Int ionalei Aktenzeichen PCT/DE 95/00877 C.(FortscCung) ALS WESENTLICH ANGESEHENE UNTERLAGEN Kate gone' Bezeichnung der Veroffenllichung, soweit erforderlich unter Angabe der in Betracht kommenden Teiie Betr. Anspruch Nr.

X JOURNAL OF MEDICINAL CHEMISTRY, 1,3,4 Bd. 37, Nr. 2, 21.Januar 1994 WASHINGTON US, Seiten 219-221, HOWARTH N M ET AL 'Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential1 siehe Seite 219; Beispiele 4-6

X GB,A,1 398 026 (VEB JENAPHARM;E. GER.) 1,3,4 18.Juni 1975 siehe Anspruch 31; Beispiele 2,4-6,18

Y FR,A,2 429 797 (JENAPHARM VEB) 25.Januar 1-4 1980 siehe Seite 1, Zeile 21 - Zeile 33; Beispiele 2,4,7

Y ΕΡ,Α,Ο 430 386 (SCHERING AG) 5.Juni 1991 1-4 siehe das ganze Dokument }

Y WO,A,94 01450 (SCHERING AG ) 20.Januar 1-4 1994 siehe das ganze Dokument

Y HELVETICA CHIMICA ACTA, 1-4 Bd. 50, Nr. 1, 1967 BASEL CH, Seiten 281-288, J. KALVODA ET AL '7-alpha-Methy1ostrogene1 siehe Seite 282 - Seite 283; Beispiele V,IX,XI,XV

Y STEROIDS, 1-4 Bd. 45, Nr. 3-4, 1985 SAN FRANCISCO US, Seiten 325-340, N. UBEROI ET AL 'Structure Activity Reltionships of some Unique Estrogens Related to Estradiol Are Predicted by Fit into DNA* siehe Seite 325 - Seite 334

Y JOURNAL OF MEDICINAL CHEMISTRY, 1-4 Bd. 32, Nr. 7, 1989 WASHINGTON US, Seiten 1642-1652, R. PETERS ET AL '17-Desoxy Estrogen Analogues' siehe Seite 1646; Tabelle II

1 ■ ■ ' ■ *

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FormblaU PCT/1SAJ2»O (FortMtiung von Blau 3} puli 1992) %

WWI"

INTERNATIONALER RECHERCHENBERICHT Ink onalea Aktenzeichen PCT/DE 95/00877

C.(Forttetzung) ALS WESENTLICH ANGESEHENE UNTERLAGEN

Kate gone* Bezeichnung der Veroffcntiichung, soweit erforderhch unter Angabe der in Bctracht kommcnden Tcile Beer. Arapruch Nr.

Y STEROIDS: STRUCTURE, FUNCTION, AND 1-4 REGULATION, Bd. 56, Nr. 4, 1991 MA US, Seiten 201-210, B. BHAVNANI ET AL 'Interaction of Ring-B Unsaturated Estrogens with Estrogen Receptors of Human Endometrium and Rat Uterus' siehe das ganze Dokument

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Fomblrtt PCT/lSA/aiO (Fomtuunt wn Btllt J) j lull IW| <«.· 1

INTERNATIONALER RECHERCHENBERICHT Ink .onaies Aktenzcichen Angaben zu Veroflcntlichbugen, die zur aelben Patentfamilie gehoren PCT/DE 95/00877

Im Recherchenbericht Datum der Mitglied(er) der Datum der angefiihrles Patentdokument Veroffentlichung Patentfamilie Veroffentlichung

FR-A-2133484 01-12-72 FR-A- 2036997 31-12-70 BE-A- 756922 16-03-71

GB-A-1317373 16-05-73 KEINE

DD-A-114806 KEINE

DE-A-1949095 24-09-70 AT-A.B 314743 15-03-74 CH-A- 539028 31-08-73 SE-B- 368569 08-07-74

DD-Z-201143 KEINE

DD-A-207447 KEINE

GB-A-1398026 18-06-75 KEINE

FR-A-2429797 25-01-80 BE-A- 877197 15-10-79 DE-A- 2911612 10-01-80 GB-A.B 2027030 13-02-80 JP-A- 55009071 22-01-80 NL-A- 7905020 03-01-80 SE-A- 7905658 29-12-79 SU-A- 1087525 23-04-84 US-A- 4231946 04-11-80

EP-A-0430386 05-06-91 DE-A- 3939893 06-06-91 DE-A- 3939894 06-06-91 DE-A- 4033871 23-04-92 AT-T- 122053 15-05-95 AU-B- 649239 19-05-94 AU-A- 6884191 26-06-91 CA-A- 2069880 30-05-91 WO-A- 9108219 13-06-91 DE-D- 59009011 08-06-95 HU-A- 67420 • 28-04-95 JP-T- 5503080 27-05-93 CN-A- 1052677 03-07-91

W0-A-9401450 20-01-94 DE-A- 4222316 05-01-94

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