Claims
- 1. A 19, 11.beta.-bridged steroid of general formula I ##STR20## wherein R.sup.1 is a methyl or ethyl radical;
- R.sup.2 is hydrogen, chlorine or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, being the same or different, are each hydroge or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, together, can also be a second bond between carbon atoms 6 and 7;
- B and R.sup.2, together, can also be a methylene or ethylene group;
- Z is a substituted or unsubstituted, saturated or unsaturated, 5- or 6-member ring;
- V is an unsubstituted or substituted, carbocyclic or heterocyclic, aryl radical; ring A is ##STR21## wherein M and N, together, are a second bond, or M is hydrogen and N is hydroxy, in which case B, R.sup.2, G, R.sup.3, D and E are all each hydrogen.
- X is an oxygen atom, two hydrogen atoms or one hydroxyimino group (N.about.OH),
- R.sup.3 and D, being the same or different, are each hydrogen nitrile, or C.sub.1 -C.sub.4 -alkyl radical,
- R.sup.3 and D, together, can also be a methylene or ethylene group,
- E is hydrogen or C.sub.1 -C.sub.4 -alkyl radical,
- D and E, together, can also be a second bond between carbon atoms 1 and 2 or, together, can also be a methylene group;
- or Ring A is ##STR22## or Ring A is ##STR23## wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical; and pharmaceutically tolerated acid addition salts thereof.
- 2. A compound in accordance with claim 1, wherein R.sup.2, B and G are each a hydrogen atom.
- 3. A compound in accordance with claim 1, wherein B and G, together, are a second bond and R.sup.2 is a hydrogen atom.
- 4. A compound in accordance with claim 1, wherein V is a phenyl ring according to the formula ##STR24## wherein R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyanide, --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 --;
- R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical;
- R.sup.12 is R.sup.11, cyanide or C.sub.1 -C.sub.10 -acyl radical;
- R.sup.13 is perfluorated C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.14 is C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.11 and R.sup.12, in an --N(O).sub.n R.sup.11 R.sup.12 group, can also be, together with the inclusion of N, a 5- or 6-member heterocyclic ring, optionally containing another heteroatom selected from N, O or 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 or triple bond(s), and optionally substituted with 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 -- groups, or a substituted or unsubstituted aryl radical;
- R.sup.4 --Y and R.sup.4' --Y', together, can also be substituted or unsubstituted, saturated or unsaturated or aromatic, 5-or 6-member ring with 0 to 2 oxygen, sulfur atoms and/or --NR.sup.11 -- groups;
- k is 0, 1 or 2; and
- n is 0 or 1;
- with the proviso that k and n are greater than 0 only if R.sup.11 is a C.sub.1 -C.sub.8 -alkyl radical.
- 5. A compound in accordance with claim 4, wherein Y and Y' are each a direct bond and R.sup.4 and R.sup.4' are each a hydrogen atom.
- 6. A compound in accordance with claim 4, wherein Y and Y' are each a direct bond, R.sup.4 is a hydrogen atom, R.sup.4' is N(O).sub.n R.sup.11 R.sup.12, n is 0, and R.sup.11 and R.sup.12 are each C.sub.1 -C.sub.8 -alkyl.
- 7. A compound in accordance with claim 4, wherein Y and Y' are each a direct bond, R.sup.4 is a hydrogen atom, and R.sup.4' is a C.sub.1 -C.sub.8 alkoxy group.
- 8. A compound in accordance with claim 4, wherein Y is a direct bond, R.sup.4 and R.sup.4' are each a hydrogen atom, and Y' is a straight-chain or branched alkylene group having up to 20 carbon atoms, optionally containing double and/or triple bond(s), and which is substituted with an oxo- or OR.sup.11 -group, R.sup.11 being a hydrogen atom or a C.sub.1 -C.sub.8 -alkyl radical.
- 9. A compound in accordance with claim 4, wherein R.sup.4 --Y and R.sup.4' --Y together are a saturated, unsaturated or aromatic 5- or 6-member ring with 0 to 2 oxygen, sulfur atoms and/or --NR.sup.11 -groups with R.sup.11 being a hydrogen atom or a C.sub.1 -C.sub.8 -alkyl radical.
- 10. A compound in accordance with claim 4, wherein
- Y'--R.sup.4' is a hydrogen atom, and
- Y--R.sup.4 is ethyl, vinyl, isopropyl, isopropenyl, prop-1(Z)-enyl, prop-1(E)-enyl, prop-2-enyl, ethinyl, propinyl, prop-2-inyl, methoxy, thiomethyl, thioethyl, 1-hydroxyethyl, diethoxyphosphoryl, trifluoromethyl sulfonate, or a substituted or unsubstituted, carbocyclic or heterocyclic aryl radical.
- 11. A compound in accordance with claim 10, wherein Y--R.sup.4 is phenyl, naphthyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-tolyl, 3-tolyl, 4-tolyl, 2-dimethylamino, 3-dimethylamino, 4-dimethylamino, furyl-2, furyl-3, thienyl-2, thienyl-3, pyridyl-2, pyridyl-3, pyridyl-4, thiazolyl, or imidazolyl.
- 12. A compound in accordance with claim 4, wherein V is furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, oxazolyl, pyridazinyl, or pyrazinyl.
- 13. A compound in accordance with claim 1, wherein V is a 5- or 6-member heteroaromatic ring with 1 to 2N, O or S atoms of the formula ##STR25## wherein R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyanide, --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 --;
- R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical;
- R.sup.12 is R.sup.11, cyanide or C.sub.1 -C.sub.10 -acyl radical;
- R.sup.13 is perfluorated C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.14 is C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.11 and R.sup.12, in an --N(O).sub.n R.sup.11 R.sup.12 group, can also be, together with the inclusion of N, a 5- or 6-member heterocyclic ring, optionally containing another heteroatom selected from N, O or 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 or triple bond(s), and optionally substituted with 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 -- groups, or a substituted or unsubstituted aryl radical;
- R.sup.4 --Y and R.sup.4' --Y', together, can also be substituted or unsubstituted, saturated or unsaturated or aromatic, 5-or 6-member ring with 0 to 2 oxygen, sulfur atoms and/or --NR.sup.11 -- groups;
- k is 0, 1 or 2; and
- n is 0 or 1;
- with the proviso that k and n are greater than 0 only if R.sup.11 is a C.sub.1 -C.sub.8 -alkyl radical.
