DE19535851A1 - New 18-nor-steroid cpds. - Google Patents

Abstract

18-Norsteroid cpds. of formula (I) are new. W = O, NOH or (H,H); R6a, R6b = H and R7 = H or 1-4C alkyl; or R6a+R6b = CH2 or CH2CH2 and R7 = H; or R6a, R6b = F, Cl, Br, I, or 1-4C alkyl, and R7 = H or R6b + R7 = bond; or R6a = H and R6b + R7 = bond or CH2; R9, R10 = H; or R9 + R10 = bond; R11b = H, 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl and R11a, R12 = H or R11a + R12 = bond; or R11a + R11b = 1-4C alkylidene and R12 = H; R15 = H; R16 = H or 1-4C alkyl; or R15 + R16 = bond or CH2; R17a = OR21 and R17b = (CH2)nA, (CH2)mC?=C-B or (CH2)pCH=CH(CH2)k-D; or R17a = COR22 and R17b = OR23, 1-4C alkyl or F; or R15 = H, R16 + R17a = CH2, and R17b = COR22; or R17a + R17b = a gp. of formula (a)-(c); x = 1 or 2; y = 0 or 1; dotted line = optional bond; U = O or (H, OH); E, G = H; or E+G = bond; R21, R23 = H, 1-4C alkyl or 1-4C alkanoyl; R22 = 1-3C alkyl or 1-hydroxy-(1-3C) alkyl; A = H, CN, COOR24 or OR25; R24 = 1-4C alkyl; R25 = H, 1-4C alkyl or 1-4C alkanoyl; B = H, 1-4C alkyl, 2-3C alkynyl, F, Cl, Br, I, 1-4C hydroxyalkyl, 1-4C alkoxy-(1-4C)alkyl or 1-4C alkanoyloxy-(1-4C)alkyl; D = H, OH, 1-4C alkoxy or 1-4C alkanoyloxy; n = 1-4; m = 0-2; p = 0 or 1; k = 0-3. Also claimed are certain intermediates.

Description

The present invention relates to the 18-norsteroids of the general formula I.

wherein
W represents an oxygen atom, the hydroxyimino group (= N∼OH) or two hydrogen atoms,
R ^6a and R ^6b each represent a hydrogen atom and R⁷ represents a hydrogen atom or a straight-chain or branched-chain saturated α- or β-position C₁-C₄-
Alkyl radical or
R ^6a and R ^6b together represent a methylene group or a triple ring formed together with the carbon atom 6 and R⁷ represents a hydrogen atom or
R ^{6a represents} a fluorine, chlorine, bromine or iodine atom or a straight-chain or branched-chain saturated C₁-C₄alkyl radical, in which case R ^6b and R⁷ each represent a hydrogen atom or together form an additional bond and if R ^6b and R⁷ each represent a hydrogen atom or R⁷ is a C₁-C₄ alkyl radical, R ^{6a can be} α or β, or
R ^{6a represents} a hydrogen atom and R ^6b and R⁷ together represent an additional bond or an α- or β-methylene group,
R⁹ and R¹⁰ represent hydrogen atoms, or together represent an additional bond,
R ^{11b represents} a hydrogen atom, a C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl radical and R ^11a and R¹² represent hydrogen atoms or a common additional bond or
R ^11a and R ^11b together represent a C₁-C₄ alkylidene radical and R¹² in this case represents a hydrogen atom,
R¹⁵ and R¹⁶ each represent a hydrogen atom or together for an additional bond or an α- or β-methylene bridge,
or R¹⁶ represents an α- or β-position C₁-C₄-alkyl group and R¹⁵ represents a hydrogen atom,
R ^17a / R ^17b one of the substituent combinations

means
or R¹⁶ together with R ^17a for an α- or β-permanent methylene bridge and
R ^17b for a rest

stands, in which case R¹⁵ also represents a hydrogen atom,
or R ^17a / R ^17b together

mean,
with X = 1 or 2, U = O or

and E and G are hydrogen or a common additional bond,
R²¹ and R²³ independently of one another have the meaning of a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-alkanoyl group,
R²² is a C₁-C₃-alkyl group or a 1-hydroxy-C₁-C₃- alkyl group,
A has the meaning of a hydrogen atom, the cyano group, a radical of the formula COOR²⁴ or -OR²⁵ where R²⁴ is C₁-C₄-alkyl and R²⁵ is hydrogen, C₁-C₄-alkyl or C₁-C₄-alkanoyl,
B is a hydrogen atom, a C₁-C₁ alkyl group, a C₂ or C₃ alkynyl group, a fluorine, chlorine, bromine or iodine atom, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl -, alkoxy or alkanoyloxy part,
D has the meaning of a hydrogen atom, a hydroxy, C₁-C₄-alkoxy or C₁-C₄-alkanoyloxy group,
n has the meaning 1, 2, 3 or 4,
m has the meaning 0, 1 or 2,
p has the meaning 0 or 1,
k have the meaning 0, 1, 2 or 3.

The serpentine lines in the representation of the general formula I mean that the relevant substituent can be α- or β-permanent.

The following radicals are primarily suitable for the substituents mentioned in the general formula I:
straight or branched chain saturated C₁-C₄ alkyl radical: preferably the methyl, but also the ethyl, n and isoPropyl, n, iso and tert-butyl radical;
C₂-C₄ alkenyl radical: vinyl radical;
C₂-C₄ or C₂ or C₃ alkynyl: preferably ethynyl, but also 1-propynyl;
C₁-C₄ alkylidene: preferably methylene, but also ethylidene;
C₁-C₄ alkanoyl group: formyl, propionyl and especially acetyl;
1-hydroxy-C₁-C₃-alkyl group: hydroxymethyl, 1-hydroxypropyl and in particular 1-hydroxyethyl radical;
Hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group: preferably hydroxymethyl, but also 2-hydroxyethyl, 3-hydroxypropyl or corresponding ethers or esters;
C₁-C₄ alkoxy group: methoxy, ethoxy, propoxy and butoxy;
C₁-C₄ alkanoyloxy group: formyloxy, acetyloxy and propionyloxy.

According to the present invention, preference is given to those compounds of the general formula I in which:
W for one oxygen atom or two hydrogen atoms;
R ^6a and R ^6b each represent a hydrogen atom;
R ^6a for a chlorine atom or a straight-chain saturated C₁-C₄ alkyl radical or
R ^6b and R⁷ represent hydrogen atoms or together for an additional bond;
R⁷ represents a hydrogen atom or an α- or β-alkyl radical having up to 4 carbon atoms;
R ^11a , R ^11b and R¹² each represent a hydrogen atom;
R ^11b for a hydrogen atom and R ^11a and R¹² together for an additional double bond;
R ^11b for a C₁-C₄ alkyl radical and R ^11a and R¹² each for a hydrogen atom, or R ^11a and R ^11b together for a C₁-C₄ alkylidene radical and R¹² for a hydrogen atom;
R¹⁵ and R¹⁶ represent hydrogen atoms, a common additional bond or a common α- or β-permanent methylene bridge, and
R ^17a / R ^17b
-OH / -CH₃;
-OC (O) CH₃ / CH₃;
-OH / -C≡CH;
-OC (O) CH₃ / -C≡CH;
-OH / -C≡CCH₃;
-OC (O) CH₃ / -C≡CCH₃;
-C (O) CH₃ / -OC (O) CH₃;
-C (O) CH₃ / -CH₃ or
-C (O) CH₂CH₃ / -CH₃

mean,
and the other substituents can have the meanings given in formula I.

The compounds mentioned below are particularly preferred according to the invention:
17α-ethynyl-17β-hydroxygon-4-en-3-one;
17α-ethynyl-17β-hydroxygona-4,15-dien-3-one;
17β-hydroxy-17α- (1-propynyl) gon-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,15-dien-3-one;
17α-ethynyl-17β-hydroxy-11-methylgonon-4-en-3-one;
17α-ethynyl-1713-hydroxy-11-methylenegona-4,15-dien-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) gon-4-en-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) gona-4,15-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methylg on-4-en-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,15-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gon-4-en-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona4,15-dien-3-one;
17- (acetyloxy) -18,19-dinorpregn-4-ene-3,2 0-dione;
17- (acetyloxy) -18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-18,19-dinorpregn-4-en-3,20-di on;
17-methyl-18,19-dinorpregn-4-en-3,20-dione;
17-methyl-18,19-dinorpregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinorpregna-4,6-diene-3,20-dione;
6-chloro-17-methyl-18,19-dinorpregna-4,6-en-3,20-dione;
6α, 17-dimethyl-18,19-dinorpregn-4-ene -3,20-dione;
17,21-dimethyl-18,19-dinorpregn-4-en-3,20-dione;
6,17,21-trimethyl-18,19-dinorpregna-4,6-diene-3,20-dione;
17α-ethynylgon-4-en-17β-ol;
17α-ethynylgona-4,15-dien-17β-ol;
17α- (1-propynyl) gon-4-en-17β-ol;
17α- (1-propynyl) gona-4,15-dien-17β-ol;
17α-ethynyl-11-methylengon-4-en-17β-ol;
17α-ethynyl-11-methylenegona-4,15-dien-17β-ol;
11-methylene-17α- (1-propynyl) gon-4-en-17β-ol;
11-methylene-17α - (1-propynyl) gona4,15-dien-17β-ol;
17α-ethynyl-17β-hydroxygona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxygona-4,9,15-trien-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,9-dien-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,9,15-triene-3one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,9,15-tnen-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona4,6-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona -4,6,15-trien-3-one;
17- (acetyloxy) -18,19-dinorpregna-4,9-diene-3,20-dione;
17-methyl-18,19-dinorpregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinorpregna-4,9-diene-3,20-dione;
17α-ethynyl-17β-hydroxy-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-13α-gon-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-17β- (1-propynyl) -13α-gon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11-methylene-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-11-methylene-13α-gon-4-en-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-11-methylene-17β- (1-propynyl) -13α-gon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11β-methyl-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-11β-methyl-13α-gon-4-en-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-11β-methyl-17 (3- (1-propynyl) -13α-gon-4-en-3-one;
17- (acetyloxy) -18,19-dinor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-m ethyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -6α-methyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17-methyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
6-chloro-17-methyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
6-chloro-17-methyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
6α, 17-dimethyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
6α, 17-dimethyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
17,21-dimethyl-18,19-dinor-13α-pregn-4-en-3,20-d ion;
17,21-dimethyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
6,17,21-trimethyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
6,17,21-trimethyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17α-ethynyl-13α-gon-4-en-17β-ol;
17 β-ethynyl-13α-gon-4-en-17α-ol;
17α- (1-propynyl) -13α-gon-4-en-17β-ol;
17β- (1-propynyl) -13α-gon-4-en-17α-ol;
17α-ethynyl-11-methylene-13α-gon-4-en-17β-ol;
17β-ethynyl-11-methylene-13α-gon-4-en-17α-ol;
11-methylene17α- (1-propynyl) -13α-gon-4-en-17β-ol;
11-methylene-17β- (1-propynyl) -13α-gon-4-en-17α-ol;
17α-ethynyl-17β-hydroxy-13α-gona-4,9-dien-3-one;
17β-ethynyl-17α-hydroxy-13α-gona-4,9-dien-3-one;
17β-hydroxy-17α- (1-propynyl) -13α-gona-4,9-dien-3-one;
17α-hydroxy-17β- (1-propynyl) -13α-gona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methyl-13α-gona-4,9-dien-3-one;
17β-ethynyl-17α-hydroxy-11β-methyl-13α-gona-4,9-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) -13α-gona-4,9-dien-3-one;
17α-hydroxy-11β-methyl-17 (3- (1-propynyl) -13α-gona-4,9-dien-3-one;
17- (acetyloxy) -18,19-dinor-13α-pregna-4,9-diene-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregna-4,9-diene-3,2 0-dione;
17-methyl-18,19-dinor-13α-pregna-4,9-diene-3,20-dione;
17-methyl-18,19-dinor-13α, 17α-pregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinor-13a-pregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinor-13α, 17α-pregna-4,9-diene-3,2 0-dione;
18-nor and 18,19-bisnor analogs of the natural hormone progesterone have been described in the literature for a long time (see, for example, BNA Nelson and RB Garland, J.Am.Chem.Soc. 79, 6313 (1957) and R Anliker et al., Helv.Chim.Acta 42, 1071 (1959)). These compounds showed a drastically reduced activity in vivo compared to the natural hormone.

