US 5,478,956 AGranted

8-En-19 11 .beta.-bridged steroids, their production and pharmaceutical preparations containing them

AssigneeSchering Corporation

InventorsEckhardt Ottow, Gunter Neef, Walter Elger, Martin Schneider, Karl Fritzemeier

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Abstract

8-En-19,11.beta.-bridged steroids of general formula I ##STR1## that have the 8,9-double bond as a new structural feature, and a process for their production are described. The substituents R.sup.1 R.sup.4 -Y, R.sup.4' -Y.sup.', X and Z have the meaning indicated in the description. The new compounds especially have at their disposal pronounced antigestagen effectivenss and are suitable for the production of pharmaceutical preparations.

Claims20

Dependent claims

A 8-en-19, 11.beta.-bridged steroid compound of formula I ##STR14## wherein R.sup.1 is methyl or ethyl;

X is an oxygen atom, a hydroxyimino group or two hydrogen atoms;
Z is a ring of formula ##STR15## wherein -------- is a single bond or a double bond;
W is --CH.sub.2 --, =CH--, --CH.sub.2 CH.sub.2 -- or =CHCH.sub.2 --;
R.sup.5 and R.sup.6 are, respectively,
--OR.sup.7 and --C.notident.C--U, --OR.sub.7 and ##STR16## ##STR17## and --OR.sup.7, ##STR18## and --CH.sub.3, ##STR19## and --H, --OR.sup.7 and --(CH.sub.2).sub.m --CH.sub.2 --R.sup.9, --OR.sup.7 and --CH.dbd.CH(CH.sub.2).sub.k --CH.sub.2 --R.sup.9 or --R.sup.10 and --(CH.sub.2).sub.k --C.notident.C--U, or
R.sup.5 and R.sup.6, together, are ##STR20## R.sup.7 is hydrogen, alkyl having 1-4 C atoms, or acyl having 1-4 C atoms;
U is hydrogen, alkyl having 1-4 C atoms, hydroxyalkyl having 1-4 C atoms, alkoxyalkyl having 1-4 C atoms in each alkyl portion, acyloxyalkyl having 1-4 C atoms in each of the alkyl and acyl portions, or a halogen atom;
R.sup.8 is hydrogen, hydroxy, alkyl having 1-4 C atoms, O-alkyl having 1-4 C atoms, or O-acyl having 1-4 C atoms;
R.sup.9 is hydrogen, hydroxy or cyano, O-alkyl having 1-4 C atoms, or O-acyl having 1-4 C atoms;
R.sup.10 is hydrogen, alkyl having 1-10 C atoms or acyl having 1-10 C atoms,
m is 0, 1, 2 or 3;
k is 0, 1 or 2;
R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyano, --OR.sup.11, --S(O).sub.k R.sup.11, --N(O).sub.n R.sup.11 R.sup.12, --O--SO.sub.2 --R.sup.13, --P(O) (OR.sup.14).sub.2, --SiR.sub.3.sup.14 or --SnR.sub.3.sup.14 ;
k is 0, 1 or 2;
n is 0 or 1;
R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl;
R.sup.12 is H, C.sub.1 -C.sub.8 -alkyl, cyano, C.sub.1 -C.sub.10 -acyl;
R.sup.13 is a perfluorinated C.sub.1 -C.sub.4 -alkyl radical;
R.sup.14 is C.sub.1 -C.sub.4 -alkyl;
or
R.sup.11 and R.sup.12 within a --N(O).sub.n R.sup.11 R.sup.12 group can also together, with the inclusion of N, form a 5 or 6 membered heterocyclic ring optionally containing another heteroatom selected from N, O and S;
Y and Y', being the same or different, are each a direct bond, a straight-chain or branched alkylene group having up to 20 carbon atoms, optionally containing double and/or triple bond(s) and optionally substituted by one or more oxo-, C.sub.1 -C.sub.10 -acyloxy-, --OR.sup.11, --S(O).sub.k R.sup.11 and/or --N(O).sub.n R.sup.11 R.sup.12 group(s), or an aryl radical selected from the group consisting of phenyl, 4-ethylphenyl, naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-vinylphenyl, 4-acetylphenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminopbenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, thiazolyl or imidazolyl;
R.sup.4 --Y and R.sup.4' --Y' can also together be an optionally substituted saturated, unsaturated or aromatic 5 or 6 membered ring with 0 to 2 oxygen atoms, sulfur atoms and/or NR.sup.11 -groups;
with the proviso that k and n are greater than 0, only when R.sup.11 is C.sub.1 -C.sub.8 -alkyl;
or
a pharmaceutically compatible addition salt thereof with an acid.