- 14. A compound in accordance with claim 1, wherein Z is a ring according to the formula ##STR26## 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 --; and
- R.sup.5 and R.sup.6 are, respectively, --OR.sup.7 and --C.tbd.C--U, ##STR27## wherein R.sup.7 is hydrogen or C.sub.1 -C.sub.4 -acyl radical,
- U is hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -hydroxyalkyl, C.sub.1 -C.sub.4 -alkoxyalkyl, C.sub.1 -C.sub.4 -aclyoxyalkyl, or halogen,
- R.sup.8 is hydrogen, hydroxy, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -O-alkyl, or C.sub.1 -C.sub.4 -O-acyl,
- R.sup.9 is hydrogen, hydroxy, cyanide, a C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -O-acyl,
- R.sup.10 is hydrogen, C.sub.1 -C.sub.10 -alkyl, or C.sub.1 -C.sub.10 -acyl,
- m is 0, 1, 2 or 3, and
- k is 0, 1 or 2.
- 15. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.
- 16. A 19, 11.beta.-bridged steroid of general formula I ##STR28## wherein R.sup.1 is a methyl or ethyl radical;
- R.sup.2 is hydrogen, chlorine or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, being the same or different, are each hydrogen or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, together, can also be a second bond between carbon atoms 6 and 7;
- B and R.sup.2, together, can also be a methylene or ethylene group;
- Z is a ring according to the formula ##STR29## 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 --; and
- R.sup.5 and R.sup.6 are, respectively, --OR.sup.7 and --C.tbd.C--U, ##STR30## --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.sup.10 and --H, or --OR.sup.10 and --(CH.sub.2).sub.k --C.tbd.C--U, or R.sup.5 and R.sup.6 together are ##STR31## R.sup.7 is hydrogen or C.sub.1 -C.sub.4 -acyl radical, U is hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -hydroxyalkyl, C.sub.1 -C.sub.4 -alkoxyalkyl, C.sub.1 -C.sub.4 -aclyoxyalkyl, or halogen,
- R.sup.8 is hydrogen, hydroxy, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -O-alkyl, or C.sub.1 -C.sub.4 -O-acyl,
- R.sup.9 is hydrogen, hydroxy, cyanide, a C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -O-acyl,
- R.sup.10 is hydrogen, C.sub.1 -C.sub.10 -alkyl, or C.sub.1 -C.sub.10 -acyl,
- m is 0, 1, 2 or 3, and
- k is 0, 1 or 2;
- V is a 5- or 6-member heteroaromatic ring with 1 to 2N, O or S atoms of the formula ##STR32## or V is a phenyl ring according to the formula ##STR33## wherein R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyanide, --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.14.sub.3 -- or SnR.sup.14.sub.3 --;
- R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical;
- R.sup.12 is R.sup.11, cyanide or C.sub.1 -C.sub.10 -acyl radical;
- R.sup.13 is perfluorated C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.14 is C.sub.1 -C.sub.4 -alkyl radical;
- R.sup.11 and R.sup.12, in an --N(O).sub.n R.sup.11 R.sup.12 group, can also be, together with the inclusion of N, a 5- or 6-member heterocyclic ring, optionally containing another heteroatom selected from N, O or 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 or triple bond(s), and optionally substituted with 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 groups, or a substituted or unsubstituted aryl radical;
- R.sup.4-Y and R.sup.4'-Y', together, can be substituted or unsubstituted, saturated or unsaturated or aromatic, 5- or 6-member ring with 0 to 2 oxygen sulfur atoms and/or --NR.sup.11 -- groups;
- k is 0, 1 or 2; and
- n is 0 or 1;
- with the proviso that for group V, k and n are greater than 0 only if R.sup.11 is a C.sub.1 -C.sub.8 -alkyl radical;
- ring A is ##STR34## wherein M and N, together, are a second bond, or M is hydrogen and N is hydroxy, in which case B, R.sup.2, G, R.sup.3, D and E are all each hydrogen,
- X is an oxygen atom, two hydrogen atoms or one hydroxyimino group (N--OH),
- R.sup.3 and D, being the same or different, are each hydrogen nitrile, or C.sub.1 -C.sub.4 -alkyl radical,
- R.sup.3 and D, together, can also be a methylene or ethylene group,
- E is hydrogen or C.sub.1 -C.sub.4 -alkyl radical,
- D and E, together, can also be a second bond between carbon atoms 1 and 2 or, together, can also be a methylene group;
- or Ring A is ##STR35## or Ring A is ##STR36## wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical; and pharmaceutically tolerated acid additions salts thereof.
- 17. A 19, 11.beta.-bridged steroid of general formula I ##STR37## wherein R.sup.1 is a methyl or ethyl radical;
- R.sup.2 is hydrogen, chlorine or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, being the same or different, are each hydrogen or C.sub.1 -C.sub.4 -alkyl radical;
- B and G, together, can also be a second bond between carbon atoms 6 and 7;
- B and R.sup.2, together, can also be a methylene or ethylene group;
- Z is a ring according to the formula ##STR38## 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 --; and
- R.sup.5 and R.sup.6 are, respectively, --OR.sup.7 and --C.tbd.C--U, ##STR39## --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.sup.10 and --H, or --OR.sup.10 and --(CH.sub.2).sub.k --C.tbd.C--U, or R.sup.5 and R.sup.6 together are ##STR40## wherein R.sup.7 is hydrogen or C.sub.1 -C.sub.4 -acyl radical,
- U is hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -hydroxyalkyl, C.sub.1 -C.sub.4 -alkoxyalkyl, C.sub.1 -C.sub.4 -acyloxyalkyl, or halogen,
- R.sup.8 is hydrogen, hydroxy, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -O-alkyl, or C.sub.1 -C.sub.4 -O-acyl,
- R.sup.9 is hydrogen, hydroxy, cyanide, a C.sub.1 -C.sub.4 -alkyl, or C.sub.1 -C.sub.4 -O-acyl
- R.sup.10 is hydrogen, C.sub.1 -C.sub.10 -alkyl, or C.sub.1 -C.sub.10 -acyl,
- m is 0, 1, 2 or 3, and
- k is 0, 1 or 2;
- V is a phenyl ring according to the formula ##STR41## wherein R.sup.4 and R.sup.4', being the same or different, are each hydrogen, cyanide, --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.14.sub.3 -- or SnR.sup.14.sub.3 --,
- R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical,
- R.sup.12 is R.sup.11, cyanide or C.sub.1 -C.sub.10 -acyl radical,
- R.sup.13 is perfluorated C.sub.1 -C.sub.4 -alkyl radical,
- R.sup.14 is C.sub.1 -C.sub.4 -alkyl radical,
- R.sup.11 and R.sup.12, in an --N(O).sub.n R.sup.11 R.sup.12 group, can also be, together with the inclusion of N, a 5- or 6-member heterocyclic ring, optionally containing another heteroatom selected from N, O or 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 or triple bond(s), and optionally substituted with 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 groups, or a substituted or unsubstituted aryl radical,
- R.sup.4-Y and R.sup.4'-Y', together, can also be substituted or unsubstituted, saturated or unsaturated or aromatic, 5- or 6-member ring with 0 to 2 oxygen, sulfur atoms and/or --NR.sup.11 -- groups,
- k is 0, 1 or 2, and
- n is 0 or 1, with the proviso that for group V, k and n are greater than 0 only if R.sup.11 is a C.sub.1 -C.sub.8 -alkyl radical;
- ring A is ##STR42## wherein M and N, together, are a second bond, or M is hydrogen and N is hydroxy, in which case B, R.sup.2, G, R.sup.3, D and E are all each hydrogen,
- X is an oxygen atom, two hydrogen atoms or one hydroxyimino group (N--OH),
- R.sup.3 and D, being the same or different, are each hydrogen nitrile, or C.sub.1 -C.sub.4 -alkyl radical,
- R.sup.3 and D, together, can also be a methylene or ethylene group,
- E is hydrogen or C.sub.1 -C.sub.4 -alkyl radical,
- D and E, together, can also be a second bond between carbon atoms 1 or 2 or, together, can also be a methylene group;
- or Ring A is ##STR43## or Ring A is ##STR44## wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.8 -alkyl radical; and pharmaceutically tolerated acid addition salts thereof.