It was found that the 18-nor analogues of synthetic gestagens according to the present invention surprisingly both in terms of Receptor binding as well as the results from the Pregnancy maintenance test on the rat (s.c.) and the results from the Endometrial transformation test (s.c. and p.o.) in rabbits at least the same have strong activities like the corresponding 13-methyl or 13- Ethyl compounds.

The present invention further relates to pharmaceuticals which have at least one Compound of general formula I and a pharmaceutically acceptable Carrier included.

It also relates to the use of the compounds of the general formula I for Manufacture of drugs.

Because of their gestagenic effectiveness, the new compounds of general formula I alone or in combination with estrogens in preparations for Contraception can be used.

The dosage of the compounds according to the invention in contraceptive preparations should preferably be 0.01 to 2 mg per day.

The gestagenic and estrogenic active ingredient components are in Contraceptive preparations preferably administered orally together. The daily The dose is preferably administered once.

Preferred estrogens are synthetic estrogens such as ethinyl estradiol, 14α, 17α-ethano-1,3,5 (10) -estratriene-3,17β-diol (WO 88/01275) or 14α, 17α- Ethano-1,3,5 (10) -estratrien-3,16α, 17β-triol (WO 91/08219) into consideration.

The estrogen is administered in an amount that is from 0.01 to 0.05 mg Corresponds to ethinyl estradiol.

The new compounds of general formula I can also be used in preparations for Treatment of gynecological disorders and used for substitution therapy will. The compounds according to the invention are particularly suitable for  Treatment of premenstrual complaints, such as headache, depressive Upset, water retention and mastodynia. The daily dose at Treatment of premenstrual complaints is around 0.05 to 10 mg.

The formulation of pharmaceutical preparations based on the new Connections are carried out in a manner known per se by optionally in combination with an estrogen, with those in galenics usual carriers, diluents, if necessary Flavors, etc., processed and in the desired Application form transferred.

For the preferred oral application, tablets, coated tablets, Capsules, pills, suspensions or solutions in question.

Oily solutions such as, for example, are particularly suitable for parental application Suitable solutions in sesame oil, castor oil and cottonseed oil. To increase Solubility promoters such as benzyl benzoate or Benzyl alcohol can be added.

It is also possible to convert the substances according to the invention into a transdermal one Incorporate the system and thus apply it transdermally.

Finally, the new compounds can also be used as a gestagen component in the recently known compositions for the female Fertility control, which is characterized by the additional use of a competitive Label progesterone antagonists, are used (see here for example, H. B. Croxatto and A. M. Salvatierra in Female Contraception and Male Fertility Regulation, ed. By Runnebaum, Rabe & Kiesel-Vol. 2, Advances in Gynecological and Obsteric Research Series, Parthenon Publishing Group-1991, Page 245; WO-A 94/04156, Bergink E .; WO-A 93/17686, Hodgen G .; WO-A 93/21926, Hodgen G. and Chwalisz K.).

The dosage is in the range already specified; the wording can be like with conventional OC preparations. The application of the additional, competitive progesterone antagonists can also be carried out sequentially will.

The present invention also relates to a method for producing the Compounds of the general formula I.

The compounds of the general formula I are prepared according to the invention by doing

• a) a compound of the general formula II, wherein K represents a keto oxygen atom, a keto protecting group or a free or protected hydroxy group and a hydrogen atom and, R ^{4 '} and R ^{5' represent} an additional bond, in which case R ^{6 '} and R ^{10' are} hydrogen, or R ^{5 '} and R ^{6 'represent} an additional bond and R4' and R10 'represent hydrogen, or R ^5' and R ^{10 'represent} an additional bond and R ^4' and R ^{6 'represent} hydrogen, by treatment with bases or acids in a compound the general formula III, wherein K represents a keto oxygen atom, a keto protecting group or a free or protected hydroxy group and a hydrogen atom and, R ^{4 '} and R ^{5' represent} an additional bond, in which case R ^{6 '} and R ^{10' are} hydrogen, or R ^{5 '} and R ^{6 'represent} an additional bond and R4' and R10 'represent hydrogen, or R ^5' and R ^{10 'represent} an additional bond and R ^4' and R ^{6 'represent} hydrogen and L represents hydrogen or HC (O) convicted
• b) the 17-keto group and possibly also the 3-keto group are then protected, and then
• c) if R⁹, R ^11a , R ^11b and R¹² should ultimately stand for hydrogen atoms, if necessary after cleavage of an 11β-formyl (oxy) group still present, the 11β-hydroxy group is reductively removed,
• d) if R ^11a and R ^{11b are} ultimately intended to represent an alkylidene group, the 11β-hydroxy group released is first oxidized to the 11-ketone and then converted, for example by a Wittig reaction, into the alkylidene group,
• e) if R ^{11b is} ultimately intended to represent a C₁-C₄ alkyl radical, this is established by hydrogenation of the 11-alkylidene group,
• f) if R ^{11b is} ultimately to stand for a C₁-C₄ alkenyl or C₁-C₄ alkynyl radical, this is established by the Wittig reaction of the 11-carbaldehydes obtained from the 11-ketone, and by the corresponding one, the b) to f) operations obtained a compound of general formula IV, in which K and K 'represents a keto oxygen atom, a keto protective group or a free or protected hydroxyl group and a hydrogen atom, R ^4' , R ^{5 '} , R ^6' and R ^{10 '} may have the meanings already mentioned for the general formula III and R ^{11b 'represents} a hydrogen atom, a C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl radical and R ^{11'a represents} a hydrogen atom, or R ^11a' and R ^{11b '} together form a C₁-C₄ -Alkylidenrest stand, or
• g) if R ^11a and R¹² should ultimately represent an additional bond and R ^11b should have the meanings given in formula I, this substitution pattern by converting the 11-ketone into an enol trifluoromethanesulfonate and coupling with organotin or organoboron compounds or reduction under Transition metal catalysis is built up, and thereby a compound of general formula V is obtained in which R ^{11b 'represents} a hydrogen atom, a C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl radical and K, K', R ^{4 '} , R ^5' , R ^{6 '} and R ^{10 '} May have the meanings already given for the general formula IV,
• h) if R⁴ and R⁵ as well as R⁹ and R¹⁰ are ultimately to stand for an additional bond, initially either by eliminating water from the corresponding 11β-hydroxy compound or by converting the 11-ketone into an enol trifluoromethanesulfonate under thermodynamic control and reacting this enol trifluoromethanesulfonate with an organotin - Or organoboron compound with transition metal catalysis to obtain a compound of general formula VI in which K, K ', R ^4' , R ^{5 '} , R ^6' , R ^{10 '} and R ^{11' have} the meanings already mentioned in the general formula IV
• i) if desired, at least in position 13 of the steroid structure after cleavage the protecting group of the 17-keto oxygen atom by base treatment isomerized,
• j) if desired, a 15.16 double bond is introduced,  
• k) if desired, by methylenation into the corresponding 15β, 16β- Converted methylene compounds,
• l) if desired, the functionality at C-17 is built up by nucleophilic addition of the substituent R ^17a or a reactive precursor of R ^17a and, if appropriate, etherification or esterification of the 17α- or 17β-hydroxy group (R ^17b = OH) with a reagent providing the corresponding radical R²¹ or the 17α- (β) -hydroxy-17β- (α) -alkanoyl substitution pattern is built up and the 17α (or β) -hydroxy group is etherified or esterified, if appropriate, with a reagent providing the corresponding radical R²³,
• m) optionally partially or completely hydrogenates an unsaturated side chain,
• n) if desired, the corresponding 17- (3-hydroxypropyl) - or 17- (Hydroxybutyl) compound oxidized to spirolactone,
• o) if desired, the corresponding (Z) -17α- (or β) (3-hydroxypropenyl) - or (Z) -17α- (or β) (3-hydroxybutenyl) compound or the corresponding one in the side chain converts saturated compounds into the 17-spiroether, subsequently
• p) a possibly still protected 3-ketone is converted into the Δ⁴-3-keto system by acid treatment with a water-miscible solvent, further protective groups also being split off and any 9 (11) double bond according to position 9 (10 ) isomerized, and converted into a compound of the general formula VII by appropriate operations mentioned under i) to p), in which the radicals R ^{9 ′} , R ^{10 ′} , R ^{11a ′} , R ^{11b ′} , R¹² ′, R ^{15 ′} , R ^{16 ′} , R ^{17a ′} and R ^{17b ′ are} all in the description of the general formula I for R⁹, R¹⁰ , R ^11a , R ^11b , R¹², R¹⁵, R¹⁶, R ^17a and R ^17b may have meanings mentioned, and this compound of the general formula VII,
• q) if appropriate by introducing a 6,7 double bond and if appropriate Methylenation of this double bond,
• r) if desired, introduction of the rest R gewünschten,
• s) optionally epoxidation of the 6,7 double bond and opening of the epoxide with hydrogen halide (Hal = F, Cl, Br, I) and elimination of the 7α- Hydroxyl group,
• t) optionally 6α-hydroxymethylation and subsequent elimination of water to the 6-methylene compound,
• u) optionally hydrogenation of the 6-methylene group,
• v) optionally isomerization of the double bond of the 6-methylene group according to position 6 (7),
  into a compound of general formula I, wherein R ^6b , R⁷, R⁹, R¹⁰, R ^11a , R ^11b , R¹², R¹⁵, R¹⁶, R¹⁷a and R ^{17b have} the ultimately desired meaning, and R ^6a all mentioned in general formula I. May have meanings, with the exception of an α or β C₁-C₄ radical, transferred, and
• w) if R ^{6a is} ultimately intended to be a straight-chain or branched-chain saturated alkyl radical having up to 4 carbon atoms, by ketalization of the 3-keto oxygen atom with simultaneous isomerization of the 4 (5) double bond according to 5 (6), Epoxidation of the 5 (6) double bond and nucleophilic opening of the 5,6α-epoxide with a straight or branched chain alkyl magnesium halide or an alkyl lithium compound with up to 4 carbon atoms and cleavage of the 3-keto protective group in the 5α-hydroxy-6β-alkyl compound formed under mild acidic conditions for the corresponding 3-keto-5α-hydroxy-6β-alkyl compound and basic elimination of the 5α-hydroxy group in the corresponding 3-keto-4-ene compounds of the general formula I with a 6-position 6-alkyl group or by cleavage the 3-keto protective group under more drastic conditions in the corresponding 3-keto-4-ene compounds of general formula I with α-6-alkyl group, u nd
• x) if desired one of the 3-keto compounds obtained above with Hydroxylamine hydrochloride in the presence of tertiary amines at one Temperature between -20 ° and + 40 ° C in the corresponding 3- Hydroxyimino compound (W = N∼OH) transferred, or
• y) if desired into the 3-thioketal, preferably the 3- (1 ′, 3′-ethylenedithio) - Ketal, and this converted to compounds of general formula I, wherein W stands for two hydrogen atoms, is reduced.

