HRP20050009A2 - 9-alpha-substituted estratrienes as selectively active estrogen - Google Patents

9-alpha-substituted estratrienes as selectively active estrogen Download PDF

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HRP20050009A2
HRP20050009A2 HR20050009A HRP20050009A HRP20050009A2 HR P20050009 A2 HRP20050009 A2 HR P20050009A2 HR 20050009 A HR20050009 A HR 20050009A HR P20050009 A HRP20050009 A HR P20050009A HR P20050009 A2 HRP20050009 A2 HR P20050009A2
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estra
triene
compounds
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Kosemund Dirk
Mller Gerd
Hillisch Alexander
Fritzemeier Karl-Heinrich
Muhn Peter
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Schering Aktiengesellschaft
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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    • A—HUMAN NECESSITIES
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
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    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Description

Polje izuma The field of invention

Predstavljeni izum se odnosi na nove spojeve kao farmaceutske djelotvorne tvari, koje in vitro viši afinitet na preparacijama estrogenih receptora prostate štakora nego na preparacijama esterogenih receptora uterusa štakora i in vivo jedno preferencijalno djelovanje na ovarij u usporedbi sa uterusom pokazuju, njihovo spravljanje, njihovu terapijsku primjenu i farmaceutske oblike primjene, koje novi spojevi sadrže. The presented invention relates to new compounds as pharmaceutical active substances, which in vitro show a higher affinity on rat prostate estrogen receptor preparations than on rat uterus estrogen receptor preparations and in vivo a preferential action on the ovary compared to the uterus, their preparation, their therapeutic application and pharmaceutical forms of administration, which the new compounds contain.

Kod kemijskih spojeva radi se o novim steroidalnim estrogenima koji su selektivni obzirom na tkivo. The chemical compounds are new steroidal estrogens that are tissue-selective.

Pozadina izuma Background of the invention

Eficijentnost estrogena u liječenju simptoma uzrokovanih hormonskom deficijencijom kao valunzi, atropija estrogenih ciljnih organa i inkontinencija, kao i uspješna primjena terapije estrogenom za spriječavanje gubitka koštane mase kod peri- i postmenopauznih žena, je dobro objašnjena i opće prihvaćena (Grady et al. 1992, Ann. Intern. Med. 117: 1016-1037). Isto tako je dobro dokumentirano, da zamjenske estrogenske terapije kod postmenopauznih žena ili kod žena sa drugačije uzrokovanim ovarijskim disfunkcijama, da je rizik od oboljenja srca i krvotoka nasuprot žena koje se tretiraju estrogenom, reduciran (Grady et al., loc. cit.). The efficacy of estrogen in the treatment of symptoms caused by hormonal deficiency such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapy to prevent bone loss in peri- and postmenopausal women, is well explained and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with other causes of ovarian dysfunction reduces the risk of heart disease and blood flow in comparison to women treated with estrogen (Grady et al., loc. cit.).

Pri uobičajenim terapijama estrogenom ili hormonskim zamjenskim terapijama (Hormone Replacement Therapy = HRT) biti će prirodni estrogeni, kao estradiol i konjugirani estrogeni iz urina konja sami ili u kombnaciji sa gestagenom aplicirani. Namjesto prirodnih estrogena mogu isto kroz esterifikaciju dobiveni derivati, kao npr. 17β-etradiol-valerat, biti korišteni. In usual estrogen therapies or hormone replacement therapies (Hormone Replacement Therapy = HRT), natural estrogens, such as estradiol and conjugated estrogens from horse urine, alone or in combination with a progestogen will be applied. Derivatives obtained through esterification, such as 17β-etradiol-valerate, can also be used instead of natural estrogens.

Zbog stimulirajućeg djelovanja primjenjenih estrogena na endometrij, što do povišenja rizika karcinoma endometrija vodi (Harlap S. 1992, Am. J. Obstet. Gynecol. 166: 1986-1992), biti će u hormonskoj zamjenskoj terapiji primjerice estrogen/gestagen-kombinaciji preparata primjenjen. Gestagena komponenta u estrogen/gestagen-kombinaciji spriječava hipertrofiju endometrija, ali je sa kombinacijama koje sadrže gestagen povezana i pojava nepoželjnih međukrvarenja. Due to the stimulating effect of applied estrogens on the endometrium, which leads to an increase in the risk of endometrial cancer (Harlap S. 1992, Am. J. Obstet. Gynecol. 166: 1986-1992), in hormone replacement therapy, for example, estrogen/gestagen-combination preparations will be used . The progestin component in the estrogen/progestin combination prevents endometrial hypertrophy, but combinations containing progestin are also associated with unwanted bleeding.

Jedna nova alternativa za estrogen/gestagen-kombinaciju preparata predstavljaju selektivni estrogeni. Do sada se pod selektivnim estrogenima podrazumjevalo takve spojeve, koji djeluju kao estrogeni na mozak, kosti i krvožilni sustav, temeljem njihovog antiuterotrofnog (što znači antiestrogenog) parcijalnog djelovanja ali ne i proliferativno na endometrij. One new alternative to estrogen/gestagen-combination preparations is represented by selective estrogens. Until now, selective estrogens have meant such compounds, which act like estrogens on the brain, bones and vascular system, based on their anti-uterotrophic (which means anti-estrogenic) partial action, but not proliferative on the endometrium.

Jedna klasa tvari, koje željeni profil jednog selektivnog strogena djelomice ispunjavaju, su takozvani, Selective Estrogen Receptor Moduatrors (SERM) (R. F. Kauffman , H.U. Bryant 1995, DNAP 8 (9): 531-539). Pri tom se radi o parcijalnim agonistima estrogenog receptornog subtipa, ERα'. Taj tip supstanci je svakako neefektivan u pogledu terapije akutnih postmenopauznih poteškoća, kao npr. valunzi. Kao primjer za SERM je nedavno za indikaciju osteoporoze uvedeni Raloksifen naveden. One class of substances, which partially meet the desired profile of a selective estrogen, are the so-called Selective Estrogen Receptor Modulators (SERM) (R.F. Kauffman, H.U. Bryant 1995, DNAP 8 (9): 531-539). These are partial agonists of the estrogen receptor subtype, ERα'. This type of substance is certainly ineffective in the treatment of acute postmenopausal problems, such as hot flashes. Raloxifene, recently introduced for the indication of osteoporosis, is listed as an example of a SERM.

DE-A-19906159 opisuje nove spojeve kao farmaceutski djelotvorne tvari, koje in vitro viši afinitet na estrogenreceptorskim preparacijama prostate štakora nego na estrogenreceptorskim preparacijama uterusa štakora u in vivo jedno preferencijalno djelovanje na kosti u usporedbi sa uterusom pokazuju, njihovo spravljanje, terapeutsku primjenu i rafmaceutske oblike aplikacije, koje novi spojevi sadrže. Kod spojava radi se o 16α-, i 16β-hidroksi-estra,1,3,5(1O)-estratrienima, koji na steroidnom kosturu daljnje supstituente nose u kojima B, C i/ili D-prsteni jedan ili više dodatnih dvostrukih veza mogu pokazati. DE-A-19906159 describes new compounds as pharmaceutically effective substances, which in vitro show higher affinity on estrogen receptor preparations of rat prostate than on estrogen receptor preparations of rat uterus and in vivo a preferential action on bone compared to uterus, their preparation, therapeutic application and pharmaceutics forms of application, which the new compounds contain. The compounds are 16α-, and 16β-hydroxy-ester, 1,3,5(1O)-estratrienes, which carry further substituents on the steroid skeleton in which the B, C and/or D-rings have one or more additional double bonds I can show.

Za tretman smetnji fertiliteta kod žena, često uzrokovanih kirurškim, medikamentoznim ili drugim ovarijskim disfunkcijama, otvara se upotrebom novih selektivnih estrogena isto tako nove terapeutske mogućnosti. In vitro fertilizacijski tretman je jedan od prije više od 20 godina etablirani postupak. Brojne metode za tretman ovarijski uzrokovanog infertiliteta sa eksogenim gonadotropinom su poznati. Dodatkom gonadotropina kao FSH (FSH=folikularni stimulirajući hormon) treba jednu stimulaciju ovarija prouzrokočiti, koja može omogućiti zdravo sazrijevanje folikula. For the treatment of fertility disorders in women, often caused by surgical, medicinal or other ovarian dysfunctions, the use of new selective estrogens also opens up new therapeutic possibilities. In vitro fertilization treatment is one of the procedures established more than 20 years ago. Numerous methods for the treatment of ovarian-caused infertility with exogenous gonadotropin are known. With the addition of gonadotropins as FSH (FSH=follicular stimulating hormone), a stimulation of the ovaries should be caused, which can enable the healthy maturation of the follicles.

Folikul je jedna funkcionalna jedinica ovarija i ima dvije zadaće: ona čuva oocite i omogućuje im uvjete za rast i sazrijevanje. Folikulogeneza obuhvaća razvoj jednog ovarijskog folikula primordijalnog stadija do jednog antralnog folikula, koji se stalno povećava, koji posljednji stadij prije ovuacije predstavlja. Samo jedan optimalno razvijen antralni folikul može osloboditi jednu sazrelu jajnu stanicu kroz ovulaciju. The follicle is one functional unit of the ovary and has two tasks: it protects the oocytes and provides conditions for their growth and maturation. Folliculogenesis includes the development of one ovarian follicle of the primordial stage to one antral follicle, which is constantly increasing in size, which represents the last stage before ovulation. Only one optimally developed antral follicle can release one mature egg through ovulation.

Pacijentice sa ovarijski uzrokovanim fertilitetom (PCOS = sindrom policističnih ovarija) boluju od poremećaja sazrijevanja folikula, koji su povezani sa hormonalnim i ovulacijskim smetnjama kao i sa nedovoljno sazrelim jajnim stanicama. Broj primarnih i sekundarnih folikula je ovdje otprilike 2 x veći od onog u normalnom ovariju (Hughesden et al., Obstet. Gynecol. Survey 37, 1982, S. 59-77). Patients with ovarian-related fertility (PCOS = polycystic ovary syndrome) suffer from follicle maturation disorders, which are associated with hormonal and ovulatory disorders as well as insufficiently matured egg cells. The number of primary and secondary follicles here is approximately 2 x greater than that in a normal ovary (Hughesden et al., Obstet. Gynecol. Survey 37, 1982, S. 59-77).

Ima naznaka, da je raniji razvojni stadiji folikulogeneze (što se odnosi na razvoj primordijalnih do antralnih folikula) gonadotropin ovisan. Nije jednoznačno objašnjeno, koliko je visok utjecaj poznatih parakrinih i autokrinih faktora na ranu folikulogenezu (Elvin et al., Mol. Cell Endocrinol. 13, 1999, S. 1035-1048; McNatty et al., J. Reprod. Fertil. Suppl. 54, 1999, S. 3-16). There are indications that the earlier developmental stages of folliculogenesis (which refers to the development of primordial to antral follicles) are gonadotropin dependent. It is not clearly explained how high the influence of known paracrine and autocrine factors is on early folliculogenesis (Elvin et al., Mol. Cell Endocrinol. 13, 1999, S. 1035-1048; McNatty et al., J. Reprod. Fertil. Suppl. 54, 1999, S. 3-16).

Gonadotropini kao FSH su prvenstveno u posljednjem razvojnom stadiju folikulogeneze na sazrijevanju folikula djelotvori, što znači kod razvoja ranih antralnih folikula do jednog zrelog ovulacijski sposobnog folikula. Gonadotropins such as FSH are primarily effective in the last developmental stage of folliculogenesis on the maturation of follicles, which means the development of early antral follicles to one mature ovulatory follicle.

In vivo i in vitro infertilitet biti će primjerice sa gonadotropinima (FSH i antiestrogeni) tretirani (White et al., J. Clin. Endocrinol. Metab. 81, 1996, S. 3821-3824). Kod tretmana fertiliteta in vitro biti će oocite iz preovulacijskih antralnih folikula uzete da bi se in vitro mogle dovesti do sazrijevanja jedne jajne stanice koja je sposobna za oplodnju. Nakon oplodnje i preembrionalnog razvoja biti će 1 do 3 embrija u uterus žene implantirana. In vivo and in vitro infertility will be treated, for example, with gonadotropins (FSH and antiestrogens) (White et al., J. Clin. Endocrinol. Metab. 81, 1996, S. 3821-3824). In the case of in vitro fertility treatment, oocytes from preovulatory antral follicles will be taken in order to lead to the maturation of one egg cell capable of fertilization in vitro. After fertilization and pre-embryonic development, 1 to 3 embryos will be implanted in the woman's uterus.

Tretman sa eksogenim gonadotropinom je u puno aspekata praćen brojnim rizicima i dodatnim pojavama. Najveći rizik sastoji se u jednoj prekomjernoj stimulaciji ovarija, koja u teškim slučajevima može predstavljati ozbiljan rizik po život (OHSS = Ovarian Hyperstimulation Syndrome). In many aspects, treatment with exogenous gonadotropin is accompanied by numerous risks and additional phenomena. The greatest risk consists in an excessive stimulation of the ovaries, which in severe cases can pose a serious risk to life (OHSS = Ovarian Hyperstimulation Syndrome).

Daljnji dodatni efekti su visoki troškovi in vitro tretmana fertilizacije, koji moraju plaćati parovi (bračni). Negativne dodatne pojave kao porast težine, nadutost, mučnina, povraćanje i jedan do sada nepoznati rizik po život, oboljevanje od raka, pripisuju de tretmanu gonadotropinom. Further additional effects are the high costs of in vitro fertilization treatment, which must be paid by couples (married). Negative additional phenomena such as weight gain, flatulence, nausea, vomiting and one hitherto unknown risk to life, cancer, are attributed to gonadotropin treatment.

Metoda kojom se mogu rečene negativne posljedice i rizici izbjeći, biti će stoga smatrana, koja sazrijevanje i stimulaciju folikularnog rasta kod ovarijski uzrokovanog infertiliteta in vivo s jednom prikladnim djelotvornom tvari provesti, prije nego otpočne tretman sa eksogenim gonadotropinom. The method by which said negative consequences and risks can be avoided, will therefore be considered, which maturation and stimulation of follicular growth in ovarian-caused infertility in vivo with a suitable active substance, before starting the treatment with exogenous gonadotropin.

Estrogeni receptor beta (ERβ) Estrogen receptor beta (ERβ)

Prije nekoliko godina bio je estrogeni receptor-β (ERβ) kao drugi subtip estrogenog receptora otkriven (Kuiper et al. (1996), Proc. Acad. Sci. 93: 5925-5930; Moselmann, Dijkema (1996) Febs. Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). Ekspresijski uzorak ERβ razlikuje se od onog za ERα (Kuiper et al. (1996), Endocrinology 138: 863-870). Tako prevladava ERβ nasuprot ERα u prostati štakora, dok u uterusu štakora ERα prevladava nasuprot ERβ. U ovarijima je bila najveća koncentracija ERβ mRNA pronađena (Couse et al. Endocrinology 138, 1997, S. 4612-4613). Several years ago, estrogen receptor-β (ERβ) as a second estrogen receptor subtype was discovered (Kuiper et al. (1996), Proc. Acad. Sci. 93: 5925-5930; Moselmann, Dijkema (1996) Febs. Letters 392: 49-53; Tremblay et al. (1997), Molecular Endocrinology 11: 353-365). The expression pattern of ERβ differs from that of ERα (Kuiper et al. (1996), Endocrinology 138: 863-870). Thus, ERβ predominates over ERα in the rat prostate, while in the rat uterus, ERα predominates over ERβ. The highest concentration of ERβ mRNA was found in the ovaries (Couse et al. Endocrinology 138, 1997, S. 4612-4613).

Daljnji sistemi sa usporedno visokom ERβ ekspresijom obuhvaćaju kosti (Onoe Y et al., 1997, Endocrinology 138: 4509-4512), da sustav krvnih žila (Register TC, Adams MR 1998, J Steroid Molec Biol 64: 187-191), urogenitalni trakt (Kuiper GJM et al. 1997, Endocrinology 138: 863-870), gastrointestinalni trakt (Campbell-Thopson 1997, BBRC 240:478-483), kao i testis (Moselmann S et al. 1996 FEBS Lett. 392 49-53) uključujući spermatide (Shugrue et al. 1998, Steroids 63: 498-504). Raspored tkiva leži blizu tome, da estrogeni preko ERβ reguliraju funkciju organa. Da je ERβ u tom pogledu funkcionalan, proizlazi isto i iz ispitivanja na ERα-(ERKO) odnosno ERβ-(βERKO)-Knockout-miševa: ovariektomija uzrokuje gubitak koštane mase u ERKO-miševa, što se može spriječiti supstitucijom estrogenom (Kimbro et al. 1998, sažetak OR7-4, Endocrine Society Meeting New Orleans). Isto tako spriječava estradiol u krvim žilama ženskih ERKO-miševa proliferaciju medija krvnih žila i glatkih mišićnih stanica (Lafrati MD et al. 1997, Nature Medicine 3: 545-548). Takvo zaštitno djelovanje estradiola slijedi u ERKO-miševa vjerojatno preko ERβ. Further systems with comparatively high ERβ expression include bones (Onoe Y et al., 1997, Endocrinology 138: 4509-4512), the vascular system (Register TC, Adams MR 1998, J Steroid Molec Biol 64: 187-191), urogenital tract (Kuiper GJM et al. 1997, Endocrinology 138: 863-870), gastrointestinal tract (Campbell-Thopson 1997, BBRC 240:478-483), as well as the testis (Moselmann S et al. 1996 FEBS Lett. 392 49-53 ) including spermatids (Shugrue et al. 1998, Steroids 63: 498-504). The arrangement of tissues lies close to the fact that estrogens regulate organ function via ERβ. The fact that ERβ is functional in this regard also results from the tests on ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy causes bone loss in ERKO mice, which can be prevented by estrogen replacement (Kimbro et al. 1998, abstract OR7-4, Endocrine Society Meeting New Orleans). Likewise, estradiol in the blood vessels of female ERKO-mice prevents the proliferation of the media of blood vessels and smooth muscle cells (Lafrati MD et al. 1997, Nature Medicine 3: 545-548). Such a protective effect of estradiol follows in ERKO-mice probably via ERβ.