- 18. A compound according to claim 17, wherein M and N together are a double bond.
- 19. A compound according to claim 17, wherein X is an oxygen atom.
- 20. A compound according to claim 17, wherein X is N.about.OH.
- 21. A compound according to claim 17, wherein D and E together are a double bond.
- 22. A compound according to claim 17, wherein B and G together are a double bond.
- 23. A compound according to claim 17, wherein R.sup.2 is chlorine.
- 24. A compound according to claim 17, wherein G is methyl.
- 25. A compound according to claim 17, wherein B and R.sup.2 together are methylene.
- 26. A compound according to claim 17, wherein X is two hydrogen atoms.
- 27. A compound according to claim 17, wherein M and N together are a double bond and X is an oxygen atom.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 3708942 |
Mar 1987 |
DEX |
|
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of U.S. Ser. No. 07/415,359, filed on Sept. 18, 1989, now abandoned, based on International Application No. PCT/DE88/00150, filed 11 Mar. 1988.
The invention relates to the subject matter designated in the patent claims, i.e., new 19,11.beta.-bridged steroids, methods for the manufacture of these compounds, pharmaceutical preparations containing these compounds, their use in the manufacture of pharmaceuticals as well as the new intermediate products required for this purpose.
The 19,11.beta.-bridged steroids in accordance with the invention are described by general formula I ##STR4## where R.sup.1 stands for a methyl or ethyl radical,
Aryl radical V can be substituted and unsubstituted carbocyclic or heterocyclic radicals like, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl. The invention relates in particular to compounds of general formula I, in which V implies the radical of a phenyl ring of general formula ##STR7## where R.sup.4 and R.sup.4', which are the same or different, mean respectively a hydrogen atom, a cyanide radical, an --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 -- group with k in the meaning of number 0, 1 or 2, n in the meaning of number 0 or 1,
Y and Y', which are the same or different, mean respectively a direct bond, a straight-chain or branched alkylene group, possibly containing double or triple bond(s), with as many as 20 carbon atoms, which, as the case may be, is substituted with one or more oxo-, C--, --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 possibly a substituted aryl radical, or R.sup.4 --Y and R.sup.4' --Y' together mean the radical of a possibly substituted, saturated, unsaturated or aromatic 5- or 6-member ring with 0 to 2 oxygen, sulfur atoms and/or NR.sup.11 groups, provided that k and n are greater than 0 only if R.sup.11 imply a C.sub.1 -C.sub.8 -alkyl radical.
If Y--R.sup.4 .dbd.H and Y' is the ethylene group replaced with an oxo group in position 1 and R.sup.4' .dbd.H, then Y'--R.sup.4' is the acetyl group that plays a preferential role within the scope of the invention.
In the substitution of the phenyl ring preference is given to monosubstitution in position 3, 4 or 5 and to disubstitution in position 4 and 5 or 3 and 4, with the formation of a second ring condensed on, e.g. a cyclohexene, pyrrole, furyl, pyrroline, 1,3-dioxacylopentene, pyrazoline, didehydromorpholine, didehydropiperidine, didehydropiperazine, dehydropyrane, pyrimidine, pyridine, pyrazine, 1,4-dioxacyclohexane ring. The alkyl radicals standing for R.sup.1, R.sup.11, and respectively R.sup.2, R.sup.3, B, G and D, are to carry 1 or 2 carbon atoms in the case of R.sup.1, 1 to 8 in the case of R.sup.11 and otherwise 1 to 4, the methyl, ethyl, propyl, isopropyl, butyl respectively methyl, ethyl, propyl groups being preferred. If R.sup.12 implies an acyl radical, the formyl, acetyl, propionyl, butyryl and benzoyl group is preferred. R.sup.11 and R.sup.12 also imply together, with the inclusion of the nitrogen atom, a heterocyclic five- or six-member ring that can contain an O or S atom in addition to the N and C atoms; examples being the pyrrole, pyrrolidine, piperidine, piperazine, morpholine, oxa and thiazolidine as well as the thiadiazolidine rings.
Moreover, the invention also relates in particular to compounds of general formula I, in which Z implies the radical of a ring of the formula ##STR8## where R.sup.1 has the meaning stated in claim 1, the broken line originating at W means the possible presence of a double bond,
The alkyl, alkoxy and acyloxy groups contained in R.sup.5 and R.sup.6, respectively R.sup.7, R.sup.8, R.sup.9, R.sup.10 and U can contain 1 to 4 carbon atoms, with the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, formyl, acetyl, propionyl and isopropionyl groups being preferred.
Of the alkenyl radicals in R.sup.6 the propenyl and butenyl group, which can be present in the E or Z configuration, are preferred, i.e. if R.sup.6 implies --CH.dbd.CH--(CH.sub.2).sub.k --CH.sub.2 --R.sup.9, k should preferably mean 0 or 1.
