TW201026718A - Use of 17β-cyano-19-androst-4-ene derivatives for preparing a medicament in depot form for parenteral administration and depot medicaments comprising 17β-cyano-19-androst-4-ene derivatives for parenteral administration - Google Patents

Abstract

The 17β-cyano-19-androst-4-ene derivatives of the general chemical formula 1 having gestagenic activity in which Z is selected from the group comprising O, two hydrogen atoms, NOR and NNHSO2R, in which R is hydrogen or C1-C4-alkyl, R1, R2 independently of one another are hydrogen or methyl or R1 and R2 together form methylene or are omitted with formation of a double bond between C1 and C2, R4 is hydrogen or halogen, furthermore either: R6a, R6b together form methylene or 1,2-ethanediyl or R6a is hydrogen and R6b is selected from the group comprising hydrogen, methyl and hydroxymethylene, and R7 is selected from the group comprising hydrogen, C1-C4-alkyl, C2-C3-alkenyl and cyclopropyl, or: R6a is hydrogen and R6b and R7 together form methylene or are omitted with formation of a double bond between C6 and C7, or: R6a is methyl and R6b and R7 are omitted with formation of a double bond between C6 and C7, R15, R16 are hydrogen or together form methylene, R17 is selected from the group comprising hydrogen, C1-C4-alkyl and allyl, and in addition their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, with the proviso that certain compounds are excluded, can be used for preparing depot medicaments for parenteral, for example intrauterine or intravaginal, administration of these compounds, for example in the form of an intrauterine system or vaginal ring. The present invention also relates to such systems themselves which comprise at least one compound of the general chemical formula 1 and are adapted for parenteral, in particular intrauterine or intravaginal, administration.

Description

201026718 VI. Description of the invention: [Technical field to which the invention pertains] The present invention is a use of a non-oral supply of a certain type of cyano- 19-methyl-andrazine derivative, and also relates to the inclusion of such a cyano group. -19-The non-anthraquinone of the Jiaxiong (10)·4_埽 derivative is supplied to the drug itself. [Prior Art] a cyano]9-methyl-andrazine _4_dilute derivative itself, which is used, for example, for the treatment of premenopausal, near menopause and postmenopausal symptoms, as well as the use of premenstrual symptoms and includes the presence of a surname Drugs of such derivatives of the relevant effects are described in PCT/EP2008/057427+, the disclosure of which is hereby incorporated by reference. Compounds based on steroid structures and having a genus-related, anti-mineral corticosteroid, anti-androgen or anti-estrogen action are known from this document, which are derived, for example, from 19·methylxanthene-4-ene-3 or a derivative thereof. (The steroid structure number is available, for example, from Fresenius/G5rlitzer, 3rd edition 1991, "Chemische Nomenklatur" [Organic Chemistry Nomenclature, page 6 and subsequent pages). ' Therefore WO 20_72467 indicates that the compound dimercapto group _3 · side oxy group _17 _ 4 _ thin 21, carboxy carbaryl lactone (dr 〇 Spirenone), which has been used For example, in oral contraceptives and in the treatment of post-menopausal symptoms. However, since trospireone has a relatively low affinity for the progesterone receptor and its ovulation inhibitor is relatively high, trospireone is present in the contraceptive at a relatively high daily dose of 3 mg. In addition, trospireone differs in that, in addition to pregnancy-related effects, it also has 144922.doc 201026718 antagonistic aldosterone (anti-mineral corticosteroid) and has anti-androgenic effects (s〇wie antiandrogene Wirkung verfttgt). These two properties make the pharmacological profile of trochodrone very similar to the natural progesterone progesterone, whereas the natural progesterone progesterone differs from trospireone in that it does not have an appropriate oral bioavailability. In order to reduce the dosage of administration, it is further proposed in WO 2006072467 A1 that the pregnancy-related efficacy is higher than that of the 18-methyl-19·demethyl-l7_pregnane-4-ene-21,1 7-carboxylactone of trochodrone and Contains pharmaceutical preparations thereof.

Furthermore, for example, US-A 3,705,179 discloses steroids which have antiandrogenic activity and are suitable for the treatment of androgen related diseases. In particular, ΐ7β-cyano-17α-methylmethylanthryl _4-female _3_ 鲷 derivatives are disclosed. In DE 22 26 552 Β 2, other 17•cyano-19-nor-norsine-4-,3 compounds are shown which exhibit exogenous characteristics of the pseudo-mesh, antiandrogen and anti-hormonal effects. SUMMARY OF THE INVENTION The object of the invention described herein is to obtain a compound that binds strongly to a progestin receptor. In addition, these compounds preferably also have anti-mineralocorticoid action. 49-Hexagonal indicates that this target is achieved by the cyano-retaining _4_ feminine derivative of the formula 1 described herein. An advantageous embodiment of the invention is hereby attached to claim A. 17β-cyano-19_methylxine of the formula 1 The invention described herein relates to the chemical 甾-4-dilute derivative 144922.doc 201026718

N

Wherein Z is selected from the group consisting of 0, two hydrogen atoms, NOR and NNHS02R wherein R is hydrogen or Cl_C4 alkyl, R1, R2 are independently hydrogen or methyl or R'R form a methylene group or are omitted A double bond is formed between c 1 and c 2 , R 4 is hydrogen or _, and further: RR forms a methylene group or a 1,2-ethanediyl group or R 6a is hydrogen and R 6b is selected from the group consisting of hydrogen, a thiol group and a hydroxyl group. a group of fluorenyl groups, and R? is selected from the group consisting of hydrogen, alkyl, C2-C3 alkenyl, and cyclopropyl, or: R6a is hydrogen and R6b and R7 together form a fluorenylene group or are omitted at C6 and C7 A double bond is formed between them, or: 144922.doc 201026718 R6a is methyl and 1161) is omitted from R7 and a double bond is formed between C6 and C7, /R15 » P16 ^ ^ is wind or co-formed methylene, r17 Selected from the group consisting of hydrogen, CVCU alkyl and allyl groups, which are agents, hydrates, stereoisomers, diastereomers, anomers and salts, the limitation of which is exclusion a compound having the following chemical formula A:

(A) wherein X is hydrogen or methyl, and the double bond between Θ and ^ and between b and ～ is a double bond as the case may exist, and the restriction condition is also excluded, and cyanomethyl@@ · 4 leptone. The compound of the general formula 排除 excluded from the present invention is the following compound: Excluding compound 1 X c1=c2 c6=c7 17β-cyano-17α-methylmethylandrosin_4·en-3-one^'. 17β-Cyano-6α,17α-dimercaptopurine, _4-indol-3-one~~ + ./. 17|3-cyano-17α-indenyl-methyl---- 4-, 4- Alkene_3-copper L./. + ./., -Cyano group such as '^-monomethyl oxime ^+diene ^- + + ./. 17β-^-yl-α-methyl oxime -4,6-dico-3-one/ / + 17β-cyano-6α,17α-dimethylindole-4,6-di suspect-3-lii^ ·/. + »/ · + 17β -Cyano-17α-methyloxime male-1,4,6-trien-3-one+ 17戸-cyano-6〇1,17〇1-indolyl-1,4,6- Tris--3-嗣+ + + 144922.doc -9- 201026718 "./.". does not exist; "+": the structure number of the derivative of the chemical formula 1 of the present invention is generally described in, for example, the above citation The steroid structure number in Fresenius. apply for patent

The group number stated in the range similarly corresponds to the position at which it is bonded to the structure of the derivative C. For example, the group R4 is bonded to the C4 position of the derivative of the invention. With respect to the group defined for Z, the group]^0 ft and >11^18〇211 are in each case a double bond via N bond to the c structure of the derivative, such as =N〇R and =N- NH-S02R. The NHS〇2R in the NOR can be in the same or inverted position. C-C4 alkyl is understood in each case to mean a straight or branched alkyl group, such as a decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group. , especially unbranched groups. Methyl, ethyl and n-propyl are preferred. Further, the alkyl group bonded at the position 17ct may be perfluorinated, so that in this case, it may additionally be a trifluoromethyl group, a pentafluoroethyl group, a n-heptafluoropropyl group, an isoheptafluoropropyl group or a n-hexafluorobutyl group. , isohexafluorobutyl and third nonafluorobutyl. C2-C3 alkenyl is preferably understood to mean vinyl or allyl. Halogen is understood in each case to mean fluorine, gas, bromine or iodine. Isomers are understood to mean compounds which have the same empirical formula but differ in chemical structure. All possible isomers and isomer mixtures (racemates) are specifically included in the derivatives of the invention to specify the 7p-cyano position. In general, s ' should distinguish between structural isomers and stereoisomers. The structural formula of the isomer is the same 'but the bonding mode of its atom or atomic group is different. These include S energy isomers, positional isomers, tautomers or covalent isomers 144922.doc 201026718

In principle, the structures (structures) of stereoisomers are the same and therefore the empirical formula is the same, but the spatial arrangement of atoms is different. In general, the configuration isomers and conformational isomers should be distinguished. The configuration isomers are stereoisomers which can only be converted by a bond cleavage. These include enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers that appear as images and mirror images of each other and do not have a plane of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. The double bond E/z (cis/trans) isomer is a special case. The conformation isomers are stereoisomers which can be converted into each other by rotating a single bond. For a description of the distinction between heterogeneous types, see also the UJPAC rules, Part E (Pure Αρρι % Η.% (1976)) 〇 'Chemical Formula 1 derivatives also contain possible tautomeric forms and The rectifying or purine isomer' or, if present, the racemate and enantiomer. It is understood that the double bond isomer is also in it. The derivative may also be present in the form of a solvate, especially a hydrate, and the compound of the invention accordingly contains a polar solvent, especially water, as a structural element of the crystal lattice of the present invention, a beta polar solvent, especially water. Ratio or non-stoichiometric ratio exists. In the case of stoichiometric solvates, hydrates, these are also referred to as semi-, (semi-), mono-, sesqui-, -, di-, tetra-, five (etc.) solvates or Hydrate. Formula 1 is used. In addition, it is an anti-agent. The compound or derivative has an excellent in vivo living name - some related compounds of the present invention are used as the mineralocorticoid receptor. Preferably, the above chemical formula! Derivatives of which 2 are selected from the group consisting of 144 144922.doc 201026718 NOH and NNHS02H. Z is especially good. Regardless of the choice of hydrazine, it is further preferred to have the above-described chemical formula w derivatives, wherein the following variants are alternatively or at least in some cases co-occurring and are selected independently of each other: R15 and R "are better together form a sub- a group wherein both the α-methylene group and the methylene group may be bonded at these positions. R and R are each preferably each hydrogen or a methylene group, and R1 is more preferably α-methyl. Further, R4 is preferably hydrogen or gas. /^R6b preferably further forms H ethylenediyl or in each case hydrogen. ", 'R7 is further preferably selected from the group consisting of hydrogen and methyl, " The base can be both α_ and β-. And R7 additionally preferably together form a methylene group, wherein the methylene group can be both & and β-. R is further preferably selected from the group consisting of hydrogen and methyl. The oxime groups R6a, R6b, · ρ 7 〇 15 and R may additionally be both α- and β-. The Ηβ-cyano_19_methanosine derivative is preferably selected from the group consisting of:

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佳 0 144922.doc -18 - 201026718 The novel chemical compound of formula 1 may be used alone or in combination with estrogen for contraceptives due to its pregnancy-related activity. The compounds of formula 1 are therefore particularly useful in the manufacture of oral contraceptives and in the treatment of menopause - sputum, near menopause and postmenopausal symptoms, including preparations for hormone replacement therapy (HRT). The compounds of formula 1 are particularly suitable for the treatment of symptoms of obstruction, such as headache, depression, water retention and breast pain, due to their suitable mode of action. The compounds of formula 1 are particularly suitable for use in the manufacture of medicaments having (iv) related and anti-salt corticosteroid effects. Treatment with a compound of formula 1 is preferably carried out in humans, but may also be carried out on related mammalian species such as dogs and cats. For the use of the compound of formula 1 as a medicament, it is combined with at least one suitable pharmaceutically injurious additive, such as a vehicle. The additive is administered, for example, in a non-dose administration, preferably by oral administration. In this case, it should be a pharmaceutically suitable organic or inorganic inert additive such as Φ water, gelatin, gum arabic, lactose, powder, magnesium stearate, talc, vegetable oil, polyglycol. The drug may be in a solid form, such as a key, a coated tablet, a suppository, a capsule, or in the form of a liquid, such as a solution, suspension or % solution. It may optionally contain a salt or buffer which changes the osmotic pressure, such as preservatives, stabilizing hydrazine, wet _ or emulsifier. For non-oral administration of 'oily solutions' such as sesame oil solution, sesame oil solution and cotton oil solution, it is particularly suitable. In order to increase the solubility, a solubilizing agent such as benzoic acid vinegar or stilbene alcohol may be added. It is also possible to incorporate the general formula "incorporation into the saliva system for transdermal administration. For oral administration, lozenges, coated tablets 144922.doc -19- 201026718 agents, capsules, pills, suspensions or solutions Particularly suitable. The dose of the compound of formula 1 in the contraceptive preparation should be 〇〇1 to 1 〇〇 per day. In the case of treating premenstrual symptoms, the sputum dose is about 〇丨 to buckle. The pregnancy-related derivative of the present invention is in the contraceptive preparation. And the oral administration of the drug for treating premenstrual symptoms is preferred. The sputum dose is preferably administered in a single dose. The pregnancy-related and estrogen-related active substance components are preferably co-administered in a contraceptive preparation. The daily dose is preferably A single dose is administered. Possible estrogen is synthetic estrogen, preferably ethinyl estradiol, but also estradiol methyl ether. Estrogen is dosed in a dose corresponding to 0_01 to 0.04 rng ethinyl estradiol.