Da ERβ i ERα funkcionalno različitio djeluju, bilo je nakon uspješnog začeća αERKO-miševa i βERKO-miševa potvrđeno. That ERβ and ERα act functionally differently was confirmed after the successful conception of αERKO-mice and βERKO-mice.

Slijedom toga igra ERα jednu važnu ulogu u adultnom uterusu, u tkivu mliječnih žlijezda, kod negativne regulacije aktiviteta gonadotropina, dok je ERβ prije svega vezan za razvojni slijed ovarijske fiziologije, posebice folikulogenoze i ovulacije (Couse et al., Endocrine Reviews 20, 1999, S. 358-417). Consequently, ERα plays an important role in the adult uterus, in the mammary gland tissue, in the negative regulation of gonadotropin activity, while ERβ is primarily related to the developmental sequence of ovarian physiology, especially folliculogenesis and ovulation (Couse et al., Endocrine Reviews 20, 1999, S. 358-417).

Promatranja na βERKO-miševima daju spoznaje o funkciji ERβ u prostati i mjehuru; kod satrijim mužjaka miševa javljaju se simptomi hiperplazije prostate i mjehura (Krege JH et al. 1998, Proc. Natl. Acad. Sci. 95: 15677-15682). Osim toga pokazuju ženke (Lubahn DB et al. 1993, Proc. Natl. Acad. Sci. 90:11162-11166) i mužjaci ERKO-miševa (Hess RA et al. 1997, Nature 390: 509-512) kao i ženke βERKO-miševa (Krege JH, 1998, Proc. Natl. Acad. Sci. 95: 15677-15682) smetnje fertiliteta. Stoga je važna funkcija estrogena u pogledu održavanja funkcije ovarija i testisa kao i fertiliteta dokazana. Observations on βERKO-mice provide insights into the function of ERβ in the prostate and bladder; in satria male mice, symptoms of prostate and bladder hyperplasia occur (Krege JH et al. 1998, Proc. Natl. Acad. Sci. 95: 15677-15682). In addition, female (Lubahn DB et al. 1993, Proc. Natl. Acad. Sci. 90:11162-11166) and male ERKO mice (Hess RA et al. 1997, Nature 390: 509-512) as well as βERKO females show - mice (Krege JH, 1998, Proc. Natl. Acad. Sci. 95: 15677-15682) fertility disorders. Therefore, the important function of estrogen in maintaining ovarian and testicular function as well as fertility has been proven.

Jedno selektivno estrogeno djelovanje na određene ciljne organe može se na temelju različitog rasporeda tkiva i organa oba subtipa ERs-a preko subtipspecifičnih liganda postići. Supstance s preferencom za ERβ uspoređene sa ERα u in vitro testu vezivanja receptora bile su od Kuiper et al. opisane (Kuiper et al. (1996), Endocrinology 138: 863-870). Jedno selektivno djelovanje subtipspecifičnih liganda estrogenih receptora na estrogensenzitivne parametre in vivo nije bilo do sada dokazano. A selective estrogenic effect on certain target organs can be achieved based on the different arrangement of tissues and organs of both subtypes of ERs via subtype-specific ligands. Substances with a preference for ERβ compared to ERα in an in vitro receptor binding assay were from Kuiper et al. described (Kuiper et al. (1996), Endocrinology 138: 863-870). A selective action of subtype-specific estrogen receptor ligands on estrogen-sensitive parameters in vivo has not been proven so far.

Zadaća predloženog izuma je, proizvesti spojeve koji pokazuju in vitro disocijaciju u pogledu na stvaranje preparacija estergenih receptora prostate i uterusa štakora. Spojevi bi trebali pokazati in vitro viši afinitet esterogen-receptor preparcija na prostati štakora nego na esterogen-receptor preparacijama uterusa štakora. The task of the proposed invention is to produce compounds that show in vitro dissociation with regard to the creation of preparations of estrogenic receptors of the prostate and uterus of rats. The compounds should show in vitro higher affinity for estrogen-receptor preparations on rat prostate than on estrogen-receptor preparations of rat uterus.

ERβ-specifični spojevi trebali bi in vitro u ovariju izazvati jedno profertilitetno djelovanje. Istovremeno trebali bi spojevi jednu disocijaciju u pogledu djelovanje na ovarij u odnosu na djelovanje na uterus pokazati. Izumom predočeni spojevi trebaju određeno zaštitno djelovanje nasuprot hormon-deficijntno-uzrokovanih gubitaka koštane mase u odnosu na uterus-stimulirajuće djelovanje posjedovati. ERβ-specific compounds should induce a profertility effect in vitro in the ovary. At the same time, the compounds should show a dissociation regarding the effect on the ovary in relation to the effect on the uterus. The compounds presented by the invention should have a certain protective effect against hormone-deficient-caused bone mass loss in relation to the uterus-stimulating effect.

Nadalje treba preko predočenog izuma jedan odnos između struktrure i djelovanja biti stavljen na raspolaganje, koji daje pristup spojevima, koji posjeduju gore formuliran farmakološki profil. Izumom predočeni spojevi trebaju kod ovarijski uzrokovanog infertiliteta u ovariju jedno poboljšanje fertiliteta kod istovremeno manjeg djelovanja na uterus pokazati. Furthermore, a relationship between structure and action should be made available through the presented invention, which gives access to compounds that possess the pharmacological profile formulated above. In case of ovarian-caused infertility, the compounds presented by the invention should show an improvement in fertility while at the same time having less effect on the uterus.

Prema izumu, zadaća će biti ispunjena stavljanjem na raspolaganje 9α-supstituiranih estra-1,3,5(10)-trienderivata opće formule I According to the invention, the task will be fulfilled by making available 9α-substituted ester-1,3,5(10)-triene derivatives of the general formula I

[image] [image]

pri čemu ostaci R3,R7,R7',R9,R13,R16 kao i R17 i R17', neovisno međusobno slijedeće značenje posjeduju: whereby the residues R3, R7, R7', R9, R13, R16 as well as R17 and R17' independently have the following meaning:

R3 jedan atom vodika ili jednu skupinu R18, pri čemu R3 one hydrogen atom or one group R18, wherein

R18 jedan ravno ili razgranjeno lančani, zasićeni ili nezasićeni ugljikovodični ostatak sa do 6 atoma ugljika, jednom trifluormetilnom skupinom, jednim aril, heteroaril ili aralkilnim ostatkom, jednim supstituiranim aril, heteroarilnim ostatkom sa jednim metil, etil, trifluormetil, pentafluoretil, trifluormetiltio, metoksi, etoksi, nitro, cijano, halogen (fluor, klor, brom, jod), hidroksi, amino, mono(C1-8alkil) ili di(C1-8-alkil) amino, pri čemu su obje alkilne skupine identične ili različite, di(aralkil) amino, pri čemu obje aralkilne skupine su identične ili različite, karboksil, karboksalkoksi, C1-C20-acil ili C1-C20-aciloksi-skupine kao supstituente, jedan acilni ostatak COR19, pri čemu jedan ravni ili razgranjeni, zasićeni ili do 3-struko nazasićeni, djelomice ili potpuno halogenirani ugljikovodični ostatak sa do 10 atoma ugljika, ili R18 one straight or branched chain, saturated or unsaturated hydrocarbon residue with up to 6 carbon atoms, one trifluoromethyl group, one aryl, heteroaryl or aralkyl residue, one substituted aryl, heteroaryl residue with one methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(C1-8 alkyl) or di(C1-8 alkyl) amino, both alkyl groups being identical or different, di( aralkyl) amino, wherein both aralkyl groups are identical or different, carboxyl, carboxyloxy, C1-C20-acyl or C1-C20-acyloxy-groups as substituents, one acyl residue COR19, wherein one is straight or branched, saturated or up to 3 -polysaturated, partially or fully halogenated hydrocarbon residue with up to 10 carbon atoms, or

R18 jednu skupinu R20SO2-označava, pri čemu R18 denotes one group R20SO2-, whereby

R20 jedna R21R22N-skupina je, pri čemu R21 i R22 međusobno neovisni jedan atom vodika, jednim C1-C5-alkilnim ostatkom, jednu skupinu C(O)R23, pri čemu R23 jedan ravno ili razgranjeno lančani, zasićeni ili 3-struko nezasićeni, djelomice ili potpuno halogenirani ugljikovodični ostatak sa do 10 atoma ugljika, jednom ciklopropil, butil, pentil, heksil ili heptil skupinom, jedan C4-C15-cikloalkil-alkil ostatak sa jednim 3 do 7 atoma ugljika u cikloalkilnom udjelu i sa jednim alkilnim dijelom sa do 8 atoma ugljika ili jedan aril, heteroaril, ili aralkilni ostatak predstavlja, ili jedan supstituirani aril, heteroarilni ostatak sa jednim metil, etil, trifluormetil, pentafluoretil, trifluormetiltio, metoksi, etoksi, nitro, cijano, halogen (fluor, klor, brom, jod), hidroksi, amino, mono(C1-8-alkil) ili di(C1-8-alkil) amino, pri čemu su obje R20 is one R21R22N-group, wherein R21 and R22 are mutually independent one hydrogen atom, one C1-C5-alkyl residue, one group C(O)R23, wherein R23 is one straight or branched chain, saturated or 3-fold unsaturated, partially or fully halogenated hydrocarbon residue with up to 10 carbon atoms, one cyclopropyl, butyl, pentyl, hexyl or heptyl group, one C4-C15-cycloalkyl-alkyl residue with one 3 to 7 carbon atoms in the cycloalkyl part and with one alkyl part with up to 8 carbon atoms or one aryl, heteroaryl, or aralkyl residue represents, or one substituted aryl, heteroaryl residue with one methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine ), hydroxy, amino, mono(C1-8-alkyl) or di(C1-8-alkyl) amino, where both

alkilne skupine identične ili različite, di(aralkil) amino, pri čemu obje aralkilne skupine su identične ili različite, karboksil, karboksialkoksi, C1-C20-acil ili C1-C20-aciloksi-skupine kao supstituenti ili zajedno sa N-atomom, jedan polimetileniminoostatak sa 4 do 6 C-atoma ili jednim morfolino ostatkom, označava, alkyl groups identical or different, di(aralkyl) amino, where both aralkyl groups are identical or different, carboxyl, carboxyloxy, C1-C20-acyl or C1-C20-acyloxy-groups as substituents or together with the N-atom, one polymethyleneimino residue with 4 to 6 C-atoms or one morpholino residue, means,

R7 i R7' svaki neovisno međusobno jedan atom vodika ili jedan atom halogena, R7 and R7' each independently one hydrogen atom or one halogen atom,

R9 jedan ravnolančani ili razgranjeni alkenil ili alkinil ostatak sa 2 do 6 atoma ugljika ili djelomice ili potpuno može biti fluoriran, ili jedan etinil ili prop-1-inil ostatak R9 is one straight-chain or branched alkenyl or alkynyl radical with 2 to 6 carbon atoms or can be partially or completely fluorinated, or one ethynyl or prop-1-ynyl radical

R13 jedna metilna skupina ili jedna etilna skupina, R13 one methyl group or one ethyl group,

R16 jedna hidroksi skupina ili jedna skupina R18O, R20SO2 ili OC(O)R23 sa R18, R20 i R23 svaki sa značenjem navedenim pod R3, R16 one hydroxy group or one group R18O, R20SO2 or OC(O)R23 with R18, R20 and R23 each having the meaning given under R3,

R17 i R17' svi međusobno neovisni za jedan atom vodika ili jedan atom halogena R17 and R17' are all mutually independent for one hydrogen atom or one halogen atom

R16 može stajati na poziciji α ili β. R16 can be in position α or β.

Prema jednoj varijanti izuma biti će u prednosti derivati gonatriena, pri čemu R7 i R7' jedan atom vodika, R9 jedna vinil, etinil, ili prop-1-inil skupina, R16 jedna hidroksi skupina i R17 i R17' svaki po jedan atom vodika jesu. According to one variant of the invention, gonatriene derivatives will be preferred, where R7 and R7' have one hydrogen atom, R9 has one vinyl, ethynyl, or prop-1-ynyl group, R16 has one hydroxy group, and R17 and R17' each have one hydrogen atom. .

Nadalje su slijedeće kombinacije iz halogenih supstitucija, od prednosti su fluor, na C-atomu 7 ili 17: 7-mono ili 7-di i R17 kao i R17' svaki za jedan vodik, 17-mono ili 17-di i R7 kao i R7' svaki za jedan vodik kao i 7-mono/ 17-mono, 7 mono/17-di, 7-di/ 17-mono, 7-di/ 17-di. Furthermore, the following combinations of halogen substitutions, preferably fluorine, on C-atom 7 or 17: 7-mono or 7-di and R17 as well as R17' each for one hydrogen, 17-mono or 17-di and R7 as well R7' each for one hydrogen as well as 7-mono/ 17-mono, 7 mono/17-di, 7-di/ 17-mono, 7-di/ 17-di.

7α odnosno 17β-pozicija je kod monofluorspojava u prednosti. 7α or 17β-position is preferred in monofluoro compounds.

Jedna daljnja varijanta izuma predviđa posebice spojeve, u kojima R16 za skupine R18O ili R20SO2-O- sa R18 i R20, gdje svaki ima značenje navedeno pod R3. A further variant of the invention envisages in particular compounds, in which R16 for the groups R18O or R20SO2-O- with R18 and R20, where each has the meaning given under R3.

Prednost imaju prema predočenom izumu slijedeći spojevi According to the present invention, the following compounds are preferred

9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

9α-alil-estra-1,3,5(10)-trien-3,16α-diol 9α-allyl-estra-1,3,5(10)-triene-3,16α-diol

18a-homo-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

18a-homo-9α-alil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol

3-metoksi-9α-vinil-estra-1,3,5(10)-trien-16α-ol 3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol

9α-alil-3-metoksi-estra-1,3,5(10)-trien-3,16α-ol 9α-allyl-3-methoxy-estra-1,3,5(10)-trien-3,16α-ol

18a-homo-3-metoksi-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-3-methoxy-9α-vinyl-ester-1,3,5(10)-triene-3,16α-diol

18a-homo-9α-alil-3-metoksi-estra-1,3,5(10)-trien-3,16α-ol 18a-homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-3,16α-ol

[image] [image]

Daljnje mogućnosti predočenog izuma biti će naznačene u zahtjevima. Further possibilities of the presented invention will be indicated in the claims.

Ostatak ugljikovodik R18 je primjerice jedan metil, etil, propil, izopropil, butil, izobutil, terc.-butil, pentil, izopentil, neopentil, heksil ostatak. The hydrocarbon residue R18 is, for example, one methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl residue.

Aloksi skupine OR18 u spojevima opće formule I mogu po 1 do 6 atoma ugljika sadržavati, pri čemu metoksi, etoksi, propoksi, izopropoksi i t-butiloksi skupine imaju prednost. Aloxy groups of OR18 in compounds of the general formula I can each contain 1 to 6 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.

Zamjena za C1-C5-alkilne ostatke R21 i R22 su metil, etil, propil, izopropil, butil, izobutil, terc.-butil, pentil, izopentil, neopentil. Substitutes for C1-C5-alkyl radicals R21 and R22 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl.

Kao zamjena za ravno lančane ili razgranjene ostatke ugljikovodika R23 sa 1 do max. 10 atoma ugljika su primjerice metil, etil, propil, izopropil, butil, izobutil, terc.-butil, pentil, izopentil, neopentil, heptil, heksil i decil za navesti; metil, etil, propil i izopropil su u prednosti. As a substitute for straight chain or branched hydrocarbon residues R23 with 1 to max. 10 carbon atoms are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl to name a few; methyl, ethyl, propyl and isopropyl are preferred.

Kao C3-C7-cikloalkilna skupina je jedna ciklopropil, butil, pentil, heksil ili heptilna skupina za navesti. As a C3-C7-cycloalkyl group is one cyclopropyl, butyl, pentyl, hexyl or heptyl group to be mentioned.

Jedan C4-C15-cikloalkilalkil ostatak pokazuje 3 do 7 atoma ugljika u cikloalkilnom dijelu; tipični predstavnici su direktno nazvane cikloalkilne skupine. One C4-C15-cycloalkylalkyl radical shows 3 to 7 carbon atoms in the cycloalkyl part; typical representatives are directly named cycloalkyl groups.

Alkilni dio pokazuje do 8 atoma ugljika. The alkyl part shows up to 8 carbon atoms.

Kao primjeri za jedan C4-C15-cikloalkilalkilostatak jesu ciklopropilmetil, ciklopropiletil, ciklopentilmetil, ciklopentilpropil skupine itd. navedene. Cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl groups etc. are mentioned as examples of a C4-C15-cycloalkylalkyl radical.

Kod jednog arilnog ostatka radi se u smislu predočenog izuma o jednom fenil, 1 ili 2 naftil-ostatku; fenilni ostatak je u prednosti. In the sense of the present invention, one aryl residue means one phenyl, 1 or 2 naphthyl residue; the phenyl residue is preferred.