The new compounds of general formula I are manufactured in accordance with the invention by the method wherein the compounds of formula II ##STR10## where R.sup.1 means a methyl or ethyl radical,
To manufacture the intermediate products of general formula II ##STR12## where R.sup.1 means a methyl or ethyl radical,
The new compounds of general formula II are cyclized after protection of the functional groups possibly present in V'. The protective hydroxy, mercapto and keto groups subsumed by V' and K are groups that are easy to split off in an acid medium, examples being the methoxymethyl, ethoxymethyl, tetrahydropyranyl, ethylenedioxyketal, ethylenedithioketal or 2,2-dimethyltrimethylenedioxyketal group.
Protective groups for amino and terminal acetylene groups (e.g., the trimethylsilyl and tert.-butyldimethylsilyl group) are likewise familiar to the expert and are also separated by methods described in the literature after the desired sequence of reactions [Synthesis 1980, 627, J. Org. Chem. 46 (1986) 2280].
Conversion of the compounds in accordance with II into the new 19,11.beta.-bridged steroids of general formula IVa ##STR15## which are likewise the subject matter of the invention and where R.sup.1, K and l have the aforementioned meaning and V" the same meaning as V, but any hydroxy, mercapto, amino, oxo and/or terminal acetylene groups present in V are protected, is achieved, in the event that the .alpha.-halogen substituent in V' is a bromine or iodine atom, by methods known per se (Tetrahedron Letters 1982, 2575; 1985, 6001; 1986, 2833; J. Am. Chem. Soc. 1982, 104, 2321; Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press, 1986) by reductive radical cyclization.
A corresponding method for fluorine and chlorine-substituted aromatic compounds has been unknown hitherto. It was now discovered that this cyclization is surprisingly successful, with a good yield, when the educt is treated with an electropositive metal, e.g. sodium, potassium, lithium or calcium, in liquid ammonia, mixed with one or more suitable organic solvent(s), e.g., diethyl ether, dimethoxyethane (DME), dioxane, or tetrahydrofurane at temperatures between -100.degree. and -30.degree. C., preferably -78.degree. to -60.degree. C. That this cyclization is also feasible with the fluoride ion as the leaving group must be viewed as especially surprising.
This new method is also to be applied in the case of bromine and iodine-replaced aromatic compounds.
The cyclization products yielded thereby are converted into the final products of general formula I, which are desired in the end, by analogous methods described in the literature (e.g., J. Fried, J. A. 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. 1-12), in as much as one either first
In the course of these reactions it might become necessary to introduce intermediately protective groups into intermediate products once again, e.g., for functional groups contained in Z, with subsequent functionalization of rings A and B, or for the 3-keto group with subsequent construction of ring D.
The oxidation of the 17.beta.-hydroxy group, which is required for the manufacture of nearly every final product, is effected in the way known per se, e.g., by Oppenauer oxidation or chromic acid reagents (Jones' reagent or chromic acid pyridine).
The 3-keto function is released at the same time as the water is split off and the 4(5) double bond created by treatment with acid or an acid ion exchanger. The acid treatment is carried out in the way known per se by dissolving the corresponding 5.alpha.-hydroxy-3-ketal in a solvent miscible with water, such as aqueous methanol, ethanol or acetone, and subjecting the solution to catalytic quantities of mineral or sulfonic acid like hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid or p-toluene sulfonic acid, or an organic acid like acetic acid, until any protective groups have been removed and any water has been split off. The conversion, which takes place at temperatures from 0.degree. to 100.degree. C., can also be done with an acid ion exchanger. The course of the conversion can be followed by analytical methods, e.g., by thin-layer chromatography of specimens.
In general, the protective groups are removed and water split off in a one-step reaction by letting the corresponding 5.alpha.-hydroxy-3-ketal and, respectively, 5-en-ketal react in a strongly acid medium for a certain period of time, as described in example 1c). But it is just as possible, in accordance with the invention, to remove the protective groups and split off the water in two separate reaction steps by first obtaining and, as the case may be, isolating the corresponding 5.alpha.-hydroxy-3-keto compound by first treating the corresponding 5.alpha.-hydroxy-3-ketal for a short while in a moderately acid medium. The 5.alpha.-hydroxy-3-keto compound is then converted into the 3-keto-4-en compound by further reaction with acid, the water being split off.
A very special advantage of this invention is to be seen in the great bandwidth of substituents that can be introduced in the carbocyclic or heterocyclic aryl radical V (M. Pereyre, J.-P. Quintard, A. Rahm, Tin in Organic Synthesis; Butterworths, 1987). For one, the substituents R.sup.4 --Y and, respectively, R.sup.4' --Y' present in the later final product can be directly introduced by coupling an arylmethyl halogenide of general formula V, V'CH.sub.2 Hal, which arylmethyl halogenide is correspondingly substituted in the aryl radical, by Grignard's reaction with a suitable 5.alpha.,10.alpha.-epoxide of general formula III and processing the intermediate product of general formula II in the way already described.
The number of compounds substituted in V that can be manufactured in this way is relatively limited, since not all the substituents desired in the final product do withstand unharmed the conditions for Grignard's reaction, which has to take place at V'CH.sub.2 Hal prior to coupling with the respective 5.alpha.,10.alpha.-epoxide III, and, in particular, the reductive conditions during cyclization of intermediate product II into a 19,11.beta.-bridged steroid of general formula IV.
In another practical embodiment of the method in accordance with the invention, however, it is possible to vary the substituent(s) in aryl radical V throughout a wide range by only introducing the substituent(s) after cyclization, namely before, simultaneously with or only after completion of the structure of rings A, B, and D. For this purpose at least one of the protected hydroxy groups present in radical V" respectively V is liberated from its protective group and the corresponding perfluoroalkylsulfonate compound produced from the free OH-compound by conversion with perfluoroalkylsulfonic acid anhydride (alkyl.dbd.C.sub.1 -C.sub.4) by methods known per se [P. J. Stang, M. Hanack and L. R. Subramanian, Synthesis 85 (1982)].