23 more elements

[Compounds]A compound according to claim [1]1, wherein said compound is:

17 .beta.-hydroxy-11.beta., 19-(4-methoxy-o-phenylene)-17.alpha.-(prop-1-inyl )-4,8-androstadien-3-one;
11.beta., 19-(4-ethylphenyl-o-phenylene)-17.beta.-hydroxy-17.alpha.-(prop-1-inyl )-4,8-androstadien-3-one;
11.beta., 19-[4-(4-cyanophenyl)-o-phenylene]-17.beta.-hydroxy-(prop-1-inyl)-4,8-andr ostadien-3-one
11.beta., 19-[4-(4-cyanophenyl)-o-phenylene]-17.beta.-(ethinyl)-17 .beta.-hydroxy-4,8-androstadien-3-one;
11.beta., 19-[4-(4 -cyanophenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1-iny l)-4,8-androstadien-3-one;
11.beta., 19-[4-(4-cyanophenyl)-o-phenylene]-17.beta.-hydroxy-17.beta.-( 3 -hydroxylprop-1(Z)-enyl)-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(prop-1-inyl) -11.beta., 19- [4- (5-pyrimidinyl)-o-phenylene]-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1-inyl) -11.beta., 19-[4-(3-pyridyl)-o-phenylene]-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1-inyl)-11.beta., 19-[4-(4-methoxyphenyl)-o-phenylene]-4,8-androstadien-3- one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1-inyl)-11.beta., 19-[4-(4-methylthiophenyl)-o-phenylene]-4,8-androstadien-3-one;
11.beta., 19-(4-acetyl-o-phenylene)-17.beta.- hydroxy-17.alpha.- (3-hydroxyprop-1-inyl)-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-[4-(3-pyridyl)-o-phenylene]-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-[4-( 4-methoxyphenyl)-o-phenylene]-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-[4(4-methylthiophenyl)-o-phenylene]-4,8-androstadien-3-one;
1.beta. . 19-(4-acetyl-o-phenylene)-17.beta.-hydroxy-17.alpha.-(3-hydroxypr op-1(Z)-enyl)-4,8-androstadien-3-one;
11.beta., 19-(4-acetyl-o-phenylene)-17.beta.-hydroxy-17.alpha.-(prop-1-inyl )-4,8-androstadien-3-one;
17.beta.-hydroxy-11.beta., 19 -[4-(4-methylthiophenyl)-o-phenylene]-17.alpha.-(prop-1-inyl)-4,8-androsta dien-3-one;
17.beta.-hydroxy-11.beta., 19- [4-(3-furanyl)-o-phenylene]-17.alpha.-(prop-1-inyl)-4,8-androstadien-3-one ;
17.beta.-hydroxy-17.alpha.- (prop-1-inyl)-11.beta., 19-[4-(3-pyridyl)-o-phenylene]-4,8-androstadien-3-one;
m);
3.17 (1H,
17.beta.-hydroxy-17.alpha.-methyl -11.beta., 19-[4-(4-cyanophenyl )-o-phenylene]-4,8-androstadien-3-one;
17.alpha.-cyanomethyl-17.beta.-hydroxy-11.alpha., 19-[4-(4-cyanophenyl)-o-phenylene]-4,8-androstadien-3-one;
17.alpha.-cyanomethyl-17.beta.-hydroxy-11.beta., 19-[4-(4-dimethylaminophenyl)-o-phenylene]-4,8-androstadien-3-one;
17.alpha.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-(4-vinylphenyl-o-phenylene)-4,8-androstadien-3-one;
17.beta.-hydroxy-11.beta., 19-(4-methylthiophenyl-o-phenylene)-(prop-1-inyl)-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-(4-methylsulfinylphenyl-o-phenylene)-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-(4-methylthio-o-phenylene)-4,8-androstadien-3-one;
17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1(Z)-enyl)-11.beta., 19-(4-methylsulfinyl-o-phenylene)-4,8-androstadien-3-one;
11.beta.19-(4-dimethylamino-o-phenylene)-17.beta.-hydroxy-17.alpha.-(3-hydr oxylprop-1(Z)-enyl)-4,8-androstadien-3-one;
11.beta., 19-[4-(4-dimethylaminophenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-h ydroxyprop-1(Z)-enyl)-4,8-androstadien-3-one;
11.beta., 19-[4-(3-furyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxylprop-1( Z)-enyl)-4,8-androstadien-3-one;
11.beta., 19-[4-(4-cyanophenyl)-o-phenylene]spiro[androsta-4,8-diene-17.alpha., 2' (5'H)-furan]-3-one;
11.beta., 19-[4-(4-cyanophenyl)-o-phenylene]-4', 5'-dihydrospiro[androsta-4,8-diene-17.beta., 2' (3'H )-furan]-3-one;
1.beta. . 19-[4-(4-acetylphenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.(3- hydroxylprop-1-inyl)-4,8-androstadien-3-one;
11.beta., 19-[4-(4-acetylphenyl)-o-phenylene]-17.beta.-hydroxy-17.alpha.-(3-hydroxyl prop-1(Z)-enyl)-4,8-androstadien-3-one;
11.beta., 19-[4-(4-acetylphenyl)-ophenylene]spiro [androsta-4,8-diene-17.beta., 2' (5' H)-furan]-3-one;
11.beta., 19- [4-(4-acetylphenyl)-o-phenylene]-4', 5'-dihydrospiro[androsta-4,8-diene-17.beta., 2' (3'H)-furan]-3-one;
11.beta., 19- [4-(4-methylthiophenyl)-ophenylene]spiro [androsta-4,8-diene-17.beta., 2' (5' H)-furan]-3-one;
11.beta., 19-[4-(4-methylthiophenyl)-o-phenylene]-4', 5'-dihydrospiro[androsta-4,8-diene-17.beta., 2' (3'H)-furan]-3-one;
11.beta., 19-(4-acetyl-o-phenylene)spiro [androsta-4,8-diene-17.beta., 2' (5'H)-furan]-3-one;
or 11.beta., 19-(4-acetyl-o-phenylene)-4', 5'-dihydrospiro [androsta-4,8-diene-17.beta., 2' (3'H)-furan]-3-one;