versus. X Estrogen is of course mainly used as an estrogen in the treatment of premenopausal, near menopausal and postmenopausal symptoms and hormone replacement therapy, especially estradiol and its esters, such as estradiol valerate or bound estrogens ( CEE = ^ ^ 妗 people,,, ° mouth two hormones). If the preparation of the starting compound is not described herein, it is known to those skilled in the art or can be prepared analogously to known compounds or processes described herein. The mixture of isomers can be separated into enantiomers, E/Z isomers or epimers by conventional methods such as crystallization, chromatography or salt formation. [Examples] A compound of Chemical Formula 1 was prepared as described below. Suitable starting materials for the 17β-cyanoandrost-4-ene-3-one derivatives described in PCT/EP2008/057427 are various steroid starting materials, such as methylandrazine-4·ene-3,17-di Ketones (see, for example, 丄s〇c 8' 27 27 144922.doc -20- 201026718 (1965)), or partially reduced analogs, such as testosterone or prasterone. Suitable starting materials having 15α, 16α- or 15β, 16β-fluorenylene groups are also known from the literature (for example 15α, 16α-indenyl-indole-5-en-17-keto-3β-ol, See CTzew 106, 888 (1973); corresponding ^4-3, 17-:8^^ See DE-A 21 09 555 (1972)). 15β,16β-亚曱基曱雄甾-4-稀-3,17-二_ Described in /zv. iVawA: and Ser·8,1893 (1985) and C/iew. 107,128-134 (1974) The corresponding Δ5-3-ol is described in "gew. C/zew. 94 (9), 718 (1982). It will be apparent to those skilled in the art that in the description of synthetic transformations, other functional groups that are to be protected in a suitable form, as appropriate, are present on the steroid structure. The introduction of the nitrile in position 17 (C17) of the steroid structure can be carried out in various ways. Both one-step and multi-step variants are possible here. It is preferred here that the method of replacing the oxygen functional group with cyanide is preferred. Many possible method variants are described in *SWewce 〇/ Synthesis Houben-Weyl Methods of Molecular Transformations Category 3 Volume 19, pages 197-213 (2004 Georg Thieme Verlag Stuttgart, New York) and Houben-Weyl Methoden der organischen Chemie [ Houben-Weyl Methods of organic chemistry, Vol. 5, Part 2, pages 1318-1527 (1985 Georg Thieme Verlag Stuttgart, New York). One step envisaged is, for example, direct replacement of the carbonyl oxygen atom by cyano reduction. For this purpose, the 17-ketosteroid and the indenesulfonylmethyl isocyanide are suitable in a solvent such as dimethoxyethane, dimethylhydrazine, ether, alcohol or a mixture thereof in 144922.doc -21 - 201026718. Medium's use of a suitable base such as an alkali metal alkoxide, an alkali metal hydride, potassium hexamethyldioxanhydride or an alkali metal guanamine such as lithium diisopropylguanidinium at a temperature between 0 ° C and loot The next reaction. The 17-epimer mixture which may be formed may be separated by chromatography, fractional crystallization or a combination of such methods. It is also possible to replace the suitable cleavage group of position 17 with a cyanide SN2 type, such as a dentate (preferably iodine or bromine) or a 17-alcohol sulfonate. The source of the fragrance used is preferably inorganic cyanide such as lithium cyanide, sodium cyanide and potassium cyanide. The following may be mentioned as an example of a multi-step variant in which nitrile is introduced. The ketone is converted to the corresponding 17-exomethylene compound by means of hydrazinolation (Wittig 〇lefinati〇n) and is oxidized to The aldehyde can be reacted to give the corresponding 17-mole. Subsequent dehydration produces a 17-nitrile. The introduction of the guess can be made at the beginning of the synthesis sequence and also at any desired point in time later, as long as other functional groups that may be present are protected in a suitable manner. The 1 7-gas-based compound may optionally be subjected to alkylation to give a stereochemically uniform 171 17β-cyano-17α substituted derivative. To this end, the 17-cyanosteroid is deprotonated in a suitable agent such as an ether such as tetrahydrofuran. Here, various tests such as a metal-strength amine such as a diisopropyl-branched amine chain can be used. After the addition of an alkylating agent such as a decyl dentate or a dilute dentate and treatment, a 17β-cyano-17α substituted derivative is obtained. For example, 0 1 illustrates the further synthetic procedure by means of a synthetic scheme below the force, referring to the compound 2 already described (G.K W 1835 144922.doc, 22·201026718 (1976); US-A 3,705,179 (197 1)) as Starting material: Process 1

The introduction of a 1,2-double bond to compound 2 produces 3. In addition to other dehydrating agents, it is suitable for cerium oxide (J. Og. CTzem. 21, 239 (1956)) or 2,3-dichloro-5,6-dicyanobenzoquinone 3 5 (5), 481 (1980)). The 1-methyl derivative can be obtained, for example, by adding trimethylsulfonium alkylate and copper bromide in a suitable solvent to a 1-methyl derivative 105 (9), 1429 (1993). The introduction of the 6,7-double bond is carried out by brominating the 3,5-dienol ether 5 and subsequently eliminating hydrogen bromide (see for example J. Fried, JA Edwards, Reactions in Steroid Chemistry, von Nostrand Reinhold 144922.doc) -23- 201026718

Company 1972, pp.). The introduction of the substituent R4 can, for example, start with a compound of the formula 2, by epoxidizing the 4,5-double bond using hydrogen peroxide under basic conditions and bringing the resulting epoxide in a suitable solvent with a chemical formula An acid of H_R4 (wherein R4 may be a halogen atom or a pseudo iS), or by reacting with a catalytic amount of a mineral acid and optionally obtaining a 4-bromo compound of the formula 1 (wherein R4 = bromine) The 2, difluoro-2-(fluorosulfonyl)acetic acid oxime ester is reacted in the presence of ruthenium decylamine in the presence of copper ruthelium iodide. The bisenool ether bromination of compound 5 can be carried out, for example, analogously to the procedure of 汾丄 233 (1963). The elimination of hydrogen can be achieved by combining & evolution with an alkaline reagent such as LiBr or LiWO3 in an aprotic solvent such as dimethylformamide. (Compound to 12 or at a temperature of 2 or by heating a 6-g compound in a solvent such as trimethylpyridine or lutidine to obtain compound 6. By using a known process, for example, two Methyl oxidized dimethylsulphoxonium methylide methylates 67• double bonds (see for example DE-A U 83 500, de_a 29 22 500, ep_a 〇〇 & 690 US-A 4,291,029, J. Am Chem. Soc. 84, 867 (1962)) While converting compound 7 to compound 8, a compound of the ?-isomer and the ?-isomer is obtained, which can be separated into individual derivatives, for example, by chromatography. The type 7 compound can be obtained as described in the examples or similar to the procedures described above using reagents similar to those described therein. The synthesis of spiro compound 12 is carried out with 2 as the starting material, which is first Conversion to 3-amino-3,5-di(tetra)-organism 9. By reacting with formalin (f. leg Ηη) in alcohol solution 144922.doc -24· 201026718 to obtain 6-methylidene derivative 1). Conversion of a mesogenic group to a leaving group such as a mesylate group, an anthracenyl ester group (compound u) or a benzene After the acid ester group, compound 13 can be prepared by reacting with a solution of nickel methoxide such as a base such as an alkali metal hydroxide or an alkali metal alkoxide in a suitable solvent such as diterpene; The 6-fluorenylene group can be introduced, and the compound 10 can be dehydrated using, for example, hydrochloric acid in dioxane/water. The 6-fluorenylene group can also be produced by η (see DE-A 34 02 3291 ^ EP-A 0 150 157 ^ US-A 4,584,288 ; J. Med. Chem. 34, 2464 (1991)) Another possibility for the preparation of 6-methylene compounds by hydrazine is to make 4(5) unsaturated 3 ketones, such as the acetal of compound 2 with formaldehyde in the presence of sodium acetate. The direct reaction is carried out using a (s) oxygenated dish or a five gasification fill in a suitable solvent such as chloroform (see for example K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, j. (1982)). 6. The fluorenylene compound can be used to prepare a Si compound, wherein R6a is equal to a methyl group, and the ruler "and R7 are omitted to form a double bond between c6 and c7. For this, for example, it can be used as described in 1619 (1965). a method in which a 6-fluorenylene compound in ethanol and a 5% saturated/charcoal catalyst pretreated with hydrogen are used The temperature is raised or the isomerization of the double bond is achieved by heating with a small amount of cyclohexene. If a small amount of cyclohexene is added to the reaction mixture, the isomerization can also be carried out using a catalyst without pretreatment. A small amount of hydrogenated product is prevented from occurring by the addition of excess sodium acetate. However, it is also possible to directly prepare 6-mercapto-4,6-dien-3-one derivatives (see Κ. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. 144922.doc •25· 201026718

Ann. 712 (1983)) ° Compounds (wherein R, a-methyl functional groups) can be prepared from 6 methylene compounds by hydrogenation under suitable conditions. The best result (selective hydrogenation of the exo-f-functional group) is achieved by transfer hydrogenation (j cw ^ 578 (1954)) to the right 6-methylene derivative in a suitable solvent such as ethanol. Heating in the presence of a hydride donor such as hexene gives an excellent yield of the 6α methyl derivative. A small amount of qi-methyl compound can be isomerized by acid {Tetrahedron 1619 (1965)) 6 It is also possible to selectively prepare 6β-methyl compound. To this end, a 4-olefin-3-one (such as compound 2) is reacted with, for example, ethylene glycol or trimethyl ortho-decanoate in dioxane in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid. , the corresponding 3' ketal is obtained. During this ketalization, the double bond at position 5 (c5) is isomerized. This 5-double bond may be selectively epoxidized, for example, by using an organic peracid 'e, such as meta-formic acid, in a suitable solvent such as dichloromethane. Alternatively, hydrogen peroxide can be used to epoxidize T at, for example, hexa-gas acetone or hydrazine nitrotris benzene. The formed 5,6〇1_epoxide can then be opened axially in the appropriate home base or alkyllithium compound. Thus, a 5a-hydroxy-6β-alkyl compound was obtained. The cleavage of the 3-keto protecting group can be carried out by treatment under weakly acidic conditions (acetic acid or 4 hydrazine hydrochloride, hydrazine) to obtain a 5?-hydroxyl functional group. The alkaline elimination of the 5?-hydroxyl group using, for example, an aqueous solution of dilute sodium hydrogensulfate provides a 3-keto-4-ene compound having a ?6 alkyl group. Alternatively, ketal cleavage can be carried out under more severe conditions (aqueous hydrochloric acid or another strong aqueous acid solution) to provide the corresponding 6a-alkyl compound. The obtained chemical formula 1 compound (wherein 2 is an oxygen atom) can be obtained by reacting with hydroxylamine 144922.doc -26- 201026718 hydrochloride in the presence of a tertiary amine at -20 ° C and +40 ° C The reaction at the temperature is converted to its corresponding oxime (Chemical Formula 1, wherein Z represents NOH, wherein the light base can be ipsilateral- or opposite--). Suitable for tertiary assays such as trimethylamine, triethylamine, pyridine, N,N-dimethylaminopyridine, 1>5-diazabicyclo[4.3.0]壬_5_ene (DBN) & 5_ Diazabicyclo[5 4 undecene (DBU)' is preferably pyridine. This reaction is similar to that described in WO-A 98/24801 for the preparation of the corresponding 3-methoxyimino derivative of trospireone.