In this connection is necessary to proceed either in such a way that in a reaction catalyzed by transition metals (preferably Pd.degree.) the perfluoro transition group is displaced by the desired substituent or its preceding stage, the substitution to take place, essentially, almost simultaneously (J. E. McMurry and S. Mohanraj, Tetrahedron Letters, 24, No. 27, p. 2723-2726, 1983; X. Lu and J. Zhu, Communications, p. 726-727, 1987; Q.-Y. Chen and Z.-Q. Yang, Tetrahedron Letters 27, No. 10, p. 1171-1174, 1986; S. Cacchi, P. G. Ciattini, E. Morera and G. Ortar, Tetrahedron Letters, 27, No. 33, p. 3931-3934, 1986; A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc. 1987, 109, p. 5478-5486), or a corresponding tri-organylstannyl compound, preferably tri-n-alkylstannyl compound, is produced intermediately from the perfluoroalkylsulfonate compound by catalysis with transition metals [J. K. Stille, Angew. Chem. 98 (1986), p. 504-519]. In a single-pot reaction with a halogen-substituted, preferably bromine- or iodine-substituted carbocyclic or heterocyclic aromatic compound [Y. Yamamoto, Y. Azuma, H. Mitoh, Communications, p. 564-565, 1986; T. J. Bailey, Tetrahedron Letters, 27, No. 37, p. 4407-4410), 1986], which can, as the case may be, also carry further substituents, this is converted into a 19,11.beta.-bridged steroid; aryl radical V and, respectively, V" therein contains the desired substituent or a predecessor.
The intermediately occurring tri-n-alkylstannyl compounds can also be isolated as a substance, as is substitutionally demonstrated by example 39a).alpha.) in the case of the 11.beta.,19-(4-tri-n-butylstannyl-O-phenylene)-3,3-(2.2-dimethyltrimethylenedioxy)-androstan-5.alpha.,17.beta.-diol.
1,2 and/or 6,7 double bonds are introduced in addition to the 3,4 double bond by familiar methods, e.g., with dehydrating agents like selenium dioxide, chloranil, thalliumtriacetate or dichlorodicyanobenzoquinone (DDQ), and, respectively, by allyl or dienol ether bromination and subsequent separation of the hydrogen bromide [J. Fried, J. A. Edwards, Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company, 1972, p. 265-374), 1; Tetrahedron 42, (1986) 2971].
The allyl bromination is done, for example, with N-bromosuccinimide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin or dibromotetrachlorethane in the presence of a radical former like dibenzoylperoxide in a solvent. Possible solvents are aprotic solvents like dioxane and chlorated hydrocarbons, e.g., carbon tetrachloride, chloroform or tetrachloroethylene. Conversion takes place between 0.degree. C. and the boiling temperature of the solution. The dienol ether bromination is effected, for example, analogous to the specification in Steroids I, 233.
The hydrogen bromide is split off, and the .DELTA..sup.6 double bond established, by heating the 6-bromine compound with alkaline agents, preferably with lithium bromide and lithium carbonate or with lithium bromide and calcium carbonate in an aprotic solvent like dimethylformamide at temperatures between 50.degree. and 120.degree. C. Another possibility of splitting off the HBr is to heat the 6-bromine compound in collidine or lutidine.
Proceeding from a staturated ring A it is possible to introduce double bonds in the 1,2 and 4,5 positions at the same time, e.g., by brominating to form 2,4-dibromo-3-ketone and dehydrobromination of the dibromide with, for example, lithium or calcium carbonate and lithium bromide in dimethylformamide.
The 6-methylene group can be introduced for example, by proceeding from a 3-amino-3(4),5(6)-diene derivative through conversion with formalin in an alcoholic solution (Helv. Chim. Acta. 56 (1973) 2396) into a 6.alpha.-hydroxymethyl group and subsequent acid separation of the water, e.g., with hydrochloric acid in dioxane/water, or by proceeding from a 3-alkoxy-3(4),5(6)-diene derivative, analogous to the method described in U.S. Pat. No. 4,544,555 or directly by proceeding from a 3-oxo-4(5)-ene derivative analogous to the specification in Synthesis (1982) 34.
The 6-methylene compound is methylenated with dimethylsulfoxoniummethylide to form the 6,6-ethylene compound. To do so, the 6-methylene steroid is added to a suspension of trimethylsulfoxoniumiodide with sodium hydride in mineral oil and dimethylsulfoxide or to a solution of trimethylsulfoxoniumiodide and sodium hydroxide in dimethylsulfoxide. The reaction is completed after 15 to 60 minutes at 20.degree. to 40.degree. C. (J. Am. Chem. Soc. 84 (1962) 866; European patent application 0150157).
A 2-methylene group is introduced analogous to the method of A. J. Manson and D. Wood [J. Org. Chem. 32 (1967) 3434] or the methods cited there.
The 2-methylene compound is methylenated to form the 2,2-ethylene compound analogous to the methylenation of the 6-methylene compound [cf. also Chem. Ber. 98 (1965) 1470].
Monoalkylated and, respectively, dialkylated compounds in position 2 can, for example, be obtained analogous to the method of L. Nedelec, Tetrahedron 30 (1974) 3263.
Alkylated compounds in position 1 and, respectively, position 7 are obtained by 1,4 and, respectively, 1,6 addition to the corresponding enones by familiar methods [J. Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company, 1972, pp 75 to 82, 2; and J. Am. Chem. Soc. 99 (1977) 1673].
Alkylated compounds in position 6 can, for example, be obtained by opening the corresponding 5.alpha.,6.alpha.-epoxides and subsequent reactions (J. Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company, 1972, pp 82 to 86, 2).
1.alpha.,2.alpha.-, 6.alpha.,7.alpha.-, 6.beta.,7.beta.-methylene compounds or a combination of the 1.alpha.,2.alpha.-methylene structural element with the two 6,7-methylene structural elements can be obtained by the addition of diazomethane or dimethylsulfoxoniummethylide to the corresponding enones by the Simmons-Smith reaction (J. Fried, J. A. Edwards: Reactions in Steroid Chemistry, Van Nostrand Reinhold Company, 1972, pp 100-126; Rev. Soc. Quim. Mex. (1969) 171A; Chem. Ber. 101 (1986) 935; Chem. Ber. 99 (1966) 1118; Zeitschr. f. Naturf. 19b (1964) 944) of the corresponding allyl alcohols.
The isoxazole ring annellated to positions 2 and 3 is produced by synthesis of the 2-hydroxymethylene compounds [Steroids 6 (1962) 178; J. Amer. Chem. Soc. 83 (1961) 1478] and their conversion with hydroxylamine [J. Med. Chem. 6 (1963) 1].
[2,3-d]isoxazoles are also good starting materials for the synthesis of 2-cyano-steroids [J. Med. Chem. 6 (1963) 1].
The pyrazole ring annellated to positions 2 and 3 is produced by conversion of 2-hydroxymethylene-3-oxo educts with R.sup.11 -substituted hydrazine (U.S. Pat. No. 3,704,295).