It is not mandatory that the process steps described above in the specified order must be carried out. Separate Process steps or blocks of related process steps can may be interchanged. For example, the execution of the Process step h) for isomerization of the proton in position 13 by Base treatment possible at any level, with a free 17- Keto oxygen atom can be present.

Finally, the present invention relates to the new, for the production of the Compounds of the general formula I required intermediates general formulas IV, V, VI and VII taken together as compounds of the general formula VIII

wherein K represents a keto oxygen atom, a keto protective group or a protected hydroxy group and a hydrogen atom, and
R ^{4 '} and R ^5' stand for an additional bond, in which case R⁶ and R ^{10 'represent} hydrogen, or R⁵, and R ^6' stand for an additional bond and
R ^{4 '} and R ^{10' are} hydrogen, or R ^{5 '} and R ^{10' are} an additional bond and R ^{4 '} and R ^{6' are} hydrogen, R ^{11a '} , R ^11b' and R ^{12 '} are in the general formula I can have the meanings mentioned for R ^11a , R ^11b and R¹², and Q for an a- or b-position hydroxyl group and S for a hydrogen atom, or Q and S together for a keto-oxygen atom or Q and S one of those in general Formula I for R ^17a / R ^17b mentioned substituent combination, including the spiro compounds can mean, hydroxy and / or keto groups present therein can be protected.

The synthetic route for the preparation of the 18-nor compounds is shown in Scheme 1 shown:  

Representation of the basic structure Scheme 1

K is a common ketal protecting group, for example the ethylenedioxy or the 2,2- Dimethylpropylene-1,3-dioxy group. Other common keto protection groups are also coming into consideration. K can also be a protected hydroxy group and a hydrogen atom mean, the hydroxyl group then, for example, as methoxymethyl, Methoxyethyl, tetrahydroxypyranyl or silyl ether is protected. By splitting off the protective group and oxidation of the free hydroxy group leads to Keto group.  

The in Recl. Trav. Chim. Pays. Bas. Lactone 1, 107, 331 (1988) initially z. B. with diisobutylaluminium hydride in a suitable solvent, such as B. tetrahydrofuran at temperatures between -100 ° C and 0 ° C to lactol 2 reduced, which is isolated as a mixture of the 18 isomers.

The following cleavage of the ketal protective groups (2 to 3) takes place through Treatment with dilute acids in a water miscible Solvents such as B. methanol, ethanol or acetone. As acids come e.g. B. Mineral or sulfonic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, Perchloric acid or p-toluenesulfonic acid or an organic acid such as Acetic acid in question. The reaction takes place at temperatures from 0 ° C to 100 ° C from.

The resulting 3,17-diketone 3 then serves as the starting material for the illustration of the 18-nor compounds. For this connection 3 z. B. with weak bases such as trialkylamine, e.g. B. triethylamine, in a suitable solvent such as. B. Implemented dichloromethane. The 11β-formate 4 is then obtained as a mixture of 13 isomers, which can be separated chromatographically. The ratio of the 13- Isomers depend on the chosen reaction conditions.

The breakdown of the C-18 atom can, for. B. also by chromatography of Crude product 3 on silica gel or aluminum oxide (Alox).

The cleavage of the formate by known methods, e.g. B. by implementation with Potassium carbonate in methanol, based on both 13 isomers Compound 5 as a mixture of the 13 isomers.

The reaction of 3 with acids at an optionally elevated temperature (25 ° C to 100 ° C) and extended reaction time leads to the breakdown of the 18 C atom, whereby additional formate splitting to 5 frequently occurs here.

The treatment of the crude product 3 under basic conditions, which are also used for Lead formate splitting, e.g. B. the reaction with potassium carbonate in methanol, also gives directly the 11β-hydroxy compound 5.

Starting from compound 5, the carbonyl functions on the C atoms 3 and 17 are usually protected as ketals. This produces (in addition to the 13 isomers) a mixture of the double bond isomers (Δ⁵ and Δ ^{5 (10)} ), which can be separated by chromatography. With regard to the stereochemistry at C-13, the trans-linked products (13β-H) usually arise in a very large excess. Both double bond isomers are suitable for the preparation of compounds of general formula I, so that either the mixture of isomers can be reacted further, or both double bond isomers can be converted separately into compounds of general formula I.

For this purpose, the radicals R⁹, R ^11a , R ^11b , and R¹² are generally modified first.

Compounds of the general formula I in which R⁹, R ^11a , R ^11b and R¹² are intended to represent hydrogen atoms are obtained by reductive removal of the 11β-hydroxy function. For this, the 11β-hydroxy function z. B. as described in Tetrahedron 39, 2609 (1983), in thiocarbonyl derivatives of the type

wherein R²⁶ is S-alkyl, phenyl or imidazoyl, transferred and then by treatment with trialkyltin hydride, preferably Tributyltin hydride or tris (trimethyl) silane in the deoxy compounds transferred. In principle, the reduction of the hydroxyl group is also below nucleophilic conditions possible. For this purpose, the OH group is first divided into one Escape group, e.g. B. tosylate or mesylate and then transferred by treatment with complex hydrides, such as. B. lithium aluminum hydride removed.

Compounds in which R ^11a and R ^{11b should} together represent an alkylidene group can, for. B. by oxidation of the 11β-hydroxy group according to common methods for 11-ketone also prepared by methods known from the literature. Such as In US-A 3,927046, US-A 3,325,520 or Recl. Trav. Chim. Pays-Bas., 94, 35 (1975), the 11-ketones are converted into the 11-alkylidene group by the Wittig reaction.

Alternatively, alkyl grignard or alkyl lithium compounds can also be used first added to the 11-ketones, then by water elimination to get the 11-alkylidene compounds. With the latter However, the 11-alkylidene compounds occur in water elimination Usually in mixtures with the corresponding 11 (12) - or 9 (11) -unsaturated Products that can be separated chromatographically.

The representation of compounds in which R⁹, R ^11a and R¹² represent hydrogen atoms and R ^{11b represents} a C₁-C₄ alkyl radical, z. B. by hydrogenation of the 11-alkylidene compounds analogously to the process described in US Pat. No. 3,984,144.

The preparation of compounds in which R⁹, R ^11a and R¹² represent hydrogen atoms and R ^{11b represents} a C₂-C₄ alkenyl or C₂-C₄ alkynyl group is also carried out by methods known from the literature, such as. B. described in DE-A 2,805,490 and US-A 4,291,251. For this purpose, the 11-ketone is either converted into the corresponding 11-nitrile using tosyl methyl isocyanate and this is then converted into the 11-carbaldehyde by reduction (for example with diisobutylaluminum hydride).

Alternatively, the 11-carbaldehyde can also be obtained directly from the 11-ketone Wittig reaction with e.g. B. methoxymethyltriphenylphosphonium chloride and Potassium tert.butylate and acidic cleavage of the enol ether obtained will. The 11β-carbaldehyde is then either by another Wittig reaction in the 11β-alkenyl derivatives or, such as. B. in Liebigs Ann. Chem. 2061 (1980) described, converted into the 11β-alkynyl derivatives.

Type I compounds are sought in which R⁹ and R¹⁰ together The introduction of the 11β substituent can represent an additional bond but also analogous to the z. B. described in Steroids 39, 607 (1982) respectively.

Compounds in which R⁹ represents a hydrogen atom and R ^11a and R¹² together represent an additional bond and R ^{11b has} the meanings mentioned in general formula I can be prepared analogously to the processes described in DE-A 42 32 521. For this purpose, an enol trifluoromethanesulfonate is first generated starting from the 11-ketone and this then under transition metal catalysis, for. B. with palladium tetrakis triphenylphosphine, by coupling with z. B. organotin or organoboron compounds or by reduction z. B. with ammonium formates (for R ^11b is hydrogen) to establish the rest of R ^11b . However, all of the alternatives for establishing R ^11b mentioned in DE-A 42 32 521 can also be used in the present case.

The next steps then include functionalizations in the D- Ring. For this purpose, the ketal protecting group in position 17 is first shown in Scheme 1 selectively cleaved with a weak acid (e.g. oxalic acid or acetic acid). The stereochemistry at C-13 usually remains under these reaction conditions obtained so that here too the C / D-trans-linked derivatives (13β-H) as clear main products. Are connections of general Formula I aimed in which a cis link between the rings C and D  is present (13α-H), the C / D-trans-linked can be converted Compounds of formula 7 with bases, such as. B. sodium or potassium hydride in suitable solvents, such as. B. tetrahydrofuran or diethyl ether, a Equilibration at C-13 can be achieved. If the thermodynamic equilibrium, the 13α-connections lie in all Usually in a large excess.

The introduction of a 15.16 double bond (R¹⁵ and R¹⁶ together form one additional binding) takes place, for example, through a modified Saegusa- Oxidation (I. Minami, K. Takahashi, I. Shimizu, T. Kimura and J. Tsuji, Tetrahedron 42, 2971 (1986); EP-A 0299913) of the corresponding Enol compounds of the 17-ketone.

For examples in which R¹⁵ and R¹⁶ together have an α or β position Represent methylene bridge, this 3-ring is introduced for example by reacting the corresponding 15,16-en-17-one compound with Dimethylsulfoxonium methylide (see e.g. DE-A 11 83 500, DE-A 29 22 500, EP-A 0 019 690, US-A 4,291,029, E. J. Corey and M. Chaykovsky, J.Am. Chem. Soc. 84, 867 (1962)).

After the D-ring modification has taken place, the further steps initially apply to the introduction of the residues R¹⁷a and R ^17b on the C-17 atom. This introduction is carried out analogously to methods known from the literature (e.g. Fried Fried, JA Edwards, "Organic Reactions in Steroid Chemistry", van Nostrand Reinhold Company, 1972, Vol. 1 and 2; "Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society , London, Vol 1-2) by nucleophilic addition to the C-17 atom. If there is a cis link between the rings C and D, the addition also occurs in the present case, analogously to previously described 13α-configured connections (see, for example, DE-A 38222770/71, US Pat. No. 5,273,971) C-17 not stereoselective. Depending on the nucleophile used, the ratio of the two isomers to each other varies. In the case of a 13 β configuration, the attack of the nucleophile is largely selective from the α side.

The introduction of the substituent -C≡CB as R ^17a with the meanings for B given in formula I takes place with the aid of the metalated compounds, which can also be formed in situ and reacted with the 17-ketone. The metalated compounds are formed, for example, by reacting the acetylenes with alkali metals, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia. For the lithiation of acetylenes, however, z. B. methyl or butyllithium in question. Compounds in which B = bromine or iodine are prepared from the 17-ethynyl compounds in a known manner (see, for example, BH Hofmeister, K. Annen, H. Laurent and R. Wiechert, Angew. Chem. 96, 720 (1984) ).

The introduction of the 3-hydroxy-1-propynyl residue in the 17-position is carried out by Reaction of the 17-ketone with the dianion of propargyl alcohol (3- Hydroxypropin), e.g. B. the dipotassium salt of propargyl alcohol generated in situ or with corresponding derivatives protected on the hydroxy function, such as. B. the lithium compound of 3 - [(tetrahydro-2H-pyran-2-yl) oxy] -1-propyne.

The hydroxypropyl and hydroxypropenyl compounds can be derived from the Hydroxypropinyl derivatives are shown. The representation of the Hydroxypropyl chain is made e.g. B. by hydrogenation of the hydroxypropinyl derivatives at room temperature and normal pressure in solvents such as methanol, ethanol, Tetrahydrofuran or ethyl acetate with the addition of precious metal catalysts such as Platinum or palladium.

The display of connections with a Z-configured double bond in the Side chain is done by hydrogenating the acetylenic triple bond with a deactivated noble metal catalyst, e.g. B. 10% palladium on barium sulfate in Presence of an amine or 5% palladium on calcium carbonate with the addition of Lead (II) acetate. The hydrogenation is after the inclusion of an equivalent Hydrogen canceled.