39 more elements

A compound of formula III ##STR21## wherein R.sup.4a and R.sup.4a, being the same or different, are each hydrogen, cyano, --OR.sup.11, --S(O).sub.k R.sup.11, --N(O).sub.n R.sup.11 R.sup.12, --O--SO.sub.2 --R.sup.13, --P(O)(OR.sup.14).sub.2 --SiR.sup.3.sup.14 or --SnR.sub.3.sup.14 ;

k is 0, 1 or 2;
n is 0 or 1;
R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl;
R.sup.12 is H, C.sub.1 -C.sub.8 -alkyl, cyano, C.sub.1 -C.sub.10 -acyl;
R.sup.13 is a perfluorinated C.sub.1 -C.sub.4 -alkyl radical;
R.sup.14 is C.sub.1 .ident.C.sub.4 -alkyl;
R.sup.11 and R.sup.12 within a --N(O).sub.n R.sup.11 R.sup.12 group can also together, with the inclusion of N, form a 5 or 6 membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S;
Y.sup.a and Y.sup.'a, being the same or different, are each a direct bond, a straight-chain or branched alkylene group having up to 20 carbon atoms, optionally containing double and/or triple bond(s) and optionally substituted by one or more oxo-, C.sub.1 -C.sub.10 -acyloxy-, --OR.sup.11, --S(O).sub.k R.sup.11 and/or --N(O).sub.n R.sup.11 R.sup.12 group(s), or an [optionally substituted carbocyclic or heterocyclic]aryl radical selected from the group consisting of phenyl, 4-ethylphenyl, naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-vinylphenyl, 4-acetylphenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, thiazolyl or imidazolyl;
with the proviso that k and n are greater than 0 only when R.sup.11 is C.sub.1 -C.sub.8 -alkyl;
and
optionally any hydroxy, mercapto, amino, oxo and/or terminal acetylene groups present can be in protected form, or
R.sup.4a -Y.sup.1 -- and R.sup.4'a -Y.sup.'a -- can each also be methoxy, hydroxy or perfluoroalkylsulfonate;
Q and S together are an oxygen atom or one of the substituent combinations listed in the description of R.sup.5 and R.sup.6 which will survive a subsequent dehydration reaction step undamaged or in which free hydroxy groups are protected.