The chlorine and, respectively, the methyl substituents are introduced into C-6 of the steroid structure by, for example, the methods indicated in German patent specification 1,158,966 and, respectively, U.S. Pat. Nos. 4,544,555 and 4,196,203 via the corresponding 6,7-epoxides and, respectively, 6-methylene derivatives as well as by oxidation of the 6-chloro-3,5-dienol ether with dichlorodicyanobenzoquinone (DDQ) in acid conditions [Belgian patent 621,197 (1962)].
The 3-oxo group can be removed to form a final product of general formula I, with X in the meaning of two hydrogen atoms, e.g., by thioketalization and subsequent reductive separation in accordance with the specification set out in DOS 2805490.
Educts with a D-homo steroid structure can also be obtained, for example, by Tiffeneau's rearrangement analogous to the specification published in Australian J. Chem 8 (1955), 519, and in "Organic Reactions in Steroid Chemistry" Vol. 2, 388. The requisite 17.alpha.-aminomethyl-17.beta.-hydroxy compounds are, for example, rendered accessible by opening the 17,20-spiroepoxides with ammonia or also by lithium-aluminum reduction of acetylated 17.beta.-hydroxy-17.alpha.-cyano compounds. The spiroepoxides are rendered accessible by converting the corresponding 17-ketones with dimethylsulfoniummethylide in dimethylformamide [Journal f. prakt. Chemie 314 (1972), 667-668]. The acetylated cyanohydrins are rendered accessible by adding hydrocyanic acid to the corresponding 17-ketones and subsequent acetylation in accordance with known specifications (e.g., Australian J. Chem. 8 (1955), 519).
Educts with an unsaturated D ring are, for example, accessible by modified Saegusa oxidation (Tetrahedron 42 (1986) 2971) of the corresponding enol compounds of the 17-ketone. For example, the trimethylsilylenol ether can be obtained by converting the 17-ketone into the corresponding enolate with lithiumdiisopropylamide in tetrahydrofuran and recovery with trimethylchlorosilane (Synthesis 1983, 1).
The substituents R.sup.5 and R.sup.6 are introduced by the customary methods used to build up the C-17 side chain by nucleophile addition to the 17-ketone--obtained, for example, by Oppenauer's oxidation of the C-17-hydroxy group--and subsequent reactions ("Terpenoids and Steroids", Specialist Periodical Report, The Chemical Society, London, Vol. 1-12).
The substituent --C.tbd.C--U, with U in the aforementioned meaning, is introduced as R.sup.6 with the help of a compound of general formula MC.tbd.C--U', in which U' is the radical U protected by, for example, trimethylsilyl or tert.-butyldimethylsilyl, or if U is an alkyl group with 1-4 C atoms, U' itself is the radical U.
The organometallic compound can also be formed in situ and made to react with the 17-ketone. Thus, for example, the 17-ketone can be allowed to react in a suitable solvent with acetylene and an alkali metal, in particular potassium, sodium or lithium, in the presence of an alcohol or in the presence of ammonia. The alkali metal can also be allowed to react in the form of, for example, methyl- or butyllithium. Suitable solvents are, in particular, dialkyl ether, tetrahydrofuran, dioxane, benzene and toluene.
The 3-hydroxy-propine, -propene and, respectively, -propane can be introduced into position 17 by converting the 17-ketone with the dianion of the propargyl alcohol (3-hydroxypropine), e.g., with the dipotassium salt of the propargyl alcohol generated in situ, to form the 17.alpha.-(3-hydroxyprop-1-inyl)-17.beta.-hydroxy derivative or with metallized derivatives of the 3-hydroxypropine, e.g. with 1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1-in-1-ide, to form the 17-[3-(tetrahydropyran-2'-yloxy)-prop-1-inyl]-17.beta.-hydroxy derivative, which can subsequently be hydrated to form the 17-(3-hydroxypropyl- and, respectively, hydroxy-propenyl)-17.beta.-hydroxy compounds. This is effected, for example, by hydration at room temperature and normal pressure in solvents like methanol, ethanol, propanol, tetrahydrofuran (THF) or acetic ether with the addition of precious-metal catalysts like platinum or palladium.
Homologous hydroxyalkine, hydroxyalkene and hydroyalkane groups are introduced in a similar way with homologues of the propargyl alcohol.
The compound with the Z-configured double bond in the hydroxypropenyl group is obtained by hydration of the acetylenic triple bond with a disactivated precious-metal catalyst (J. Fried, J. A. Edwards: Organic Reactions in Steroid Chemistry, Van Nostrand Reinhold Company, 1972, p. 134; and H. O. House: Modern Synthetic Reactions, 1972, p. 19). Possible disactivated precious-metal catalysts are, for example, 10% palladium on barium sulfate in the presence of an amine or 5% palladium on calcium carbonate with the addition of lead (II) acetate. Hydration is discontinued after one equivalent of hydrogen has been taken up.
The compound with the E-configured double bond in the hydroxypropenyl group is obtained by reduction of the acetylenic triple bond in a manner known per se. A large number of methods for the conversion of alkines into trans-olefines are described in the literature, e.g. reduction with sodium in liquid ammonia (J. Am. Chem. Soc. 63 (1941) 216), with sodium amide in liquid ammonia (J. Chem. Soc. 1955, 3558), with lithium in low-molecular amines (J. Am. Chem. Soc. 77 (1955) 3378), with boranes (J. Am. Chem. Soc. 93 (1971) 3395 and 94 (1972) 6560), with diisobutyl aluminum hydride and methyl-lithium (J. Am. Chem. Soc. 89 (1967) 5085) and, in particular, with lithium aluminum hydride/alcoholate (J. Am. Chem. Soc. 89 (1967) 4245). Another possibility is reduction of the triple bond with chromium (II) sulfate in the presence of water or dimethylformamide in a slightly acid medium (J. Am. Chem. Soc. 86 (1964) 4358) as well as, in general, reduction by reaction with transition-metal compounds with a change of the oxidation stage.
The hydroxyalkenes can also be introduced directly by addition of a corresponding metallized hydroxyalkenyl compound, e.g., 1-lithium-3-(tetrahydropyran-2'-yloxy)-prop-1(E)-ene (J. Org. Chem. 40, 2265) or 1-lithium-3-tetrahydropyran-2'-yloxy)-prop-1(Z)-ene. (Synthesis 1981, 999). Homologues can likewise be introduced in this manner.
The introduction of 3-hydroxypropane in position 17 can likewise be effected by converting the 17-ketone with metallized derivatives of 3-halogen-propanols--the hydroxy group being present in the metallization stage in the form of an alcoholate (Tetrahedron Letters 1978, 3013) or in the form of a protected function (J. Org. Chem. 37, 1947)--to form the 17-(3-hydroxypropyl)-17.beta.-hydroxy compound respectively the compound protected at the terminal hydroxy group. Possible protective groups are, for example, the ethoxyethyl, tetrahydropyranyl and methoxymethyl groups.