Removal of the 3_sideoxy group to prepare the final product of the chemical formula 1 (wherein Z represents two hydrogen atoms) can be 'reductively cleaved 3-keto compounds by, for example, the procedure described in DE-A 28 05 490 The thioketal is carried out. The compounds described in PCT/EP2008/057427 are surprisingly superior for their strong pregnancy-related activity and their potency in maintaining a pregnancy test after subcutaneous administration to rats. Maintenance of pregnancy test in rats: In pregnant rats, corpus luteum removal or oophorectomy induces miscarriage. Pregnancy can be maintained by exogenously administering progesterone (progestin) and a suitable dose of estrogen. The maintenance test for ovariectomized rats was used to determine the peripherai gestagenie activity of the s. Rats were paired overnight before estrus. The pairing was checked the next morning by evaluating the vaginal smear. The presence of sperm is assessed here as the first day of the start of pregnancy. On the 8th day of pregnancy, the animals were given an ovariectomized under ether anesthesia. Treatment with the test compound and exogenous estrogen _, 5 § § / day is performed subcutaneously on the 8th day to the 15th day or the 21st day of pregnancy. On the 8th day, the first administration was performed two hours before the nest resection. The intact control animals received only 144922.doc -27· 201026718 receiving vehicle. Assessment: At the end of the experiment (Day 15 or Day 21), the surviving fetus (fetal with heartbeat) and the implantation site (early absorption and Including autolysis and placental atrophy of the stillbirth). On day 22, fetal malformations may be additionally examined. The number of uterine implantation sites was determined by staining with a 10% ammonium sulfide solution in the uterus without fetus or implant site. Maintaining the surname rate is calculated as the number of live fetuses and the total number of uterine implantation sites (absorbed fetuses and stillbirths and uterine implantation sites). For certain test items, the pregnancy maintenance dose (ED5〇) indicated in Table 1 was determined. For tromethamine, the value of δ ' is 3.5 mg/kg/day. The derivative of the chemical formula 1 has extremely strong pregnancy-related activity. Further, it has been found that the derivative of the chemical formula 1 exhibits an action against mineralocorticoid in vitro. Therefore, it should have potassium in the body and urinary sodium excretion (anti-mineral corticosteroids). The following tests were used to determine these characteristics: The medium used to culture the cells used for assay was DMEM (Dulbecco's Modified Eagle Medium: 4500 mg/ml glucose; paA, E15- 009) and 1〇〇/0 FCS (Biochrom, S0115 'batch 615B), 4 mM L-glutamine, 1% penicillin/streptomycin, 1 mg/ml G418 and 0.5 pg/ml puromycin. The reporter cell line was grown in a white opaque tissue culture plate at a density of 4 X 1 〇 4 cells per well 'in each case 96 wells (PerkinElmer, No. P12-106-017) and kept at 6% DCC- FCS (activated carbon-treated serum to remove interfering components contained in serum). Compounds to be studied were added after 8.4922.doc -28-201026718, and the cells were incubated with the compounds for 16 hours. Experiments were performed in triplicate. At the end of the incubation, the medium containing the effector was removed and replaced with a lysis buffer. After the addition of the luciferase assay host (promega, No. El5〇1), a 96-well culture plate was introduced into a micro-quantitative disc luminometer (Pherastar, BMG labtech), and the luminescence was measured. The IC50 value was evaluated using a software that calculates the dose-activity relationship. The experimental results are presented in Table 1: Table 1 Compound MR antagonism IC50 [_ mr antagonism activity [% of maximum effect] PR in vivo ED50 [mg/kg/d, subcutaneous] 6β, 7β; 15β, 16β-double Ardenyl·17β-cyanoindole-4-4-en-3-one 4.7 98.06 7.3 Πβ-cyano-6,6-ethylenediyl-androst-4-en-3-one 20.0 99.16 25.0 Πα- Allyl-17β-cyanoguanidine male-4-pyrene-3-indole 990.0 65.30 17β-fluoroyl-17α-mercapto-15β,16β-methylene-androstene-3-one 42.0 98.30 10.0 The following examples of the synthesis of preferred compounds are used to further illustrate the invention described in PCT/EP2008/057427. The novel intermediates disclosed in the following individual synthesis examples, such as the 17β-cyano-19-nor-androst-4-ene derivative, are part of the invention described in PCT/EP2008/057427. Many of the reactions described below produce an epimer mixture. Typically, separation of these mixtures via preparative HPLC chromatography is carried out under the following conditions: separation of the positive palm phase, the usual stationary phase being Chiralpak AD-H 5μ. Usually, a mixture of hexane and ethanol is used for dissolution. However, in some cases, other dissolving agent mixtures are used, such as a mixture of methanol and ethanol 144922.doc -29- 201026718: Preparation Example 1: 17P-fluoro-15p, 16p-methylenemethylanthrene-4 -en-3-one la) 3-methoxy-15β,16β-methylenemethylanthrene_3(4),5(6)-dien-17-one will be 5〇§150,160-亚Methyl anthraquinone-4-ene-3,17-dione was dissolved in 11 sterol and 175 ml of trimethyl orthoformate. 25 mg of p-toluenesulfonic acid was added with stirring at 25 °C. After a short time, the product precipitated. At 25. The mixture was stirred under ankle for 1 hour and at -5 °C for 1 hour. Neutralize the mixture with η ratio and filter by suction to obtain 3-methoxy-ΐ5β, 16β-arylene-nor-androst-3(4),5(6)-dien-17-one (48 g). (300 MHz, CDC13 TMS as internal standard, selected signal): δ=3·54 (s,0-CH3), 5.12 (m,4-Η), 5·25 (m,6-H). MS (CI+) m/z (relative density) = 312 (1〇〇); corresponds to C2iH28〇2. Lb) 17P-cyano-3-methoxy_i5p, l6p-methylene methylandrostane-3(4),5(6)-diene, under ice cooling, will be 23 43 over a period of 1.5 hours g TOSMIC® in 140 ml of dimethoxyethane is slowly added to 25 g of 15β16, methylene-3-oxooxy oxime _3 (4), 5 (6) _ diene _17 ketone And 458 a solution of potassium t-butoxide in 1 1 dimethoxy ethane and 300 ml of tributanol, and then the mixture was further stirred at room temperature for 3 hours. The reaction product was poured into ice-cold semi-saturated sodium carbonate solution, and the precipitated product was filtered off by suction, washed with water and dried in a vacuum drying oven (5 (rc, 2 mbar). .doc 201026718 night. 17β-|1yl-3-carbamimido-indole 5β, 16β_methylene hydrazin-3(4),5(6)-diene (23.7 g) in beige crystals iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.42 [m, 15·-Η(β)], 2.73 [d, /=4,5 Hz, 17-Η(α )], 5.14 (br. s,4-H), 5.27 (m,6-H) 〇MS (CI+) m/z (relative density)=324 (100), 341 (85); corresponds to C22H29NO. lc )

B-17P-fluoro-15β,16ρ-methylenemethylandrost-4-en-3-one 5 ml of sulfuric acid (8% by weight) was added to 700 mg of 17β cyano-3-anthracene at room temperature Oxyquinone 5β, ι6β·methylenemethylhectoride _3(4) 5(6)·diene was dissolved in 1 〇ml of sterol' and the mixture was stirred at this temperature for 2 hours. The reaction was quenched with saturated bicarbonate solution, then the mixture was extracted with dioxane and the extract was washed with EtOAc and sat. sodium sulphate, dried over sodium sulfate and concentrated on a rotary evaporator. This resulted in the crystallisation of 17β-cyano-15β,16β-methylene φ methylandroin-4·ene (599 mg). hAMR (300 MHz, CDC13 TMS as internal standard, selected signal): 6=0.44 [m, 15'-Η(β)]5 2.74 [d, J=4.5 Hz, 17-Η(α)], 5.44 ( Br. s, 4-H). MS (EI+) m/z (relative density) = 3〇9 (5〇); corresponds to c2iH27N〇. Preparation Example 2: 17β-fluoro-6p-hydroxymethyl-15p,16p methylenemethylandrosine_4_ene_3 9.5 g 17β-cyano-1Sp, 16p_arylene-androstene The _3_ ketone was dissolved in 〇ml曱, adding 4.8 mlD to the bite and the mixture was raised under reflux 144922.doc •31 - 201026718 The temperature was 1 hour. After cooling, the precipitate was filtered off by suction, washed with a little cold methanol and blotted dry. The crystals (11 g) were dissolved in j 3 5 mi of toluene and 23 5 ml of ethanol, and 11.5 ml of a 30% strength formaldehyde solution was added. After stirring at room temperature for 2 hours, the mixture was concentrated to dryness and chromatography. I7β_cyano-6β-hydroxyindenyl-purine 5β, 16β-methylenemethyl-androst-4-ene-3-one (4·7 g) was obtained. H_NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.47 [m, 15'-Η(β)], 2.76 [d, /=4.5 Ηζ, 17-Η(α)], AB signal (δΑ=3_68, δΒ=3·80, *7^10.5 Hz, additionally with ^=7.4 Hz, Aw, 6-7/=10.5 Hz split), 5.84 (s, 4-H). MS (EI+) m/z (relative density) = 339 (37); corresponds to c22H29N〇2. Preparation Example 3: 17Bu-based-6,6-Extended Ethyl-15p, 16-methylenemethyl-androstene_4_ene_3__ 3a) 17β-cyano-15ρ,16β-methylene-6β·toluene Mercaptooxymethylmethylxanthine·4-baked tau-3- Ming added 2.93 g of toluenesulfonyl chloride to 174 g ΐ7β_cyano-6β-pyridinyl-15β,16β-Asia曱基曱雄甾-4-en-3-one in 20 ml. Stir in the solution in the bite and at room temperature for 6 hours. Thereafter, the reaction mixture was poured into ice-cold 1 N hydrochloric acid and the precipitated crude product was filtered off with suction and dissolved again in ethyl acetate. After washing twice with water, a saturated bicarbonate solution and a saturated sodium hydride solution, and drying the organic phase with sodium sulfate, after concentration to dryness, 17β_cyano-15β, 16β_# methyl- 6β-Toluenesulfonyloxyindolyl-methyl- 4-ene ketone, which was immediately used in the next step, 144922.doc •32- 201026718. iH-NMR (300 MHz' CDC13 TMS as internal standard, selected signal): δ = 0.46 [m, 15'-Η(β)], AB signal (3a=3.95, 5b=4.2〇, heart tolerance = 9 $ Hz 'extra heart (4), <^=7.0 Hz, Hz split), 5 72 (s 4-H). 3b) 17P-cyano-6,6-extended ethyl-15β,16β-methylenemethylandrost-4-ene-freely added 913 mg of sodium hydride in batches to 6.02 g of trimethyl sulphate The solution of iodine in 50 ml of anhydrous DMSO and after the addition was completed, the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 3_13 g of 17β-cyano-ΐ5ρ,16β_methylene-6β-nonylsulfonyloxymethylmethyl-methyl- 4-ene--3-one is added to the formed internal rust salt. The mixture was stirred at room temperature for 6 hours. After the reaction was terminated by adding 350 ml of water, the mixture was extracted twice with 15 〇 (6) ethyl acetate. The organic phase was washed with water and a saturated sodium carbonate solution and dried over sodium sulfate, and the organic phase was treated with activated carbon at room temperature. minute. After filtration through the Celite® layer, 17β-cyano-6,6-extended ethyl-ΐ5β,16β·methylenemethyl-androst-4-en-3-one crystals (Κ1 503 mg, Κ2) when the organic phase is concentrated. 379 mg). ^-NMRQOO MHz' CDCh TMS as internal standard, selected signal): δ=〇·38-0·53 [m,(3H) spiroethyl),〇88 [m,(ih)spiro[ethyl] ' 2_75 [d, J=4.5 Hz, 17-H(4)], 5.65 (s, 4-H). MS (then m/z (relative density) = 335 (i 〇〇); corresponds to. Preparation Example 4: 17P-cyano·6_exomethylene _lsp, 16p subf group 甲雄^4 _3 At room temperature, add 1 ml of 6 N hydrochloric acid to 1 g of 17β-cyano-6β_ via ketone 144922.doc ·33· 201026718 base _1 邛 亚 甲基 甲基 _ _ _ _ _ _ 3, The solution was dissolved in methane, and the mixture was maintained at this temperature for 2 hours. The reaction mixture was then added to 2 s of ice-cold, half-saturated bicarbonate solution and extracted twice with 15 〇 (4) ethyl acetate. After the combined organic phases were treated with sodium sulphate and activated carbon, the mixture was filtered through Celite® layer and concentrated to dryness. EtOAc (hexane/ethyl acetate (0-25%)). 6_exomethylene-15β,16β-indolylmethylandrosine_4_ene_3_one (399 mg) H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 5.12 ( Dd->t, in each case j=2.〇Hz,=CH2), 5.94 (d, J=0.6 Hz, 4-H) MS (EI+) m/z (relative density)=321 (96 Corresponding to c22h27N〇. Preparation Example 5: 17β-cyano-6α-methyl-Ι5β, 16β-methylenemethylandrost-4-ene- 3-ketone in an argon atmosphere's addition of 300 mg Wilkinson catalyst (Wilkinson, catalyst) to 330 mg 17β-cyano-6-exo-indenyl-15β,16β-arylene-indenyl-indole-4-ene -3-In a solution of 40 ml of toluene and 10 ml of ethanol, and hydrogenating the mixture under hydrogen at atmospheric pressure for 3 hours using an oscillating device. Rapid chromatography by phthalocyanine [hexane/ethyl acetate (0- 50%)] remove the catalyst to obtain 17β-cyano·6β-methyl-15β,16β-arylene-indolyl-4-ene-3-enone: 17β-cyano-6α-mercapto-15β,16β- The ratio of methylene methyl androst-4-ene-3-indole = 2.5: 1 to 6-epimer mixture. The catalytic amount of p-sulfonic acid in dichlorosilane is used for acidic epimerization. And another gelatin flash chromatography [hexane / ethyl acetate (0-50%)] to obtain pure 17β-cyano_6α-mercapto-15β, ΐ6β_亚144922.doc -34- 201026718 methylmethyl male -4-thin-3-one (39 mg) ^•NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·46 [m,15·-Η(β)], ι· Ϊ́2 (d, "7=6.3 Hz, 6-CH3), 2.75 [d, J=4.6 Hz, 17_H(cx)], 5.82 (d, "7=1.3 Hz, 4-H). MS (EI+) m/z (relative density) = 324 (95), 341 (55); corresponds to C22H29NO 0 Preparation Example 6 : 17P-cyano-15β,16ρ-methylenemethylanthrene-4,6• Diene _3_阑® will be 3.4 g 17 cyano-3-indolyl-15β,16β·arylene-methyl-androst-3(4),5(6)-diluted in 1〇〇mi A The suspension of the base 2_0 洛 洛 〇 以 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Processing, in the embarrassing. The mixture was stirred for 0.5 hour under hydrazine (ice bath), treated with 1.5 g of lithium bromide and 3 g of lithium carbonate, and stirred at a bath temperature of 100 ° C for 3.5 hours. The mixture was then stirred into ice-water/vaporized sodium and the precipitate was filtered off.丨7β_Cyano-丨5 p, 丨6buy^methylmethyl-androst-4,6-dien-3-one (2.42 g) was obtained. W-NMR (300 MHz, CDCI3 TMS as internal standard, selected signal): 6=0.53 [m, 15·-Η(β)], 2.78 [d, J=4.5 Hz, 17-Η(α)], 5.7〇(s, 4-H), 6.18 (dd, 7=2.8 Hz, /=9.8 Hz, 5-H*), 6.33 (dd, J=2.1 Hz, *7=9.8 Hz, 6-H*) , * = allocation is reversible. Preparation Example 7: 6ρ,7ρ-15ρ,16β·bismethylene-ΐ7ρ·cyanomethine-4_dilute_3 leisure and 6α,7α-15ρ,16ρ-bismethylene-17Ρ-氱基甲Male-4-ene-3__ Add 468 mg of sodium hydride in batches to 3.09 g of trimethoate 144922.doc •35- 201026718 Iodine in 25 ml of anhydrous dimethyl hydrazine in solution and added After that, the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 丨.〇g 17β_cyano-15β,16β-methylenemethylandrazine-4,6-dien-3-one is added to the formed internal salt and is given at temperature. The mixture was 6 hours. After the reaction was terminated by the addition of 15 〇 ml of the chlorinated solution, the organic phase was extracted twice with 75 ml of ethyl acetate, and the organic phase was washed with water and a saturated sodium chloride solution and dried over sodium sulfate, and the organic phase was concentrated to dryness. Two chromatographic flash chromatography [hexane/ethyl acetate (0-50%)] gave 6α,7α15β,16β bismethylene-17β-cyanoindole _4_ene as a lower polar dissolving fraction. 3-ketone (59 mg) and 6β,7β-15β,16β-bis-indenyl-17β·cyanoquinonexiong_xinene-3-one (67 mg) as a highly polar dissolving component. Dissolved fraction 1 : 6 (*, 7 < 1-15 cedar, 1 called - bismethylene _17 _ cyanomethyl guanidine _4-zinc-3 · Ming H-NMR (300 MHz, CDC13 TMS as Standard, selected signal): δ = 0.53, 0.63, 0.87 and 0.98 [4xm, (in each case 1H) cyclopropyl], 2·80 [d'"/=4·3 Ηζ, 17-Η(α )], 6.01 (s,4-H) MS (CI+) m/z (relative density) = 322 (1〇〇), 339 (33); corresponds to 〇C22H27NO. Dissolved fraction 2: 6p,7p-isp , l6p-bismethylene_17p_fluoromethyl-androsine·4_ dilute-3-93⁄4: H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0_57 and 0.92 [2xm, (in each case 1H) cyclopropyl], 2 84 [d, •7=4.3 Ηζ, 17-Η(α)], 6 07 (s, 4_H) MS (EI+) m/z (relative density) =322 〇〇〇), 339 (33); corresponds to 144922.doc • 36 · 201026718 C22H27NO. Preparation Example 7 - Variant 2: 6卩, 7 at -15, 16 cedar-bismethylene_17-cyanomethylandrost-4-ene-3-_ 7_ variant 2_a) 6p, 7p -15p,16p-bismethylene_3p_5p_dihydroxy-17p_cyanomethyl androstane and 6β,7β-15ρ,16β-bismethylene-3P-5P-dihydroxy-17α-cyanomethyl The residual alkane is similar to the method given in Example lb. 6β,7β-15β,16β-bis-indenyl _3β,5β-diylmethyl oxazepine-17-one c/zewz'e 1982, Ρ4, 718- 719) Reaction. Using a mixture of hexane and ethyl acetate to obtain 6β,7β-15β,16β-bismethylene_3β-5β-bis-carbyl-ΐ7β-cyanomethyl-androstane and 6β,7β-15β,16β. - bismethylene_3β-5β-dihydroxy_17〇[_cyanomethylandrostane. 6, 73-15, 1 Qiu-bismethylene-3, -5, - bis, sylylene, succinyl, fluoro, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate, sulphate 2Η), 〇.61 (m,1H), 〇73 (s, 3H), 0.83 (s, 3H), 2.97 (width single bee '1H), 3.79 (width single peak, 1H) 4.31 (wide single peak, 1H), 4.79 (wide single peak, 1H) 6 shirts, 7 to -15 choices, 16?-bismethylene-;^-5 shirts-double warp groups _17〇1_cyanomethyl-androsterane: W -NMR (D6-DMSO): 0.41 (m, 2H), 0.61 (m, 1H), 0.73 (s, 3H), 0.80 (s, 3H), 3.05 (single singular, 1H) 7-variant 2- b) 6p,7p-15p,16p-bismethylene-ΐ7ρ·cyanomethylxine retention_4_lean_3_discussion 144922.doc 37· 201026718 Similar to the procedure given in Example 30e, 6β, 7β- Ϊ́5β,16β-bis-indenyl-3β-5β-dihydroxy-17β-cyanomethyl-androstane. This gave 6β 7β _ 15β, 16β-bis-indenyl-17β-cyanoindole 甾4· ene-3-one. The NMR data were identical to those given in Example 7. Preparation Example 8: 17β-cyano-7α-methyl-15β, 16β-methylenemethylanthrene_4 dilute_3_one Add 67 mg of gasified steel (1) to 1〇g 17b at room temperature A solution of cyano-15β,16β-indenyl-androstane-4,6-dien-3-one in 50 ml of tetrahydrofuran was stirred and mixed for 1 min and then cooled to -15. Then, 450 mg of aluminum chloride was added, and the mixture was stirred at this temperature for 3 minutes, 4.5 ml of a solution of ruthenium bromide (3 M in tetrahydrofuran) was added dropwise, and the mixture was stirred at -15 C for one hour. For processing, at _15. 30 ml of 2 hydrazine hydrochloride was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 hr, added to water and extracted three times with ethyl acetate and dried over sodium sulfate. /ethyl acetate (〇-5〇%) gelatin chromatography. This gave 丨7^cyano_7af*_ΐ5β ΐ6ρ methylenemethylandrost-4-en-3-one (149 mg). iNMR (3〇〇MHz, CDCl3 TMS as internal standard, selected signal): δ=〇·45 [m, 15·-Η(β)], 〇>88 (dj j=7.l Hz, 7- Me), 1.08^1.21 Μ, in each case (3H), 2xMe], 2 75 [mountain j=4 6Hz i7_ H(a)], 5.76 (s, 4-H). MS (CI+) m/z (relative density) = 324 (1〇〇), % (55); corresponds to C22H29NO. Preparation Example 9: 144922.doc 201026718 17P-cyano_17α-methyl-15β,16β-methylenemethylandrosta-4-en-3-one 9a) 17P-cyano-3-methoxy-17α -methyl·ΐ5β,16β-methylenemethylandrostane-3(4),5(6)-diene, fresh cold solution of lithium diisopropylamide (LDA) at -78 °C (Prepared by preparing 12.1 ml of diisopropylamine and 54.1 ml of n-BuLi (1.6 Μ in hexane) in 82 ml of tetrahydrofuran at 0 ° C) to 8 g of 17-cyano-3-methoxy -15β, 16β-methylenemethylhistane-3(4), 5(6)-diene in solution, and ¥ kept the mixture at -78 ° C for 1 hour. The mixture was cooled back to -90 °C before the subsequent addition of 6.9 ml of methyl iodide. After the end of the addition, the reaction mixture was slowly warmed to room temperature overnight. The reaction was quenched by the addition of a saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate and washed with water and saturated sodium chloride. The organic phase was dried over sodium sulfate (concentrated to dryness and flash chromatography eluting hexane/ethyl acetate (0-30%) to afford Ι7β- cyano-3- methoxy s s s s s s s s s s Azinyl-androstane-3(4), 5(6)-diuret (6.5®g). iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 6 = 0.40 [m, 15'-Η(β)], 1.01 (s, Me), l.l5 (s, Me), 1.38 (s,