Aril uključuje uvijek i jedan heteroarilni ostatak. Primjeri za jedan heteroarilni ostatak su 2, 3 ili 4-piridinil, 2 ili 3-furil, 2 ili 3 – tienil, 2 ili 3-pirolil, 2,4 ili 5-imidazolil, pirazinil, 2,4 ili 5-pirimidinil ili 3 ili 4-piridazinil ostatak. Aryl always includes one heteroaryl residue. Examples of a heteroaryl radical are 2, 3 or 4-pyridinyl, 2 or 3-furyl, 2 or 3-thienyl, 2 or 3-pyrrolyl, 2,4 or 5-imidazolyl, pyrazinyl, 2,4 or 5-pyrimidinyl or 3 or 4-pyridazinyl residue.

Kao supstituenti, koji na jednom aril ili heteroaril ostatku mogu biti prisutni, jesu npr. metil, etil, trifluormetil, pentafluoretil, trifluormetiltio, metoksi, etoksi, nitro, cijano, halogen (fluor, klor, brom , jod), hidroksi, amino, mono(C 1-8-alkil) ili di(C 1-8-alkil)amino, pri čemu su obje skupine identične ili različite, di(aralkil)amino, pri čemu su obje aralkilne skupine identične ili različite, karboskil, karboskialkoksi, C1-C20-acil ili C1-C20-aciloksi-skupine navedene. As substituents, which can be present on one aryl or heteroaryl residue, are, for example, methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(C 1-8-alkyl) or di(C 1-8-alkyl)amino, wherein both groups are identical or different, di(aralkyl)amino, wherein both aralkyl groups are identical or different, carboxyl, carboskialkyloxy, C1-C20-acyl or C1-C20-acyloxy-groups indicated.

Kod jednog aralkilnog ostatka radi se o jednom ostatku, koji u prstenu do 14, a u prednosti je onaj sa 6 do 10, C-atoma, a u alkilnom lancu 1 do 8, u prednosti je onaj sa 1 do 4, C-atoma, sadrži. Tako dolaze kao aralkilni ostaci primjerice u obzir benzil, feniletil, naftilmetil, naftiletil, furilmetil, tieniletil, piridilpropil. An aralkyl residue is one residue, which in the ring has up to 14, preferably the one with 6 to 10, C-atoms, and in the alkyl chain 1 to 8, preferably the one with 1 to 4, C-atoms, contains . For example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl come into consideration as aralkyl residues.

Alkilne skupine odnosno ostaci ugljikovodika mogu djelomice ili potpuno biti supstituirani preko 1-5 atoma halogena, hidroksi skupine ili C1-C4-alkoksiskupine. Alkyl groups, i.e. hydrocarbon residues, can be partially or completely substituted by 1-5 halogen atoms, hydroxy groups or C1-C4-alkoxy groups.

Sa jednim C2-C6-alkenil ostatkom je u prvom redu jedan vinil ili alil-ostatak predviđen. With one C2-C6-alkenyl residue, one vinyl or allyl residue is primarily intended.

Pod jednim C2-C6-alkilnil ostatkom se podrazumjeva i u prednosti je jedan etinil ili prop-1-inil ostatak. One C2-C6-alkylnyl residue is understood to mean and preferably one ethynyl or prop-1-ynyl residue.

C1-10-acil ostaci označuju primjerice aceti, propionil, butiril, valeroil, izovaleroil, pivaloil, heksanoil, oktil, nonil, dekanoil. C1-10-acyl residues denote, for example, acetyl, propionyl, butyryl, valeroyl, isovaleroyl, pivaloyl, hexanoyl, octyl, nonyl, decanoyl.

Jedna ili obje hidroksil skupine na C-atomima 3 i 16 mogu sa jednim alifatičkim, ravnolančanim ili razgranjenim, zasićenim ili nezasićenim C1-C14-mono ili polikarbonske kiseline ili jedne aromatične karbonske kiseline biti esterificirani. One or both hydroxyl groups on C-atoms 3 and 16 can be esterified with an aliphatic, straight-chain or branched, saturated or unsaturated C1-C14-mono or polycarboxylic acid or an aromatic carboxylic acid.

Kao takve karbonske kiseline za esterifikaciju dolaze primjerice u obzir: Examples of such carboxylic acids for esterification include:

Monokarbonske kiseline: mravlja kiselina, octena kiselina, propionska kiselina, maslačna kiselina, izo-maslačna kiselina, valerijanska kiselina, izovalerijanska kiselina, pivalinska kiselina, laurinska kiselina, miristinksa kiselina, akrilna kiselina, propionska kiselina, metakrilna kiselina, krotonska kiselina, izokrotonska kiselina, uljna kiselina, elaidinska kiselina. Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, iso-butyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propionic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid.

Esterifikacija sa octenom kiselinom, valerijanskom kiselinom ili pivalinskom kiselinom je u prednosti. Esterification with acetic acid, valeric acid or pivalic acid is preferred.

Dikarbonske kiseline: oksalna kiselina, malonska kiselina, bernštajn kiselina, glutarna kiselina, adipinska kiselina, pimelinska kiselina, plutena kiselina, azelainska kiselina, sebacinska kiselina, maleinska kiselina, fumarna kiselina, mukonska kiselina, citrakonska kiselina, mezakonska kiselina. Dicarboxylic acids: oxalic acid, malonic acid, bernsteinic acid, glutaric acid, adipic acid, pimelic acid, sulfuric acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, mesaconic acid.

Aromatske karbonske kiseline: benzoeva kiselina, ftalna kiselina, izoftalna kiselina, tereftalna kiselina, naftoeva kiselina, o, m, i p-toluilna kiselina, hidratropa kiselina, atropa kiselina, cimetna kiselina, nikotinska kiselina, izonikotinska kiselina. Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o, m, and p-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, isonicotinic acid.

Esterifikacija sa benzoevom kiselinom je u prednosti. Esterification with benzoic acid is preferred.

Izumom predočeni ester 9α-supstituiranih estratriena pokazuju kao protolijekovi prednosti nasuprot neesterificiranih djelotvornih tvari u pogledu njihovog aplikacijskog modusa, njihovog načina djelovanja, jačine djelovanja i trajanja djelovanja. The ester of 9α-substituted estratrienes presented by the invention show as protodrugs advantages over non-esterified active substances in terms of their mode of application, their mode of action, strength of action and duration of action.

Farmakokinetičke i farmakodinamičke prednosti pokazuju posebice izumom predočeni sulfamati 9α-supstituiranih estratriena. Takvi efekti bili su već kod drugih steroid-sulfamata opisani (J. Steroid Biochem. Molec.Biol., 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)). Pharmacokinetic and pharmacodynamic advantages are shown especially by the sulfamates of 9α-substituted estratrienes presented by the invention. Such effects were already described with other steroid-sulfamates (J. Steroid Biochem. Molec. Biol., 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).

U predočenoj patentnoj prijavi biti će steroidi, kojima je osnova kostura 9α-supstituirani estra-1,3,5(10)-trien, za tretman estrogen-receptora β-naznačenih smetnji i stanja kao selektivni estrogeni opisani, koji u in vitro disocijaciji u pogledu njihove veze na estrogen-receptor-preparacijama prostate i uterusa štakora i onih u in vivo primjerice jedne disocijacije obzirom na ovarij u usporedbi sa In the submitted patent application, the steroids, whose backbone is 9α-substituted estra-1,3,5(10)-triene, for the treatment of estrogen-receptor β-specified disorders and conditions will be described as selective estrogens, which in vitro dissociation in regarding their connection on estrogen-receptor-preparations of the prostate and uterus of rats and those in vivo for example one dissociation regarding the ovary in comparison with

Djelovanjem na uterus pokazuju. Spojevi posjeduju osim toga određeno zaštitno djelovanje protiv gubitka koštane mase uzrokovano hormonskom deficijencijom. By acting on the uterus, they show. The compounds also have a certain protective effect against the loss of bone mass caused by hormonal deficiency.

U tvrđeno je da 9α-supstituirani estra-1,3,5(10)-trieni prema općoj formuli I kao selektivni estrogeni za tretman različitih stanja i smetnji jesu primjereni, koje preko jedan visoki sadržaj estrogenih receptora β nego estrogenih receptora α u odgovarajućem ciljnom tkivu ili organu jesu naznačeni. It was found that 9α-substituted estra-1,3,5(10)-trienes according to the general formula I are suitable as selective estrogens for the treatment of various conditions and disorders, which have a higher content of estrogen receptors β than estrogen receptors α in the corresponding target tissue or organ are indicated.

Izum se odnosi i na fermaceutske preparate, koji najmanje jedan spoj opće formule I (ili fiziološki podnošljive aditivne soli s njihovim organskim ili anorganskim kiselinama) sadrže i primjena spojeva opće formule I za spravljanje lijekova, posebice za slijedeće navedene indikacije. The invention also relates to pharmaceutical preparations, which contain at least one compound of general formula I (or physiologically tolerable additive salts with their organic or inorganic acids) and the use of compounds of general formula I for the preparation of medicines, especially for the following indicated indications.

Ovdje opisani novi selektivni estrogeni mogu kao pojedinačne komponente u farmaceutskoj pripremi ili u kombinaciji posebno sa gestagenima biti upotrebljeni. Posebnu prednost ima kombinacija selektivnih estrogena sa ERα-selektivnim antiestrogenima, koji su periferno selektivni, što znači oni koji ne prolaze kroz stijenke moždanih krvnih žila, kao i sa selektivnim estrogen-receptor-modulatorima (SERM). Izumom predočeni ERβ-selektivni spojevi mogu posebno za spravljanje lijekova za tretman smetnji fertiliteta, za prevenciju i terapiju hiperplazije prostate, za prevenciju i tretman hormonskom deficijencijom uzrokovanih promjena ponašanja kod žena i muškaraca, kao i za primjenu u zamjenskoj hormonskoj terapiji (HRT) kod muškaraca i kod žena, biti primjenjeni. The new selective estrogens described here can be used as individual components in a pharmaceutical preparation or in combination especially with gestagens. A special advantage is the combination of selective estrogens with ERα-selective antiestrogens, which are peripherally selective, which means those that do not pass through the walls of brain blood vessels, as well as with selective estrogen-receptor-modulators (SERMs). The ERβ-selective compounds presented by the invention can be used especially for the preparation of drugs for the treatment of fertility disorders, for the prevention and treatment of prostate hyperplasia, for the prevention and treatment of behavioral changes caused by hormonal deficiency in women and men, as well as for use in hormone replacement therapy (HRT) in men and in women, be applied.

Jedan terapeutski produkt, koji sadrži jedan estrogen i jedan čisti antiestrogen za istovremenu, sekvencijalnu ili odvojenu primjenu za selektivnu estrogensku terapiju perimenopauzalnih ili postmenopauzalnih stanja je već u EP-A 0 346 014 opisan. A therapeutic product, containing one estrogen and one pure antiestrogen for simultaneous, sequential or separate administration for selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.

Supstance i farmaka koji ih sadrže su na temelju njihove djelotvorne disocijacije na ovariju u usporedbi s djelovanjem na uterus posebno primjereni za tretman kod kirurških, medikamentoznih ili drugačije uzrokovanih ovarijskih disfunkcija kao ženski infertilitet za stimulaciju folikulogeneze za pojedinačni tretman u smislu poboljšanja fertiliteta, za potporu in vitro tretmana fertiliteta (IVF) u spoju s jednim in vivo tretmanom i za tretman ovarijski uzrokovanih smetnji u starosti (“kasni fertilitet”) kao i za tretman hormonalno uzrokovanih poteškoća. Based on their effective dissociation on the ovary compared to the effect on the uterus, the substances and pharmaceuticals containing them are particularly suitable for the treatment of surgical, medicinal or otherwise caused ovarian dysfunctions as female infertility for the stimulation of folliculogenesis for individual treatment in terms of improving fertility, for support in of in vitro fertility treatment (IVF) in combination with one in vivo treatment and for the treatment of ovarian-caused disorders in old age ("late fertility") as well as for the treatment of hormonally-caused difficulties.

Supstance su isto tako za terapiju ovarijskih oboljenja kao i policističnog ovarijskog sindroma POF (Premature Ovarian Failure)-sindrom i ovulacijskih smetnji primjereni. The substances are also suitable for the treatment of ovarian diseases as well as polycystic ovarian syndrome POF (Premature Ovarian Failure) and ovulation disorders.

Konačno, mogu spojevi opće formule I u spoju sa selektivnim estrogen-receptor-modulatorima (SERM), odnosno Raloxifen biti primjenjeni, i to posebice za primjenu u hormonskoj zamjenskoj terapiji (HRT) i za tretman ginekoloških smetnji. Finally, compounds of the general formula I in combination with selective estrogen-receptor-modulators (SERMs), i.e. Raloxifene can be used, especially for use in hormone replacement therapy (HRT) and for the treatment of gynecological disorders.

Isto i kao pojedinačne komponente su supstance primjerene za tretman peri i postmenopauzalnih poteškoća posebno napada vrućine, smetnji u snu, razdražljivosti, promjenama ponašanja, inkontinencije, vaginalne atrofije i hormonskom deficijencijom izazvanih duševnih oboljenja. Isto tako su te supstance za hormonsku supstituciju i terapiju hormonskom deficijencijom izazvanih poteškoća kod kirurških, medikamentoznih ili drugačije uzrokovanih ovarijskih disfunkcija primjereni. Also as individual components, the substances are suitable for the treatment of peri- and postmenopausal problems, especially hot flashes, sleep disturbances, irritability, changes in behavior, incontinence, vaginal atrophy and mental illnesses caused by hormonal deficiency. Likewise, these substances are suitable for hormone replacement and therapy of difficulties caused by hormonal deficiency in ovarian dysfunction caused by surgery, medication or otherwise.

Supstance su osim toga za profilaksu protiv gubitka koštane mase uzrokovanu hormonskom deficijencijom i osteoporozu, za profilaksu oboljenja krvo-žilnog sustava, posebno oboljenja krvnih žila kao ateroskleroza, visoki krvni tlak i za sprječavanje neurodegenerativnih oboljenja uzrokovanih hormonskom deficijencijom, kao Alzheimerova bolest, kao i hormonalnom deficijencijom prouzročeno djelovanje na pamćenje i sposobnost učenja, upotrebljivo. The substances are also for the prophylaxis against bone loss caused by hormonal deficiency and osteoporosis, for the prophylaxis of diseases of the circulatory system, especially diseases of blood vessels such as atherosclerosis, high blood pressure and for the prevention of neurodegenerative diseases caused by hormonal deficiency, such as Alzheimer's disease, as well as hormonal deficiency-induced effect on memory and learning ability, usable.

Nadalje su supstance kao djelotvorne tvari u preparatima za tretman upalnih i oboljenja imunološkog sustava, posebice autoimunih oboljenja, kao npr. reumatoidnog artritisa, multiple skleroze, lupusa, Morbus Kronove-bolesti i drugih upalnih oboljenja crijeva, upalnih oboljenja kože, kao psorijaza, kao i za tretman endometrijoze, moguće koristiti. Furthermore, the substances are active substances in preparations for the treatment of inflammatory and immune system diseases, especially autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease and other inflammatory bowel diseases, inflammatory skin diseases, such as psoriasis, as well as for the treatment of endometriosis, can be used.

Nadalje su te supstance djelotvorne protiv upalnih oboljenja dišnih puteva, pluća i bronhija, kao npr. astma. Furthermore, these substances are effective against inflammatory diseases of the respiratory tract, lungs and bronchi, such as asthma.

Lijekovi su primjereni za terapiju i profilaksu oboljenja uzrokovanih deficijencijom estrogena kod žena kao i kod muškaraca. The drugs are suitable for therapy and prophylaxis of diseases caused by estrogen deficiency in women as well as in men.

Spojevi su kod muškaraca posebice primjereni za terapiju gubitka koštane mase uzrokovane hormonalnom deficijencijom i osteoporoze, za prevenciju oboljenja srca i krovotoka, posebno oboljenja krvnih žila kao ateroskleroza, visoki krvni tlak i za prevenciju protiv neurodegenerativnih oboljenja uzrokovanih hormonalnom deficijencijom, kao Alzheimerova bolest, kao i utjecaja uslijed hormonalne deficijencije, na pamćenje i sposobnot učenja, kao što su i primjenjivi za prevenciju i terapiju hiperplazije prostate. In men, the compounds are particularly suitable for the treatment of bone loss caused by hormonal deficiency and osteoporosis, for the prevention of heart and circulatory diseases, especially blood vessel diseases such as atherosclerosis, high blood pressure, and for the prevention of neurodegenerative diseases caused by hormonal deficiency, such as Alzheimer's disease, as well as impact due to hormonal deficiency, on memory and learning ability, as they are also applicable for the prevention and therapy of prostate hyperplasia.

Supstance mogu za profilaksu i terapiju disfunkcija uzrokovanih starenjem ili oboljenja kod muškaraca, biti primjenjivane. Posebno su primjenjive za prevenciju i tretman, uslijed starenja, smanjivanja androgena, kao testosteron i DHEA, kao i hormona rasta. Substances can be used for prophylaxis and therapy of dysfunctions caused by aging or diseases in men. They are especially applicable for prevention and treatment, due to aging, reduction of androgens, such as testosterone and DHEA, as well as growth hormones.