If final products of formula I are desired with R.sup.5 /R.sup.6 in the meaning of ##STR16## then the 17-(3-hydroxypropyl)-compound is oxidized in the known manner, e.g., with Jones' reagent, manganese dioxide, pyridinium dichromate, pyridinium chlorochromate, chromic acid pyridine or the Fetizon reagant silver carbonate/celite (Compt. rend. 267 [1968] 900).
The final products of formula I with R.sup.5 /R.sup.6 in the meaning of ##STR17## are yielded by the ring-closure reaction of the corresponding 17-(3-hydroxyprop-1-(Z)-enyl)-17.beta.-hydroxy educt.
The 17-cyanomethyl side-chain is built from the 17-ketone in the way known per se, e.g., by way of the 17-spiroepoxide and separation of the spiroepoxide with HCN in accordance with Z. Chem 18 (1978) 259-260.
The 17-hydroxyacetyl side-chain is also introduced by methods known per se, e.g., in accordance with the methods described in J. Org. Chem. 47 (1982), 2993-2995, Chem. Ber. 113 (1984), 1184, or U.S. Pat. No. 4,600,538.
To introduce the groups ##STR18## the 17-ketone is converted with tosylmethylisocyanide (Chem. Ind. 1972, 213) to form the 17-nitrile compound (Tetrahedron 31 (1975), 2151), which can be converted directly with methyl lithium or methylmagnesium bromide into the 17-acetyl compound, which yields the desired 17.alpha.-methyl-17.beta.-acyl group after enolization with K-tert.-butylate in tetrahydrofuran and reaction with methyl iodide. This sequence involving the addition of methyl to the nitrile and subsequent alkylation can also be performed in the reverse order.
Free hydroxy and, respectively, hydroxy, mercapto, and/or amino groups present in Z and, respectively, V can be alkylated or acylated in the way known per se.
Sulfides and/or dialkylamines contained in V can be converted by means of suitable oxidants (e.g., hydrogen peroxide or peracids) into the desired sulfoxides (n=1), N-oxides (n=1) [see, for example, Kontakte (Darmstadt) 1986, 3, p. 12] respectively sulfones (n=2).
Compounds with a dialkylamine substituent in V can be converted into the corresponding (N-cyano-N-alkylaminoaryl) derivatives with a good yield by reaction with cyanogen bromide in aprotic solvents like, for example, dioxane, benzene or toluene at a raised temperature (amine separation by Braun's method) analogous to the specifications in, for example, Org. Reactions 7, 198 (1953), K. W. Bentley, Techniques of Organic Chemistry 11, 773 (1963) and Houben-Weyl, 5/4, 151 (1960). Depending on the meaning R.sup.12 is to have in the final product the latter are reduced in the way known per se to form the corresponding dialkylamine compounds (e.g., with diisobutyl aluminum hydride in toluene to form the N-formyl-N-alkylaminophenyl intermediate products and subsequently with lithium aluminum hydride) and, respectively, N--H--N-alkyl compounds (e.g., with lithium aluminum hydride or with lithium in liquid ammonia). If desired, the latter are subsequently acylated in the way known from the literature and, as the case may be, subsequently reduced with, for example, lithium aluminum hydride in the way known to yield the new dialkylamine derivative (cf. DE 36 23 038).
The compounds of general formula I yielded with X in the meaning of an oxygen atom can, if desired, be converted by reaction with hydroxylamine hydrochloride in the presence of tertiary amines at temperatures between -20.degree. and +40.degree. C. to form the oximes (formula I with X in the meaning of the hydroxyimino grouping N.about.OH, it being possible for the hydroxy group to be in the syn- or anti-position). Suitable tertiary bases are, for example, trimethylamine, triethylamine, pyridine, N,N-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN) and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU), pyridine being preferred.
The new compounds of general formula I and their addition salts with pharmaceutically tolerated acids are valuable pharmaceuticals. Thus, they have great affinity for the gestagen receptor and have a surprisingly wide range of gestagenic, antigestagenic, antiglucocorticoid, antimineralcorticoid and antiandrogenic properties. These important biological effects can be used for medical purposes.
Active ingredients of this kind, with marked antigestagenic activity, are suitable for initiating abortions since they displace the progesterone required to maintain pregnancy from the receptor. They are therefore valuable and interesting with regard to their use in postcoital control of fertility.
They can also be used against hormonal disorders, to provoke menstruation and induce labor. Moreover, they can be used to treat hormone-dependent carcinomas.
The compounds of general formula I and their addition salts with pharmaceutically tolerated acids also display antiglucocorticoid activity and can therefore be used as pharmaceuticals for the treatment of corticoid-induced disorders (glaucoma) and to combat the side effects occurring during long-term treatment with glucocorticoids (Cushing's syndrome). Thus, they also permit to combat disorders attributable to a supersecretion of glucocorticoids, above all obesity, areteriosclerosis, hypertension, osteoporosis, diabetes and insomnia. The compounds of general formula I and their addition salts with pharmaceutically tolerated acids displaying gestagenic activity can be used, for example, in the treatment of amenorrhoe, dysmenorrhoe, hypermenorrhoe and luteal insufficiency, and those with antimineralcorticoid properties in the treatment of diseases involving hyperaldosteronism.
The compounds of general formula I and their addition salts with pharmaceutically tolerated acids displaying antiandrogenic activity can be used to treat hypertrophy and carcinoma of the prostate. Moreover, they permit specific therapy of androgenization symptoms in women: pathological growth of hair in the case of hirsutism, androgenetic alopecia and an elevated sebaceous gland function in the case of acne and seborrhoe can be influenced favorably.
The invention thus relates also to pharmaceuticals based on pharmaceutically tolerated compounds of general formula I, i.e., non-toxic compounds in the doses used, as well as their addition salts with pharmaceutically tolerated acids, possibly in conjunction with customary adjuvants and vehicles.
The compounds in accordance with the invention and their salts can be processed by galenical methods known per se to yield pharmaceutical preparations for enteral, percutaneous, parenteral or local application. They can be administered in the form of tablets, coated tablets, gelatine capsules, granulates, suppositories, implants, injectable, sterile, aqueous or oleaginous solutions, suspensions or emulsions, ointments, creams and gels.