Me), 3.58 (s, 0-CH3), 5.15 (m, 4-H), 5.27 (m, 6-H) » MS (CI+) m/z (relative density) = 355 (100), 338 (53 ); corresponds to C23H31NO. 9b) 17β-cyano-17α·methyl-15β,16β-methylenemethylandrosine-4_lean_3_ Ming according to the example lc method, 385 mg 17β-cyanodecyloxy-17α-methyl 144922. Doc -39- 201026718 -15β,16β-fluorenylene hydrazin-3-3(4),5(6)·diene obtained 17β-nitrogen-ΐ7α-fluorenyl group after scavenging from ethyl acetate -15β, 16β-indenyl 曱 xisculin-3-one (285 mg). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.43 [m, 15'-Η(β)], 1.16; 1.21 and 1.38 [3xs, in each case (3H), 3xMe ], 5.75 (d, "7 = 1.1 Hz, 4-H). MS (CI+) m/z (relative density) = 324 (38), 341 (100); corresponds to C22H29NO. Preparation Example 10: 17α-allyl-17p-cyano-indenyl 5β,16ρ-indenyl-androstino- 4-ene-3-one 10a) 17α-dilyl-17β-cyano-3-methoxy Base-15β,16β-methylenemethylhistrol-3(4),5(6)-diene According to the method of Example 9a, allyl bromide was used as the alkylating agent, 1 g of 17-cyano group -3-decyloxy-15β,16β-methyleneindole-hydroxanthine_3(4) 5(6)_diene obtained by flash chromatography to obtain 17α-dilyl-17β-amino-3-methyl Oxy-15-β, 16β-arylene-androstane-3(4), 5(6)-diene (358 mg). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.41 [m, 15*-Η(β)], 3.58 (s, O-CH3), 5.15 (m, 4-H) , 5.25 [m, (3H), 6-H and =CH2], 6.05 [m, (1H), -CH=]. 10b) 17a-allyl-17P-cyano-15p, 16p-methylenemethylandrosine_4_ene_3• ketone according to the example lc method, 300 mg 17α-l-propyl-Ι7β-cyano·3 -Methoxy-15β,16β-methylenefxixane-3(4),5(6)-diene after flash chromatography 144922.doc -40· 201026718 Obtain 17α_allyl_17β- Cyano-15β, 16β-methylenemethylanthrene-4-4-ene-3-one (210 mg). ^-NMR (300 MHz, CDCl3 is an internal standard, selected signal): 6=0.45 [m, 15'-Η(β)]5 5.1 8-5.30 [m5 (2H), =CH2], 5.76 (d, J = 1.7 Hz, 4-H), 6.03 [m, (ih), -CH=]. MS (CI+) m/z (relative density) = 350 (1〇〇), 367 (68); corresponds to C24H31NO. Preparation Example 11: 17β-cyano-6ρ·hydroxymethyl·17α_methyl_15p, 16p_methylenemethylanthrene 4-dil-3· Ming according to the method of Example 2, 5.90 g 17β-cyanide Base····················································· After the %)], 17β·cyano·6β-hydroxyindolyl-17α-mercapto-15β,16β-arylenemethylandrost-4-en-3-one (2.22 g) was obtained. WNMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.50 [m, 15'-Η(β)], 1.21; 1_27 and 1.43 [3xs, in each case (3Η), 3xMe], ΑΒ Signal (δΑ=3_73, δΒ=3.85, is a wide signal of about 10_0 Hz, extra is u=7.5 Hz, about 1〇.〇Hz split), 5.89 (s,4-H). MS (CI+) m/z (relative density) = 341 (100), 354 (35), 371 (22); corresponds to c23h31no2. Preparation Example 12: 17P-cyano-15α,16α-methylenemethylandrost-4-en-3-one 12a) 144922.doc •41 · 201026718 17P-cyano-3P-hydroxy-15α,16α-亚Methyl anthraquinone _5(6)-ene According to the method of Example lb, 24.2 g of 3β-acetoxy-15α,16α-arylene-methyl-Congxiu-5(6)-ene was rapidly chromatographed on silica gel [ Hexane/ethyl acetate (0-50%)] and crystallization from ethyl acetate to give 17β-cyanohydroxy-15α,16α-methylenemethylpyrazine-5(6)-ene (3·2) g) and i7<x-cyano_3β-carboxy-15α, 16α-methyleneindole-5(6)-ene (3.6 g). 17β-|1 yl-3β-radio-15α,16α-arylene-methyl-methyl ketone _5(6)_thin: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0.54 [m, (2H), cyclopropyl], 〇·9〇[m,(1H), cyclopropyl], 1.03 and 1.17 [2xs, in each case (3H), 2xMe], 3.52 Ο, 3- H), 5.37 (m, 6-H) » MS (EI+) m/z (relative density) = 311 (88); corresponds to C21H29NO. 17<*-gas-based-3p-radio-ΐ5α,16α-methylenemethyl-xanthine_5(6)-diluted: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal)·· δ =0.78 [m,(1H),cyclopropyl],〇.89_0 99 [m,(2H),cyclopropyl]' 1.02 and 1.08 [2xs, in each case (3h), 2><Me] , 2.79 [d, •7=7.7 Ηζ, 17-Η(β)], 3.54 (m,3-H), 5.38 (m, 6-H). MS (EI+) m/z (relative density) = 3n (18); corresponds to C2ih29NO. 12b) 17P-cyano-15α, ΐ6α_methylenemethylanthrene _4_ene_3赃 Add 2.10 g of aluminum triisopropoxide to 32 g Ι7β-cyano-3β-hydroxy _15α,16α_ The methylene methyl male-5-(6)-ene was dissolved in a solution of 80 ml of 2-butanone and the mixture was heated under a phort for 15 hours. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium sulphate, and the mixture was extracted three times with ethyl acetate and the organic phase was washed with saturated 144922.doc • 42- 201026718 sodium carbonate solution and dried over sodium sulfate. After concentration, the minced fish was subjected to flash chromatography [hexane/ethyl acetate (0-50%)] to give 17β-cyano-purine 5α, ΐ6α_methylenemethylxanthine-4-female-3-indole (3.0 g ). ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.55 [m, (2H), cyclopropyl; |, 〇·8ι_〇_97 [m, (3H)] , i 21 ^ (6H), 2xMe], 5.74 (br. s, 4-H). MS (CI+) m/z (relative density) = 310 (100), 327 (23); corresponds to C21H27NO 0 Preparation Example 13 : 17β-|1 -6-β-methyl- Ι5α, 16α-methylene Astragalo-4-pyrim-3-one according to the method of Example 2, 3·〇g ι7β_cyano _15α, 16α_methylene oxime oxime-4-en-3-one in gelatin flash chromatography [ After calcination/ethyl acetate (〇_5〇〇/.)], 17β-cyano-6β-hydroxymethyl-ΐ5α,16α-arylene-androst-4-en-3-one (850 mg) was obtained. ). W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.56 [m, (2H) 'cyclopropyl], 0.91 [m, (1H), cyclopropyl], 1.22 [s, (6H), 2xMe], AB signal (δΑ=3.68, δΒ=3.77, very wide signal), 5.83 (s,4-Η). MS (CI+) m/z (relative density) = 340 (100), 357 (51); corresponds to C22H29NO2 0 Preparation Example 14: 17β-fluoro-15α,16α-methylene-6β-toluenesulfonyloxy Methylmethylandrosine-4-diphenyl-3-copper and 17β-mercapto-6-exomethylene-Ι5α,16α-methylenemethylanthrene-4-diazon-3-嗣144922.doc -43 - 201026718 According to the method of Example 3a, 700 mg of 17β-cyano-6β-pyridylmethyl-15α,16α-arylene-androst-4-en-3-one was subjected to flash chromatography on silica gel [hexane/acetic acid] Ethyl ester (0-50%)] gave 17β-cyano-15α,16α·methylene·6β_toluene methoxymethylmethylindole-4-pyrim-3-one (880 mg) and In its pre-run, 17β-cyano-6-exomethylene-15α,16α-arylene-androst-4-indole-3-one (a minor component) was obtained. 22 mg). Dissolved fraction 1 : 17p-cyano-6-exomethylene-15α, 16α-methylenemethylxanthine_4_ dil-3-嗣: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal ): δ = 0.64 [m, (2H), cyclopropyl], 1·〇9 [m, (1H), cyclopropyl], 116 and 1.25 [2xs, in each case (3H), 2xMe], 5.04 and 5.15 (dd-n, in each case /=1.9«^, =(:1^2), 5.97(8,4-11). MS (CI+) m/z (relative density)=322 (1 〇〇), 339 (28); corresponds to C22H27NO. Dissolved fraction 2: 17P-cyano-15α, 16α-methylene-6β-toluene decyloxymethylmethyl-androst-4-ene-3- Ketone: W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.56 [m, (2H), cyclopropyl], 0.91 [m, (1H), cyclopropyl], j 13 And 1.22 [2xs, in each case (3H), 2xMe], 2.50 [s, (3H), C6H4, CH3], AB signal (δΑ=3·95, δΒ=4·29, 4=9.7 Hz, extra From 6-//=6.2 Hz, Hz split), 5.77 (s, 4~jj) AA'BB' signal [δΑ=7·40, δΒ=7.82, in each case (2H), c6h4]. CI+) m/z (relative density) = 494 (5), 511 (15); corresponds to c29h35no4s. 144922.do c 44- 201026718 Preparation Example is : 17β-cyano-6,6-extended ethyl-hydrazine 5α,16α·methylenemethylandrost-4-en-3-one According to the method of Example 3b, 860 mg 17β-cyanide -15α,16α-methylene-6β-nonylbenzenesulfonyloxymethylmethyl-androst-4-en-3-one in gelatin chromatography [hexane/ethyl acetate (0-50%) After that, 17?-cyano-6,6-extended ethyl 15?,16?-methylenemethylandrost-4-en-3-one (265 mg) was obtained.