Nadalje je lijek za tretman upalnih i oboljenja imunog sustava, posebice autoimunih oboljenja kod čovjeka, kao npr. reumatoidni artritis, MS (multipla skleroza) i Morbus Kron te druge upalne bolesti crijeva, kao upalne bolesti dišnih puteva, pluća i bronhija. Količina spoja opće formule, koja se aplicira mijenja se unutar jednog širokog područja i može svaku djelotvornu količinu pokriti. U ovisnosti stanja koje se tretira i načina aplikacije, može količina apliciranog spoja iznositi od 0,01 µg/kg – 100 mg/kg tjelesne težine, odnosno prednost imaju količine od 0,04 µg/kg – 1 mg/kg tjelesne težine, na dan. Furthermore, it is a medicine for the treatment of inflammatory and diseases of the immune system, especially autoimmune diseases in humans, such as rheumatoid arthritis, MS (multiple sclerosis) and Crohn's disease and other inflammatory diseases of the intestines, such as inflammatory diseases of the respiratory tract, lungs and bronchi. The amount of compound of the general formula that is applied varies within a wide range and can cover any effective amount. Depending on the condition being treated and the method of application, the amount of the applied compound can be from 0.01 µg/kg - 100 mg/kg of body weight, that is, amounts of 0.04 µg/kg - 1 mg/kg of body weight are preferred, on day.

Kod ljudi odgovara takva doza jednoj dozi od 0,8 µg do 8 g, odnosno 3,2 µg do 80 mg, dnevno. In humans, such a dose corresponds to a single dose of 0.8 µg to 8 g, or 3.2 µg to 80 mg, per day.

Jedna jedinica količine (doza) izumom predočeno je 1,6 µg do 2000 mg jednog ili više spojeva opće formule I. One quantity unit (dose) according to the invention is 1.6 µg to 2000 mg of one or more compounds of the general formula I.

Izumom predočeni spojevi i aditivne soli kiselina su za spravljanje farmaceutskih pripravaka i pripremu prikladni. Farmaceutski sastav odnosno lijek sadrže djelotvornu tvar jednog ili više izumom predočenih spojeva ili njihovih aditivnih soli kiselina, isto tako u mješavini sa drugim farmakološkim odnosno farmaceutski djelotvornim tvarima. The compounds and additive acid salts presented by the invention are suitable for the preparation and preparation of pharmaceutical preparations. The pharmaceutical composition or drug contains the active substance of one or more of the compounds presented by the invention or their additive acid salts, also in a mixture with other pharmacologically active substances.

Spravljanje lijekova slijedi na poznati način, pri čemu poznati i uobičajeni farmaceutski pomoćni spojevi kao i inače uobičajene nosive- i tvari za razrijeđivanje mogu biti primjenjivane. Medicines are prepared in a known manner, whereby known and usual pharmaceutical auxiliary compounds as well as usual carriers and diluents can be used.

Kao takve nosive i pomoćne tvari mogu doći u obzir one, koje na slijedećim literaturnim mjestima kao pomoćne tvari u farmaciji, kozmetici i sličnim područjima jesu preporučene ili navedene: Ullmans Encyklopädie der technischen Chemie, svezak 4 (1953), str. 1 do 39; Journal of Pharmaceutical Sciences, svezak 52 (1963), str. 918 ff., H. v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind., knjiga 2, 1961, str. 72 u. ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebite, Cantor KG. Aulendorf in Wurttemberg 1971. As such carriers and auxiliary substances, those that are recommended or listed in the following literature as auxiliary substances in pharmacy, cosmetics and similar fields can be considered: Ullmans Encyklopädie der technischen Chemie, volume 4 (1953), p. 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), p. 918 ff., H. v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind., book 2, 1961, p. 72 in. ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebite, Cantor KG. Aulendorf in Wurttemberg in 1971.

Spojevi mogu biti aplicirani oralno ili parenteralno, odnosno intraperitonealno, intramuskularno, subkutano ili perkutano. Spojevi mogu isto tako biti implantirani u tkivo. The compounds can be administered orally or parenterally, i.e. intraperitoneally, intramuscularly, subcutaneously or percutaneously. Compounds can also be implanted into tissue.

Za oralnu aplikaciju dolaze u obzir kapsule, pilule, tablete, dražeje itd. Jedinica doziranja može pored djelotvorne tvari biti i farmaceutski podnošljivi “nosač tvari”, kao npr. škrob, šećer, sorbit, želatina, vazelin, talk, kremena kiselina itd. For oral application, capsules, pills, tablets, dragees, etc. are considered. The dosage unit can, in addition to the active substance, also be a pharmaceutically acceptable "substance carrier", such as starch, sugar, sorbitol, gelatin, vaseline, talc, silicic acid, etc.

Za parenteralnu aplikaciju mogu biti tvari u jednom fiziološki podnošljivom sredstvu za razrijeđivanje otopljene ili suspendirane. Kao sredstvo za razrijeđivanje biti će vrlo često ulja sa ili bez dodatka otapala, jednog površinski aktivnog sredstva, jednog suspendirajućeg ili emulgirajućeg sredstva primjenjivana. Primjeri za primjenjena ulja su maslinovo ulje, kikirikijevo ulje, ulje sjemenki iz pamuka, sojino ulje, ricinusovo ulje i sezamovo ulje. For parenteral administration, the substances may be dissolved or suspended in a physiologically tolerable diluent. Oils with or without the addition of a solvent, a surface-active agent, a suspending or emulsifying agent will very often be used as a diluting agent. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

Spojevi se dadu primjenjivati u obliku jednog implantirajućeg preparata, što može biti formulirano, da je moguće produljeno oslobađanje djelotvorne tvari. The compounds can be applied in the form of a single implantable preparation, which can be formulated to allow prolonged release of the active substance.

Implantati mogu kao inertni materijali npr. biološki razgradive polimere sadržavati ili sintetičke silikone kao npr. silikonski kaučuk. Te djelotvorne tvari mogu osim toga za perkutanu aplikaciju npr. u flaster biti implantirane. Implants can contain inert materials such as biodegradable polymers or synthetic silicones such as silicone rubber. These active substances can also be implanted in a patch for percutaneous application, for example.

Za spravljanje aktivnih spojeva opće formule I intravaginalnih (npr. vaginalni prsteni) ili intrauterinih sustava (npr. Pessare, spirale, IUSs, Mirena®) za lokalnu aplikaciju primjereni su razni polimeri kao npr. silikonski polimeri, etilen-vinil-acetat, polietilen ili polipropilen. Various polymers such as silicone polymers, ethylene-vinyl-acetate, polyethylene or polypropylene.

Da bi se postigla bolja biološka dostupnost, mogu spojevi i kao ciklodekstrinklatrati biti formulirani. K tome biti će spojevi sa α, β, ili γ-ciklodekstrin ili derivati istih korišteni (PCT/EP95/02656). In order to achieve better bioavailability, compounds can also be formulated as cyclodextrin clathrates. In addition, compounds with α, β, or γ-cyclodextrin or their derivatives will be used (PCT/EP95/02656).

Izumom predočeno mogu spojevi opće formule I isto i sa liposomima biti stavljeni u kapsule. According to the invention, compounds of the general formula I can also be placed in capsules with liposomes.

Metode Methods

Studije o vezivanju estrogenih receptora: Studies on estrogen receptor binding:

Afinitet vezanja novo selektivnih estrogena bio je kroz kompeticijske eksperimente zu primjenu 3H-estradiola kao liganda na estrogen-receptivnim preparacijama prostate i uterusa štakora testiran. Preparacija citosola prostate i estrogen-receptor test sa citosolom prostate bio je, kao od Testas et al. (1981) opisan, proveden (Testas J. et al., 1981, Endocrinology 109: 1287-1289). The binding affinity of newly selective estrogens was tested through competition experiments using 3H-estradiol as a ligand on estrogen-receptive preparations of the prostate and uterus of rats. Prostate cytosol preparation and estrogen-receptor assay with prostate cytosol was, as by Testas et al. (1981) described, conducted (Testas J. et al., 1981, Endocrinology 109: 1287-1289).

Preparacija citosola uterusa štakora, kao i test receptora sa ER-sadržavajućim citosolom bio je principijelno proveden kao od Stacka i Gorskog (1985) opisano (Stack, Gorski 1985, Endocrinology 117, 2024-2032) sa nekim modifikacijama kao kod Fuhrmanna et al. (1995) opisano (Fuhrmann U. et al. 1995, Contraception 51: 45-52). The preparation of rat uterine cytosol, as well as the receptor assay with ER-containing cytosol, was basically performed as described by Stack and Gorski (1985) (Stack, Gorski 1985, Endocrinology 117, 2024-2032) with some modifications as in Fuhrmann et al. (1995) described (Fuhrmann U. et al. 1995, Contraception 51: 45-52).

Ovdje opisane supstance pokazale se viši afinitet vezanja prema estrogenim receptorima prostate štakora nego prema estrogenom receptoru iz uterusa štakora. Pri tom se pošlo od toga, da ERβ nasuprot ERα u prostati štakora, u uterusu štakora ERα nasuprot ERβ prevladava. Tabela 1 pokazuje, da odnos vezanja na prostata- i uterus-receptor kvalitativno kvocijentu relativnog afiniteta vezanja (RBA) humanog ERβ i ERα od štakora (prema Kuiper et al. (1996), Endocrinology 138: 863-870) odgovara (tabela 1). The substances described here showed a higher binding affinity to the estrogen receptors of the rat prostate than to the estrogen receptor from the rat uterus. In doing so, it was assumed that ERβ versus ERα in the prostate of rats, in the uterus of rats, ERα versus ERβ predominates. Table 1 shows that the relationship of binding to the prostate- and uterus-receptor qualitatively corresponds to the quotient of relative binding affinity (RBA) of human ERβ and ERα from rats (according to Kuiper et al. (1996), Endocrinology 138: 863-870) (table 1) .

Tabela 1 Table 1

[image] [image]

*: citirano iz: Kuiper et al. (1996), Endocrinology 138: 863-870 *: quoted from: Kuiper et al. (1996), Endocrinology 138: 863-870

Tabela 2 pokazuje rezultate za 4 izumom predočena 9α-vinil-estra-1,3,5(10)-trien-3,16α-diol-derivata (spojevi 1;2;4;5). Table 2 shows the results for 4 9α-vinyl-ester-1,3,5(10)-triene-3,16α-diol derivatives presented by the invention (compounds 1;2;4;5).

Tabela 2 Table 2

[image] [image]

Pojašnjenje: Verbindung = spoj; RBA, Rattenuterus = uterus štakora; RBA Rattenprostata = prostata štakora Clarification: Verbindung = connection; RBA, Rattenuterus = rat uterus; RBA Rattenprostata = rat prostate

Izumom predočeni spojevi 1;2;4;5 pokazuju jedan veći afinitet vezanja na estrogen-receptor iz prostate štakora nego na estrogen receptor iz uterusa štakora. The compounds 1;2;4;5 presented by the invention show a higher binding affinity to the estrogen receptor from the rat prostate than to the estrogen receptor from the rat uterus.

Nadalje je bio prediktivitet prostata-ER verzus uterus-ER-test-sustava u pogledu tkivno-selektivnog djelovanja preko in vivo ispitivanja potvrđen. Supstance s preferencom za prostata-ER su in vivo u prednosti u pogledu ovar- i uterus- kao i djelovanja na hipofizu u korist djelovanja na ovarij, disocirane. Furthermore, the predictability of the prostate-ER versus uterus-ER test-system in terms of tissue-selective action was confirmed through in vivo testing. Substances with a preference for the prostate-ER are dissociated in vivo in favor of the ovary- and uterus- as well as the effect on the pituitary gland in favor of the effect on the ovary.

Istraživanja disocijacija djelovanja na ovar/uterus i hipofizu Research on the dissociation of effects on the ovary/uterus and the pituitary gland

Istraživanja obzirom na djelovanje na rast uterusa i ovulaciju (indirektni efekt krod utjecaj sekrecije hormona hipofize) bila su na adultnim ženkama štakora (tjelesne težine 220-250 g) provedena. Supstance su bile 4x u 4 dana u slijedu supkutano aplicirane. Prva aplikacija uslijedila je u metestrusu. Jedan dan nakon posljednje aplikacije uslijedila je autopsija. Bio je broj jajnih stanica u jajovodu (efekt na ovulaciju) kao i težina uterusa određivana. Research regarding the effect on uterine growth and ovulation (indirect effect through the influence of pituitary hormone secretion) was conducted on adult female rats (body weight 220-250 g). The substances were applied subcutaneously 4 times in 4 consecutive days. The first application followed in metestrus. An autopsy followed one day after the last application. The number of oocytes in the fallopian tube (effect on ovulation) as well as the weight of the uterus were determined.

Dok estradiol jedno sprječavanje ovulacije ovisno o dozi i jedno povećanje težine uterusa sa jednom ED50 od 0,004 mg/kg tjelesne težine uzrokuje, izumom predočena supstanca 1 uzrokuje, sve do doze od 0,4 mg/kg tjelesne težine, nikakav efekt na ovulaciju i težinu uterusa. While estradiol causes a dose-dependent prevention of ovulation and an increase in uterine weight with an ED50 of 0.004 mg/kg body weight, substance 1 presented by the invention causes, up to a dose of 0.4 mg/kg body weight, no effect on ovulation and weight uterus.

Istraživanja na ovariju: Research on the ovary:

Supstance su bile in vivo na juvenilnim štakorima kojima je ektomirana hipofiza provjerene. U jednoj modifikaciji tih operativnih metoda bio je životinjama jedan GnRH-antagonist apliciran. Zatim je provjeravano, da li supstanca proliferaciju folikula (sazrijevanje) u ovariju stimulira. Mjerni parametar je težina ovarija. The substances were tested in vivo on juvenile rats whose pituitary gland had been excised. In one modification of these operative methods, one GnRH-antagonist was applied to the animals. Then it was checked whether the substance stimulates follicle proliferation (maturation) in the ovary. The measuring parameter is the weight of the ovaries.

Po 5 životinja (tjelesne težine 40-50 g) bilo je tretiranim skupinama randomizirano dodjeljeno. Životinje su bile u makrolon-kavezima u klimatiziranim prostorijama sa svjetlosnim programom (10 h mračno, 14 h svjetlo) zu jednu standardnu dijetu (Altromin) ad libidum hranjene i sa zakiseljenom tekućom vodom napajane. 5 animals each (body weight 40-50 g) were randomly assigned to the treated groups. The animals were kept in macrolon cages in air-conditioned rooms with a light program (10 h dark, 14 h light) on a standard diet (Altromin) fed ad libidum and fed with acidified running water.

Za s.c.-aplikacije bile su test-supstance kao i kontrolne supstance (estradiol E2) u benzilbenzoat/ricinusovo ulje (1+4 v/v) otopljene. For s.c.-applications, test substances as well as control substances (estradiol E2) were dissolved in benzylbenzoate/castor oil (1+4 v/v).

Juvenilnim ženkama štakora bile su ili na dan 0 hipofize ektomirane i od dana 1 do dana 4 sa estradiolom, izumom predočenim spojem 1 odnosno 2 ili sa jednom mješavinom (ricinusovo ulje/benzil benzoat) subkutano tretirane (aplikacije 1x na dan). U modificiranoj verziji metode, dobivale su životinje istovremeno sa spojevima 2 odn. s mješavinom i kontrolnom supstancom estradiol, kroz 4 dana tretmana 0,5 mg/po životinji/dan cetrorelix apliciran. U oba slučaja bile su životinje 24 sata nakon posljednje aplikacije žrtvovane i težina ovarija je bila određena. Juvenile female rats had their pituitary glands ectomized either on day 0 and from day 1 to day 4 treated subcutaneously with estradiol, compound 1 or 2 presented by the invention or with a mixture (castor oil/benzyl benzoate) (applications 1x a day). In a modified version of the method, the animals received compounds 2 or with the mixture and the control substance estradiol, for 4 days of treatment 0.5 mg/per animal/day cetrorelix was applied. In both cases, the animals were sacrificed 24 hours after the last application and the weight of the ovaries was determined.

0,5 mg/po životinji/dan spoja 1 kroz 4 dana subkutano aplicirano uzrokuju kad životinja kojima je ektomirana hipofiza, jedno usporedivo povećanje težine ovarija kao estradiol kod jedne doze od 0,1 mg/po životinji/na dan. Mješavina ne uzrokuje nikakve efekte. 0.5 mg/animal/day of compound 1 administered subcutaneously for 4 days caused a comparable increase in ovarian weight as estradiol at a single dose of 0.1 mg/animal/day in hypopituitarized animals. The mixture does not cause any effects.

Time pokazuje izumom predočeni spoj 1 jednu disocijaciju djelovanja na ovarij u usporedbi sa uterusom i djelovanjem na hipofizu i stoga je temeljem njihovog stimulirajućeg djelovanja na folikul odličan za željene indikacije, za tretman ženskog infertiliteta, prikladan. Thus, the compound 1 presented by the invention shows a dissociation of the effect on the ovary compared to the uterus and the effect on the pituitary gland and therefore, based on their stimulating effect on the follicle, it is excellent for the desired indications, for the treatment of female infertility, suitable.

Kod GnRH-antagonistima-tretiranih životinja pokazuju već koncentracije od 0,1 i 0,3 mg/po životinji/na dan spoja 2 na ovariju isto djelovanje kao korištena doza od 1 mg/po životinji/na dan etradiola (prikaz 1). Već i niže doziranje (0,01, 0,03 mg/po životinji/na dan) pokazuju jedno djelovanje na ovarij i mogu antagonistički efekt centrorelixa povećati (prikaz 2). In GnRH-antagonist-treated animals, concentrations of 0.1 and 0.3 mg/per animal/day of compound 2 already show the same effect on the ovary as the used dose of 1 mg/per animal/day of estradiol (shown 1). Even lower dosages (0.01, 0.03 mg/per animal/day) show an effect on the ovary and can increase the antagonistic effect of centrorelix (shown 2).

