11.beta.-aryl-4-estrenes, process for their production as well as their use as pharmaceutical agents

A process for the production of 11.beta.-aryl-4-estrenes of general formula I ##STR26## wherein X is an oxygen atom, the hydroxyimino grouping >N.about.OH or two hydrogen atoms,

• R.sup.1 is hydrogen or a methyl group,
• R.sup.2 is a hydroxy group, a C.sub.1 -C.sub.10 alkoxy or C.sub.1 -C.sub.10 alkanoyloxy group,
• R.sup.3 is hydrogen, the grouping --(CH.sub.2).sub.n CH.sub.2 Z, wherein
• n is 0, 1, 2, 3, 4 or 5,
• Z is hydrogen, cyano or the radical --OR.sup.5 wherein R.sup.5 is H, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkanoyl,
• the grouping --(CH.sub.2).sub.m C.tbd.C--Y, wherein
• m is 0, 1 or 2 and
• Y is hydrogen, fluorine, chlorine, bromine or iodine atom,
• a C.sub.1 -C.sub.10 hydroxyalkyl, C.sub.1 -C.sub.10 alkoxyalkyl, C.sub.1 -C.sub.10 alkanoyloxyalkyl, the grouping --(CH.sub.2).sub.p --CH.dbd.CH--(CH.sub.2).sub.k CH.sub.2 R.sup.6, wherein
• p is 0 or 1,
• k is 0, 1 or 2 and
• R.sup.6 means a hydrogen atom, a hydroxy group, a C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkanoyloxy radical,
• or else R.sup.2 and R.sup.3 together stand for a radical of the formula ##STR27## wherein x=1 or 2;
• R.sup.4 is hydrogen;
• cyano;
• chlorine;
• fluorine;
• bromine;
• iodine;
• trialkylsilyl;
• trialkylstannyl;
• a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical;
• an amino group ##STR28## in which R.sup.7 and R.sup.8, each independently of one another, is hydrogen or a C.sub.1 -C.sub.4 alkyl group;
• a corresponding amine oxide ##STR29## a grouping --OR.sup.9 or --S(O).sub.i R.sup.9, wherein i is 0, 1 or 2,
• R.sup.9 means hydrogen, a methyl, ethyl, propyl, isopropyl, methoxyphenyl, allyl or a 2-dimethylaminoethyl group;
• a heteroaryl radical of the formula I.alpha. ##STR30## wherein A is an nitrogen, oxygen or sulfur atom,
• --B--D--E-- is the element sequence --C--C--C--,
• --N--C--C-- or --C--N--C--, and
• R.sup.10 is hydrogen;
• cyano;
• chlorine;
• fluorine;
• bromine;
• iodine;
• trialkylsilyl;
• trialkylstannyl;
• a straight-chain or branched, saturated or unsaturated C.sub.1-8 hydrocarbyl, C.sub.1-8 alkanoyl or C.sub.1-8 alkoxyalkyl radical;
• an amino group ##STR31## or the radical --OR.sup.9 or --S(O).sub.i R.sup.9, wherein R.sup.7, R.sup.8, R.sup.9, and i each independently having one of the meanings already indicated;
• a heteroaryl radical of formula I.beta. ##STR32## wherein A is a nitrogen atom,
• --B--D--E-- is the element sequence --C--C--C--,
• --N--C--C--, --C--N--C-- or --C--C--N--, and
• R.sup.10 has the meaning already indicated;
• or a phenyl radical of formula I.tau. ##STR33## wherein R.sup.10 has the meaning already indicated, or a pharmacologically compatible addition salt thereof with acid, comprising
• converting by heating in the presence of acid, a compound of general formula II ##STR34## wherein R.sup.1 and R.sup.4 have the meanings indicated in formula I,
• A is for a .beta.-hydroxy group or the radical OR.sup.2 and
• B is for an .alpha.-hydrogen atom, an .alpha.-position radical
• R.sup.3 or
• A and B together are a keto oxygen, into a compound of formula Ia ##STR35## wherein R.sup.1, A and B have the meanings indicated in formula II and R.sup.4' has the same meaning as R.sup.4 in formula I, provided that R.sup.4 is stable under said reaction conditions;
• producing a compound of formula III ##STR36## wherein Z is a keto group protected in the form of a dithioketal, by either
• (1)
• (a) optionally oxidizing the 17-hydroxy group to the 17-keto group in the compound of general formula Ia, if, in said compound Ia, A is a .beta.-hydroxy group and B is an .alpha.-hydrogen atom,
• b) converting the 3-keto group into a dithioketal, and all other optionally present keto groups are also ketalized, or else first b) and then a) are performed,
• c) when R.sup.4' in the 3-thioketalized compound stands for a methoxy or a hydroxy group and R.sup.4 in the finally desired compound of general formula I is not a methoxy or hydroxy group, converting the hydroxy compound, optionally after cleavage of the methoxy compound, into a corresponding perfluoroalkyl sulfonic acid compound, wherein -alkyl- is a C.sub.1 -C.sub.4 alkyl radical, and from the latter either
• directly by reaction with a corresponding substituted tin(trialkyl) compound R.sup.4" --Sn(alkyl).sub.3, or with a corresponding substituted boron compound R.sup.4" --BL.sub.2, wherein L is hydroxy or alkyl, wherein R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomer precursor of R.sup.4 and alkyl is C.sub.1 -C.sub.4 alkyl radical, or
• indirectly by reaction with a compound substituted in the 4 position of the 11.beta.-phenyl radical with a tin(trialkyl) radical, wherein alkyl is C.sub.1 -C.sub.4, which was obtained by reaction of the perfluoroalkyl sulfonate compound with Sn.sub.2 alkyl.sub.6, and further treatment of the 11.beta.-(4-trialkylstannyl)-phenyl compound with a compound R.sup.4" --Y, in which R.sup.4" is identical with R.sup.4 of general formula I or represents a tautomer precursor of R.sup.4 and Y is a starting group, in the presence of a transition metal catalyst, and
• d) if R.sup.2 and R.sup.3 in the compound of formula I are not a hydroxy group or a hydrogen atom, or R.sup.2 and R.sup.3 together are not a keto oxygen atom, introducing the desired substituents R.sup.2 and R.sup.3 on the C 17 atom of the steroid skeleton of the compound of formula III;
• or
• (1) performing step d) first and then step c);
• cleaving protecting groups;
• optionally alkylating or acylating free hydroxy groups;
• optionally
• converting the 3-keto group with hydroxylaminohydrochloride into a 3-hydroxyimino grouping >N.about.OH, or
• the converting the 3-keto group into the dihydro compound;
• and
• optionally producing a pharmaceutically compatible addition salt thereof with an acid.