W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.45-0.63 [m, (4H) spiroethyl and cyclopropyl], 0.88 [m, (1H) spiroethyl ], 1.02 [m, (1H), cyclopropyl], 1.28 and 1.32 [2xs, in each case (3H), 2xMe], 5.69 (s, 4-H). MS (EI+) m/z (relative density) = 335 (88); corresponds to C23H29NO. Preparation Example 16: 17β-cyano-17α-methyl-15α,16α-methylenemethylandrost-4-en-3-one 16a) 17α-cyano-15α,16α-methylene-3β-three Isopropyl nonyloxymethylandrost-5(6)-ene was slowly added to a solution of 5.44 ml of triisopropyl sulphate in 2.5 ml of tetrahydrofuran to 3.6 g of 17α-cyano at 0C. 3β-hydroxy-15α,16α-arylene-indole-5(6)-ene, 1.7 g imidazole and 141 mg dimethylaminopyridine in 20 ml of dimethyl decylamine (DMF) . The mixture was then warmed to room temperature overnight, poured into saturated bicarbonate solution and extracted with ethyl acetate. The organic phase was washed 5 times with water and finally washed with a saturated sodium carbonate solution and concentrated to dryness. The crude product 1 7α-cyano-1 5α,1 6α-methylene-3β-triisopropyldecyloxymethylxanthracene-5(6)-ene (7.3 g) was used directly in I44922.doc •45 - 201026718 In the next step. ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal):

δ = 0.78 [m, (1H), cyclopropyl], 〇.88_〇.99 [m, (2H), cyclopropyl], 1.02 and 1.08 [2xs, in each case (3H), 2xMe, overlap 5=1.05, br. s, (18H), TiPS-Me], 2.79 [d, J=7.1 Hz, 17-H (β)], 3.56 (m,3-H), 5.33 (d, *7=4.8 Hz, 6-H). MS (EI+) m/z (relative density) = 468 (12); corresponds to c30H49NOSi. 16b) 17β-cyano-17α-methyl-ΐ5α,ΐ6α-methylene_3p_triisopropyldecyloxycarbonylmethyl-androst-5-(6)-ene and 17α-cyano-17β- Mixture of ΐ_α5α, ΐ6α-methylene-3p-triisopropylmethaneoxymethylxanthine-5(6)-ene According to the method of Example 9a, using PCT as an alkylating agent, 5· 29 g 17α-cyano-15α,16α-indenyl_3β_triisopropyldecyloxymethylandrosin-5(6)-ene obtained by flash chromatography to obtain ι7_cyano_17_fluorenyl -15 (χ16α_ fluorenyl-3β-triisopropyldecyloxy oxime male _5(6) olefin 17·episomeric complex (3.65 g). Zero (300 MHz, CDC13 TMS As an internal standard, the selected signal): δ = 0·60-0·72 [m, (1H), cyclopropyl*], i.05, [br.s, (i8H), TiPS-Me], 3· 54 (m,3-H), 5.33 (m,6-H) MS (CI+) m/z (relative density) = 499 (55); corresponds to c3iH51NOSi. · 16c) 17P-cyano-3p-hydroxyl -17a-methyl_15α16α methylene-methylandroxine_5(6)_ene and 144922.doc -46- 201026718 17α-cyano-3β-hydroxy·ΐ7β_methyl-15α,16α-methylene A mixture of methylaxoride-5(6)-ene at room temperature '9 ml of fluoride Base ammonium (TBAF) (1 Μ in tetrahydrofuran) was added to 3.0 g of 17-cyano-17-methyl-15α, 16α-methylene-3β-triisopropyl oxalate oxime oxime-5 (6)-Alkene 17-epimer in a solution of 5 ml of tetrahydropurine, and the mixture was stirred for 4 hours. After the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness, followed by flash chromatography to give 17-cyano-3? -Hydroxy-17-mercapto-purine 5α, 16α-arylene-methyl-andrazine-5(6)-alkene 17-epimomer mixture (1.9 g). iH-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.74 [m, (1H) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 16d) 17 cedar-cyano-17(*-methyl-15&lt;*,16&lt;*-methylenemethylandrost-4_ene_3_one according to the method of Example 12b' 1.9 g 17-cyano group 3β_Hydroxy-17-methyl-15α,16α-indenylmethyl-andrazine _5(6)-ene 17_epimer, after preparative HPLC chromatography, 17β_cyano-17α-A _15α16α methylene methyl male-4-pyrim-3-ylide (335 mg) W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·69 [m, (2H ), cyclopropyl]' 〇.82 [m,(1H), cyclopropyl], 〇% [m,(1H) 'cyclopropyl], M4; 丨上和丨七[3xs, in each case (3H), 3xMe], 5.74 (s, 4-H) MS (EI+) m/z (relative density) = 323 (100); corresponds to C22H29N〇. Preparation Example 17: 144922.doc -47- 201026718 17P -Cyano-15α,16α-methylenemethylanthridine a-4,6-disali-3-one 17a) 17β-fluoro-3-methoxy-15α,16α-methylenemethylanthrene_ 3(4),5(6&gt;diene-17-anthracene and 17α-fluoro-3-methoxy-15α,16α-methylenemethylxanthine_3(4),5(6)diene- 17-ketone mixture according to the method of Example la, 17 g of 17-cyano-I5a, 16cx-methylenemethylandrost-4-en-3-one 17-difference The isomer is treated to give 17-cyanomethoxyl-15α,16α-methyleneindole male-3(4),5(6)-diene 17-epimer (7.6 g) , which was used directly in the next step. 17b) 17β-Cyano-15α,16α-methylenemethylandrost-4,6-dithia-3-one according to the method of Example 6 7.6 g 17-cyanomethyl Oxy·15〇1,16〇1_methylene oxime Cui-3(4), 5(6)-diene gives 17β-cyano-15 after some crude product obtained by preparative HPLC chromatography α, 16α-methylenemethylanthridine-4,6-diindole-3-_ (48 mg). W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.66 [m, (1H), cyclopropyl]' 0.78 [m, (1H), cyclopropyl], i 19 And 1.32 [2xs, in each case (3H), 2xMe], 5 74 (s, 4_H), 621 (dd, /=2.8 Hz, J=9.8 Hz, 5-H*), 6.34 (dd, *7 =1.9 Ηζ,·7=10.0