[image] [image]

Pojašnjenje: Feuchtgewicht (%) = postotak vlažnosti Explanation: Feuchtgewicht (%) = percentage of humidity

Prikaz 1: Promjena težine ovarija pod utjecajem jednog GnRH-antagonista kod tretmana sa estradiolom (Sub 3) ili različitim doziranjem spoja 2 Figure 1: Changes in ovarian weight under the influence of one GnRH-antagonist during treatment with estradiol (Sub 3) or different dosing of compound 2

[image] [image]

Pojašnjenje: Feuchtgewicht (%) = postotak vlažnosti Explanation: Feuchtgewicht (%) = percentage of humidity

Prikaz 2: Pozitivni efekt spoja 2 u niskim dozama na težinu ovarija za vrijeme jednog kombiniranog tretmana sa GnRH-antagonistom Centrorelix. Figure 2: Positive effect of compound 2 in low doses on ovarian weight during one combined treatment with the GnRH-antagonist Centrorelix.

Time pokazuje i izumom predočena supstanca 2 jedno znatno pozitivno djelovanje na ovarij, pri čemu dozrijevanje folikula stimulira i stoga je isto tako prikladna za tretman ženskog sub- i in-fertiliteta. Thus, the substance 2 presented by the invention also shows a significant positive effect on the ovary, whereby it stimulates the maturation of the follicles and is therefore also suitable for the treatment of female sub- and in-fertility.

Spravljanje izumom predočenih spojeva Preparation of the compounds presented by the invention

U spravljanju izumom predočenih spojeva opće formule I biti će prije svega 2 generalno primjenjive strategije sinteza primjenjene. In the preparation of the compounds of the general formula I presented by the invention, 2 generally applicable synthesis strategies will be applied.

S jedne strane dadau se posebno 3,16-zaštićeni “potomci” estra-1,3,5(10)-trien-3,16ξ-diola, isto tako i slobodni dioli, za modifikacije pojedinih pozicija steroidnog kostura upotrijebiti. On the one hand, especially 3,16-protected "descendants" of ester-1,3,5(10)-triene-3,16ξ-diol, as well as free diols, can be used to modify certain positions of the steroid skeleton.

S druge strane nude odgovarajuće modificirani estroanalozi, koji u velikom broju na poznati način [egzemplarni postupci sinteze, vidi J. Chem. Soc. Perk. 1, 1973, 2095 za C(9); Steroids 54, 1989, 71 za C(7)] mogu biti dobiveni, preko transpozicije kisikove kunkcionalnosti (Z. Chem. 1970, 221) od C(17) prema C(16) jedan fleksibilan prilaz k izumom predočenim spojevima. On the other hand, they offer suitably modified estrogen analogs, which in large numbers in a known manner [for exemplary synthesis procedures, see J. Chem. Soc. Perk. 1, 1973, 2095 for C(9); Steroids 54, 1989, 71 for C(7)] can be obtained, via transposition of the oxygen functionality (Z. Chem. 1970, 221) from C(17) to C(16), a flexible approach to the compounds of the invention.

Za slučaj 3-metiletera slijedi nakon prevođenja ketona u jedan sulfonilhidrazon, u najjednostavnijem slučaju prevođenjem sa fenilsulfonhidrazidom, u jednoj reakciji razgradnje, do stvaranja C(16)-C(17)olefina (Z. Chem. 1970, 10, 221ff; Liebigs Ann. Chem. 1981, 1973ff), na in regio / stereokontrolirani način, gdje hipobromid bude nataložen. Reduktivno dehalogeniranje i odstranjivanje zaštitnih skupina na C(3) daju 16β-alkohol, prema poznatoj metodi u kojoj 16α-epimer može biti preveden. In the case of 3-methylether, it follows the conversion of the ketone into a sulfonylhydrazone, in the simplest case, by conversion with phenylsulfonhydrazide, in one decomposition reaction, to the formation of a C(16)-C(17)olefin (Z. Chem. 1970, 10, 221ff; Liebigs Ann . Chem. 1981, 1973ff), in an in regio / stereocontrolled manner, where the hypobromide is deposited. Reductive dehalogenation and deprotection at C(3) give the 16β-alcohol, according to a known method in which the 16α-epimer can be converted.

Jedna od daljnjih varijanti za uvođenje hidroksilne skupine na C-atom 16 sastoji se u hidroboriranju 16(17)-dvostruke veze sa sterično zahtjevnim boranima. Prije te reakcije je poznato, da ona k 16-oksigeniranim produktima vodi (Indian J. Chem. 1971, 9, 287-8). Tome odgovarajuće daje prevođenje estra-1,3,5(10),16-tetraena sa primjerice 9-borabiciklo[3.3.1]nonanom nakon oksidacije s alkaličnim vodik-peroksidom, 16α-hidroksiestratriene. U manjoj mjeri biti će kod te reakcije epimerni 16β-hidroksisteroidi stvoreni. Nakon odcjepljenja 3-metoksiskupine biti će estra-1,3,5(10)-trien-3,16α-dioli dobiveni. Preko inverzije konfiguracije na C-atomu 16, npr. preko Mitsunobu-reakcije (Synthesis 1980, 1) biti će 16β-hidroksiestratrieni dobiveni. One of the further variants for the introduction of a hydroxyl group on C-atom 16 consists in the hydroboration of the 16(17)-double bond with sterically demanding boranes. Before this reaction, it was known that it leads to 16-oxygenated products (Indian J. Chem. 1971, 9, 287-8). This corresponds to the translation of estra-1,3,5(10),16-tetraene with, for example, 9-borabicyclo[3.3.1]nonane after oxidation with alkaline hydrogen peroxide, 16α-hydroxyestratriene. Epimeric 16β-hydroxysteroids will be created in this reaction to a lesser extent. After the separation of the 3-methoxy group, ester-1,3,5(10)-triene-3,16α-diols will be obtained. Through the inversion of the configuration at C-atom 16, for example through the Mitsunobu reaction (Synthesis 1980, 1), 16β-hydroxyestratrienes will be obtained.

Za daljnje mogućnosti spravljanja C16(17) olefinskih intermedijara pogledaj DE 199 06 159 A1. For further possibilities of making C16(17) olefinic intermediates see DE 199 06 159 A1.

Uvođenje fluornih supstituenata slijedi preko nukleofilnih supstitucijskih reakcija hidroksi skupina sa fluoraminskim reagencijama (Org. React. 1974, 21, 158-173). Ako će hidroksi skupine prije toga biti prevedene u odgovarajuće tozilate, tada će fluorirani spojevi biti dobiveni prevođenjem sa tetra-n-butilamonijfluoridom (J. Chem. Res. (M) 1979, str. 4728-4755). Isto tako dostupni su spojevi fluora preko reakcije odgovarajućih alkohola sa dietilaminosumpor-trifluoridom (DAST) (US 3 976 691). Geminalni difluorspojevi biti će primjerice preko reakcije karbonilnih spojeva sa sumportetrafluoridom (US 3 413 321) ili dimetilaminosumpor-trifluoridom (DAST) spravljeni (US 3 976 691). The introduction of fluorine substituents follows via nucleophilic substitution reactions of hydroxy groups with fluoramine reagents (Org. React. 1974, 21, 158-173). If the hydroxy groups will be previously converted to the corresponding tosylates, then the fluorinated compounds will be obtained by conversion with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, pp. 4728-4755). Also available are fluorine compounds via the reaction of the corresponding alcohols with diethylaminosulfur trifluoride (DAST) (US 3,976,691). Geminal difluoro compounds will be prepared, for example, by reacting carbonyl compounds with sulfur tetrafluoride (US 3 413 321) or dimethylaminosulfur trifluoride (DAST) (US 3 976 691).

Za sintezu izumom predočenih 9α-supstituiranih 17β-fluorestra-1,3,5(10)-trien-3,16-diola, biti će 17-okso-estra1,3,5(10)-trieni u 17,17-difluorestra-1,3,5(10)-triene prevedeni (US 3 976 691). Tako dostupni 17,17-difluorestra-1,3,5(10)-trieni biti će preko tretmana sa aluminijoksidom u 17-fluorestra-1,3,5(10),16-tetraene pretvoreni (US 3 413 321). Jedna daljnja mogućnost za spravljanje fluorolefina sastoji se u prevođenju odgovarajućih ketona sa dietilaminosumpor-trifluoridom (DAST) u prisutnosti polarnih katalizatora, kao dimna sumporna kiselina (US 4 212 815). Pretvaranje 17-fluorestra-1,3,5(10),16-tetraena sa boranima i nastavna oksidacija sa alkaličnim vodik peroksidom daje 17β-fluorestra-1,3,5(10)-trien-16α-ole (Org. React. 1963, 13, 1-54). For the synthesis of the 9α-substituted 17β-fluoroester-1,3,5(10)-triene-3,16-diol presented by the invention, there will be 17-oxo-ester 1,3,5(10)-triene in 17,17-difluoroester -1,3,5(10)-triene translated (US 3,976,691). Thus available 17,17-difluoroestra-1,3,5(10)-trienes will be converted into 17-fluoroestra-1,3,5(10),16-tetraenes by treatment with aluminum oxide (US 3 413 321). A further possibility for the preparation of fluoroolefins consists in the conversion of the corresponding ketones with diethylaminosulfur trifluoride (DAST) in the presence of polar catalysts, such as fuming sulfuric acid (US 4 212 815). Conversion of 17-fluorestra-1,3,5(10),16-tetraene with boranes and further oxidation with alkaline hydrogen peroxide gives 17β-fluorestra-1,3,5(10)-trien-16α-ol (Org. React. 1963, 13, 1-54).

Prilaz k izumom predočenim 9α-alkenil-, odnosno 9α-alkinil-supstituiranim estra-1,3,5(10)-trien-3,16α-diolima slijedi najprije iz 3- i 16- pozicije zaštićenim 3,16-dihidroksi-estra-1,3,5(10)-trienima. Preko prevođenja sa trimetilsililcijanidom u prisutnosti litij perklorata slijedi regio- i stereoselektivno uvođenje jedne 9α-cijanogrupiranja (Synlett, 1992, 821-2). Nakon odcjepljenja zaštitnih skupina biti će 9α cijano spoj preko reakcije nadalje u jedan 9α-formilspoj i taj nastavno preko jedne Wittig-reakcije (Org. React. Vol. 14, 270) u 9α-alkinil-supstituirani spoj preveden. The approach to the 9α-alkenyl- and 9α-alkynyl-substituted ester-1,3,5(10)-triene-3,16α-diols presented in the invention follows first from the 3- and 16-position protected 3,16-dihydroxy-esters -1,3,5(10)-trienes. Regio- and stereoselective introduction of a single 9α-cyano group follows via translation with trimethylsilylcyanide in the presence of lithium perchlorate (Synlett, 1992, 821-2). After the removal of the protective groups, the 9α cyano compound will be further converted into a 9α-formyl compound and then converted into a 9α-alkynyl-substituted compound through a Wittig reaction (Org. React. Vol. 14, 270).

Izumom predočeni estratrien-sulfamati su na poznati način iz odgovarajućih hidroksi-steroida preko esterifikacije u prisutnosti jedne baze dostupni (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)). The estratriene-sulfamates presented by the invention are available in a known manner from the corresponding hydroxy-steroids via esterification in the presence of a base (Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)).

Aciliranje sulfamat skupine koje slijedi, vodi do izumom preočenih (N-acil)sulfamata. Za (N-acil)sulfamate bili su već farmakokinetičke prednosti dokazane (usporedi DE 195 40 233 A1). The acylation of the sulfamate group that follows leads to (N-acyl)sulfamates overlooked by the invention. Pharmacokinetic advantages have already been proven for (N-acyl)sulfamates (compare DE 195 40 233 A1).

Regioselektivno esterificiranje polihidroksiliranih steroida sa N-supstituiranim i N-nesupstituiranim sulfamoilkloridima slijedi prema parcijalnoj zaštiti onih hidroksilnih skupina, koje trebaju ostati neesterificirane. Kao zaštitne skupine, sa ovdje prikladnom selektivnom reaktivnošću, pokazali se se sililesteri, jer oni pod uvjetima sulfamat razgradnje jesu stabilni i sulfamat skupine ostaju intaktne, ako silileter do regeneriranja (preostalih) u molekuli još preostalih hidroksilskupina budu opet odcjepljene (Steroids 61, 710-717 (1996)). Regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides follows partial protection of those hydroxyl groups, which should remain unesterified. As protective groups, with the appropriate selective reactivity here, silyl esters have proven themselves, because they are stable under the conditions of sulfamate decomposition and the sulfamate groups remain intact, if the silyl ether is cleaved again until the (remaining) hydroxyl groups in the molecule are regenerated (Steroids 61, 710- 717 (1996)).

Spravljanje izumom predočenih sulfamata sa jednom dodatnom hidroksilnom skupinom u molekuli je isto tako moguće, da se od odgovarajućih hidroksi-steroidnih ketona polazi. Nadalje, biti će, već prema ciljnoj postavci, jedna ili više prisutnih hidroksilnih skupina jednom sulfamoiliranju podvedeno. Tada mogu sulfamat skupine isto tako sa jednim željenim acilkloridom u nazočnosti jedne baze u odgovarajući (N-acil)sulfamat biti prevedeni. Predočeni oksosulfamati ili okso-(N-acil)sulfamati biti će preko reakcije u odgovarajuće hidroksisulfamate odnosno hidroksi-(N-acil)sulfamate prevedeni (Steroids 61, 710-717 (1996)). Kao prikladna sredstva za redukciju dolaze natrijborhidrid i boran-dimetilsulfoksid-kompleks u obzir. Preparation of the sulfamates presented by the invention with one additional hydroxyl group in the molecule is also possible, starting from the corresponding hydroxy-steroid ketones. Furthermore, according to the target setting, one or more hydroxyl groups present will be subjected to sulfamoylation. Then the sulfamate groups can also be converted with one desired acyl chloride in the presence of a base into the corresponding (N-acyl)sulfamate. The presented oxosulfamates or oxo-(N-acyl)sulfamates will be converted into corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates through a reaction (Steroids 61, 710-717 (1996)). Suitable reducing agents are sodium borohydride and borane-dimethylsulfoxide-complex.

Slijedeći primjeri služe bližem pojašnjenju izuma. The following examples serve for a closer explanation of the invention.

Analogno izgradnji 9α-vinil grupiranja mogu zu primjenu homolognih reagencija do, u primjerima opisanim reagensima, daljnji spojevi opće formule I biti dobiveni. Analogous to the construction of 9α-vinyl grouping, further compounds of the general formula I can be obtained by using homologous reagents until, in the examples described with the reagents.

Eterifikacija i/ili esterifikacija slobodnih hidroksi skupina slijedi prema struci prikladnim metodama. Etherification and/or esterification of free hydroxy groups is carried out according to methods suitable to those skilled in the art.

Primjer 1 Example 1

9α-vinilestra-1,3,5(10)-trien-3,16α-diol 9α-vinyl ester-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

9α-cijano-3-metoksi-estra-1,3,5(10)-trien-16α-il-acetat 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate

Suspenziji iz 2,13 g (6,49 mmol) 3-metoksi-estra-1,3,5(10)-trien-16α-il-acetata, 2,07 ml (16,54 mmol) trimetilsililcijanida i 0,14 g litijperklorata u 100 ml metilenklorida doda se zu miješanje dokapavanjem jedna otopina od 2,21 g (9,73 mmol) 2,3-diklor-5,6-dicijano-1,4-benzoekinona u 80 ml metilenklorida. Reakcijska mješavina se oboji zeleno. Nakon 1 sata reakcijskog vremena, kod sobne temperature, biti će mješavina sa otopinom natrijhidrogenkarbonata pomiješana. Odvojena organska faza se ispere sa vodom i reducira volumen. Mješavina produkta biti će na Kieselgelu (cikloheksan/octeni ester, 6/1) kromatografirana. Dobije se 0,44 g (21%) 9α-cijano-3-metoksi-estra-1,3,5(10)-trien-16α-il-acetata. A suspension of 2.13 g (6.49 mmol) of 3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate, 2.07 ml (16.54 mmol) of trimethylsilylcyanide and 0.14 g of lithium perchlorate in 100 ml of methylene chloride is added dropwise with stirring to a solution of 2.21 g (9.73 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 80 ml of methylene chloride. The reaction mixture turns green. After 1 hour of reaction time, at room temperature, the mixture will be mixed with sodium hydrogencarbonate solution. The separated organic phase is washed with water and the volume is reduced. The product mixture will be chromatographed on Kieselgel (cyclohexane/acetic ester, 6/1). 0.44 g (21%) of 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate is obtained.

Stupanj 2 Degree 2

9α-cijano-3-hidroksi-estra-1,3,5(10)-trien-16α-il-acetat 9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate

Otopini iz 0,59 g (1,67 mmol) 9α-cijano-3-metoksi-estra-1,3,5(10)-trien-16α-il-acetata u 30 ml acetonitrila, doda se zu miješanje u atmosferi zasićenoj argonom, 7,51 g (50,1 mmol) natrijjodida i 8,87 ml (70,14 mmol) trimetilklorsilana. Nakon ca. 3 sata na 60-70ºC reakcija je prekinuta. Reakcijska mješavina će biti dodana u otopinu natrijhidrogensulfita i ekstrahirana sa octenim esterom. Organska faza će biti više puta isprana vodom, sušena nad MgSO4 i volumen reduciran do suha. A solution of 0.59 g (1.67 mmol) of 9α-cyano-3-methoxy-estra-1,3,5(10)-trien-16α-yl-acetate in 30 ml of acetonitrile was added with stirring in an atmosphere saturated argon, 7.51 g (50.1 mmol) of sodium iodide and 8.87 ml (70.14 mmol) of trimethylchlorosilane. After approx. 3 hours at 60-70ºC, the reaction is stopped. The reaction mixture will be added to sodium hydrogen sulfite solution and extracted with ethyl acetate. The organic phase will be washed several times with water, dried over MgSO4 and the volume reduced to dryness.