In this connection the active ingredient(s) can be mixed with adjuvants customary in galenicals, e.g., arabic gum, talcum, starch, mannitol, methylcellulose, lactose, tensides like Tweens.RTM. or Myrj.RTM., magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives and aromatic substances for adjustment of the taste (e.g., essential oils).
The invention thus relates also to pharmaceutical compositions that contain at least one compound in accordance with the invention as the active ingredient or one of its addition salts with pharmaceutically tolerated acids. Hydrochlorides and methane sulfonates must be especially mentioned as addition salts of the invented products with acids. A unit of dose contains approx. 1-100 mg of active ingredient(s). The dosage of the compounds in accordance with the invention is approx. 1-1000 mg per day in the case of humans.
The abortive effect was selected to identify the antigestagenic effect. The tests were carried out on female rats weighing approx. 200 g. After copulation, the beginning of pregnancy was ascertained by demonstrating the presence of sperm in vaginal smears. The day on which sperm are verified is considered the first day of pregnancy (=d1 p.c.).
The animals were treated with the respective substance to be tested or the solvent after nidation of the blastocysts from d5 p.c. to d7 p.c. The animals were killed on d9 p.c. and the uteri examined for implants and points of resorption. Photographs were made of all the uteri. The lack of implants, pathological hemorrhagic or otherwise abnormal points of nidation were evaluated to be an abortion.
The test substances are dissolved in a mixture of benzylbenzoate and castor oil (ratio of 1+4). The vehicle volume per individual dose amounted to 0.2 ml. The treatment was subcutaneous.
The superiority of the compounds in accordance with the invention is to be shown by a comparison of the abortive action of 17.alpha.-(prop-1-inyl)-17.beta.-hydroxy-11.beta.,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one (A), 17.alpha.-(prop-1-inyl)-17.beta.-hydroxy-11.beta.,19-(4-acetyl-o-phenylene)-4-androsten-3-one (B), 17.alpha.-(3-hydroxyprop-1-(Z)-enyl)-17.beta.-hydroxy-11.beta.,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one (C) and 17.alpha.-(3-hydroxyprop-1-(Z)-enyl)-17.beta.-hydroxy-11.beta.,19-(4-methylthio-o-phenylene)-4-androsten-3-one (D) with the 11.beta.-(4-dimethylaminophenyl)-17.beta.-hydroxy-17.alpha.-(propin-1-yl)-4,9(10)-estradien-3-one (E) described in European patent specification 0 057 115 and the 11.beta.-(4-dimethylaminophenyl)-17.beta.-hydroxy-17.alpha.-(3-hydroxyprop-1-(Z)-enyl)-4,9(10)-estradien-3-one (F) found in European patent specification 84730147.0.
From Table 1 it can be seen that only compounds A-D in accordance with the invention and compound F, which also goes back to the applicant, are still fully abortive at a dose of 1.0 mg/d s.c. The comparative substance E displayed only 50% effectiveness at this dose. Compound B in accordance with the invention still displays full effectiveness even at a dose of 0.3 mg/d s.c. while F is no longer effective at this dose.
To evaluate the antiglucocortoid activity the antithymolysis test was performed on the rat with 17.alpha.-(3-hydroxyprop-1-(Z)-enyl)-17.beta.-hydroxy-11.beta.,19-(4-dimethylamino-o-phenylene)-4-androsten-3-one (C), as representative of all compounds of general formula I, and the results were compared in turn with comparative substances E and F.
There is a great decline in the weight of the rat's thymus (=thymolitic effect) under the influence of glucocorticoids. If substances antagonistic to glucocorticoids are administered at the same time, inhibition respectively cancellation of the glucocorticoid-induced suppression of the thymus can be expected.
The tests were performed on adrenalectomized, juvenile, male rats weighing 100 to 130 g. Conditions in which the rats were kept: conventional, illumination rhythm: 10 hours of darkness/14 hours of light, average temperature 20.degree..+-.2.degree. C., standard rat diet (pellets), supply of tap water and 0.9% NaCl solution via separate drinking bottles.
For subcutaneous application the substances were dissolved in a mixture of benzyl benzoate and castor oil (ratio of 1+4) and the respective daily dose injected in a vehicle volume of 0.2 ml. The dosages selected can be seen from Table 2.
The standard glucocorticoid substance used was dexamethasone in a dose of 0.01 mg/animal/day s.c. This dose induces--as related to the solvent control--an approximately 75% reduction in the weight of the thymus gland. Solvent: benzyl benzoate/castor oil (1+4), vehicle volume per daily dose: 0.2 ml.
Approx. 5 days prior to be commencement of treatment the animals were adrenalectomized under ether narcosis. They are assigned to the different test groups on a random basis; the extent of the random test can be seen from Table 2.
The treatment lasted for 4 days (day 1-4). On day 5 the animals were killed with CO.sub.2. The weight of the thymus was determined and converted for mg/100 g of body weight.
To evaluate the antiglucocorticoid effect of a substance the difference between the solvent control and dexamethasone (0.01 mg/animal/day s.c.) is set at 100%.
The anti-glucocorticoid effect in mean percentage (cancellation of the thymus suppression induced by dexamethasone expressed in %) is calculated on the basis of the mean random-sample values by the following formula: ##EQU1## In this connection ##EQU2##
As can be seen from Table 2, compound C produces a slight cancellation of the dexamethasone-induced suppression of the thymus only with the maximum test dose of 30.0 mg/d s.c. At lower doses (3.0; 10.0 mg/d s.c.) it was not possible to ascertain any antiglucocorticoid effect.
In comparison with compounds E (FIG. 2) and F (FIG. 1) the antiglucocorticoid activity of compound C is thus clearly reduced.
It is true that structurally similar steroids with a substituted aryl radical in position 10 and a 9(11) double bond are known from French patent application 86 400 057.5; but the known compounds always have an alkyl, alkenyl or alkinyl group in position 17.alpha.. These compounds, however, display considerable antiglucocorticoid activity, while their activity with regard to the progesterone receptor, and thus their antigestagenic effectiveness, is negligible.
With the compounds in accordance with the invention substances are thus made available which possess a new profile of effectiveness compared with the nearest state of the art, namely much higher antigestagenic effectiveness with only moderate antiglucocorticoid activity.
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| Morrison et al., Organic Chemistry, 3rd Ed., Allyn & Bacon, Inc., Boston, pp. 622 and 631 (1979). |
| Stork et al., "Cyclization of Vinyl Radicals: A New Versatile Method for the Construction of Five- and Six-Membered Rings", J. Am. Chem. Soc., 104:2321-2323 (1982). |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
415359 |
Sep 1989 |
|
Patent Grant
5095129