Hz, 6-H*), * = allocation is reversible. MS (EI+) m/z (relative density) = 307 (26); corresponds to c21h25NO. Preparation Example 18: 17β-cyano-7α·methyl-15α,16α-methylenemethylandrosine-4-ene-3-butanone 144922.doc -48- 201026718 According to the method of Example 8, 2.2 g of 17-cyano -15α,16〇ι-methylene oxime, male-4,6-diene_3_辋, ι7_epimer, 17β-cyano-7α-methyl, after preparative hplc chromatography 15α, 16α_-indenyl-androst-4-ene-3-one (257 mg). iHMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ=0·58 [m,(1H),cyclopropyl]' 〇69 [m,(1H),cyclopropyl],〇% ( d, /= 7.2 Hz, 6-Me), 1.25 and 1.26 [2xS, in each case (3H), 2xMe], 5.79 (s, 4-H). MS (EI+) m/z (relative density) = 323 (1〇〇); corresponds to c22H29N〇. Preparation Example 19: 17β-fluoro-methyl-androstene-4,6·disali-3-one 19a) 17P-cyano-3-ethoxymethylanthrene_3,5-diene is similar to Example 1a In the procedure given, the original triethyl decanoate was used instead of trimethyl orthoformate to react with 17β-cyanomethyl-4-in-3-one. This gave 170-cyano-3-ethoxyindole _3,5-di-! H-NMR (D6-DMSO): 0.81 (s, 3H), 0.86 (s, 3H), 1.17 (t, 3H, J=7.1 Hz, 3-0-CH2-CH3), 3.36 (m, 2H, 3-0-CH2-CH3), 5.09 (m, 2H, H-4 and H-6). 19b) 17β-cyanomethylandrosine_4,6-dicarbea-3-oxime similar to the procedure given in the example, with 17β-cyano-3 ethoxy oxime-3,5-di Alkenes reaction. This gave Ι7β-cyanoindole male-4,6-dien-3-indole. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 144922.doc •49- 201026718 δ=1.02 (s,3H),113 (S,3H),5.68 (s,1H,H-4 ), 6.06 6-H), 6.13 (s, 1H, 7-H). , old, Preparation Example 20: 17P-cyano 7α-methylmethylandrosin-4-4-ene-3-enketone is similar to the procedure given in Example 8 to give 17β-cyanomethine _4 6 ene- 3. Ketone reaction. This gave 17|3-cyano-7{χ_mercapto-androst-3-ene. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal) 6=0.77 (d, 3H, 7-CH3, J=7.3 Hz)), 0.98 (s, 3H), 1&gt;2l 3H), 5.74 (s, 1H, H-4) 〇Bend Preparation Example 21: 17P-Cyano-7α-ethylmethanoyl _4-ene-3-one is similar to the method given in Example 8 'Using ethylmagnesium bromide Substituting the ruthenium bromide-based town to react 17β·cyanomethyl-oxo-6•diene_3_one. Obtained, -7-α-ethyl guanidine, _4_ ene ketone. iH-NMR (300 MHz, CDCl3 TMS as internal standard selection signal) 5=0.88 (t? 3H, 7-CH2-CH3, J=7.3 Hz)), 〇.98 (s, 3H)5 1.22 ❹ (s , 3H), 5.74 (s, iH, H_4). Preparation Example 22: 17P_gas-based·6α,7α-methylene-methyl-androsterin I-III_ _ and 17p_ ιyl-6p,7p-methylene-methyl-androstene-4-4-ene-3-one is similar to Example 7 Recognized by this, the procedure of the mouth, the reaction of P, cyanomethyl male-4,6-dithia-3-one. This gave 17β. cyano-cut α-methylenemethyl-andrazine-4·en-3-one and 17β-cyano-6Μρ_arylene-methyl-methyl group. 144922.doc -50. 201026718 17β-cyano-6α,7α-methylenemethylanthrene-4-zinc-3-gg: H-NMR (3 00 MHz, CDCI3 TMS as internal standard, selected for number) : 5 = 0.46 (m, 1H), 0.77 (m, 1H), 0.85 (m, 1H), l.〇l (s, 3H), 1.15 (s, 3H), 5.95 (s, 1H, H-4 ). 17P-Cyano-6β,7β-methylenemethylandrosine_4·ene_3_鲷·· H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ-0.79 (m, 1H ), 0.95 (s, 3H), 1.09 (s, 3H), 6.01 (s, 1H, H-4). Preparation Example 23: 17β-Cyano-6β-radiomethylmethylxanthine_heart thinning Similar to the procedure given in Example 2, 17p-cyanoguanidine was left to react with _4-ene-3-one. This gave 17β-cyano-6β-hydroxymethylmethylxanthene-4_ene-3-one. W-NMR (300 MHz' CDC13 TMS as internal standard, selected signal): δ-0.98 (s, 3H), 1.21 (s, 3H), 3.68 (m, 2H, 6-CH2-OH), 5.82 (s5 1H, H-4) 〇Preparation Example 24: 17β-cyanoethylidene 曱4_ene_3_鲷 is similar to the examples given in Examples 3a and 3b, such that 17 cyano _6 hydroxy Methyl-androst-4-ene-3-enone reaction 'wherein the crude sulfonate intermediate is further reacted. This gave 17 戸 cyano-6,6-ethylidene oxime _4_ene_3 ketone. W-NMR (300 MHz, CDCi3 TMS as internal standard, selected signal): 6 = 0.42 (m, 2H), 0.77 (m} 1H), 0.99 (s, 3H), 1.26 (s, 3H), 5.62 ( s, 1H, H-4). 144922.doc -51 · 201026718 Preparation Example 25: 17P-cyano-17α-methylmethylandrosine-4-lean_3_net 25a) 17-carbyl-3,3-ethanediyldimethoxymethyl Leave _5_ dilute at room temperature, 5 g of cyano compound in 56 m]1 dioxane, 14 (6) ethylene glycol, 37 ml trimethyl orthoformate and 丨·5 g to methyl sulfonate mixture Stir for two hours. After the addition of sodium bicarbonate solution and ethyl acetate, the phases were separated and washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The 17?-cyano-3,3-ethanediyloxymethylstano-5-ene obtained in this manner can be used without any further purification. 25b) 17β-cyano-3,3-ethanediyldioxy_ΐ7α-methyl.methylanthogamine _5•rare similar to the method given in Example 9a, such that 17ρ•cyano_33_乙二The bis-dimethoxymethyl male-5-ene reaction. This gave 17 as _cyano-3,3-ethanediyl hydroxy-17α-indenyl-androst-5-ene. H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 1.04 (wide single peak '6H), 1.28 (s, 3H), 3.94 (m, 4H, ketal), 5.34 (s, 1H, H-6). 25c) 17β-cyano-17α-methylmethylandrosine 4-4-ene-3-_ Similar to the method given in Example lc, 17 17-cyano-3,3-ethanediyldioxy-17α - methylmethyl male to _5_ene reaction. This gave 17 cyano _17 〇 1 _ methyl ketone -4- -3- -3-. H-NMR (300 MHz, CDC13 TMS as internal standard, selected signal factory 144922.doc • 52· 201026718 δ=1.09 (s, 3H), 1.20 (s, 3H), 1.28 (s, 3H), 5.73 (s , 1H, H-4). Preparation Example 26: 17β-fluoroyl·6ρ·ylmethyl-17α-methylmethylanthryl-4-pyrimidin-3-yl is similar to the procedure given in Example 2, Ι7β-cyano-Ι7α·methylmethylandrost-4-en-3-one is reacted. This gives 17β-cyano-6β-hydroxymethyl-ΐ7α-indenyl-androst-4-en-3-one丨H-NMR (D6-DMSO): 1.01 (s, 3Η), 1.15 (s, 3Η), 1.25 (s, 3Η), 3.35 (m, 1H, 6-CH2-OH), 3.57 (m, 1H) , 6-CH2-OH), 4.73 (t, 1H, J = 5.8 Hz, 6-CH2-OH), 5.65 (s, 1H, H-4). Preparation Example 27: 17β-Alkyl-6,6- Ethylenediyl-17 α-methylmethylandrosine-4-lean_3__ is similar to the procedure given in Examples 3a and 3b, allowing ΐ7β-cyano-6β_ via thiol-17α-methyl oxime 4- 4-en-3-one reaction in which the crude benzene sulfonate intermediate is further reacted. This gives 17β·cyano-6,6-ethanediyl_17〇1_fluorenylanthen-4- Dilute-3-branched 1. ^-NMR (300 MHz, CDCI3 TMS as internal standard, selected signal): δ = 0.42 (m, 2 Η), 0.78 (m, 1Η), 1.10 〇, 3Η), 1.27 (s, 3Η) 1.29 (s, 3H), 5.63 (s, 1H, H-4). Preparation Example 28: 17α-allyl-17p-cyanomethylanthryl-4-4-ene-3-one ketone 28a) 17P-cyano-17α-methylmethylandrost-4-en-3-one analogous to the example The method given in 9a, the reaction of 17-cyano·3,3_ethanediyldioxyanthracene 崔5-ene, in which allyl bromide is used instead of methyl iodide 144922.doc •53· 201026718 Compound. This gave 17?-allyl-ΐ7?-cyano-3,3-ethanediyldioxaindole-5-ene. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 1.10 (s, 3H), 1.13 (s, 3H), 3.99 (m, 4H, ketal), 5.26 (m, 2H, _CH=CH2), 5.39 (s, 1H, H-6), 5.97 (m, 1H, -CH=CH2). 28b) 17a-allyl-17P-cyanoandrost-4-en-3-one is similar to the method given in Example lc, such that 17a-allyl-17β-cyano-3,3-ethyl Dikis bisoxyindole male-5-ene reaction. This gave 17〇1_allylyl-17β-cyanomethyl-androst-4-ene-3-. ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 5 = 0.97 (m5 1H), 1.17 (s, 3H), 1.25 (s, 3H), 5.25 (m, 2H, -CH=CH2 ), 5.79 (s, 1H, 4-H), 5.96 (m, 1H, -CH=CH2). Preparation Example 29: 17β-cyano-la-methylmethyl-androst-4-iso-3-oxime 29a) 17P-fluoromethylandrostene-1,4-dien-3-one to give 2.5 g of 17β-cyanide The base of the male fluorene-4-ene-3-_ and 2.7 g of the di-dioxanyl cyanide in the 50 ml two e-dark in the Buddha for 3 hours. After cooling, the mixture was diluted with a second gas and filtered. The filtrate was washed with sodium hydrogen carbonate solution, water and a saturated sodium carbonate solution. After drying over sodium sulfate, filtration and concentration of the filtrate, the residue was chromatographed using hexane/ethyl acetate mixture. This gave 17?-aza-methyl-androst-1,4-dien-3-one. W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): 144922.doc •54- 201026718 δ = 1_00 (s,3H), 1.25 (s,3H),6·07 (s,1H, H -4), 6.25 (wide single peak, 1H, H-2), 7.06 (s, 1H, Hl). 29b) 17β-cyano-la-methyl-methyl-androst-4, -3- ketone 6 mg "smelting copper (i), ii ml of trimethylaluminum and cerium 31 w tridecyl decyl alkyl vapor It was continuously added to a solution of 〇_6 g 17 cyanomethyl male oxime Μ_diene _3_ oxime in 6 ml of tetrahydrofuran. After stirring at room temperature for three hours, the mixture was partitioned between water and ethyl acetate. The organic phase was washed successively with water and a saturated sodium carbonate solution, dried over sodium sulfate and filtered, and the filtrate was concentrated. Chromatography using a mixture of hexane/ethyl acetate afforded 17p-cyano-la-methylmethano-4-pyrimidine-3-indole. H-NMR (3 00 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.94 (d, 3H, 1-CH3), 0.98 (s, 3H), 1.29 (s, 3H), 5.71 (s, 1H, H-4) 〇Preparation Example 30: 0 6p, 7p-15p, 16P·bismethylene-17P-fluoro-l7〇t-methylmethylanthryl-4-4-en-3-one 30a) 6p, 7p-15p, 16p-bismethylene·3ρ·t-butyldimethylsilyloxy-5β- via keto-methyl _17-lang according to the method of Example l6a '6β,7β_15β,16β^ Mercapto- 3β 5β·di-based oxime-bearing -17-one c /2 k 1982, Ρ 4, 718-719) and as a butyl dimethyl hydrazide chloride After crystallization, 60,70-150,160-bismethylene_3|3_t-butyldimethylmethylalkyloxy 144922.doc •55- 201026718 keto-5β-hydroxyindole _17_ ketone. ^-NMR (300 MHz, CDCh ^ ^ , i3 is the internal standard, selected signal): δ=0·08 and 0.11 [2xs, in the long/1 (3H), Si-Me], 4 · 13 (s, 3-Η), 4·40 (s, 5-ΟΗ). MS (CI+) m/z (relative density) = 445 (5〇), 462 (ΐ5) ·, corresponding to C27H44N〇3Si 〇30b) 6β,7β-15β,16β-bismethylene_3β_third Methyl dimethyl seroyloxy-17-cyano-5β- via ketone male _17_ 闺 similar to the method described in Example lb to make 6β,7β_15β16ρ bis methylene-3 β-second Butyl dimethyl decyloxy _ 5 β hydroxymethyl male alkane 4 7-one reaction. This gave 6β,7β_15β,16β_bis-indenyl-3β-t-butyldimethylmethylalkyloxy_17-cyano-5β-hydroxymethylhectorol-17 as a mixture of 17-episo-nitrile nitriles. - Ketone, which is further processed without the need to separate the epimers. 'H-NMR (D6-DMSO): 〇.〇2 (s, 3H), 0.04 (s, 3H), 0.40 (m, 2H), 0.60 (m, 1H), 0.74 (s, 3H), 0.82 ( Wide single peak '12H), 2·36 (m, 2H), 2.97 (m, 1H), 4.01 (m, 1H). 30c) 6p, 7p-15p, 16p-bismethylene_3p_5p_bis-lightyl_17p_cyano_17a_methyl-androstane similar to the methods of Examples 9a and 16c, such that 6β, 7β-15β, 16β-bis-indenyl-3β-tert-butyldimethylsilyloxy_17-cyano-5 5-hydroxy-indole and oxane-17-one. This gave 6?,7?-15?,16?-bismethylene-3?-5?-bishydroxy-17?-cyano-17?-methyloxime. 144922.doc •56- 201026718 丨H-NMR (D6-DMSO): 0.40 (m, 2H), 0.61 (m, 1H), 0.74 (s' 3H), 0.93 (s, 3H), 1.36 (s, 3H) ), 1.93 (m, 1H), 2.03 (m, 1H), 3.79 (m, 1H). 30e) 6β,7β-15β,16β-bismethylene-ΐ7β_cyano·ΐ7α•methylmethine _4· 稀-3-闲将 310 mg 6β,7β-15β,16β-bis-indenylene -3β-5β-bishydroxy-17β-cyano-17α-methylindolerol was dissolved in 10 m guanidine acetone, and 〇42 ml Jones reagent was added. After 15 minutes, 4 ml of isopropanol was added to the mixture. The mixture was then partitioned between water and ethyl acetate. The organic phase was washed with saturated sodium sulfate, dried over sodium sulfate and filtered and concentrated. Using a mixture of hexane and ethyl acetate to obtain 6β,7β_15β,16β-bismethylene-17β-cyano-17 α-methyloxime 甾4_women-3- ketone. 'H-NMR (D6-DMSO): 0.41 (m, 1H), 0.85 (m, 1H), 0.99 (s, 3H), 1.02 (s, 3H),1·31 (s,3H), 5.86 (s) , 1H, 4-H). Preparation Example 31: 17α-dipropyl-6 release, 73-15 release, 16 release-bismethylene_173_氦基甲雄甾_4_ 稀-3-闲31a) 17α-propylpropyl-6p, 7p-15p, 16p-bis-indenyl_3β_5β-dihydroxy-Ι7β-cyanomethyl-androstane is similar to the method given in Example 9a (using allyl bromide instead of methyl moth) and 16c. , 70-150, 16-di-indenyl _3, butyl butyl dimethyl sulphate oxy-17-cyano-5β-hydroxymethylxiongrein _ 17-ketone reaction. This is 144922.doc •57- 201026718 to 17α-allyl_6β,7β_15β,16β_bismethylene_3β邛dihydroxy"邛_cyanomethyl male sulphonate. !Η-ΝΜΚ (D6-DMSO) : 0.40 (m, 2H), 〇.6i 1H), 〇.?4 (S} 3H), 0.96 (s, 3H), 2.02 (m, 2H), 3.79 (m, 1H), 4.78 (m, 1H) 5.19 (s,1H), 5.24 (m,1H), 5.94 (m,1H). 31b) Allyl-6υ,7Ρ-15Μ6Ρ-bismethylene_17p_cyanomethyl group _4_ene -3-3⁄4 Similar to the method given in Example 30e, the 17α-allyl_6β, 邛_ 15β, Ι6β_ bis-sub-fyl _3β_5β· bis-cyano cyanomethyl was decocted. This gave 17α- Allyl _6β,7β_15 (3,16ρ_bismethylene fluorenyl-cyanomethyl-andrazine-4-thin-3 _嗣. •H-NMR (D6-DMSO): 0.43 (m, 1H), 〇.86 (m, 1H), i.