Sirovi produkt će biti na Kieselgelu (cikloheksan/octeni ester, 4/1) kromatografiran. Dobije se 0,43 g (76%) produkta. The crude product will be chromatographed on Kieselgel (cyclohexane/acetic ester, 4/1). 0.43 g (76%) of the product is obtained.

Stupanj 3 Degree 3

3,16α-dihidroksiestra-1,3,5(10)-trien-9-karbonitril 3,16α-dihydroxyester-1,3,5(10)-triene-9-carbonitrile

Na sobnoj temp., biti će 0,43 g (1,27 mmol) 9α-cijano-3-hidroksi-estra-1,3,5(10)-trien-16α-il-acetata sa 1,0 g (7,24 mmol) kalijkarbonata u 40 ml Metanola (1% vode), 2 sata miješano. Nastavno, oddestilira se metanol, a org. produkt se otopi u metilenkloridu. Org. faza se ispere vodom i reducira. Dobije se 3,5 g (93%) 9α-cijano-estra-1,3,5(10)-trien-3,16α-diola. At room temp., there will be 0.43 g (1.27 mmol) of 9α-cyano-3-hydroxy-estra-1,3,5(10)-trien-16α-yl-acetate with 1.0 g (7 .24 mmol) of potassium carbonate in 40 ml of methanol (1% water), stirred for 2 hours. Next, methanol is distilled off, and org. the product is dissolved in methylene chloride. Org. phase is washed with water and reduced. 3.5 g (93%) of 9α-cyano-ester-1,3,5(10)-triene-3,16α-diol is obtained.

Stupanj 4 Degree 4

3,16α-dihidroksiestra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde

Jedna suspenzija iz 100 mg (0,34 mmol) 3,16α-dihidroksiestra-1,3,5(10)-trien-9-karbonitrila u 40 ml toluola, biti će zu miješanje na ca. -20ºC ohlađena. Nakon dodatka 0,9 ml (1,35 mmol) diizobutilaluminijhidrida, biti će reakcija nakon ca. 10 min sa otopinom natrijhidrogenkarbonata pomijaša, preko celita filtrirana i pomoćno sredstvo za filtriranje sa octenim esterom dodatno ekstrahirano. Sjedinjene org. faze biti će sa vodom isprane. Reduciranjem otopine u volumenu, dobije se 84,6 mg jedne svjetlo žute pjene. U mješavini sadržani produkti odgovaraju iskoreštenosti od ca. 52% Th i biti će bez dodatnog kromatografskog pročišćavanja u slijedeću stepenicu uključena. A suspension of 100 mg (0.34 mmol) of 3,16α-dihydroxyester-1,3,5(10)-triene-9-carbonitrile in 40 ml of toluene, will be stirred at ca. -20ºC cooled. After the addition of 0.9 ml (1.35 mmol) of diisobutylaluminum hydride, there will be a reaction after approx. It is mixed with sodium hydrogencarbonate solution for 10 min, filtered through celite and the filter aid with acetic ester is additionally extracted. United org. phases will be washed with water. By reducing the solution in volume, 84.6 mg of a light yellow foam is obtained. The products contained in the mixture correspond to the utilization of approx. 52% Th and will be included in the next step without additional chromatographic purification.

Stupanj 5 Grade 5

9α-vinilestra-1,3,5(10)-trien-3,16α-diol 9α-vinyl ester-1,3,5(10)-triene-3,16α-diol

U atmosferi inertnih plinova, biti će 3,1 g (7,9 mmol) trifenilmetilfosfonijjodida i 0,24 g (8 mmol) natrijhidrida (80%-ni u parafinskom ulju) u 20 ml DMSO u ultravioletnoj kupelji, biti će dovedeno do reakcije na 55ºC. Nakon 10 minuta doda se otopini 80 mg (0,16 mmol, ca. 60%) 3,16α-dihidroksiestra-1,3,5(10)-trien-9-karbaldehid i mješavina se ostavi još 60 min. na ca. 55ºC u ultravioletnoj kupelji reagirati. Nakon dodatka vode, biti će sa octenim esterom ekstrahirano. Sakupljene org. faze ispiru se s vodom, a org. faza se reducita. Under an inert gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethylphosphonium iodide and 0.24 g (8 mmol) of sodium hydride (80% in paraffin oil) in 20 ml of DMSO in an ultraviolet bath will be reacted at 55ºC. After 10 minutes, 80 mg (0.16 mmol, ca. 60%) of 3,16α-dihydroxyester-1,3,5(10)-triene-9-carbaldehyde was added to the solution and the mixture was left for another 60 minutes. at approx. 55ºC in an ultraviolet bath to react. After adding water, it will be extracted with acetic ester. Collected org. phases are washed with water, and org. phase is reduced.

Sirovi produkt će biti kromatografijom na koloni na Kieselgelu; (cikloheksan/octeni ester, 2/1) i nastavno prekristalizacijom iz kloroforma pročišćena. Iskorištenost: 24 mg (50%), točka taljenja 88-95ºC. The crude product will be chromatographed on a Kieselgel column; (cyclohexane/acetic ester, 2/1) and further purified by recrystallization from chloroform. Yield: 24 mg (50%), melting point 88-95ºC.

1H-NMR (400 MHz, DMSO-d6, TMS): 9,00 (s, 3-OH); 6,98 (d, J = 8,6 Hz, H-1); 6,49 (dd, J = 8,6/2,7 Hz, H-2); 6,41 (d, J = 2,7 Hz, H-4); 6,25 (dd, J = 17,2/10,5 Hz, -CH=CH2); 5,00 (dd, 10,5/1,9 Hz, -CH=CH2); 4,47 (d, 4,69 Hz, 16α-OH); 4,45 (dd, 17,2/1,9 Hz, -CH=CH2); 4,24 (m, 16β-H); 2,68 (m, H-6); 0,69 (s, H-18) 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 9.00 (s, 3-OH); 6.98 (d, J = 8.6 Hz, H-1); 6.49 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 6.25 (dd, J = 17.2/10.5 Hz, -CH=CH2); 5.00 (dd, 10.5/1.9 Hz, -CH=CH2); 4.47 (d, 4.69 Hz, 16α-OH); 4.45 (dd, 17.2/1.9 Hz, -CH=CH2); 4.24 (m, 16β-H); 2.68 (m, H-6); 0.69 (s, H-18)

Primjer 2 Example 2

9α-vinil-18a-hono-estra-1,3,5(10)-trien-3,16α-diol 9α-vinyl-18a-hono-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

1,03 g (2,26 mmol) 3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-triena, 48,2 mg (0,45 mmol) litijperklorata i 0,71 ml (5,66 mmol) trimetilsililcijanida biti će u 10 ml metilenklorida (molekularno sito) potopljeno i pod inertnim plinom na ca. -70ºC zu miješanje ohlađeno. Nastavno se dokapa 0,77 g (3,39 mmol) 2,3-diklor-5,6-dicijano-1,4-benzokinona, otopljenog u 65 ml metilenklorida, u roku od 1 sata. Nakon 1 sata ( zagrijavanje na sobnu temp.) biti će reakcijska mješavina sa otopinom natrijhirogenkarbonata pomiješana, a reakcijski produkti sa metilenkloridom ekstrahirani. Redukcijom org. faze dobiveni sirovi produkt, biti će kromatografski pročišćen. Nakon kromatografije na Kieselgelu (cikloheksan/octeni ester, 4/1), dobije se 0,74 g (68%, teoretski) produkta. 1.03 g (2.26 mmol) 3,16α-bi[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene, 48.2 mg (0, 45 mmol) of lithium perchlorate and 0.71 ml (5.66 mmol) of trimethylsilylcyanide will be immersed in 10 ml of methylene chloride (molecular sieve) and under inert gas at approx. -70ºC zu mixing cooled. 0.77 g (3.39 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dissolved in 65 ml of methylene chloride, was added dropwise over the course of 1 hour. After 1 hour (heating to room temperature), the reaction mixture will be mixed with sodium hydrogencarbonate solution, and the reaction products with methylene chloride will be extracted. By reducing org. stage, the raw product obtained will be chromatographically purified. After chromatography on Kieselgel (cyclohexane/acetic ester, 4/1), 0.74 g (68%, theoretical) of the product is obtained.

Stupanj 2 Degree 2

3,16α-dihidroksi-18a-homo-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde

1,3 g (2,7 mmol) 3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-trien-9-karbonitril, biti će u 40 ml toluola otopljeno i na sobnoj temp. pod inertnim plinom sa 7,2 ml (10,8 mmol) otopine diizobutilaluminijhidrida (1,5 M u toluolu) pomiješana. Nakon vremena reakcije od 30 min , doda se reakcijskoj otopini jedna mješavina iz 30 ml metanola i 5 ml razrijeđene solne kiseline (1/1). Reakcijska otopina će u vakumu biti reducirana i ostatak u octenom esteru otopljena. Dobivena org. faza ekstrahira se s vodom i ispire s otopinom natrijhidrogen karbonata. 1.3 g (2.7 mmol) of 3,16α-bi[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile, will be in 40 ml of toluene dissolved and at room temperature. under inert gas with 7.2 ml (10.8 mmol) of a solution of diisobutylaluminum hydride (1.5 M in toluene) was mixed. After a reaction time of 30 min, a mixture of 30 ml of methanol and 5 ml of diluted hydrochloric acid (1/1) is added to the reaction solution. The reaction solution will be reduced in a vacuum and the residue will be dissolved in acetic ester. Obtained org. phase is extracted with water and washed with sodium hydrogen carbonate solution.

Nakon sušenja otapala i redukcije u vakumu, biti će 0,73 g (86% teortski) žutih kristala dobiveno. After drying of the solvent and reduction in vacuum, 0.73 g (86% of theory) of yellow crystals will be obtained.

Stupanj 3 Degree 3

9α-vinil-18a-homo-estra-1,3,5(10)-trien-3,16α-diol 9α-vinyl-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

U atmosferi inertog plina, biti će 13,7 g (34,8 mmol) triefenilemtil-fosfonijjodida i 1,0 g (34,8 mmol) natrijhidrida (ca. 80% na parafinskom ulju) u 80 ml DMSO u ultravioletnoj kupelji, na ca. 50ºC dovedeno u reakciju. Nakon 30 min. doda se 0,73 g (2,3 mmol) 3,16α-dihidroksi-18a-homo-estra-1,3,5(10)-trien-9-karbaldehida, otopljenog u 10 ml DMSO, k reakcijskoj otopini i ostavi se mješavinu daljnjih 60 min u ultravioletnoj kupelji reagira. Nakon dodatka vode biti će ekstrahirano sa octenim esterom, org. faza s vodom isprana, osušena i reducirana. Under an inert gas atmosphere, there will be 13.7 g (34.8 mmol) of triphenylemthylphosphonium iodide and 1.0 g (34.8 mmol) of sodium hydride (ca. 80% in paraffin oil) in 80 ml of DMSO in an ultraviolet bath, at what. 50ºC brought to the reaction. After 30 min. add 0.73 g (2.3 mmol) of 3,16α-dihydroxy-18a-homo-ester-1,3,5(10)-triene-9-carbaldehyde, dissolved in 10 ml of DMSO, to the reaction solution and leave the mixture is reacted for another 60 min in an ultraviolet bath. After adding water, it will be extracted with acetic ester, org. phase with water washed, dried and reduced.

Sirovi produkt se pročišćava preko kromatografije na koloni s Kieselgelom (cikloheksan/octeni ester, 2/1) i kristalizira iz kloroforma. The crude product is purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 2/1) and crystallized from chloroform.

Iskoristivost: 0,59 g (81% teoretski) nakon kromatografije Yield: 0.59 g (81% theoretical) after chromatography

Talište: 214-220ºC Melting point: 214-220ºC

1H-NMR (400 MHz, DMSO-d6, TMS): 9,00 (s, 3-OH); 6,96 (d, J = 8,6 Hz, H-1); 6,49 (dd, J = 8,6/2,7 Hz, H-2); 6,41 (d, J = 2,7 Hz, H-4); 6,29 (dd, J = 17,2/10,5 Hz, -CH=CH2); 5,00 (dd, 10,5/1,9 Hz, -CH=CH2); 4,48 (d, J= 4,7 Hz, 16α-OH); 4,43 (dd, J = 17,2/1,9 Hz, -CH=CH2); 4,18 (m, 16β-H); 2,68 (m, H-6); 0,72 (t, J = 6,8 Hz, H-18a) 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 9.00 (s, 3-OH); 6.96 (d, J = 8.6 Hz, H-1); 6.49 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 6.29 (dd, J = 17.2/10.5 Hz, -CH=CH2); 5.00 (dd, 10.5/1.9 Hz, -CH=CH2); 4.48 (d, J= 4.7 Hz, 16α-OH); 4.43 (dd, J = 17.2/1.9 Hz, -CH=CH2); 4.18 (m, 16β-H); 2.68 (m, H-6); 0.72 (t, J = 6.8 Hz, H-18a)

Primjer 3 Example 3

9α-(2',2'-difluorvinil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(2',2'-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-triena, analogno primjeru 1, stupnju 1, daje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitril. Iskorištenost: 58% teoretski. Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene, analogously to Example 1, step 1, gives 3,16α-bi[(perhydropyran-2-yl )oxy]-ester-1,3,5(10)-triene-9-carbonitrile. Utilization: 58% theoretical.

Stupanj 2 Degree 2

3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-ester-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitrila, analogno primjeru 1, stupanj 2 daje 3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile, analogously to example 1, step 2 gives 3,16α-dihydroxy-estra-1 ,3,5(10)-triene-9-carbaldehyde;

Iskorištenost: 83% teoretski Utilization: 83% theoretical

Stupanj 3 Degree 3

9α-(2,2-difluorvinil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

U jednoj inertiziranoj reakcijskoj tikvici, biti će 1,5 ml dimetoksietana (molekularno sito), 0,3 ml pentana i 0,13 ml (0,77 mmol) dietil(difluormetil)-fosfonata natopljeno i na ca. -75ºC ohlađeno. Nakon dodatka 0,72 ml (1,07 mmol) terc.-butillicija (1,5 M u pentanu) i 30 minuta reakcijskog vremena, doda se u reakcijsku mješavinu 0,14 g (0,31 mmol) 3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehida otopljenog u jednoj mješavini od 1,5 ml dimetoksietana / 0,3 ml pentana. Reakcijska otopina će biti do potpunog kraja reakcije na povratnom hladilu zagrijavana. Nakon dodatka u hlađenu otopinu amonij klorida, ekstrahira se s octenim esterom. Org. faza će biti u vakumu reducirana, ostatak u 5 ml metanola otopljen i sa 0,5 ml razrijeđene solne kiseline (1/1) pomiješana. Reakcijskoj otopini se doda octeni ester, org. faza se ispere sa otopinom natrijhidrogenkarbonata i reducira u vakumu. Dobiveni sirovi produkt će biti preko kromatografije na koloni s Kieselgelom (cikloheksan/octeni ester, 2/1) pročišćen. In one inertized reaction flask, there will be 1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl(difluoromethyl)-phosphonate soaked and at ca. -75ºC cooled. After the addition of 0.72 ml (1.07 mmol) of tert.-butyllithium (1.5 M in pentane) and 30 minutes of reaction time, 0.14 g (0.31 mmol) of 3,16α-dihydroxy is added to the reaction mixture -ester-1,3,5(10)-triene-9-carbaldehyde dissolved in a mixture of 1.5 ml dimethoxyethane / 0.3 ml pentane. The reaction solution will be heated until the end of the reaction on the return cooler. After addition to the cooled ammonium chloride solution, it is extracted with acetic ester. Org. phase will be reduced in a vacuum, the residue dissolved in 5 ml of methanol and mixed with 0.5 ml of diluted hydrochloric acid (1/1). Acetic ester, org., is added to the reaction solution. the phase is washed with sodium hydrogencarbonate solution and reduced in a vacuum. The crude product obtained will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 2/1).

Iskorištenost: 22 mg (21% teoretski) Utilization: 22 mg (21% theoretical)

1H-NMR (400 MHz, DMSO-d6, TMS): 9,08 (s, 3-OH); 7,10 (d, J = 8,6 Hz, H-1); 6,51 (dd, J = 8,6/2,3 Hz, H-2); 6,41 (d, J = 2,3 Hz, H-4); 4,76 (dd, J = 25,4/10,9 Hz, -CH=CH2); 4,51 (d, J = 4,69 Hz, 16α-OH); 4,25 (m, 16β-H); 2,68 (m, H-6); 0,68 (s, H-18). 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 9.08 (s, 3-OH); 7.10 (d, J = 8.6 Hz, H-1); 6.51 (dd, J = 8.6/2.3 Hz, H-2); 6.41 (d, J = 2.3 Hz, H-4); 4.76 (dd, J = 25.4/10.9 Hz, -CH=CH2); 4.51 (d, J = 4.69 Hz, 16α-OH); 4.25 (m, 16β-H); 2.68 (m, H-6); 0.68 (s, H-18).