10 more elements

Dependencies are inferred from the claim text.

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Abstract

A 8-en-19, 11.beta.-bridged steroid compound of formula I ##STR14## wherein R.sup.1 is methyl or ethyl;

X is an oxygen atom, a hydroxyimino group or two hydrogen atoms;
Z is a ring of formula ##STR15## wherein -------- is a single bond or a double bond;
W is --CH.sub.2 --, =CH--, --CH.sub.2 CH.sub.2 -- or =CHCH.sub.2 --;
R.sup.5 and R.sup.6 are, respectively,
--OR.sup.7 and --C.notident.C--U, --OR.sub.7 and ##STR16## ##STR17## and --OR.sup.7, ##STR18## and --CH.sub.3, ##STR19## and --H, --OR.sup.7 and --(CH.sub.2).sub.m --CH.sub.2 --R.sup.9, --OR.sup.7 and --CH.dbd.CH(CH.sub.2).sub.k --CH.sub.2 --R.sup.9 or --R.sup.10 and --(CH.sub.2).sub.k --C.notident.C--U, or
R.sup.5 and R.sup.6, together, are ##STR20## R.sup.7 is hydrogen, alkyl having 1-4 C atoms, or acyl having 1-4 C atoms;
U is hydrogen, alkyl having 1-4 C atoms, hydroxyalkyl having 1-4 C atoms, alkoxyalkyl having 1-4 C atoms in each alkyl portion, acyloxyalkyl having 1-4 C atoms in each of the alkyl and acyl portions, or a halogen atom;
R.sup.8 is hydrogen, hydroxy, alkyl having 1-4 C atoms, O-alkyl having 1-4 C atoms, or O-acyl having 1-4 C atoms;
R.sup.9 is hydrogen, hydroxy or cyano, O-alkyl having 1-4 C atoms, or O-acyl having 1-4 C atoms;
R.sup.10 is hydrogen, alkyl having 1-10 C atoms or acyl having 1-10 C atoms,
m is 0, 1, 2 or 3;
k is 0, 1 or 2;
R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyano, --OR.sup.11, --S(O).sub.k R.sup.11, --N(O).sub.n R.sup.11 R.sup.12, --O--SO.sub.2 --R.sup.13, --P(O) (OR.sup.14).sub.2, --SiR.sub.3.sup.14 or --SnR.sub.3.sup.14 ;
k is 0, 1 or 2;
n is 0 or 1;
R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl;
R.sup.12 is H, C.sub.1 -C.sub.8 -alkyl, cyano, C.sub.1 -C.sub.10 -acyl;
R.sup.13 is a perfluorinated C.sub.1 -C.sub.4 -alkyl radical;
R.sup.14 is C.sub.1 -C.sub.4 -alkyl;
or
R.sup.11 and R.sup.12 within a --N(O).sub.n R.sup.11 R.sup.12 group can also together, with the inclusion of N, form a 5 or 6 membered heterocyclic ring optionally containing another heteroatom selected from N, O and S;
Y and Y', being the same or different, are each a direct bond, a straight-chain or branched alkylene group having up to 20 carbon atoms, optionally containing double and/or triple bond(s) and optionally substituted by one or more oxo-, C.sub.1 -C.sub.10 -acyloxy-, --OR.sup.11, --S(O).sub.k R.sup.11 and/or --N(O).sub.n R.sup.11 R.sup.12 group(s), or an aryl radical selected from the group consisting of phenyl, 4-ethylphenyl, naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-vinylphenyl, 4-acetylphenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminopbenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, thiazolyl or imidazolyl;
R.sup.4 --Y and R.sup.4' --Y' can also together be an optionally substituted saturated, unsaturated or aromatic 5 or 6 membered ring with 0 to 2 oxygen atoms, sulfur atoms and/or NR.sup.11 -groups;
with the proviso that k and n are greater than 0, only when R.sup.11 is C.sub.1 -C.sub.8 -alkyl;
or
a pharmaceutically compatible addition salt thereof with an acid.

23 more elements