Connections with an E-configured double bond in the side chain are created by reducing the triple bond z. B. with sodium in liquid ammonia (K. N. Cambell and L. T. Eby, J.Am.Chem.Soc. 63, 216 (1941)), with Sodium amide in liquid ammonia or with lithium in low molecular weight Amines (R.A. Benkeser et al., J.Am. Chem. Soc. 77, 3378 (1955)).

The introduction of the hydroxyalkenes and hydroxyalkanes can also be done directly The 17-ketone is reacted with metalated derivatives (E. J. Corey and R. H. Wollenberg, J.Org.Cem. 40: 2265 (1975); H. P. On, W. Lewis and G. Doubt, Synthesis 999 (1981); G. Gohiez, A. Alexakis and J.F. Normant, Tetrahedron Lett. 3013 (1978); P.E. Eaton et al., J.Org.Chem. 37, 1947 (1972)). The  Introduction of homologous hydroxyalkyne, hydroxyalkene and hydroxyalkane groups is possible in a corresponding manner.

Products where R ^17a / R ^17b for

with X = 1 or 2, can be omitted 17- (3-hydroxypropyl) or 17- (4-hydroxybutyl) compounds Oxidation in a known manner, e.g. B. with the Jones reagent, Braunstein, Pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the Represent Fetizon reagent.

Products where R ^17a / R ^17b for

with X = 1 or 2, can by ring closure reaction of the corresponding (Z-17α (or β) - (3- Hydroxyprop-1) -enyl) or (Z-17α (or β) - (4-hydroxy-1-butenyl) -17β-hy droxy compounds or those correspondingly saturated in the side chain Connections are shown. For this, z. B. the primary hydroxy function selectively transferred to an escape group, for example tosylate, and then each cyclized either directly or in a second stage according to the reaction conditions. Compounds with a saturated spiro ether can also be obtained by hydrogenation of unsaturated spiroethers on platinum or palladium catalysts will.

The 17-cyanomethyl side chain is either built from the 17-ketone directly by adding acetonitrile or by cleaving the spiroepoxide HCN according to K. Ponsold et al., Z. Chem. 18, 259-260 (1978).

The synthesis of 16.17 (α or β) -methylene-17 (β or α) -alkanoyl-substituted Connections are made using methods known from the literature. So you can for example starting from the 17-ketones Δ¹⁶-17- Perfluorosulfonyloxyverbindungen represent in the presence of Transition metal catalysts with alkoxyvinyltin or zinc compounds can be coupled (see e.g. M. Kosugi, T. Sumiya, Y. Obara, M. Suzuki, H. Sano and T. Migati, Bull.Chem.Soc.Jpn. 60: 767 (1987); P.G. Ciattini, E. Morera and G. Ortar, Tetrahedron Lett. 31, 1989 (1990)). Acid hydrolysis of the coupling products gives the Δ¹⁶-17-acetyl compounds. This enone can be according to the above for the cyclopropanation of the Δ¹⁵-17 ketones specified method with trimethylsulfoxonium iodide to 16,17-methylene-17-  implement acetyl compounds, or by conjugate addition of Alkyl copper compounds in the 16α- or β-alkyl progesterone derivatives convict.

Compounds in which R ^{17a is} an alkanoyl radical and R ^{17b is} an alkyl radical can be prepared, for example, from Δ¹⁶-17-alkanoyl compounds or 17α (or β) - hydroxy-17β (or α) -alkanoyl compounds by reducing in liquid with lithium Ammonia mixed with tetrahydrofuran 17-enolate anions are generated which can be alkylated with alkyl halides to the desired compounds (see e.g. BMJ Weiss, RE Schaub, GR Allen, Jr., JF Poletto, C. Pidacks, RB Conrow and CJ Coscia, Tetrahedron 20 , 357 (1964)).

As an alternative, it can also be based on the corresponding 17-ketones with tosyl methyl isocyanate (TosMic) and z. B. potassium tert.butylate as base in a suitable solvent such as diethyl ether or dimethoxyethane of the 17α / 17β nitriles. After separation of the isomers e.g. B. deprotonated with lithium diisopropylamide or other strong bases and then alkylated with alkyl halides. The nitriles can eventually pass through Reaction with alkyl magnesium halides or alkyl lithium compounds in the Alkanoyl compounds are transferred.

The representation of derivatives, in the R ^17a and R ^17b together for

stand, takes place starting from the 17-ketone according to literature Methods (e.g. EP-A-0 444 3951, 1991; and EP-A-0 154 429, 1989). For this are, for example, by reductive allylation of the above-mentioned Δ¹⁶-17- Acetyl compounds the corresponding 17α (or β) - (2) -propenyl) compounds shown. The terminal double bond is then either over Hydroboration, e.g. B. with 9-BBN (9-borabicyclononane), oxidative workup and further oxidation to the corresponding C₃ aldehyde or by ozonolytic degradation converted into the C₂ aldehyde. The 6-ring or 5- Ring spiroketones can then be prepared via an aldol reaction. Here First arise the α, β-unsaturated ketones, which may follow known methods can be reduced to the saturated ketones.  

The introduction of a hydroxyprogesterone substitution pattern (R ^17a = acetyl, R ^17b = hydroxy) or the construction of the corresponding homologous compounds with R ^17a = alkanoyl is carried out according to methods known from the literature. The route via a 17β-cyano-17α-hydroxy compound (cyanohydrin method; see, inter alia, DE-A 39 31 064 (1989); GDR patent) is particularly suitable in the case of the present trans linkage of the rings C and D (13β-H) 147 669 (1981); DE-A 21 10 140 (1971); Japanese Patent 57062296-300 (1982); JC Gase and L. Nedelec, Tetrahedron Lett. 1971, 2005; JNM Batist, NCME Barendse, AF Marx, Steroids 1990, 1009).

Here, the 17-ketone is reacted with, for example, acetone cyanohydrin (2-Hydroxy-2-methylpropannitrile) in suitable solvent systems, e.g. B. Ethanol or methanol and dichloromethane with a suitable (mostly light basic) pH value implemented. Under these reaction conditions, a Crystallization of the 17β-cyano compound can be achieved. The 17α- The hydroxyl group is then usually protected and then the Cyano group with C₁-C₄ alkyl lithium compounds, e.g. B. methyl lithium or C₁-C₄- Alkyl magnesium halides, e.g. B. methyl magnesium halides react, and then after acidic cleavage to the 17α-hydroxy-17β-alkanoyl compound reach. The execution of the last described sequence is however also possible without prior protection of the 17α-hydroxy group (see EP 0 443 000 B1).

The formal water addition to 17α- (or 17β-) ethynyl-17β (or 17α) -hydroxy derivatives, for example by means of Oxymercuration. This results from the 17α-ethynyl isomer 17α-acetyl and, starting from the 17β-ethynyl isomer, the 17β-acetyl Connection. The introduction of the hydroxyprogesterone chain is also from the 17-ethynyl compounds reversing the original stereochemistry at C-17 possible (17α-ethynyl-17β-hydroxy gives 17β-acetyl-17α-hydroxy and vice versa). The transfer of 17α- (or β) -ethynyl- 17β- (or α) nitrooxy compounds (see H. Hofmeister, K. Annen, H. Laurent and R. Wiechert, Chem.Ber. 111, 3086 (1978)) or from 17α- (or β) - Ethynyl 17β- (or α) -hydroxy compounds generated allenesulfoxides (see V. VanRheenen and K.P. Shephard, J.Org.Chem. 44, 1582 (1979)) in the corresponding 17β- (or α) -acetyl-17α- (or β) -hydroxy compounds to emphasize.  

Starting from the 17α- (or β-) hydroxy-17β- (or α-) alkanoyl- Compounds can then the 17α-alkanoyloxy derivatives in a known manner be preserved.

17β- (or α) -acetyl-17α- (or β) -fluorine compounds can also be prepared by methods known from the literature. For this purpose, e.g. B. the 17-ketones first converted into Δ ^{17 (20)} -20-methoxy-21-alcohols. These are then obtained by reaction with DAST (diethylaminosulfur trifluoride) 17α (or β) -fluoro-20-enol ether. Acid cleavage of the enol ether finally gives the 17β- (or α) -acetyl-17α) - (or β) -fluoro compounds (G. Neef et al., Tetrahedron Lett. 35, 8587 (1994)). The representation of the 17β- (or. Α) -acetyl) - 17α- (or .beta.) Fluorine compounds can also, for. B. from the 17α- (or. Β) -Brom- 17β- (or. Α) acetyl compounds (see R. Deghenghi et al., Can. J. Chem. 39, 1553 (1961)).

The subsequent release of the 3-keto function to form the 4 (5) - Double binding is done by treatment with acids or an acid Ion exchanger. The acidic treatment is carried out in a manner known per se by the corresponding 3-ketal in a water-miscible solvent, such as methanol, ethanol or acetone, dissolves and catalytic amounts on the solution Mineral or sulfonic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, Perchloric acid or p-toluenesulfonic acid, or an organic acid such as Acetic acid, so long act until protective groups are removed. The reaction takes place at temperatures from 0 to 100 ° C.

Compounds in which R⁹ and R¹⁰ together form an additional bond can represent z. B. by water elimination from the 11β-hydroxy derivatives to 9 (11) -unsaturated compounds, because after cleavage of the 3- Ketal protecting group isomerizes the 9 (11) double bond according to position 9 (10).

Alternatively, starting from the 11-ketone, such as. B. in Synthesis 85 (1982), a thermodynamically stable enol trifluoromethanesulfonate be generated, and this then under catalysis with a transition metal (analogous to the procedure described above for the representation of 9 (11) -un saturated compounds) can be reduced.

Compounds in which both R⁹ and R¹⁰ as well as R ^11a and R¹² represent additional common bonds can from the dienones described above (R⁹ and R¹⁰ form an additional common bond) by oxidation z. B. can be obtained using dichlorodicyanobenzoquinone (DDQ).

The next steps usually apply to the structure of the radicals R ^6a , R ^6b and R⁷.

A 6,7-double bond can be introduced starting from the 3-ketone (W = Carbonyl oxygen) via dienol ether bromination and subsequent Hydrogen bromide elimination (see e.g. J. Fried, J.A. Edwards, Organic Reactions in Steroid Chemistry, by Nostrand Reinhold Company 1972, pp. 265-374).

The dienol ether bromination can e.g. B. analogous to the instructions of J.A. Zderic, Humberto Carpio, A. Bowers and Carl Djerassi in Steroids 1, 233 (1963) respectively. The hydrogen bromide is split off by heating the 6- Bromine compound with basic agents, such as. B. LiBr or LiCO₃ in aprotic Solvents such as dimethylformamide at temperatures of 50-120 ° C or else by heating the 6-bromo compounds in collidine or lutidine.

The introduction is also carried out for compounds with a 6,7-methylene function from the dienone by reaction with dimethylsulfoxonium methylide, where a Mixture of the α and β isomers occurs (the ratio depends on the used substrates and is about 1: 1), the z. B. about Column chromatography can be separated.

Compounds with R⁷ are alkyl from the 4,6-diene-3one compounds prepared by 1,6 addition according to known methods (J. Fried, J.A. Edwards: "Organic Reactions in Steroid Chemistry" by Nostrand Reinhold Company 1972, pages 75 to 82; and A. Hosomi and H. Sakurai, J.Am. Chem. Soc. 99, 1673 (1977)).

Of particular note here is the addition of dialkyl copper lithium Links.