〇2 (s? 3H), 1.03 (s, 3H), 5.20 (m, 1H, -CH=CH2), 5.24 (m, 1H, -CH=CH2), 5.87 (s, 1H, 4-H), 5.94 (m, 1H, -CH=CH2) 〇Preparation Example 32: 17P-cyano-6-methyl-indole 5ρ,16ρ·methylenemethylanthrene-46 Alkenyl-3-ketone 25 mg Pd-C (10%, wetted with water) is added to 1 〇〇mg 17β_cyano-6-exomethylene_ΐ5β, ι6β_亚曱基曱雄甾_4ene _3 ketone in 1〇 In a solution in ethanol, and heating the mixture to boiling. Then, a solution of mi. 5 mi of cyclohexene in 2 mmol of ethanol was slowly added dropwise over a period of 丨 hours and heating was continued for another 7 hours under reflux. The reaction mixture was cooled, the catalyst was removed by filtration and concentrated to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& .doc 201026718 W-NMR (400 MHz, CDCl3 TMS as internal standard, selected signal): δ = 0·53 [m, (1H) cyclopropyl], 2.78 [d, plate, 5 edge, 17 H(4)], 5 and 6.18 [2xs, (1H in each case), 4_j^7_h]. MS (CI+) m/Z (relative density) = 322 (1〇〇), 339 (5〇); corresponds to C22H27NO. Example 33: 4-Gas-17P-cyano-indole 5β, 16β·methylenemethylanthrene_4_ene_3鲖 700 mg 17 cyano·15Ρ, 16 benzylidene-4-ene- 3, dissolve the solution in 8 ml ° than the bite and cool to 〇 ° C. After adding 0.32 (6) thioindole chloride, at this temperature, the mixture is mixed with a saturated aqueous solution of sodium hydrogencarbonate, water and ethyl acetate, and the phases are separated, and the organic phase is washed with water and a saturated aqueous solution of sodium sulphate. . The organic phase was dried over sodium sulfate and filtered and concentrated <RTI ID=0.0></RTI> and the product was recrystallised from ethyl acetate. This gave 4-chloro-17-mercapto- 15β,16β-indenyl-androst- 4-ene-3-one (21 l mg). H-NMR (300 MHz 'CDC13 TMS as internal standard, selected signal): ❹ δ=〇_47 [m,(1H)cyclopropyl], 2.75 [d, J=4.5 Hz, 17_H(4)], 3 33 ( (1 (ΐ£ΐ,·//-15.3Ηζ, "/2=4·5Ηζ, «/3=2.6Ηζ). Preparation Example 34: 17Ρ-cyano-3-hydroxyimino group _15p, 16pj A The base armored collar will dissolve 700 mg 17β-cyano _15p, 16 ymethylene methyl guano Cui _4 dilute 3- 嗣 in a 5 m buck bite and add 211 mg of the base amine hydrochloride. After one hour of mixing at the bath temperature, the batch was partitioned between water and ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and filtered and the filtrate was rolled. Analysis of the brick E/z mixture "Bei 144922.doc -59· 201026718 base-3-hydroxyimino- Ι5β,16β-arylene-androst-4-en-3-one (157 mg W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.43 [m, (1H) cyclopropyl], 2.73 [d, /= 4.5 Ηζ, 17-Η (α )], 3.05 (m, 5-Hj), 5.79 (m, 4-H) ° MS (CI+) m/z (relative density) = 325 (100), 342 (76); corresponds to C21H28N2O. Preparation Example 35 : 17P-Fluoro-6-exomethylene-17α-methyl-15β, 16-methylenemethyl-androsteryl _4_ 稀·3·明 According to the method of Example 4, 130 mg 17β-cyano-6β-hydroxyindenyl _ι7α_ thiol-1 5β,16β-methylene oxime oxime-4-zol-3-one obtained 17β-cyano-6-exomethylene-17α-methyl-15β after chromatography , 16β-Amidinoyl malexyl _4_ dil-3-one (86 mg). 17β-cyano-6-exomethylene_ΐ7α-mercapto-15p, 16p-methylene methyl male-lean- 3- Ming ^-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.47 [m, (1H) 'cyclopropyl] ' 1.12, 1.16 and 1.39 [3xs, (in each case) 3H), 3xMe], 5.02 and 5.12 [2xt, /=2 Hz, (1H in each case), =CH2], 5.93 (br. s, 4-H). Preparation Example 36: 17β-cyano- 17α-methyl-15p,16p-methylenemethylanthridine a_4,6·diene_3·_ According to the method of Example 6, 17.7 g 17 cyano-3-indolyl _17〇1_methyl -15β,16β-methylenemethylhistrol _3(4),5(6)_diene obtained after crystallization 144922.doc -60- 201026718 17β-cyano-17α-mercapto _15β,16| 3·Methylene oxime 甾4 4 diene (5_84 g) 〇^-NMR (300 MHz CDCl3 TMS as an internal standard, the selected signal is wide δ = 0.52 [m, (1H) 'cyclopropyl], 114, 39 [3xs, (in each case 3H), 3xMe], 5.70 (s, 4·Η),6 18 (10),Λ=9 8 Do •/2=2.8 Ηζ,6-Η), 6.33 (dd,·7;=9·6 Hz, heart=ι.8 Ηζ, 7_Η). ' MS (CI+) m/z (relative density) = 322 (1〇〇), 339 (32); Xu should be C22H27N〇2 0 V Preparation Example 37: 6P, 7p-lSp, 16p-bismethylene· 17p_cyano-17αmethylmethyl male 4ene-3-_ and ",7«_15?, called bismethylene_17ρcyano-17〇[methylmethano-4-pyrene-3- The ketone according to the method of Example 7, 3. 〇g 17ρ·cyano_1?α-methyl-methylenemethyl-methyl-K6-di-return in the Shixi rubber book ^ separation of the crude product to obtain a non-polar solvate "^ heart 丨Qiu '^ Bu 曱 曱 丨邛 丨邛 丨邛 丨邛 — — — — — — — — — — 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 Base - 170 - cyano _17 〇 1 曱 曱 曱 曱 甾 _ 4 _ ene 3 ketone (1.2 g). Dissolved fraction 1 : 6a, 7a-lSp, 16p-bis-indenyl _17 _ cyano-17 〇 [methylmethylandrost-4-zol-3-one: H_: NMR (300 MHz, CDC13 TMS as Internal standard, selected signal): δ=〇·46' 0,57, 0,80 and 0·93 [4xm, (in each case (1)), 4χ cyclopropyl]' 1.15, 1.20 and 1.39 [3xs, (3H in each case), 3xMe], 5.96 (s, 4-H). 144922.doc 61- 201026718 Dissolved fraction 2 : 6p, 7p-15p, 16p-bismethylene_17?_cyano_17α_曱基甲雄留-4·稀-3-网H_MMR (300 MHz, CDC13 TMS as an internal standard, selected signal): δ = 0.50 and 0.87 [2xm '(1H in each case), 2x cyclopropyl], 1 1〇, 1.14 and 1.41 [3xs, (3H in each case), 3xMe], 6·〇2 (s, 4_H). MS (CI+) m/z (relative density) = 336 (100), 353 (28); corresponding to C23H29NO 0 Preparation Example 38: 17β-cyano-17α-ethyl-3-decyloxy·ΐ5β, ΐ6β- Methylene methylandrostane-3(4),5(6)-diene and 17β-cyano47α-ethyl_ΐ5ρ,16β-methylenemethyl-androst-4-pyrene-3-oxime according to an example Method 9a) (using ethyl iodide instead of mercapto iodide), 18.0 g 17β-cyano-3-indolyl _15β, 16 m-methylene methyl maleoxane-3(4), 5(6)- After the diene is crystallized, 17β_cyano_17α_ethyl_3_decyloxy-15β, 16β-arylene methyl malezane-3(4), 5(6)-diene (6.85 g) is obtained. And after the mother liquor flash chromatography, 17β-cyano·17α-ethyl-15β, 16β-methylene oxime male-4-pyre-3·嗣 (338 mg) was obtained. 17β_Cyano-17α-ethyl-3-methoxy-15p,16p-methylenemethylhistane-3(4),5(6)-diene: ^-NMR (300 MHz, CDC13 TMS As an internal standard, the selected signal): δ = 0.42 [m, (1H) 'cyclopropyl], 1.00 and 1.17 [2xs, (in each case 3H), 2xMe], 1.21 (t, J = 7.1 Hz, CH2-CH3), 3.58 [s, (3H), OMe], 5·14 (m, 4-H), 5.26 (m, 6-H). MS (CI+) m/z (relative density) = 352 (90), 369 (100); corresponds to 144922.doc -62 - 201026718 C24H33NO 〇17P-cyano-17α-ethyl_iSp, 16p-methylene甲雄甾_4_稀-3,: W-NMR (300 MHZ, CDC13 TMS as internal standard, selected signal): δ=0.45 [m,(1H) 'cyclopropyl],1&gt;19 and 1.21 [ 2xs, (3H in each case), 2xMe; overlap i.23 (t, j three 6.4 Hz, Ch2_CH3)], 5 75 young 4-H). ' MS (CI+) m/z (relative density) = 338 (1〇〇), 355 (59); corresponds to c23h31no. ® Preparation Example 39: 17β-cyano-17 _ethyl-15p, 16p_methylenemethylanthrene _4 6 diene _3 ketone according to the method of Example 6, 6〇g 17 cyano _ηα• Ethyl-3 methoxyl·15β,16β-methylenemethylanthrene _3(4)5(6)-diene is obtained by crystallization and subsequent flash chromatography of the mother liquor to give 17β-cyano-17α-ethyl- 15β,16β-methylenemethylanthryl _4,6-dicarba-3-indole (4·87 g). (300 MHZ, CDC13 TMS as internal standard, selected signal): φ 5 〇·59 [ m,(1H)'cyclopropyl], 1.18 and 1.29 [2XS,(je 3H), 2xMe , ¢^1.27 (tj y=7.4 Hz, CH2-CH3)], 5.75 (s, 4-H), 6.22 (dd, J; = 9.8 Hz, J2 = 2.8 Hz, 6-H), 6.38 (dd, J}=9.6 Hz, &lt;/2=l·9 Hz, 7-H) MS (CI+) m/ z (relative density) = 336 (100), 353 (43); corresponds to C23H29NO. Preparation Example 40: όΡ, 7ρ-15β, 16ρ-bismethylene·17p cyano·i7〇[•ethylmethyl male _4_ ene_3_one and "'7α book Ρ, 16Ρ-bismethylene-17Ρ-cyano-17α-ethylmethyl 144922.doc •63· 201026718 甾-4-ene-3-one according to the example Method 7, 2_5 g 17β-cyano-17α-ethyl-15β, 16β-arylene-methyl- 4,6-di The 3-ketone was obtained by HPLC separation of the crude product to give a non-polar solvent of 6 〇 [,7〇1-150,160-bismethylene-170-cyano-17〇1-ethylmethylanthrene- 4-en-3-one (290 mg) and a polar dissolving 6β,7β-15β,16β-bismethylene·17β-cyano-17α-ethylmethylantre-4-en-3-one (670 mg). Dissolved fraction 1: 6α,7α-15β,16ρ-bismethylene-17P-cyano-17α-ethylmethylandrost-4-en-3-one: W-NMR (300 MHz, CDC13 TMS as internal standard , selected signal): δ = 0.48, 0.53, 0.80 and 0.93 [4xm, (in each case 1H), 4x cyclopropyl], 1.16 and 1.23 [2], (in each case 311), 2&gt;&lt;?^; overlaps 1.22 (t, "7=6.3 Hz, CH2-CH3)], 5.96 (s, 4-H). Dissolved fraction 2 : 6p, 7p-15p, 16p-bismethylene-17p-fluoroyl-17α-ethylmethylandrosine-4-diphenyl-3-indole H_NMR (300 MHz, CDC13 TMS as internal standard, Selection signal): δ = 0.50 and 0.86 [2xm, (1H in each case), 2χcyclopropyl], 1.09 and 1.15 [2xS' (3Η in each case), 2xMe], 1.22 (t, J=7.3 Ηζ, CH2-CH3), 6.00 (s, 4-Η). Preparation Example 41: 17Ρ-Fluoro-17α-ethyl_7ρ-methyl_15ρ, 16ρ·methylenemethylandrosten-3-enone and 17ρ-indenyl_17α_ethyl-7α_methyl 15ρ, 16ρ methylene methyl male-4 - dilute-3-free according to the method of Example 8, 1 〇g 17ρ_cyano_17α•ethyl_15ρι6ρ亚144922.doc • 64- 201026718 methylmethyl male -4,6-dien-3-one is obtained by HPLC separation of the crude product to give a non-polar solvate of 17β-cyano-17α-ethyl-7α-mercapto-purine 5β, ΐ6β-methylene oxime male -4-thin-3-_ (165 mg) and a polar dissolving group of β7β_alkyl-17α-ethyl-7β-methyl-15β,16β-arylene-based oxime-4_ene_3_ Ketone (292 mg). 17P-Cyano-17α-ethyl_7α-methyl-15β,16β-methyleneindole-4-thin-3-class W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ = 0.44 [m, (1H), cyclopropyl], 0.86 (d, / = 7.2 Hz, 7-Me), 1.08 [m, (1H), cyclopropyl], 1.19 and 1.21 [2xs, 3H), 2xMe in each case; overlap 1.22 (t, *7 = 7.4 Hz, CH2-CH3)], 5.75 (s, 4-H). 17β-cyano-17α-ethyl-7β-methyl-Ι5β,16ρ-methylenemethylandrost-4-en-3-one W-NMR (300 MHz, CDC13 TMS as internal standard, selected signal): δ =0.53 and 1.04 [2xm, (1H in each case), 2x cyclopropyl], 1 &amp; 1.26 (m,7-Me,2xMe and CH2-CH3)], 5.73 (br·s,4-H) . PREPARATION EXAMPLE 42: 17P-Indolyl-androst-4-ene is similar to the method given in Example ib, such that, for example, Helv. Chim_ Acta (45) 1962, 2575 )reaction. After the crude product was chromatographed using a mixture of ethyl acetate and n-hexane, the fractions containing the product were concentrated and re-chromatographed by HPLC. In addition to 17α-cyanomethine, 17β-cyanoindole is also obtained. 17p-cyanomethylandrosine-4-ene 144922.doc •65- 201026718 W-NMR (CDC13 TMS as internal standard, selected signal): δ=〇94 [s, 3H, -CH3], 1.04 [s, 3H, -CH3], 1.13 [m, 1H], 1.21 [m, 1H], 2.11 [m,1H], 2.20 [m,1H], 2.26 [m,1H], 5.31 [Wide single peak, 1H, 4 -H]. Preparation Example 43: 4-Gas-17β-cyanomethylandrosine-4-enene Similar to the method given in Example 33, 17β•cyanoquinonecium _4_lean-3-ketone was reacted and treated. This gave 4-gas-Ι7β-cyanomethyl-androst-4-ene-3-one. W-NMR (CDC13 TMS as internal standard, selected signal width δ=〇98 [s 3H, CH3], 1.24 [s, 3H, CH3], 2.58 [m, 1H, 17-H], 3.26 [ddd «/ 7 = 15.1 Hz, · 72 = 4.0 Hz, /3 = 2.6 Hz. Preparation Example 44: 6β,7β·15ρ,16ρ-bismethylene-17p-|L-methyl-methyl-methyl, ii_4_2 Dilute 3 Ming 60,70-150,16戸-bismethylene-170-cyanomethylanthryl _4_rare_3_ ^*4 yangbei is similar to the example 293 reaction, get 60,7 choose-1 Qiu , 16 pan-bismethylene_170-aryl-曱xiongliu·1,4-dien-3-one. ^-NMR (300 MHz, CDC13): δ=0.55 (m, 1ΗΊ 1 ιΛ , ^ ( s, 3H), 1.14 (s, 3H), 2.81 (d, 1H, H-17) 6.18 (m, 1H, H-2^) ' 1H, H-4), 6.85 (s, 1H, Hl). Preparation Example 45: 1〇1,2〇1-external, 7?-15?,16?-methyleneidene-17?-cyanomethyl-chromium m-ene-3-arsin-3 70-15戸,160-bis-indenyl-170-cyanomethyl-andrazine _14_ ketone is similar to the reaction of Example 7 to obtain 1α, 2α-6β, 7β-ΐ5βΐ6ρ moxibustion 144922.doc * 66 - 201026718 -17-17β- Cyanomethyl male-4-ene-3-one. *H-NMR (300 MHz, CDC13): 6 = 0.52 (m, 1 Η), 0.74 (m, 1H), 0.82 (m, 1H), 1.07 ( s, 3H), 114 (s, 3H), 2 81 (d, m, H i7), 5.86 (m, 1H, H-4). According to the present invention, it has now been found that the compound of the chemical formula 1 described in PCT/EP2008/057427 is also suitable for intravaginal or Intrauterine administration. This can be accomplished using a physiologically acceptable solution, such as an aqueous or oily solution, with or without suitable solubilizing, dispersing or emulsifying agents. Suitable oils are, for example, peanut oil, cottonseed oil, castor oil or sesame oil. The choice is not limited to such examples. For intravaginal or intrauterine administration, specific systems may be used, such as intravaginal systems (eg, vaginal ring, VRS) or intrauterine systems (IUS), which are for long periods of time (eg, 1, 2, 2). The active substance of the present invention is released from the reservoir within 3, 4 or 5 years. A representative example of an intrauterine system which may be mentioned is MIRENA®. This is a T-shaped uterus from the release of levonorgestrel from BAYER SCHERING PHARMA AG. system. It is additionally possible to administer via an implanted supply system consisting of an inert carrier material such as a biodegradable polymer or a synthetic polyoxyl polymer. These delivery systems release the active substance over a prolonged period of time (e.g., 3 months to 3 years) in a controlled manner and are implanted subcutaneously. The dosage of the present invention, for example, from the daily release of IUS to the oral dose equivalent to the daily oral dose, should be used orally in an amount of from 0.01 to 10 mg per day. The daily dose in the treatment of W symptoms is about 0.1 to 20 mg. The formulations of the present invention are, for example, 144922.doc-67-201026718 Formula 1 compound which is released from IUS per day in an amount of from 0.005 to 1 mg. The system of the invention can be used to administer estrogen as well as compounds of the formula. It is possible to consider the synthesis of estrogen (preferably ethynyl female disaccharide, or estramid ether) as estrogen for contraceptive preparations. Estrogen is administered at a daily dose corresponding to 0.01 to 0.4 mg of ethyl fast estrone. Estrogen is of course mainly used as an estrogen in the treatment of premenopausal, near menopausal and postmenopausal symptoms and hormone replacement therapy, especially for diols or their esters, such as estradiol valerate or conjugated estrogens ( CEE = combined with horse ginseng hormone). Accordingly, the present invention relates to a chemical formula of cyanomethyl-androstene derivatives,

