KR890003797A - Steroids with a spirogy at position 17, methods for their preparation and use thereof as intermediate pharmaceuticals, and pharmaceutical compositions containing them - Google Patents

Abstract

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Description

Steroids with a spirogy at position 17, methods for their preparation and use thereof as intermediate pharmaceuticals, and pharmaceutical compositions containing them

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Claims (18)

The products having the general formula (I) and salts thereof; Wherein R ₁ represents an optionally substituted carbon ring or heterocyclic aralkyl or aryl group, except for an optionally substituted alkynyl phenyl group, and R ₂ at the alpha or beta position is a hydrocarbon containing from 1 to 18 carbon atoms Group, the dashed line of spiro ether indicates that the oxygen atom may be in the alpha or beta position, and rings A and B represent any of the following formulas a) to e): (Wherein R 'and R are the same or different and represent an alkyl group or a hydrogen atom having from 1 to 4 carbon atoms.) (Wherein Re represents an acyl group, an optionally substituted alkyl group having 1 to 6 carbon atoms or a hydrogen atom) The products of general formula (I) and salts thereof corresponding to the following general formula (I ′) and salts thereof: Wherein R ₁ represents an optionally substituted carbon ring or heterocycle or an aralkyl or aryl group, except for an optionally substituted alkynylphenyl group, and R ₂ in an alpha or beta position represents a hydrocarbon group having 1 to 18 carbon atoms. The dashed line of spiroethero indicates that the oxygen atom is in the beta position and the dotted line in the 3 ', 4' position indicates that there may be a second bond between the carbohydrates occupying it. The product of formula (I) and salts thereof according to claim 1, wherein the oxygen atom of the spiro-ether is at position 17beta and rings A and B are represented by Wherein R 'and R represent hydrogen atoms. 4. The compound of claim 1, wherein R ₁ is an amine functional group. Wherein R ₃ and R ₄ each represent a primary, secondary or tertiary alkyl group having 1 to 8 carbon atoms, or R ₃ and R ₄ together with the nitrogen atom bonded thereto are oxygen, nitrogen, sulfur And an aryl or an aralkyl group occupying a heterocyclic group, optionally further comprising a heteroatom selected from the group formed by silium, or an aryl group occupying a methylthio or ethylthio functional group. Products of formula (I) and salts of id. The product of formula (I) and salts thereof according to any one of claims 1 to 4, wherein R ₁ represents a phenyl group, and substituents supported by the phenyl group are present in the para position. The product of formula (I) and salts thereof according to any one of claims 1 to 5, wherein R ₁ is represented by the following groups: 7. A compound according to claim 6 wherein R ₁ is a group or A product of formula (I) and salts thereof, characterized in that 8. The product of formula (I) and salts thereof according to claim 1, wherein R ₂ represents a methyl group in the alpha or beta position or an ethyl group in the beta position. 9. The product of formula (I) and salts thereof according to any one of claims 1 to 8, characterized by the following:-(17R) 4 ', 5'-dihydro-11-beta- [4 -(Dimethylamino) phenyl] -spiro (estra-4,9-diene-17,2 '(3H) -furan) -3-one,-(17R) 11-beta- [4- (dimethylamino) phenyl] -Spiro (estra-4,9-diene-17,2 '(5H) -furan) -3-one,-(17R) 11-beta- [4- (methylthio) phenyl] -spiro (estra-4, 9-diene-17,2 '(5H) -furan) -3-one,-(17R) 4', 5'-dihydro-11-beta- [4- (methylthio) phenyl] -spiro (estra- 4,9-diene-17,2 '(5H) -furan) -3-one,-(17R) 11-beta- [4- (1-pyrrolidinyl) phenyl] -spiro (estra-4,9- Diene-17,2 '(5H) -furan) -3-one,-(17R) 4', 5'-dihydro-11-beta- [4- (1-myrrolidinyl) phenyl] -spiro (estra -4,9-diene-17,2 '(3H) -furan) -3-one,-(17R) 4', 5'-dihydro-11-beta- [4- (2,3-dihydro -1-Methy)-(1H) -indol-5-yl] -spiro (estra-4,9-diene-17,2 '(3H) -furan) -3-one,-(17R) 11-beta- [4- (methyl O) phenyl] spiro (estradiol-4,9-diene -17,2 '(5H) - furan) -3-one, a) reacting with the cyclizing agent of the following formula (II) or (III) to obtain the product of formula (I _A ), wherein R 'and R are H, or the product of formula (IV) obtained getting the ketone functional group for allowing to react with a dehydrating agent which can be glass and R 'and R are H, and then the product of formula (ⅰ _a), if necessary, by the general formula (ⅰ _a) containing the R ₁ sulfur or nitrogen atom to obtain a product by oxidation of the product R ₁ comprises an oxidized sulfur as a side or suhok supon or comprising a nitrogen atom oxidized to the N- oxide, or, if necessary, and chloride of the product of general formula (ⅰ _a), or if desired, the product of formula (ⅰ _a) formula (ⅰ _a) is a strong base and by reacting then the alkyl by a halide and reaction R 'and / or R product represents an alkyl group having from 1 to 4 carbon atoms in the Get; b) the following general formula (Ⅰ _A) the product was an aromatic agent and a response by getting the product of general formula (Ⅰ _B), if desired, reacted with the soap agent and, if also desired, R _e is a hydrogen atom general formula ( Reacting the product of I _B ) with an alkylating agent or acylating agent; c) reacting the product of formula (V) with a cyclizing agent to obtain the product of formula (Ic), or reacting the product of formula (I _A ) with an acylating agent followed by saponification. Ic) to obtain the product; d) reacting the product of general formula (I _A ) with an epoxidation agent to obtain the product of general formula (I _D ); e) a process for the preparation of the product of formula (I) as defined in claim 1, characterized in that the product of formula (I _A ) is reacted with hydroxylamine to give the product of formula (I _E ); Wherein R ₁ and R ₂ are as defined above and R 'and R each represent a hydrogen atom or an alkyl group or else one represents a hydrogen atom and the other represents an alkyl group and Re is defined above As; K represents a ketoneger protecting group. Acid hydrolysis of the product of formula (I _E ) to give the product of formula (I _C ) and, if necessary, reaction with a basic reagent to obtain the product of formula (I _H ), if necessary, saponification. To obtain the product of the following general formula (I _H ) and, if necessary, esterification or chlorination, wherein R ₁ is optionally substituted by an ester 롸 or chlorinated carboxyl group The method according to claim 10 for producing the product. Wherein A, B, C and R ₂ are as defined above, X represents a carbon ring or heterocyclic aryl or aralkyl group, and Alk represents an alkyl group having from 1 to 6 carbon atoms. The process according to claim 10, wherein the cyclizing agent which reacts with the product of formula (II), (III) or (V) is tosyl chloride in the presence of pyridine. Use of the general formula (I) products and their pharmaceutically acceptable salts as defined in claim 1. Use of the general formula (I) products and their pharmaceutically acceptable salts as defined in claim 2. Use of a general formula (I) product and a pharmaceutically acceptable salt thereof as defined in any one of claims 3 to 8. Use of the general formula (I) products and their pharmaceutically acceptable salts as defined in claim 9. The pharmaceutical composition of claim 13 to claim 16 containing at least one agent according to claim 1 as an active ingredient. As an industrial product, the product of following General formula (IV); Wherein R ₁ , R ₂ and k are as defined in claim 1. ※ Note: It is to be disclosed based on the initial application.