Compounds in which R ^{6a represents} a chlorine atom and R ^6b and R⁷ form a common additional bond are also prepared starting from the 4,6-dien-3-one compounds. For this purpose, the 6,7-double bond is first used using organic peracids, such as. B. meta-chloroperbenzoic acid in methylene chloride and optionally in the presence of sodium hydrogen carbonate (see W. Adam et al., J.Org.Chem. 38, 2269 (1973)). The opening of this epoxide and the elimination of the primary 7α-hydroxy group takes place z. B. by reaction with hydrogen chloride gas in glacial acetic acid (see, inter alia, DE-A 11 58 966 and DE-A 40 06 165).

For example, the introduction of a 6-methylene group can start from one 3-Amino-3,5-diene derivative by reaction with formalin in alcoholic Solutions to form a 6α-hydroxymethyl group and subsequent acidic dehydration z. B. with hydrochloric acid in dioxane / water. The Dehydration can also take place in such a way that a first Escape group is introduced and then eliminated. As escape groups are e.g. B. that Mesylate, tosylate or benzoate are suitable (see DE-A 34 02 329, EP-A 0 150 157, U.S. 4,584,288 (1986); K. Nickisch et al., J. Med. Chem. 34, 2464 (1991)).

Another possibility for introducing the 6-methylene compounds is in the direct implementation of the 4 (5) -unsaturated 3-ketones with acetals of Formaldehyde in the presence of sodium acetate with e.g. B. phosphorus oxychloride or Phosphorus pentachloride in suitable solvents such as chloroform (see e.g. K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Synthesis 34 (1982)).

The 6-methylene compounds can be used to prepare compounds of the general formula I in which R⁶ is methyl and R⁷ and R⁸ one joint additional bond can be used.

You can do this e.g. B. one by D. Burn et al. in Tetrahedron 21, 1619 (1965) use described method in which an isomerization of the double bond by heating the 6-methylene compounds in ethanol with 5% palladium-carbon Catalyst, either with hydrogen or by heating with a small amount of cyclohexene was pretreated. The Isomerization can also be carried out with a catalyst which has not been pretreated, if a small amount of cyclohexene is added to the reaction mixture. The Small amounts of hydrogenated products can occur by adding a Excess sodium acetate can be prevented.

The preparation of 6-methyl-4,6-dien-3-one derivatives can also be done directly (see K. Annen, H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).

Compounds in which R ^{6a represents} an α-methyl function can be prepared from the 6-methylene compounds by hydrogenation under suitable conditions. The best results (selective hydrogenation of the ex-methylene function) are achieved by transfer hydrogenation (EA Brande, RP Linstead and PWD Mitchell, J. Chem. Soc. 3578 (1954)). The 6-methylene derivatives are heated in a suitable solvent, such as. As ethanol, in the presence of a hydride donor, such as. B. cyclohexene, 6α-methyl derivatives are obtained in very good yields. Small amounts of 6β-methyl compound can be acid isomerized (see, for example, BD Burn, DN Kirk and V. Petrow, Tetrahedron 1619 (1965)).

The targeted representation of 6β-alkyl compounds is also possible. Therefor the 4 (5) -unsaturated 3-ketones e.g. B. with ethylene glycol, Trimethyl orthoformate in dichloromethane in the presence of catalytic amounts Acid, (e.g. p-toluenesulfonic acid) converted to the corresponding 3-ketals. During this ketalization the double bond isomerizes to position 5 (6). A selective epoxidation of this 5 (6) double bond succeeds, for. B. by Use of organic peracids in suitable solvents such as Dichloromethane. Alternatively, the epoxidation can also be carried out with Hydrogen peroxide in the presence of e.g. B. hexachloroacetone or 3- Nitrotrifluoroacetophenone done. The 5,6α-epoxides formed can then using e.g. B. alkyl magnesium halides or Alkyl lithium compounds are opened axially. This leads to 5α-hydroxy 6β-alkyl compounds. The cleavage of the 3-keto protecting group can be maintained 5α-hydroxy function by treatment under mild acidic conditions (Acetic acid or 4N hydrochloric acid at 0 ° C). Basic elimination of the 5α- Hydroxyfunction with z. B. dilute aqueous sodium hydroxide solution gives the 3-keto-4-ene Compounds with a 6-position 6-alkyl group. Alternatively, the Ketal splitting under more drastic conditions (aqueous hydrochloric acid or a other strong acid) the corresponding 6α-alkyl compounds.

The compounds of general formula I obtained with W equal to oxygen can optionally in by reaction with hydroxylamine hydrochloride Presence of tert. Amines at temperatures between -20 and + 40 ° C in the Oximes are transferred (general formula I with W in the meaning of N∼OH, where the hydroxy group can be syn- or anti-stable).

The removal of the 3-oxo group to an end product of the general formula I with W in the meaning of two hydrogen atoms can, for example, after the specification given in DE-A 28 05 490 by reductive cleavage of the Thioketals are done.  

example 1 17β-hydroxy-17α- (1-propynyl) gon-4-en-3-one 1a) 3,3; 17,17-bis [1,2-ethanediylbis (oxy)] - 11β, 18-epoxy-5-en-18ξ-ol

To a solution of 6 g 3.3; 17,17-bis [1,2-ethanediylbis (oxy) estr-5-eno-18,11β-lactone (see Rec. Trav. Chim. Pays. Bas. 107, 331 (1988)) in 60 ml of absolute tetrahydrofuran 60 ml of a 1 molar solution of diisobutylaluminum hydride are added at -70 ° C. The mixture is stirred for two hours at -70 ° C and then 2 ml of water are added. Then it is filtered through Celite. The filtrate is dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 4.35 g 1a) as a white foam.
1 H-NMR (CDCl₃): d = 5.47 ppm dbr (J = 5 Hz, 1H, H-6); 5.12 m (2H, H-18 OH); 4.50 dbr (J = 6 Hz, 1H, H-11α); 3.90-4.05 m (8H, ketal).
MS (EI) m / z: 390 (M⁺, 5%); 344 (20); 141 (20); 99 (100).

1b) 18-ξ-Hydroxy-11β, 18-epoxyestr-4-en-3,17-dione

A solution of 4.35 g of the compound described in 1a) in 85 ml of acetone is mixed with 10 ml of 4 normal hydrochloric acid. The mixture is stirred at 40 ° C for one hour. The reaction mixture is then poured onto saturated aqueous sodium hydrogen carbonate solution. The mixture is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (3.38 g of white foam) is used in the next stage without purification.
1 H-NMR (CDCl₃): δ = 5.88 ppm sbr (1H, H-4); 5.28 m (2H, H-18 OH); 4.56 dbr (J = 6 Hz, 1H, H-11α).
MS (EI): m / z: 302 (M⁺, 10%), 256 (50), 174 (100).

1c) 11 β- (formyloxy) gon-4-en-3,17-dione (A) and 11 β- (formyloxy) -13α-gon-4-en- 3,17-dione (B)

1.6 g of the compound described under 1b) are dissolved in 30 ml of dichloromethane. 1 ml of triethylamine is added and the mixture is stirred at 25 ° C. for one hour. The reaction mixture is then poured onto water. The mixture is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate gives 116 mg (A) and 990 mg (B) as white foams.
1 H-NMR (CDCl₃): Compound (A): δ = 8.12 s (1H, formate); 5.88 sbr (1H, H-4); 5.53 m (1H, H-11α). Compound (B): δ = 7.97 s (1H, formate); 5.89 sbr (1H, H- 4); 5.32 m (1H, H-11α).
MS (EI) m / z: Compound (A): 302 (M⁺, 10%); 256 (M-HCOOH, 50); 174 (100). Compound (B): 302 (M⁺, 15%); 256 (M-HCOOH, 50); 174 (100).

1d) 11β-Hydroxygon-4-en-3,17-dione and 11β-hydroxy-13α-gon-4-en-3,17-dione from 1c)

A mixture of the two isomers obtained under 1c) (116 mg (A) and 990 mg (B)) is dissolved in 25 ml of methanol. 1 g of potassium carbonate and can be stirred at 25 ° C for 30 minutes. Then with dichloromethane diluted. It is washed with water and with saturated aqueous Sodium chloride solution, dries over sodium sulfate, filtered and concentrated in vacuo a. Column chromatography on silica gel with a mixture Hexane / ethyl acetate gives 858 mg 1d) as a mixture of the 13 isomers.

from 1b)

1.77 g of the compound described under 1b) are reacted with 2 g of potassium carbonate in 50 ml of methanol analogously to the above procedure. 1.51 g 1d) are obtained.
1 H-NMR (CDCl₃): δ = 5.88 sbr (1H, H-4); 5.87 sbr (1H, H-4) from the 13 isomer; 4.28 m (1H, H-11α); 4.12 m (1H, H-11α) from the 13 isomer.
MS (EI) m / z: 274 (M⁺, 5%); 256 (M-H₂O); 174 (100).

1e) (A): 3.3; 17,17-bis [1,2-ethanediylbis (oxy)] gon-5-en-11β-ol and (B): 3.3; 17.17-bis [1,2-ethanediylbis (oxy)] gon-5 (10) -en-11 β-ol

1.51 g of the compound described in 1d) are dissolved in 80 ml of dichloromethane. 30 ml of ethylene glycol, 18 ml of trimethyl orthoformate and 50 mg of p-toluenesulfonic acid are added, and the mixture is stirred at 25 ° C. for 12 hours. The reaction mixture is then poured onto saturated aqueous sodium hydrogen carbonate solution. It is extracted with dichloromethane, the organic phase is washed twice with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel with a mixture of hexane / ethyl acetate gives 601 mg (A) and 1.082 g (B).
1 H-NMR (CDCl₃): (A): δ = 5.45 dbr (J = 5 Hz, 1H, H-6); 4.22 m (1H, H-11α), 3.82-4.03 m (8H, ketal). (B): δ = 4.36 m (1H, H-11α); 3.80-4.02 m (8H, ketal).
MS (EI) m / z: (A): 362 (M⁺, 5%); 344 (M-H₂O, 15); 99 (100). (B): 362 (M⁺, 20%); 344 (M-H₂O, 50); 99 (100).

1f) 3.3; 17,17-bis [1,2-ethanediylbis (oxy)] - 11β - [(IH-imidazol-1-yl) thioxomethoxy] gon- 5 (10) s

1.08 g (B) from 1e) are dissolved in 40 ml dichloromethane. 5 drops of triethylamine and 6 g of N, N'-thiocarbonyldiimidazole are added. Then allowed to stir at 25 ° C for 60 hours. The reaction mixture is then poured onto water. The mixture is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After column chromatography on silica gel with a mixture of hexane / ethyl acetate, 903 mg 1f) are obtained.
1 H-NMR (CDCl₃): δ = 8.21 sbr (1H, imidazole); 7.52 sbr (1H, imidazole); 7.00 sbr (1H, imidazole); 5.90 m (1H, H-11α); 3.80-4.05 m (8H, ketal).
MS (EI) m / z: 472 (M⁺, 5%); 404 (20); 344 (100).

1g) 3,3; 17,17-bis [1,2-ethanediylbis (oxy)] gon-5 (10) -en

1 ml of tributyltin hydride and a spatula tip of azobisisobutyronitrile are added to 903 mg of the compound described in 1f) in 50 ml of toluene. The mixture is heated under reflux for one hour and then concentrated in vacuo. After column chromatography on silica gel with a mixture of hexane / ethyl acetate, 543 mg 1 g) are obtained.
1 H-NMR (CDCl₃): δ = 3.85-4.05 m (8H, ketal).
MS (EI) m / z: 346 (M⁺, 20%); 127 (30); 99 (100).