Primjer 4 Example 4

9α-(2',2'-difluorvinil)-18a-homo-estra-1,3,5(10)-trien-3,16α-diol 9α-(2',2'-difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

Prevođenje 3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-triena, analogno primjeru 1, stupnju 1 daje 3,16α-bi[(perhidropiran-2-il)oksi]-18a-homoestra-1,3,5(10)-trien-9-karbonitril Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene, analogously to Example 1, step 1 gives 3,16α-bi[(perhydropyran- 2-yl)oxy]-18a-homoester-1,3,5(10)-triene-9-carbonitrile

Iskorištenost: 58% teoretski Utilization: 58% theoretical

Stupanj 2 Degree 2

3,16α-dihidroksi-18a-homo-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-18a-homo-estra-1,3,5(10)-trien-9-karbonitril analogno primjeru 1, stupnju 2 daje 3,16α-dihidroksi-18a-homo-estra-1,3,5(10)-trien-9-karbaldehid Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-18α-homo-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 1, step 2 gives 3,16α-dihydroxy- 18a-homo-ester-1,3,5(10)-triene-9-carbaldehyde

Iskorištenost: 87% teoretski Utilization: 87% theoretical

Stupanj 3 Degree 3

9α-(2,2-difluorvinil)-18a-homo-estra-1,3,5(10)-trien-3,16α-diol 9α-(2,2-difluorovinyl)-18α-homo-estra-1,3,5(10)-triene-3,16α-diol

Pretvaranje 3,16α-dihidroksi-18a-homo-estra-1,3,5(10)-trien-9-karbaldehida; reakcijski uvjeti i provedba kao i molarno odnosi kao kod stupnja 3. Stupanj 9α-(2,2-difluorvinil)-estra-1,3,5(10)-trien-3,16α-diol Conversion of 3,16α-dihydroxy-18a-homo-ester-1,3,5(10)-triene-9-carbaldehyde; reaction conditions and implementation as well as molar ratios as in step 3. Step 9α-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

Sirovi produkt će biti kromatografijom na koloni s Kieselgelom (cikloheksan/octeni ester, 2/1) i kristalizacijom iz octenog estera pročišćen. The crude product will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 2/1) and by crystallization from ethyl acetate.

Iskorištenost: 12% teoretski Utilization: 12% theoretical

Talište: 225-232ºC Melting point: 225-232ºC

1H-NMR (400 MHz, DMSO-d6, TMS): 9,06(s, 3-OH); 7,08 (d, J = 8,6 Hz, H-1); 6,50 (dd, J = 8,6/2,7 Hz, H-2); 6,41 (d, J = 2,7 Hz, H-4); 4,78 (dd, J = 21,5/14,8 Hz, -CH=CF2); 4,47 (d, J = 4,50 Hz, 16α-OH); 4,18 (m, 16β-H); 2,68 (m, H-6); 0,72 (t, J = 6,8 Hz, H-18a). 1H-NMR (400 MHz, DMSO-d6, TMS): 9.06(s, 3-OH); 7.08 (d, J = 8.6 Hz, H-1); 6.50 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 4.78 (dd, J = 21.5/14.8 Hz, -CH=CF2); 4.47 (d, J = 4.50 Hz, 16α-OH); 4.18 (m, 16β-H); 2.68 (m, H-6); 0.72 (t, J = 6.8 Hz, H-18a).

Primjer 5 Example 5

17β-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-17β-fluor-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene-9-carbonitrile

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-17β-fluor-estra-1,3,5(10)-triena, analogno primjeru 2, stupnju 1, daje 3,16α-bi[(perhidropiran-2-il)oksi]-17β-fluor-estra-1,3,5(10)-trien-9-karbonitrila; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene, analogously to Example 2, step 1, gives 3,16α-bi[(perhydropyran -2-yl)oxy]-17β-fluoro-ester-1,3,5(10)-triene-9-carbonitrile;

Iskorištenost: 45% teoretski Utilization: 45% theoretical

Stupanj 2 Degree 2

3,16α-dihidroksi-17β-fluor-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-17β-fluor-estra-1,3,5(10)-trien-9-karbonitrila analogno primjeru 2, stupnju 2 daje 3,16α-dihidroksi-17β-fluor-estra-1,3,5(10)-trien-9-karbaldehid; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-17β-fluoro-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 2, step 2 gives 3,16α-dihydroxy- 17β-fluoro-estra-1,3,5(10)-triene-9-carbaldehyde;

Iskorištenost: 83% teoretski Utilization: 83% theoretical

Stupanj 3 Degree 3

17β-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Pretvaranje 3,16α-dihidroksi-17β-fluor-estra-1,3,5(10)-trien-9-karbaldehida analogno primjeru 2, stupnju 3 daje 17β-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diola. Conversion of 3,16α-dihydroxy-17β-fluoro-ester-1,3,5(10)-triene-9-carbaldehyde analogously to Example 2, step 3 gives 17β-fluoro-9α-vinyl-ester-1,3,5( 10)-triene-3,16α-diol.

Sirovi produkt će biti kromatografijom na koloni s Kieselgelom (cikloheksan/octeni ester, 2/1) i kristalizacijom iz kloroforma pročišćen. The crude product will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 2/1) and crystallization from chloroform.

Iskorištenost: 51% teoretski Utilization: 51% theoretical

Talište: 94-98ºC Melting point: 94-98ºC

1H-NMR (400 MHz, DMSO-d6, TMS): 9,02 (s, 3-OH); 6,97 (d, J = 8,2 Hz, H-1); 6,51 (dd, J = 8,2/2,7 Hz, H-2); 6,42 (d, J = 2,7 Hz, H-4); 6,22 (dd, J = 17,2/10,5 Hz, -CH=CH2); 5,09 (d, J 5,5/1,9 Hz, 16α-OH); 5,01 (dd, J= 10,5/1,9 Hz, -CH=CH2 ); 4,45 (dd, J = 17,2/1,9 Hz, -CH=CH2); 4,35 (dd, J = 55,1/4,7 Hz, H-17α); 4,11 (m, 16β-H); 2,68 (m, H-6); 0,79 (d, J = 1,9 Hz, H-18) 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 9.02 (s, 3-OH); 6.97 (d, J = 8.2 Hz, H-1); 6.51 (dd, J = 8.2/2.7 Hz, H-2); 6.42 (d, J = 2.7 Hz, H-4); 6.22 (dd, J = 17.2/10.5 Hz, -CH=CH2); 5.09 (d, J 5.5/1.9 Hz, 16α-OH); 5.01 (dd, J= 10.5/1.9 Hz, -CH=CH2 ); 4.45 (dd, J = 17.2/1.9 Hz, -CH=CH2); 4.35 (dd, J = 55.1/4.7 Hz, H-17α); 4.11 (m, 16β-H); 2.68 (m, H-6); 0.79 (d, J = 1.9 Hz, H-18)

Primjer 6 Example 6

17,17-difluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 17,17-difluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-17,17-difluor-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-17,17-difluor-estra-1,3,5(10)-triena, analogno primjeru 2, stupnju 1, daje 3,16α-bi[(perhidropiran-2-il)oksi]-17,17-difluor-estra-1,3,5(10)-trien-9-karbonitrila; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene, analogously to Example 2, step 1, gives 3,16α-bi[ (perhydropyran-2-yl)oxy]-17,17-difluoro-estra-1,3,5(10)-triene-9-carbonitrile;

Iskorištenost: 46% teoretski Utilization: 46% theoretical

Stupanj 2 Degree 2

3,16α-dihidroksi-17,17-difluor-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-17,17-difluoro-ester-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-17,17-difluor-estra-1,3,5(10)-triena-9-karbonitrila, analogno primjeru 2, stupnju 2, daje 3,16α-dihidroksi-17,17-difluor-estra-1,3,5(10)-trien-9-karbaldehid; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-17,17-difluoro-ester-1,3,5(10)-triene-9-carbonitrile, analogously to Example 2, step 2, gives 3, 16α-dihydroxy-17,17-difluoro-ester-1,3,5(10)-triene-9-carbaldehyde;

Iskorištenost: 88% teoretski Utilization: 88% theoretical

Stupanj 3 Degree 3

17,17-difluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 17,17-difluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol

Pretvaranje 3,16α-dihidroksi-17,17-difluor-estra-1,3,5(10)-triena-9-karbaldehida, analogno primjeru 2, stupnju 3, daje 17,17-difluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol; Conversion of 3,16α-dihydroxy-17,17-difluoro-ester-1,3,5(10)-triene-9-carbaldehyde, analogously to Example 2, step 3, gives 17,17-difluoro-9α-vinyl-ester- 1,3,5(10)-triene-3,16α-diol;

Sirovi produkt će biti kromatografijom na koloni s Kieselgelom (cikloheksan/octeni ester, 2/1) i kristalizacijom iz kloroforma pročišćen. The crude product will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 2/1) and crystallization from chloroform.

Iskorištenost: 75% teoretski Utilization: 75% theoretical

1H-NMR (400 MHz, DMSO-d6, TMS): 7,08 (d, J = 8,6 Hz, H-1); 6,63 (dd, J = 8,6/2,7 Hz, H-2); 6,54 (d, J = 2,7 Hz, H-4); 6,23 (dd, J = 17,2/10,5 Hz, -CH=CH2); 5,08 (dd, J 10,5/1,9 Hz, -CH=CH2); 4,48 (dd, J= 17,2/1,9 Hz, -CH=CH2 ); 4,44 (m, 16β-H); 2,79 (m, H-6); 0,95 (d, J = 1,9 Hz, H-18) 1H-NMR (400 MHz, DMSO-d6, TMS): 7.08 (d, J = 8.6 Hz, H-1); 6.63 (dd, J = 8.6/2.7 Hz, H-2); 6.54 (d, J = 2.7 Hz, H-4); 6.23 (dd, J = 17.2/10.5 Hz, -CH=CH2); 5.08 (dd, J 10.5/1.9 Hz, -CH=CH2); 4.48 (dd, J= 17.2/1.9 Hz, -CH=CH2 ); 4.44 (m, 16β-H); 2.79 (m, H-6); 0.95 (d, J = 1.9 Hz, H-18)

Primjer 7 Example 7

9α-(hex-1'-enil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(hex-1'-enyl)-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-triena, analogno primjeru 2, stupnju 1, daje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitrila; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene, analogously to Example 2, step 1, gives 3,16α-bi[(perhydropyran-2-yl )oxy]-ester-1,3,5(10)-triene-9-carbonitrile;

Iskorištenost: 61% teoretski Utilization: 61% theoretical

Stupanj 2 Degree 2

3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-ester-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitrila, analogno primjeru 2, stupnju 2, daje 3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile, analogously to Example 2, step 2, gives 3,16α-dihydroxy-estra- 1,3,5(10)-triene-9-carbaldehyde;

Iskorištenost: 87% teoretski Utilization: 87% theoretical

Stupanj 3 Degree 3

9α-(hex-1-enil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(hex-1-enyl)-estra-1,3,5(10)-triene-3,16α-diol

U jednoj inertiziranoj reakcijskoj tikvici će biti 8,68 g (20 mmol) pentiltrifenilfosfonij bromida + natrijamid (1g sadrži 2,3 mmol pentiltrifenilfosfonij bromida), 0,2 g (0,67 mmol) 3,16α-dihidroksi-estra-1,3,5(10)-trien- In one inertized reaction flask will be 8.68 g (20 mmol) pentyltriphenylphosphonium bromide + sodium amide (1g contains 2.3 mmol pentyltriphenylphosphonium bromide), 0.2 g (0.67 mmol) 3,16α-dihydroxy-estra-1, 3,5(10)-triene-

9-karbaldehida u 30 ml DMSO natopljeno. Reakcijska mješavina će biti ca. 2 sata u ultravioletnoj kupelji na 60ºC tretirana. Nakon potpunog pretvaranja, reakcijskoj mješavini se doda voda. Izoliran će biti sirovi proizvod ekstrakcijom sa octenim esterom, org. faza će biti ispirana vodom i reducirana do suha. 9-carbaldehyde in 30 ml DMSO soaked. The reaction mixture will be approx. 2 hours in an ultraviolet bath at 60ºC treated. After complete conversion, water is added to the reaction mixture. The crude product will be isolated by extraction with acetic ester, org. phase will be washed with water and reduced to dryness.

Sirovi produkt će biti kromatografijom na koloni s Kieselgelom (cikloheksan/octeni ester, 1/1) i kristalizacijom iz octenog estera pročišćen. The crude product will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 1/1) and by crystallization from ethyl ester.

Iskorištenost: 0,18 g (75% teoretski) nakon kromatografije Yield: 0.18 g (75% theoretical) after chromatography

Talište: 166-168ºC Melting point: 166-168ºC

1H-NMR (400 MHz, DMSO-d6, TMS): 8,97 (s, 3-OH); 7,08 (d, J = 8,6 Hz, H-1); 6,49 (dd, J = 8,6/2,7 Hz, H-2); 6,41 (d, J = 2,7 Hz, H-4); 5,73 (dd, J = 12,5 Hz, -CH=CH2-CH2-); 5,20 (dt, J 12,5/7,4 Hz, -CH=CH-CH2-); 4,48 (d, J= 4,7 Hz, 16α-OH); 4,24 (m, 16β-H); 2,66 (m, H-6); 0,68 (t, J = 7,0 Hz, CH3-CH2-H-18); 0,66 (s, H-18) 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 8.97 (s, 3-OH); 7.08 (d, J = 8.6 Hz, H-1); 6.49 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 5.73 (dd, J = 12.5 Hz, -CH=CH2-CH2-); 5.20 (dt, J 12.5/7.4 Hz, -CH=CH-CH2-); 4.48 (d, J= 4.7 Hz, 16α-OH); 4.24 (m, 16β-H); 2.66 (m, H-6); 0.68 (t, J = 7.0 Hz, CH3-CH2-H-18); 0.66 (s, H-18)

Primjer 8 Example 8

9α-(but-1'-enil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(but-1'-enyl)-estra-1,3,5(10)-triene-3,16α-diol

Stupanj 1 Degree 1

3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitril 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-triena, analogno primjeru 2, stupnju 1, daje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitrila; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene, analogously to Example 2, step 1, gives 3,16α-bi[(perhydropyran-2-yl )oxy]-ester-1,3,5(10)-triene-9-carbonitrile;

Iskorištenost: 52% teoretski Utilization: 52% theoretical

Stupanj 2 Degree 2

3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid 3,16α-dihydroxy-ester-1,3,5(10)-triene-9-carbaldehyde

Pretvaranje 3,16α-bi[(perhidropiran-2-il)oksi]-estra-1,3,5(10)-trien-9-karbonitrila, analogno primjeru 2, stupnju 2, daje 3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehid; Conversion of 3,16α-bi[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile, analogously to Example 2, step 2, gives 3,16α-dihydroxy-estra- 1,3,5(10)-triene-9-carbaldehyde;

Iskorištenost: 87% teoretski Utilization: 87% theoretical

Stupanj 3 Degree 3

9α-(but-1-enil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(but-1-enyl)-estra-1,3,5(10)-triene-3,16α-diol

U jednoj inertiziranoj reakcijskoj tikvici će biti 8,68 g (20 mmol) propiltrifenilfosfonij bromida + natrijamid (1g sadrži 2,3 mmol propiltrifenilfosfonij bromida), 0,2 g (0,67 mmol) 3,16α-dihidroksi-estra-1,3,5(10)-trien-9-karbaldehida u 30 ml DMSO natopljeno. Reakcijska mješavina će biti ca. 2 sata u ultravioletnoj kupelji na 60ºC tretirana. Nakon potpunog pretvaranja, reakcijskoj mješavini se doda voda. Izoliran će biti sirovi proizvod ekstrakcijom sa octenim esterom, org. faza će biti ispirana vodom i reducirana do suha. One inertized reaction flask will contain 8.68 g (20 mmol) propyltriphenylphosphonium bromide + sodium amide (1g contains 2.3 mmol propyltriphenylphosphonium bromide), 0.2 g (0.67 mmol) 3,16α-dihydroxy-estra-1, 3,5(10)-triene-9-carbaldehyde in 30 ml DMSO soaked. The reaction mixture will be approx. 2 hours in an ultraviolet bath at 60ºC treated. After complete conversion, water is added to the reaction mixture. The crude product will be isolated by extraction with acetic ester, org. phase will be washed with water and reduced to dryness.

Sirovi produkt će biti kromatografijom na koloni s Kieselgelom (cikloheksan/octeni ester, 1/1) pročišćen. The crude product will be purified by column chromatography with Kieselgel (cyclohexane/acetic ester, 1/1).