N

Wherein 2 is selected from the group consisting of ruthenium, two hydrogen atoms, nor and nhnso2r where R is hydrogen or an alkyl group,

Rl ' R2 is independently hydrogen or sulfhydryl or R and R together form a methylene group or is omitted and forms a double 144922.doc •68- 201026718 bond between C1 and c2, which is 虱 or 素, in addition: T? 6a, p6b j, _ together form a methylene or U. ethanediyl group or e is hydrogen and R6b is selected from the group consisting of hydrogen, methyl and hydroxymethylene groups, and is selected from hydrogen, q-C4 alkyl groups. , a group of C2_C3 alkenyl groups and cyclopropyl groups, or:

R is hydrogen and R6b and R7 together form a methylene group or are omitted to form a double bond between C6 and C7, or R is a methyl group and the ruler "and ruler 7 is omitted and a double is formed between c6 and c7" The bond, R, r16 is hydrogen or together form a methylene group, and R17 « is selected from the group consisting of hydrogen, Ci-C: 4 alkyl and allyl groups.

And the use of the solvates, hydrates, stereoisomers, diastereomers thereof, 144922.doc, and salts for the preparation of a medicament having a non-oral supply form of a compound of formula J, Eight limiting conditions are to exclude compounds having the following chemical formula A:

(A) -69- 201026718 wherein X is hydrogen or a fluorenyl group and the double bond between c1 and c2 and between C6 and c7 is a double bond which is optionally present, and the restriction further further excludes 17β-cyano Androst-4-en-3-one. According to the invention, the compound of formula 1 is preferably administered in the intrauterine system or the vaginal ring. According to a further embodiment of the invention, the administration of the compound of formula 1 can also be carried out by employing an implantable delivery system.

In a further embodiment, in the 17β-cyanoandrost-4-ene derivative of Chemical Formula 1 to be used in accordance with the present invention:

Rl5 ' Rl6 together form an anthracene group, t-Ύ is selected from the group consisting of ruthenium, NOH and NNHS02H, z is 〇, R and R are each hydrogen or form an α-methylene group,

Rl is α-fluorenyl, R4 is hydrogen or gas, and ϋ 6b is methyl or thiol,

ϋ 6a yp 6b ji , forming a methylene or ethylene group or, in each case, hydrogen, selected from the group consisting of hydrogen, methyl and ethyl, D 6b Yy 7 KR together forming a methylene group, R is selected At least the substituents R1, R2, r4, R6a, R6b, r7, Ri5, and one of the groups R16 and r17 containing hydrogen, a methyl group and an allyl group are not hydrogen. The present invention further relates to a non-oral supply type of a medicament comprising at least - 144922.doc -70 - 201026718 of the compound of the formula 1 as an active substance. Non-oral administration is, for example, intrauterine or intravaginal administration of at least one compound of the formula: and the corresponding pharmaceutical administration form is, for example, the intrauterine system (two vaginal rings (IVR). The intrauterine system or the vagina as a pharmaceutical administration form The ring is well known to those skilled in the art. The intrauterine system that can be mentioned is, for example, from a call

Schering Ph follows the product of a AG, Miren, and the vaginal ring that can be mentioned is the product Nuvaring®. The parenterally administered compound of the formula according to the present invention may be similar to the product mentioned above and the pharmaceutical dosage form of the compound:! compound may accordingly be utilized in a similar manner, such as the products Mirana® and Nuvaring®. The following examples are intended to illustrate the invention in more detail: Example ❿ Will be easy to enter the uterus and consist of a biodegradable polymer or a synthetic polyoxopolymer (from the core of the active substance in a mixture ratio of the appropriate polymer-active substance) An inert supply system consisting of a composition that surrounds the polymer membrane to ensure the desired daily release rate is introduced into the rat uterine cavity. The nests of female animals were removed beforehand and pretreated with estradiol for three days. Implants with different lengths of mm) and limited diameter (1.i to 2 mm) were maintained in the rat uterus for between 4 and 14 days to release the local and whole body of the active substance based on various parameters of different tissues. Pregnancy-related effects. The following parameters were measured: 丨 based on uterine weight, histologically detectable epithelial height and progesterone regulatory marker genes (eg KJFBP-D performance, local pregnancy related effects on the uterus; 2) based on progesterone regulation Marker genes (eg, RankL) show a systemic pregnancy-related effect on breast 144922.doc • 71· 201026718; 3) a systemic pregnancy-related effect on pituitary based on LH content (decreased estrogen-induced increase in LH content). The compound of formula 1 shows a significant pregnancy-related effect in the uterus which is comparable to the corresponding treatment using a levonorgestrel-containing supply system such as MIRENA®. 144922.doc -72-

Claims (1)

201026718 VII. Patent application scope: 1. A chemical formula of cyanoguanidine male-4-ene derivative, and solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts thereof, for preparation Non-oral administration of a compound of the formula 1 for the administration of a pharmaceutical form, N Where y Selected from the group consisting of 0, two hydrogen atoms, nor and nhnso2r where R is hydrogen or alkyl, R, R2 are independently hydrogen or methyl or R1 and R2 together form a methylene group or are omitted at C1 A double bond is formed between C2, R is hydrogen or halogen, and further: R6a' R6b together form an anthracene group or an anthracene, 2_ethanediyl or R6a is hydrogen and R6b is selected from the group consisting of hydrogen, methyl and hydroxymethylene. a group, and R? is selected from the group consisting of hydrogen, q-C4 alkyl, CVC3 alkenyl, and cyclopropyl 144922.doc 201026718, or: R6a is hydrogen and the sessile core and the ulnar 7 form a methylene group or are omitted A double bond is formed between C6 and C7, or a ruler "is a sulfhydryl group and the ruler 11 and the ruler 7 are omitted to form a double bond between C6 and c7, and R'R16 is hydrogen or a methylene group, R It is selected from the group consisting of hydrogen, Ci-C4 alkyl and allyl groups, with the proviso that compounds having the following chemical formula A are excluded: Wherein X is hydrogen or methyl and ci and C2 are double bonds as the case exists, and double I between C and 2. 2. 4. 5. == conditions are further _ step is also excluded. The use of oral month 1 is for the preparation of an intrauterine system. For example, the material of claim 1 is prepared for the preparation of the vagina. For example, the 17β-cyanomethyl@@_4_ of claim 1 is used for the use of R15, and the *K and R together form a methylene group. For example, the use of 17β-cyanomethyl group 4 olefins of claim 1 is 144922.doc t 201026718 is characterized in that Z is selected from the group consisting of ruthenium, n〇H and NNHS02H. 6. 7. « 8. 9. e 10. 11. 12. 巍13· W 14. 15. 16. The use of the 17β-cyanomethine-4-ene derivative of claim 1 is characterized in that Ζ indicates 〇. For example, the use of the 17β-cyanomethyl male-4-dilute derivative of the month 1 is characterized in that R1 and r2 are each hydrogen or form an α-methylene group together. The use of the 17β-cyanoindole _4_ene derivative of claim 1 is characterized in that R 丨 is α-methyl. For example, the use of the 17β-cyanoguanidine male _4_dilute derivative of Item 1 is characterized in that R4 is hydrogen or gas. The use of the 17β-cyanomethyl- 4-ene derivative of claim 1 is characterized in that R6b is a fluorenyl group or a hydroxymethyl group. The use of the 17β-cyanoindole _4_ene derivative of claim 1 is characterized in that R, r together form an anthracene group or an anthracene group, 2. an ethylene group or a gas. The use of the 17β-cyanomethyl- 4-ene derivative of Claim 1 is characterized in that R7 is selected from the group consisting of hydrogen, methyl and ethyl. ', as requested by the project, the use of cyanomethyl _4_ene derivatives is characterized by R6b, R7 together form an anthracene group. For example, the use of the cyanomethyl male _4_ene derivative is based on the fact that R" is selected from the group consisting of hydrogen, methyl and propyl groups. ... as requested by the cyanomethyl group, _4_ The use of the dilute derivative is characterized in that at least one of the substituents R1, R2, R4, R6a, R6b7, and Rl7 is not hydrogen. R and 144922.doc 201026718 The drug of the form 17. The use of claim 16 is characterized It is the anti-mineral corticosteroid effect of the drug. Pregnancy-related and 18.-supply-type drugs, ^ 17R . w species such as the formula 1 β-cyanomethyl- 4-ene derivatives, characterized The right-handed administration of the formula is characterized in that it is suitable for a drug other than the oral cavity (4), which is characterized in that it is an intrauterine system. The drug of claim 18 is characterized in that it is a vagina. 21. The estrogen according to any one of claims 18 to 20. The secret of $1 additionally contains at least a drug of the month 21, which is characterized in that although the hormone is a B-cell, the diol is. The drug of claim 21, which is characterized in that the estrogen is a natural estrogen. The drug, characterized in that the natural estrogen is an estradiol. A 25. The drug of claim 23, characterized in that the natural estrogen is estradiol citrate. 26. As claimed in claim 23舦廿" 'It is characterized in that the natural estrogen is a bound estrogen. 144922.doc 201026718 IV. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: Φ 5. If there is a chemical formula in this case, please reveal the characteristics that can best show the invention. Chemical formula: 144922.doc