1h) 3,3- [1,2-ethanediylbis (oxy)] gon-5 (10) -en-17-one

543 mg of the compound described in 1g) are dissolved in 20 ml of dichloromethane. 1.4 g of silica gel and 0.15 ml of saturated aqueous oxalic acid solution are added and the mixture is stirred at 25 ° C. for 5 hours. The reaction mixture is then filtered. The mixture is then concentrated in vacuo and purified by column chromatography on silica gel with a mixture of hexane / ethyl acetate. 284 mg 1h) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 3.95-4.05 m (4H, ketal); 2.70 m (1H, H-16).
MS (EI) m / z: 302 (M⁺, 10%); 258 (15); 117 (15); 86 (100).

1i) 3,3- [1,2-ethanediylbis (oxy)] - 17α- (1-propynyl) gon-5 (10) -en-17β-ol

15 ml of absolute tetrahydrofuran are saturated with propine gas at 0 ° C. for 30 minutes. Then 5.9 ml of a 1.6 molar solution of n-butyllithium in hexane are added and the mixture is stirred at 0 ° C. for 30 minutes. A solution of 284 mg of the compound described under 1h) in 10 ml of absolute tetrahydrofuran is then added. The mixture is left to stir at 0 ° C. for one hour and then the reaction mixture is poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After column chromatography on silica gel with a mixture of hexane / ethyl acetate, 210 mg 1i) are obtained as a white foam.
1 H-NMR (CDCl₃): δ = 3.95-4.02 m (4H, ketal); 1.85 s (3H, propyne).

1k) 17β-hydroxy-17α- (1-propynyl) gon-4-en-3-one from 1i)

210 mg of the compound described under 1i) are in 15 ml of acetone solved. 0.5 ml of 4 normal hydrochloric acid are added and the mixture is left at 25 ° C. for one hour stir. The reaction mixture is then saturated to aqueous Poured sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. You get after column chromatography on silica gel with a mixture Hexane / ethyl acetate 156 mg 1k) as a white foam.

from 1e) (A) 1f ′) 3.3; 17,17-bis [1,2-ethanediylbis (oxy)] - 11 β - [(1H-imidazole-1- yl) thiooxomethoxy] gon-5-ene

Analogously to 1f), 601 mg (A) from 1e) in 20 ml of dichloromethane are reacted with 5 drops of triethylamine and 3.4 g of N′N′-thiocarbonyldiimidazole. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 509 mg 1f).
1 H-NMR (CDCl₃): δ = 8.35 sbr (1H, imidazole); 7.61 sbr (1H, imidazole); 7.03 sbr (1H, imidazole), 6.11 m (1H, H-11α), 5.50 dbr (J = 6 Hz, 1H, H-6); 3.80-4.05 (8H, ketal).
MS (EI) m / z: 472 (M⁺, 10%); 344 (100).

1g ′) 3.3; 17.17-bis [1,2-ethanediylbis (oxy)] gon-5-ene

Analogously to 1g), 509 mg of the compound described under 1f ') are reacted with 0.6 ml of tributyltin hydride and azobisisobutyronitrile in 25 ml of toluene. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 280 mg 1g ').
1 H-NMR (CDCl₃): δ = 5.45 dbr (J = 5 Hz, 1H, H-6); 3.80-4.05 m (8H, ketal).
MS (EI) m / z: 346 (M⁺, 10%); 316 (M-H₂O, 20); 99 (100).

1h ′) 3,3- [1,2-ethanediylbis (oxy)] gon-5-en-17-one

Analogously to 1h), 280 mg of the compound described under 1g ') are reacted with 720 mg of silica gel and 0.08 ml of saturated aqueous oxalic acid solution in 10 ml of dichloromethane. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 154 mg 1h ').
1 H-NMR (CDCl₃): δ = 5.48 dbr (J = 5 Hz, 1H, H-6); 3.95-4.05 m (4H, ketal); 2.50 m (1H, H-16).

1i ′) 3,3- [1,2-ethanediylbis (oxy)] - 17α- (1-propynyl) gon-5-en-17β-ol

Analogously to 1i), 154 mg of the compound described under 1h ′) are reacted in absolute tetrahydrofuran with propyne gas and 3.2 ml of a 1.6 molar solution of n-butylithium in hexane. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 126 mg 1i ').
1 H-NMR (CDCl₃): δ = 5.49 dbr (J = 5 Hz, 1H, H-6); 3.95-4.05 m (4H, ketal); 1.86 s (3H, propyne).

1k)

Analogously to the process described above, from 126 mg of the compound described under 1i ') with 4 normal hydrochloric acid in acetone after column chromatography on silica gel 97 mg 1k).
1 H-NMR (CDCl₃): δ = 5.83 sbr (1H, H-4); 1.87 s (3H, propyne).
MS (EI) m / z: 298 (M⁺, 75%); 283 (M-CH₃, 45); 280 (M-H₂O, 30); 270 (M-CO, 98); 241 (70); 217 (70); 91 (95); 82 (100).

Example 2 17β-hydroxy-11-methylene-17α- (1-propynyl) gon-4-en-3-one 2a) 3,3; 17,17-bis [1,2-ethanediylbis (oxy)] gon-5-en-11on

1.5 g of chromium trioxide are added to 5 ml of pyridine in 30 ml of dichloromethane at 0 ° C. The mixture is stirred for 15 minutes at 0 ° C. and then a solution of 900 mg of product (A) from 1e) in 8 ml of dichloromethane is added. Then allowed to stir for one hour at 0 ° C and then washed twice with 5% aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution. It is dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel with a mixture of hexane / ethyl acetate gives 599 mg 2a) as a white foam.
1 H-NMR (CDCl₃): δ = 5.42 dbr (J = 5 Hz, 1H, H-6); 3.80-4.00 m (8H, ketal).
MS (EI) m / z: 360 (M⁺, 15%); 99 (100).

2b) 3,3; 17,17-bis [1,2-ethanediylbis (oxy)] - 11-methylengon-5-ene

10.4 ml of a 1.6 molar solution of butyllithium are added dropwise to a suspension of 5.9 g of methyltriphenylphosphonium bromide in 60 ml of absolute diethyl ether at 0 ° C. The mixture is stirred for one hour at 25 ° C. and then a solution of 599 mg of the compound described under 2a) in a mixture of 10 ml of absolute tetrahydrofuran and 20 ml of diethyl ether is added at 0 ° C. and the mixture is stirred for one hour at 25 ° C. It is then poured onto water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel with a mixture of hexane / ethyl acetate gives 512 mg 2b) as a white foam.
1 H-NMR (CDCl₃): δ = 5.48 dbr (J = 5 Hz, 1H, H-6); 4.89 sbr (1H, ex-methylene); 4.71 sbr (1H, ex-methylene); 3.80-4.00 m (8H, ketal).
MS (EI) m / z: 358 (M⁺, 5%); 99 (100).

2c) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylengon-5-en-17-one

Analogously to Example 1h), 512 mg of the compound described under 2b) are reacted in 20 ml of dichloromethane with 1.4 g of silica gel and 0.15 ml of saturated aqueous oxalic acid solution. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 292 mg 2c) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.50 dbr (J = 5 Hz, 1H, H-6); 4.98 sbr (1H, ex-methylene); 4.78 sbr (1H, ex-methylene); 3.90-4.02 m (4H, ketal); 2.72 dd (J = 12; 2 Hz, 1H, H-16).
MS (EI) m / z: 314 (M⁺, 10%); 99 (100).

2d) 3,3- [1,2-ethanediylbis (oxy)] - 11methylene-17α- (1-propynyl) gon-5-en-17β-ol

Analogously to 1i), 292 mg of the compound described under 2c) are reacted in absolute tetrahydrofuran with 6 ml of a 1.6 molar solution of n-butyllithium and propyne gas. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 234 mg 2d).
1 H-NMR (CDCl₃): δ = 5.48 dbr (J = 5 Hz, 1H, H-6); 4.91 sbr (1H, ex-methylene); 4.72 sbr (1H, ex-methylene); 3.92-4.02 m (4H, ketal); 1.88 s (3H, propyne).

2e) 17β-hydroxy-11-methylene-17α- (1-propynyl) gon-4-en-3-one

Analogously to 1k), 234 mg of the compound described under 2d) are reacted in acetone with 4 normal hydrochloric acid. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 182 mg 2e).
1 H-NMR (CDCl₃): δ = 5.89 sbr (1H, H-4); 5.01 sbr (1H, ex-methylene); 4, 06179 00070 552 001000280000000200012000285910606800040 0002019535851 00004 0606073 sbr (1H, exo-methylene); 1.845 (3H, propyne).
MS (EI) m / z: 310 (M⁺, 70%); 292 (M-H₂O, 38); 282 (M-CO, 45); 268 (85); 91 (100).

Example 3 17β-hydroxy-11-methylene-17α- (1-propynyl) gona-4,15-dien-3-one 3a) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-17 - [(trimethylsilyl) oxy] gona - 5,16-diene

From a 1.6 molar solution of n-butyllithium in hexane and 0.28 ml Diisopropylamine is dissolved in 10 ml of absolute tetrahydrofuran at 0 ° C Lithium diisopropylamide (LDA) manufactured. Then cooled to -78 ° C and add a solution of 250 mg of the substance described under 2c) in 7 ml  absolute tetrahydrofuran. The mixture is stirred at -78 ° C for one hour. After that 0.35 ml of trimethylchlorosilane are added. The mixture is allowed to come to 0 ° C. and stirred another 30 minutes after. The reaction mixture is then saturated poured aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous Ammonium chloride solution and with saturated aqueous sodium chloride solution, dries over sodium sulfate, filtered and concentrated in vacuo. The received Crude product (305 mg) is used in the next stage without purification.

3b) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylenegona-5,15-dien-17-one

305 mg of the compound described in 3a) are dissolved in 8 ml of acetonitrile. 197 mg of palladium (II) acetate are added and the mixture is stirred at 25 ° C. for one hour. The reaction mixture is then filtered through Celite. The filtrate is then concentrated in vacuo. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 187 mg 3b) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 7.61 dbr (J = 6 Hz, 1H, H-15); 6.10 dd (J = 6, 1.5 Hz, 1H, H-16); 5.52 dbr (J = 5 Hz, 1H, H-6); 5.02 sbr (1H, ex-methylene); 4.83 sbr (1H, exo methylene); 3.90-4.10 m (4H, ketal).

3c) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-17α- (1-propynyl) gona-5,15-dien-17β-ol

Analogously to Example 1i), 187 mg of the compound described under 3b) are reacted in absolute tetrahydrofuran with 3.8 ml of a 1.6 molar solution of n-butyllithium and propyne gas. After column chromatography on silica gel with a mixture of hexane / ethyl acetate 203 mg 3c) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 6.04 dbr (J = 6 Hz, 1H, H-15); 5.83 dd (J = 6, 1.5 Hz, 1H, H-16); 5.50 dbr (J = 5 Hz, 1H, H-6); 4.98 sbr (1H, ex-methylene); 4.78 sbr (1H, ex-methylene); 3.95-4.05 m (4H, ketal); 1.90 s (3H, propyne).

3d) 17β-hydroxy-11-methylene-17α- (1-propynyl) gona-4,15-dien-3-one

Analogously to Example 1k), 203 mg of the compound described under 3c) are reacted in acetone with 4 normal hydrochloric acid. Column chromatography on silica gel with a mixture of hexane / ethyl acetate 158 mg 3d) gives a white foam.
1 H-NMR (CDCl₃): δ = 6.07 dbr (J = 6 Hz, 1H, H-15); 5.92 sbr (1H, H-4); 5.87 dd (J = 6, 1.5 Hz, 1H, H-16); 5.05 sbr (1H, ex-methylene); 4.80 sbr (1H, ex-methylene); 1.88 s (3H, propyne).