Iskorištenost: 0,16 g (73% teoretski) nakon kromatografije Yield: 0.16 g (73% theoretical) after chromatography

Talište: 140-148ºC Melting point: 140-148ºC

1H-NMR (400 MHz, DMSO-d6, TMS): 8,98 (s, 3-OH); 7,09 (d, J = 8,6 Hz, H-1); 6,49 (dd, J = 8,6/2,7 Hz, H-2); 6,41 (d, J = 2,7 Hz, H-4); 5,70 (d, J = 12,5 Hz, -CH=CH2-CH2-); 5,19 (dt, J 12,5/7,4 Hz, -CH=CH-CH2-); 4,47 (d, J= 4,7 Hz, 16α-OH); 4,24 (m, 16β-H); 2,66 (m, H-6); 0,66 (s, H-18); 0,57 (t, J = 7,2 Hz, CH3-CH2-) 1 H-NMR (400 MHz, DMSO-d 6 , TMS): 8.98 (s, 3-OH); 7.09 (d, J = 8.6 Hz, H-1); 6.49 (dd, J = 8.6/2.7 Hz, H-2); 6.41 (d, J = 2.7 Hz, H-4); 5.70 (d, J = 12.5 Hz, -CH=CH2-CH2-); 5.19 (dt, J 12.5/7.4 Hz, -CH=CH-CH2-); 4.47 (d, J= 4.7 Hz, 16α-OH); 4.24 (m, 16β-H); 2.66 (m, H-6); 0.66 (s, H-18); 0.57 (t, J = 7.2 Hz, CH3-CH2-)

Claims (23)

1. 9α-supstituirani estra-1,3,5(10)-derivati triena opće formule I [image] koji su naznačeni slijedećim parametrima: ogranci R3, R7, R7', R9, R13, R16 kao i R17 i R17' neovisno jedan o drugome imaju slijedeća značenja: R3 predstavlja jedan atom vodika ili jednu skupinu R18, pri čemu R18 predstavlja jedan ravno-lančani ili razgranati, zasićeni ili nezasićeni ostatak ugljikovodika sa do 6 atoma ugljika, jednom trifluormetilnom skupinom, jednim aril, heteroaril, ili aralkil ostatkom, jednim supstituiranim aril, heteroaril ostatkom s jednim metil, etil, trifluormetil, pentafluoretil, trifluormetiltio, metoksi, etoksi, nitro, cijano, halogen (fluor, klor, brom, jod), hidroksi, amino, mono(C1-8-alkil) ili di(C1-8-alkil)amino, pri čemu su obje alkilne skupine identične ili različite, di(aralkil) amino, pri čemu su obje aralkilne skupine identične ili različite, karboksil, karboksialkoksi, C1-C20-acil ili C1-C20-aciloksi-skupine kao supstituenti, jedan acilni ostatak COR19, pri čemu R19 predstavlja jedan isto tako supstituirani, ravno-lančani ili razgranati, zasićeni ili do 3-struko nezasićeni, isto tako djelomice ili potpuno halogenirani ugljikovodični ostatak sa do 10 atoma ugljika, ili R18 predstavlja jednu skupinu R20SO2-, pri čemu R20 predstavlja jednu R21R22N-skupina, pri čemu R21 i R22 neovisno jedan o drugome predstavljaju jedan atom vodika, jedan C1-C5-alkilni ostatak, jednu skupinu C(O)R23, pri čemu R23 predstavlja jedan ravno-lančani ili razgranjeni, zasićeni ili do 3-struko nezasićeni, djelomice ili potpuno halogenirani ugljikovodični ostatak sa do 10 atoma ugljika, sa jednom ciklopropil, butil, pentil, heksil ili heptil-skupinom, jednim C4-C15-cikloalkil-alkilnim ostatkom sa 3 do 7 atoma ugljika u dijelu cikloalkila i sa jednim alkilnim dijelom sa do 8 atoma ugljika ili jednim aril, heteroaril ili aralkilnim ostatkom, ili pak jedan supstituirani aril, heteroaril ostatak sa jednim metil, etil, trifluormetil, pentafluormetil, trifluorometiltio, metoksi, etoksi, nitro, cijano, halogen (fluor, klor, brom, jod), hidroksi, amino, mono (C1-8-alkil) ili di(C1-8-alkil) amino, pri čemu su obje alkilne skupine identične ili različite, di(aralkil) amino, pri su čemu obje aralkilne skupine identične ili različite, karboksil, karboksialkoksi, C1-C20-acil ili C1-C20-aciloksi-skupine kao supstituenti, zajedno sa N-atomom, jedan polimetilenimino ostatak sa 4 do 6 C-atoma ili jednim morfolino ostatkom, R7 i R7' predstavljaju neovisno jedan o drugome jedan atom vodika ili jedan atom halogena, R9 predstavlja jedan ravno-lančani ili razgranati alkenil ili alkinil ostatak sa 2 do 6 atoma ugljika ili isto tako djelomice ili potpuno fluoriran može biti ili jedan etinil ili prop-1-inil ostatak R13 predstavlja jednu metilnu ili jednu etilnu skupinu, R16 predstavlja jednu hidroksi ili jednu skupinu R18O, R20SO2 ili OC(O)R23 sa R18, R20 i R23 od kojih svaki ima značenje navedeno pod R3, R17 i R17' predstavljaju neovisno jedan o drugome jedan atom vodika ili jedan atom halogena.1. 9α-substituted ester-1,3,5(10)-triene derivatives of general formula I [image] which are indicated by the following parameters: branches R3, R7, R7', R9, R13, R16 as well as R17 and R17' independently of each other have the following meanings: R3 represents one hydrogen atom or one group R18, wherein R18 represents one straight-chain or branched, saturated or unsaturated hydrocarbon residue with up to 6 carbon atoms, one trifluoromethyl group, one aryl, heteroaryl, or aralkyl residue, one substituted aryl, heteroaryl residue with one methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio , methoxy, ethoxy, nitro, cyano, halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(C1-8-alkyl) or di(C1-8-alkyl)amino, both alkyl groups being identical or different, di(aralkyl)amino, wherein both aralkyl groups are identical or different, carboxyl, carboxyloxy, C1-C20-acyl or C1-C20-acyloxy-groups as substituents, one acyl residue COR19, wherein R19 represents one the same so substituted, straight-chain or branched, saturated or up to 3-fold unsaturated, as well as partially or fully halogenated hydrocarbon residue with up to 10 carbon atoms, or R18 represents one group R20SO2-, whereby R20 represents one R21R22N-group, wherein R21 and R22 independently represent one hydrogen atom, one C1-C5-alkyl residue, one C(O)R23 group, wherein R23 represents one straight-chain or branched, saturated or up to 3-fold unsaturated, partially or fully halogenated hydrocarbon residue with up to 10 carbon atoms, with one cyclopropyl, butyl, pentyl, hexyl or heptyl group, one C4-C15-cycloalkyl-alkyl residue with 3 to 7 carbon atoms in the cycloalkyl part and with one alkyl part with up to 8 carbon atoms or one aryl, heteroaryl or aralkyl residue, or one substituted aryl, heteroaryl residue with one methyl, ethyl, trifluoromethyl, pentafluoromethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, halogen (fluoro , chlorine, bromine, iodine), hydroxy, amino, mono (C1-8-alkyl) or di(C1-8-alkyl) amino, wherein both alkyl groups are identical or different, di(aralkyl) amino, wherein both aralkyl groups identical or different, ka rboxyl, carboxyloxy, C1-C20-acyl or C1-C20-acyloxy groups as substituents, together with an N-atom, one polymethyleneimino residue with 4 to 6 C-atoms or one morpholino residue, R7 and R7' independently represent one hydrogen atom or one halogen atom, R9 represents one straight-chain or branched alkenyl or alkynyl residue with 2 to 6 carbon atoms or also partially or fully fluorinated, it can be either one ethynyl or prop-1-ynyl residue R13 represents one methyl or one ethyl group, R16 represents one hydroxy or one group R18O, R20SO2 or OC(O)R23 with R18, R20 and R23 each having the meaning given under R3, R17 and R17' independently represent one hydrogen atom or one halogen atom. 2. Spojevi opće formule I u skladu s odrednicama patentnog zahtjeva 1, koji su naznačeni time da R3 predstavlja jedan atom vodika.2. Compounds of the general formula I according to the specifications of patent claim 1, which are characterized in that R3 represents one hydrogen atom. 3. Spojevi opće formule I u skladu s odrednicama patentnih zahtjeva 1 ili 2, koji su naznačeni time da R7 predstavlja jedan atom vodika ili jedan α-krajnji atom fluora R9 predstavlja jednu vinil, etinil ili prop-1-inil skupinu, R16 predstavlja jednu hidroksi skupinu i R17 predstavlja jedan atom vodika ili jedan α-krajnji atom fluora.3. Compounds of the general formula I in accordance with the specifications of patent claims 1 or 2, which are indicated by the fact that R7 represents one hydrogen atom or one α-terminal fluorine atom, R9 represents one vinyl, ethynyl or prop-1-ynyl group, R16 represents one hydroxy group and R17 represents one hydrogen atom or one α-terminal fluorine atom. 4. Spojevi opće formule I u skladu s odrednicama patentnih zahtjeva 1 ili 2, koji su naznačeni time da R16 predstavlja skupine R18-O- ili R19SO2-O-, s tim da R18 i R19 predstavljaju funkcije koje su navedene za R3.4. Compounds of the general formula I in accordance with the specifications of patent claims 1 or 2, which are indicated by the fact that R16 represents the groups R18-O- or R19SO2-O-, with R18 and R19 representing the functions specified for R3. 5. Estratrieni opće formule I u skladu s odrednicama patentnih zahtjeva 1 ili 2, koji su naznačeni time da podrazumijevaju slijedeće spojeve: 9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 9α-alil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-9α-alil-estra-1,3,5(10)-trien-3,16α-diol 3-metoksi-9α-vinil-estra-1,3,5(10)-trien-16α-ol 9α-alil-3-metoksi-estra-1,3,5(10)-trien-3,16α-ol 18a-homo-3-metoksi-9α-vinil-estra-1,3,5(10)-trien-3,16α-ol 18a-homo-9α-alil-3-metoksi-estra-1,3,5(10)-trien-3,16α-ol 9α-(2',2'-difluorvinil)-estra-1,3,5(10)-trien-3,16α-ol 9α-(2',2'-difluorvinil)-3-metoksi-estra-1,3,5(10)-trien-3,16α-ol 16α-hidroksi-9α-vinil-1,3,5(10)-trien-3il-sulfamat 9α-alil-16α-hidroksi-estra-1,3,5(10)-trien-3il-sulfamat 18a-homo-16α-hidroksi-9α-vinil-estra-1,3,5(10)-trien-3il-sulfamat 18a-homo-9α-alil-16α-hidroksi-estra-1,3,5(10)-trien-3il-sulfamat 9α-vinil-estra-1,3,5(10)-trien-3,16α-diil-disulfamat 9α-alil-estra-1,3,5(10)-trien-3,16α-diil-disulfamat 18a-homo-9α-vinil-estra-1,3,5(10)-trien-3,16α-diil-disulfamat 18a-homo-9α-alil-estra-1,3,5(10)-trien-3,16α-diil-disulfamat 16α-hidroksi-9α-vinil-estra-1,3,5(10)-trien-3il-(N-acetil)-disulfamat 9α-alil-16α-hidroksi-estra-1,3,5(10)-trien-3il-(N-acetil)-sulfamat 18a-homo-16α-hidroksi-9α-vinil-estra-1,3,5(10)-trien-3il-(N-acetil)-sulfamat 18a-homo-9α-alil-16α-hidroksi-estra-1,3,5(10)-trien-3il-(N-acetil)-sulfamat 9α-(prop-(Z)-enil)-estra-1,3,5(10)-trien-3,16α-diol 9α-(n-propil)-estra-1,3,5(10)-trien-3,16α-diol 9α-etinil-estra-1,3,5(10)-trien-3,16α-diol 9α-vinil-estra-1,3,5(10)-trien-3,16α-diol-diacetat 18a-homo-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol-diacetat 16α-valeroiloksi-9α-vinil-estra-1,3,5(10)-trien-3-ol 16α-acetoksi-9α-vinil-estra-1,3,5(10)-trien-3-ol 18a-homo-16α-acetoksi-9α-vinil-estra-1,3,5(10)-trien-3-ol 7α-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 7α-fluor-9α-alil-estra-1,3,5(10)-trien-3,16α-diol 17β-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 17β-fluor-9α-alil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-7α-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-7α-fluor-9α-alil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-17β-fluor-9α-vinil-estra-1,3,5(10)-trien-3,16α-diol 18a-homo-17β-fluor-9α-alil-estra-1,3,5(10)-trien-3,16α-diol5. Estratrienes of the general formula I in accordance with the specifications of patent claims 1 or 2, which are indicated by the fact that they include the following compounds: 9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol 9α-allyl-3-methoxy-estra-1,3,5(10)-trien-3,16α-ol 18a-homo-3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-3,16α-ol 18a-homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-3,16α-ol 9α-(2',2'-difluorovinyl)-estra-1,3,5(10)-trien-3,16α-ol 9α-(2',2'-difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-3,16α-ol 16α-hydroxy-9α-vinyl-1,3,5(10)-trien-3yl-sulfamate 9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate 18a-homo-16α-hydroxy-9α-vinyl-ester-1,3,5(10)-trien-3yl-sulfamate 18a-homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate 9α-vinyl-ester-1,3,5(10)-triene-3,16α-diyl-disulfamate 9α-allyl-ester-1,3,5(10)-triene-3,16α-diyl-disulfamate 18a-homo-9α-vinyl-ester-1,3,5(10)-triene-3,16α-diyl-disulfamate 18a-homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate 16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-disulfamate 9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate 18a-homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate 18a-homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate 9α-(prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α-diol 9α-(n-propyl)-estra-1,3,5(10)-triene-3,16α-diol 9α-ethynyl-estra-1,3,5(10)-triene-3,16α-diol 9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate 18a-homo-9α-vinyl-ester-1,3,5(10)-triene-3,16α-diol-diacetate 16α-valeroyloxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 18a-homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol 7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol 18a-homo-17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol 6. Farmaceutski pripravci, koji su naznačeni time da sadržavaju najmanje jedan spoj u skladu s patentnim zahtjevima 1 do 5 kao i jedan farmaceutski prihvatljivi nosač tvari.6. Pharmaceutical preparations, which are characterized by the fact that they contain at least one compound in accordance with patent claims 1 to 5 as well as one pharmaceutically acceptable carrier substance. 7. Primjena spojeva opće formule I u skladu s odrednicama patentnih zahtjeva 1 do 5, koja je naznačena time da se koristi za spravljanje lijekova.7. Application of compounds of the general formula I in accordance with the specifications of patent claims 1 to 5, which is indicated by the fact that it is used for the preparation of medicines. 8. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za tretman oboljenja i stanja uzrokovanih deficijencijom estrogena kod žena i muškaraca.8. Application of compounds in accordance with the specifications of patent claim 7, which is indicated to be used for the treatment of diseases and conditions caused by estrogen deficiency in women and men. 9. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za tretman peri- i post-menopauznih poteškoća.9. Application of compounds according to the specifications of patent claim 7, which is indicated to be used for the treatment of peri- and post-menopausal problems. 10. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za in vitro tretman ženske neplodnosti.10. Application of compounds in accordance with the specifications of patent claim 7, which is indicated to be used for in vitro treatment of female infertility. 11. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za in vivo tretman ženske neplodnosti.11. Use of compounds in accordance with the specifications of patent claim 7, which is indicated to be used for in vivo treatment of female infertility. 12. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za terapijsku obradu poteškoća uzrokovanih hormonalnom deficijencijom uslijed kirurških, medikamentoznih ili drugačije uzrokovanih ovarijskih disfunkcija. 12. Application of compounds in accordance with the specifications of patent claim 7, which is indicated in that it is used for the therapeutic treatment of difficulties caused by hormonal deficiency due to surgical, medicinal or otherwise caused ovarian dysfunctions. 13. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje u hormonalnoj zamjenskoj terapiji (HRT).13. Application of compounds according to the specifications of patent claim 7, which is indicated to be used in hormone replacement therapy (HRT). 14. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 13, koja je naznačena time da se primjenjuje u kombinaciji sa selektivnim estrogen-receptor-modulatorima (SERM), primjerice Raloxifenom.14. Application of compounds according to the specifications of patent claim 13, which is indicated in that it is used in combination with selective estrogen receptor modulators (SERMs), for example Raloxifene. 15. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje u profilaksi i terapiji jednog gubitka koštane mase uzrokovanog hormonskom deficijencijom.15. Application of compounds in accordance with the specifications of patent claim 7, which is indicated by the fact that it is used in the prophylaxis and therapy of a loss of bone mass caused by hormonal deficiency. 16. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje u profilaksi i terapiji osteoporoze.16. Application of compounds in accordance with the specifications of patent claim 7, which is indicated by the fact that it is used in the prophylaxis and therapy of osteoporosis. 17. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje u profilaksi i terapiji oboljenja krvožilnog sustava.17. Application of compounds in accordance with the specifications of patent claim 7, which is indicated by the fact that it is used in the prophylaxis and therapy of diseases of the circulatory system. 18. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje u prevenciji i tretmanu hiperplazije prostate.18. Application of compounds in accordance with the specifications of patent claim 7, which is indicated by the fact that it is used in the prevention and treatment of prostate hyperplasia. 19. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 18, koja je naznačena time da se primjenjuje u kombinaciji s antiestrogenima i selektivnim estrogen-receptor-modulatorima (SERM) u profilaksi i terapiji hiperplazije prostate.19. Application of compounds according to the specifications of patent claim 18, which is indicated in that it is used in combination with antiestrogens and selective estrogen-receptor-modulators (SERM) in the prophylaxis and therapy of prostate hyperplasia. 20. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 7, koja je naznačena time da se primjenjuje za tretman oboljenja imunološkog sustava.20. Application of compounds in accordance with the specifications of patent claim 7, which is indicated by the fact that it is used for the treatment of diseases of the immune system. 21. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 20, koja je naznačena time da se primjenjuje u tretmanu autoimunoloških oboljenja.21. Application of compounds in accordance with the specifications of patent claim 20, which is indicated by the fact that it is used in the treatment of autoimmune diseases. 22. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 21, koja je naznačena time da se primjenjuje u tretmanu reumatoidnog artritisa.22. Application of compounds in accordance with the specifications of patent claim 21, which is indicated by the fact that it is used in the treatment of rheumatoid arthritis. 23. Primjena spojeva u skladu s odrednicama patentnog zahtjeva 21, koja je naznačena time da se primjenjuje u tretmanu multiple skleroze.23. Application of compounds in accordance with the specifications of patent claim 21, which is indicated by the fact that it is used in the treatment of multiple sclerosis.
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