Example 4 17β-hydroxy-11-methylene-17α- (1-propynyl) -13α-gon-4-en-3-one 4a) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-13α-gon-5-en-17-one

610 mg of the substance described under 2c) in 15 ml of absolute tetrahydrofuran are added to a suspension of 380 mg of sodium hydride (60%) in 12 ml of absolute tetrahydrofuran at 0 ° C. The mixture is left to stir at 0 ° C. for 3 hours and then the reaction mixture is poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. After column chromatography on silica gel with a mixture of hexane / ethyl acetate, 591 mg of a mixture of 4a) and starting material 2c) (approx. 3: 1) are obtained.
For connection 4a):
1 H-NMR (CDCl₃): δ = 5.50 dbr (J = 5 Hz, 1H, H-6); 4.93 sbr (1H, ex-methylene); 4.70 sbr (1H, exo-methylene); 3.90-4.10 m (4H, ketal); 2.80 dd (J = 12, 2 Hz, 1H, H-16).

4b) 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-17α- (1-propynyl) -13α-gon-5-en-17β-ol (I) and 3,3- [1,2-ethanediylbis (oxy)] - 11-methylene-17β- (1-propynyl) -13α-gon-5-en-17α-ol (II)

Analogously to Example 1i), 591 mg of the mixture obtained in 4a) are converted into absolute tetrahydrofuran with 11.7 ml of a 1.6 molar solution of n- Butyllithium and proping gas implemented. This is obtained after column chromatography on silica gel with a mixture of hexane / ethyl acetate 111 mg 4b) (I), 229 mg 4b) (II) and 113 mg of the substance already described under 2d).  

4b) (I)

1 H-NMR (CDCl₃): δ = 5.49 dbr (J = 5 Hz, 1H, H-6); 5.05 sbr (1H, ex-methylene); 4.74 sbr (1H, exo methylene); 3.90-4.05 m (4H, ketal); 1.88 s (3H, propyne).

4b) (II)

1 H-NMR (CDCl₃): δ = 5.51 dbr (J = 5 Hz, 1H, H-6); 4.97 sbr (1H, ex-methylene); 4.69 sbr (1H, exo methylene); 3.90-4.05 m (4H, ketal); 1.89 s (3H, propyne).

4c) 17β-hydroxy-11-methylene-17α- (1-propynyl) -13α-gon-4-en-3-one

111 mg 4b) (I) are reacted in acetone with 4 normal hydrochloric acid analogously to Example 1k). After column chromatography on silica gel with a mixture of hexane / ethyl acetate 78 mg 4c) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.89 sbr (1H, H-4); 5.17 sbr (1H, ex-methylene); 4.76 sbr (1H, ex-methylene); 1.88 s (3H, propyne).

Example 5 17α-hydroxy-11-methylene-17β- (1-propynyl) -13α-gon-4-en-3-one

229 mg 4b (II) are reacted in acetone with 4 normal hydrochloric acid analogously to Example 1k). After column chromatography on silica gel with a mixture of hexane / ethyl acetate 161 mg 5) is obtained as a white foam.
1 H-NMR (CDCl₃): δ = 5.89 sbr (1H, H-4); 5.03 sbr (1H, ex-methylene); 4.71 sbr (1H, ex-methylene); 1.84 s (3H, propyne).

Claims (17)

1. 18-norsteroids of the general formula I wherein
W represents an oxygen atom, the hydroxyimino group (= N-OH) or two hydrogen atoms,
R ^6a and R ^6b each represent a hydrogen atom and R⁷ represents a hydrogen atom or a straight-chain or branched-chain saturated α- or β-position C₁-C₄-alkyl radical or
R ^6a and R ^6b together represent a methylene group or a triple ring formed together with the carbon atom 6 and R⁷ represents a hydrogen atom or
R ^{6a represents} a fluorine, chlorine, bromine or iodine atom or a straight-chain or branched-chain saturated C₁-C₄alkyl radical, in which case R ^6b and R⁷ each represent a hydrogen atom or together form an additional bond and,
when R ^6b and R⁷ each represent a hydrogen atom or R⁷ is a C₁-C₄ alkyl radical, R ^{6a can be} α or β, or
R ^{6a represents} a hydrogen atom and R ^6b and R⁷ together represent an additional bond or an α- or β-methylene group,
R⁹ and R¹⁰ represent hydrogen atoms, or together represent an additional bond,
R ^{11b represents} a hydrogen atom, a C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl radical and R ^11a and R¹² represent hydrogen atoms or a common additional bond or
R ^11a and R ^11b together represent a C₁-C₄ alkylidene radical and R¹² in this case represents a hydrogen atom,
R¹⁵ and R¹⁶ each represent a hydrogen atom or together for an additional bond or an α- or β-methylene bridge,
or R¹⁶ represents an α- or β-position C₁-C₄-alkyl group and R¹⁵ represents a hydrogen atom,
R ^17a / R ^17b one of the substituent combinations means
or R¹⁶ together with R ^17a for an α- or β-permanent methylene bridge and
R ^17b for a rest stands, in which case R¹⁵ also represents a hydrogen atom,
or R ^17a / R ^17b together mean,
with X = 1 or 2, U = O or and E and G are hydrogen or a common additional bond,
R²¹ and R²³ independently of one another have the meaning of a hydrogen atom, a C₁-C₄-alkyl or a C₁-C₄-alkanoyl group,
R²² is a C₁-C₃-alkyl group or a 1-hydroxy-C₁-C₃- alkyl group,
A has the meaning of a hydrogen atom, the cyano group, a radical of the formula COOR²⁴ or -OR²⁵ where R²⁴ is C₁-C₄-alkyl and R²⁵ is hydrogen, C₁-C₄-alkyl or C₁-C₄-alkanoyl,
B is a hydrogen atom, a C₁-C₄ alkyl group, a C₂ or C₃ alkynyl group, a fluorine, chlorine, bromine or iodine atom, a hydroxyalkyl, alkoxyalkyl or alkanoyloxyalkyl group each having 1 to 4 carbon atoms in the alkyl , Alkoxy or alkanoyloxy part,
D has the meaning of a hydrogen atom, a hydroxy, C₁-C₄-alkoxy or C₁-C₄-alkanoyloxy group,
n has the meaning 1, 2, 3 or 4,
m has the meaning 0, 1 or 2,
p has the meaning 0 or 1,
k have the meaning 0, 1, 2 or 3. 2. Compounds of the general formula I, characterized in that W for is one oxygen atom or two hydrogen atoms. 3. Compounds of general formula I, characterized in that R ^6a and R ^6b each represent a hydrogen atom. 4. Compounds of the general formula I, characterized in that R ^{6a represents} a chlorine atom or a straight-chain, saturated α or β-C₁-C₄-alkyl radical. 5. Compounds of general formula I, characterized in that R ^6b and R⁷ represent hydrogen atoms or together for an additional bond. 6. Compounds of the general formula I, characterized in that R⁷ for a hydrogen atom or an α- or β-alkyl radical with up to 4 Carbon atoms. 7. Compounds of general formula I, characterized in that R ^11a , R ^11b and R¹² each represent a hydrogen atom. 8. Compounds of general formula I, characterized in that R ^11a and R¹² each represent a hydrogen atom and R ^{11b represents} a C₁-C₄ alkyl radical. 9. Compounds of the general formula I, characterized in that R ^11a and R¹² together represent an additional double bond and R ^{11b represents} a hydrogen atom. 10. Compounds of the general formula I, characterized in that R ^11a and R ^11b together represent a C₁-C₄-alkylidene radical and R¹² represents a hydrogen atom. 11. Compounds of general formula I, characterized in that R¹⁵ and R¹⁶ for hydrogen atoms, a common additional bond or one common α- or β-permanent methylene bridge. 12. Compounds of general formula I, characterized in that R ^17a / R ^17b
-OH / -CH₃;
-OC (O) CH₃ / CH₃;
-OH / -C≡CH;
-OC (O) CH₃ / -C≡CH;
-OH / -C≡CCH₃;
-OC (O) CH₃ / -C≡CCH₃;
-C (O) CH₃ / -OC (O) CH₃;
-C (O) CH₃ / -CH₃ or
-C (O) CH₂CH₃ / -CH₃ mean. 13. Compounds according to claim 1, namely:
17α-ethynyl-17β-hydroxygon-4-en-3-one;
17α-ethynyl-17β-hydroxygona-4,15-dien-3-one;
17β-hydroxy-17α- (1-propynyl) gon-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,15-diene-3one;
17α-ethynyl-17β-hydroxy-11-methylenegon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11-methylenegona-4,15-dien-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) gon-4-en-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) gona-4,15-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,15-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-prnpinyl) gon-4-en-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona-4,15-dien-3-one;
17- (acetyloxy) -18,19-dinorpregn-4-en-3,20-dione;
17- (acetyloxy) -18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinorpregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-18,19-di norpregn-4-en-3,20-dione;
17-methyl-18,19-dinorpregn-4-en-3,20-dione;
17-methyl-18,19-dinorpregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinorpregna-4,6-diene-3,20-dione;
6-chloro-17-methyl-18,19-dinorpregna-4,6-diene-3,20-dione;
6α, 17-dimethy l-18,19-dinorpregn-4-en-3,20-dione;
17,21-dimethyl-18,19-dinorpregn-4-en-3,20-dione;
6,17,21-trimethyl-18,19-dinorpregna-4,6-diene-3,20-dione;
17α-ethynylgon-4-en-17β-ol;
17α-ethynylgona-4,15-dien-17β-ol;
17α- (1-propynyl) gon-4-en-17β-ol;
17α- (1-propynyl) gona-4,1-diene-17β-ol;
17α-ethynyl-11-methylengon-4-en-17β-ol;
17α-ethynyl-11-methylenegona-4,15-dien-17β-ol;
11-methylene-17α- (1-propynyl) gon-4-en-17β-ol;
11-methylene-17α- (1-propynyl) gona-4,15-diene-17β-ol;
17α-ethynyl-17β-hydroxygona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxygona-4,9,15-trien-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,9-dien-3-one;
17β-hydroxy-17α- (1-propynyl) gona-4,9,15-trien-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methylgona-4,9,15-trien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona-4,6-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) gona-4,6,15-trien-3-one;
17- (acetyloxy) -18,19-dinorpregna-4,9-diene-3,20-dione;
17-methyl-18,19-dinorpregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinorpregna-4,9-diene-3,20-dione;
17α-ethynyl-17P-hydroxy-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-13α-gon-4-en-3-one;
17β-hydroxy-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-17β-β1-propynyl) -13α-gon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11-methylene-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-11-methylene-13α-gon-4-en-3-one;
17β-hydroxy-11-methylene-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-11-methylene-17β- (1-propynyl) -13α-gon-4-en-3-one;
17α-ethynyl-17β-hydroxy-11β-methyl-13α-gon-4-en-3-one;
17β-ethynyl-17α-hydroxy-11β-methyl-13α-gon-4-ene -3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) -13α-gon-4-en-3-one;
17α-hydroxy-11β-methyl-17β- (1-propynyl) -13α-gon-4-en-3-one;
17- (acetyloxy) -18,19-dinor-13α-pregn-4-en-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregn -4-en-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-methyl-18,1 9-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6-chloro-18,19-dinor-13c:, 17α-pregna-4,6-diene-3,20-dione;
17- (acetyloxy) -6α-methyl-18,19-dinor-13α-pregn-4en-3,20-dione;
17- (acetyloxy) -6α-methyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-130:, 17α-pregn-4-en-3,20-dione;
17-methyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
17-methyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
6,17-dimethyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
6-chloro-17-methyl-18,19-dinor-13α-pregna-4,6-dien-3,20-dione;
6-chloro-17-methyl-18,19-dinor-13a, 17α-pregna-4,6-diene-3,20-dione;
6α, 17-dimethyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
6α, 17-dimethyl-18,19-dinor-13α, 17a-pregn-4-en-3,20-dione;
17,21-dimethyl-18,19-dinor-13α-pregn-4-en-3,20-dione;
17,21-dimethyl-18,19-dinor-13α, 17α-pregn-4-en-3,20-dione;
6,17,21-trimethyl-18,19-dinor-13α-pregna-4,6-diene-3,20-dione;
6,17,21-trimethyl-18,19-dinor-13α, 17α-pregna-4,6-diene-3,20-dione;
17α-ethynyl-13α-gon-4-en-17β-ol;
17β-ethynyl-13α-gon-4-en) -17α-ol;
17α- (1-propynyl) -13α-gon-4-en-17β-ol;
17β- (1-propynyl) -13α-gon-4-en-170α-ol;
17α-ethynyl-11-methylene-13α-gon-4-en-17β-ol;
17β-ethynyl-11-methylene-13α-gon-4-en-17α-ol;
11-methylene-17α- (1-propynyl) -13α-gon-4-ene -17β-ol;
11-methylene-17β- (1-propynyl) -13α-gon-4-en-17α-ol;
17α-ethynyl-17β-hydro xy-13α-gona-4,9-dien-3-one;
17β-ethynyl-17α-hydroxy-13α-gona-4,9-dien-3-one;
17β-hydroxy-17α- (1-propynyl) -13α-gona-4,9-dien-3-one;
17α-hydroxy-17β- (1-propynyl) -13α-gona-4,9-dien-3-one;
17α-ethynyl-17β-hydroxy-11β-methyl-13α-gona-4,9-dien-3-one;
17β-ethynyl-17α-hydroxy-11β-methyl-13α-gona-4,9-dien-3-one;
17β-hydroxy-11β-methyl-17α- (1-propynyl) -13α-gona-4,9-diene) -3-one;
17α-hydroxy-11β-methyl-17β- (1-propynyl) -13α-gona-4,9-dien-3-one;
17- (acetyloxy) -18,19-dinor-13α-pregna-4,9-diene-3,20-dione;
17- (acetyloxy) -18,19-dinor-13α, 17α-pregna-4,9-diene-3,20-dione;
17-methyl-18,19-dinor-13α-pregna-4,9-diene-3,20-dione;
17-methyl-18,19-dinor-13α, 17α-pregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinor-13α-pregna-4,9-diene-3,20-dione;
17,21-dimethyl-18,19-dinor-13α, 17α-pregna-4,9-diene-3,20-dione. 14. A process for the preparation of the compounds of general formula I, characterized in that

• a) a compound of the general formula II, wherein K represents a keto oxygen atom, a keto protecting group or a free or protected hydroxy group and a hydrogen atom and, R ^{4 '} and R ^{5' represent} an additional bond, in which case R ^{6 '} and R ^{10' are} hydrogen, or R ^{5 '} and R ^{6 'represent} an additional bond and R4' and R10 'represent hydrogen, or R ^5' and R ^{10 'represent} an additional bond and R ^4' and R ^{6 'represent} hydrogen, by treatment with bases or acids in a compound the general formula III, wherein K represents a keto oxygen atom, a keto protecting group or a free or protected hydroxy group and a hydrogen atom and, R ^{4 '} and R ^{5' represent} an additional bond, in which case R ^{6 '} and R ^{10' are} hydrogen, or R ^{5 '} and R ^{6 'represent} an additional bond and R4' and R10 'represent hydrogen, or R ^5' and R ^{10 'represent} an additional bond and R ^4' and R ^{6 'represent} hydrogen and L represents hydrogen or HC (O) convicted
• b) then the 17-keto group and possibly also the 3-keto group are protected, and then
• c) if R⁹, R ^11a , R ^11b and R¹² should ultimately stand for hydrogen atoms, if necessary after cleavage of an 11β-formyl (oxy) group still present, the 11β-hydroxy group is reductively removed,
• d) if R ^11a and R ^{11b are} ultimately to stand together for an alkylidene group, the 11β-hydroxy group released is first oxidized to the 11-ketone and then converted, for example by a Wittig reaction, into the alkylidene grouping,
• e) if R ^{11b is} ultimately intended to represent a C₁-C₄ alkyl radical, this is established by hydrogenation of the 11-alkylidene group,
• f) if R ^{11b is} ultimately to stand for a C₁-C₄ alkenyl or C₁-C₄ alkynyl radical, this is established by the Wittig reaction of the 11-carbaldehydes obtained from the 11-ketone, and by the corresponding one, the b) to f) operations obtained a compound of general formula IV, in which K and K 'represents a keto oxygen atom, a keto protective group or a free or protected hydroxyl group and a hydrogen atom, R ^4' , R ^{5 '} , R ^6' and R ^{10 '} may have the meanings already mentioned for the general formula III and R ^{11b 'represents} a hydrogen atom, a C₁-C₄ alkyl, C₂-C₄ alkenyl or C₂-C₄ alkynyl radical and R ^{11a' represents} a hydrogen atom, or R ^{11a '} and R ^11b' together form a C₁-C₄- Stand alkylidene, or
• g) if R ^11a and R¹² should ultimately represent an additional bond and R ^11b should have the meanings given in formula I, this substitution pattern by converting the 11-ketone into an enol trifluoromethanesulfonate and coupling with organotin or organoboron compounds or reduction under Transition metal catalysis is built up, and thereby a compound of general formula V is obtained in which R ^{11b 'represents} a hydrogen atom, a C₁-C₄-alkyl, C₂-C₄-alkenyl or C₂-C₄-alkynyl radical and K, K', R ^{4 '} , R ^5' , R ^{6 '} and R ^{10 '} May have the meanings already given for the general formula IV,
• h) if R⁴ and R⁵ as well as R⁹ and R¹⁰ are ultimately to stand for an additional bond, initially either by eliminating water from the corresponding 11β-hydroxy compound or by converting the 11-ketone into an enol trifluoromethanesulfonate under thermodynamic control and reacting this enol trifluoromethanesulfonate with an organotin - Or organoboron compound with transition metal catalysis to obtain a compound of general formula VI in which K, K ′, R ^{4 ′} , R ^{5 ′} , R ^{6 ′} , R ^{10 ′} and R ^{11 ′ have} the meanings already mentioned in the general formula IV,
• i) if desired, isomerized in position 13 of the steroid structure after removal of at least the protective group of the 17-keto oxygen atom by base treatment,
• j) if desired, a 15.16 double bond is introduced,
• k) if desired, these are converted into the corresponding 15β, 16β-methylene compounds by methylenation,
• l) if desired, the functionality at C-17 is built up by nucleophilic addition of the substituent R ^17a or a reactive precursor of R ^17a and, if appropriate, etherification or esterification of the 17α- or 17β-hydroxy group (R ^17b = OH) with a reagent providing the corresponding radical R²¹ or the 17α- (β) -hydroxy-17β- (α) -alkanoyl substitution pattern is built up and the 17α (or β) -hydroxy group is etherified or esterified, if appropriate, with a reagent providing the corresponding radical R²³,
• m) if appropriate, an unsaturated side chain is partially or completely hydrogenated,
• n) if desired, the corresponding 17- (3-hydroxypropyl) or 17- (hydroxybutyl) compound is oxidized to the spirolactone,
• o) if desired, the corresponding (z) -17α- (or β) (3-hydroxypropenyl) or (Z) -17α- (or β) (3-hydroxybutenyl) compound or the corresponding compounds saturated in the side chain in the 17-Spiroether transferred, then
• p) a possibly still protected 3-ketone is converted into the Δ⁴-3-keto system by acid treatment with a water-miscible solvent, further protective groups also being split off and any 9 (11) double bond according to position 9 (10 ) isomerized, and converted into a compound of the general formula VII by appropriate operations mentioned under i) to p), in which the radicals R ^{9 ′} , R ^{10 ′} , R ^{11a ′} , R ^{11b ′} , R ^{12 ′} , R ^{15 ′} , R ^{16 ′} , R ^{17a ′} and R ^{17b ′ are} all in the description of the general formula I for R⁹, R¹⁰, R ^11a , R ^11b , R¹², R¹⁵, R¹⁶, R ^17a and R ^17b may have meanings mentioned, and this compound of the general formula VII,
• q) optionally by introducing a 6,7 double bond and optionally methylenating this double bond,
• r) if desired, introduction of the rest R gewünschten,
• s) optionally epoxidation of the 6,7-double bond and opening of the epoxide with hydrogen halide (Hal = F, Cl, Br, I) and elimination of the 7α-hydroxy group formed,
• t) optionally 6α-hydroxymethylation and subsequent elimination of water to give the 6-methylene compound,
• u) optionally hydrogenation of the 6-methylene group,
• v) optionally isomerization of the double bond of the 6-methylene group according to position 6 (7),
  into a compound of general formula I, wherein R ^6b , R⁷, R⁹, R¹⁰, R ^11a , R ^11b , R¹², R¹⁵, R¹⁶, R ^17a and R ^{17b have} the ultimately desired meaning, and R ^6a all in general formula I. may have the meanings mentioned, with the exception of an α- or β-C₁-C₄ radical, and
• w) if R ^{6a is} ultimately intended to be a straight-chain or branched-chain saturated alkyl radical having up to 4 carbon atoms, by ketalization of the 3-keto oxygen atom with simultaneous isomerization of the 4 (5) double bond according to 5 (6), Epoxidation of the 5 (6) double bond and nucleophilic opening of the 5,6α-epoxide with a straight or branched chain alkyl magnesium halide or an alkyl lithium compound with up to 4 carbon atoms and cleavage of the 3-keto protective group in the 5α-hydroxy-6β-alkyl compound formed under mild acidic conditions for the corresponding 3-keto-5α-hydroxy-6β-alkyl compound and basic elimination of the 5α-hydroxy group in the corresponding 3-keto-4-ene compounds of the general formula I with a 6-position 6-alkyl group or by cleavage the 3-keto protective group under more drastic conditions in the corresponding 3-keto-4-enes compounds of the general formula I with α-6-alkyl group, u nd
• x) if desired, one of the 3-keto compounds obtained above with hydroxylamine hydrochloride in the presence of tertiary amines at a temperature between -20 ° and + 40 ° C in the corresponding 3-hydroxyimino compound (W = N∼OH), or
• y) if desired, converted into the 3-thioketal, preferably the 3- (1 ', 3'-ethylenedithio) ketal, and this is reduced to compounds of the general formula I, in which W represents two hydrogen atoms.

15. Intermediate compounds of the general formula VIII, wherein K represents a keto oxygen atom, a keto protective group or a protected hydroxy group and a hydrogen atom, and
R ^{4 '} and R ^{5' represent} an additional bond, in which case R ^{6 '} and R ^{10' represent} hydrogen, or R ^{5 '} and R ^{6' represent} an additional bond and R ^{4 '} and R ^{10' represent} hydrogen, or R ^{5 '} and R ^{10' represent} an additional bond and R ^{4 '} and R ^{6' is} hydrogen, R ^{11a '} , R ^11b' and R ^{12 'have} the meanings given in the general formula I for R ^11a , R ^11b and R¹² can have, as well as Q represents an a- or b-terminal hydroxyl group and S represents a hydrogen atom, or Q and S together represent a keto oxygen atom or Q and S one of the substituent ^combinations mentioned in the general formula I for R ^17a / R ^17b , including the spiro compounds can mean that the hydroxy and / or keto groups present therein can be protected. 16. Medicament containing at least one compound of general formula I. according to claim 1 and a pharmaceutically acceptable carrier. 17. Use of the compounds of general formula I according to claim 1 for the manufacture of pharmaceuticals.