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US 5,026,882 AGranted
Phosphinic acid substituted steroids as inhibitors of steroid 5.alpha.-reductase
AssigneeSmithKline Beecham Corporation
InventorsDennis A. Holt, Mark A. Levy, Brian W. Metcalf
Life of this patent
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Abstract
The invention relates to 3-phosphinic acid steroidal compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds to inhibit steroid 5.alpha.-reductase.
Claims20
A compound represented by the formula:
- ##STR23## in which:
- The A ring has up to 2 double bonds;
- The B, C, and D rings have optional double bonds where indicated by the broken lines, provided that the A, B and C rings do not have adjacent double bonds;
- R is hydrogen or C.sub.1-4 alkyl;
- Z is CH.sub.2 or, when part of a double bond, CH
- X is H, F, Cl, Br, I, CF, or C.sub.1-6 alkyl;
- Y is H, F, Cl, CF.sub.3, or CH.sub.3 provided that Y is H when there is no C.sub.5 -C.sub.6 double bond;
- R.sup.2 is absent or present as H or CH.sub.3 provided R.sup.2 is absent when the carbon to which it is attached is double bonded;
- R.sup.1 is absent when there is a C.sub.4 -C.sub.5, C.sub.5 -C.sub.6 or C.sub.5 -C.sub.10 double bond, or present as an alpha hydrogen;
- and
- R.sup.3 is
- (1) .alpha.-hydrogen, .alpha.-hydroxyl, or .alpha.-acetoxy and/or ##STR24## where W is a bond or C.sub.1-12 alkyl, and R.sup.4 is
- (i) hydrogen,
- (ii) hydroxy,
- (iii) C.sub.1-8 alkyl;
- (iv) C.sub.1-8 alkoxy;
- (v)N(R.sup.5), where each R.sup.5 is independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 -cycloalkyl, phenyl;
- or taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or
- (vi) OR.sup.6, where R.sup.6 is hydrogen, alkali metal, C.sub.1-18 -alkyl, benzyl, or
- (b) Alk-OR.sup.7, where Alk is C.sub.1-12 -alkyl, and R.sup.7 is
- (i) phenyl-C.sub.1-16 alkylcarbonyl,
- (ii) C.sub.5-10 cYcloalkylcarbonyl,
- (iii) benzoyl,
- (iv) C.sub.1-18 alkoxycarbonyl,
- (v) aminocarbonyl or C.sub.1-8 -alkyl substituted aminocarbonyl,
- (vi) hydrogen, or
- (vii) C.sub.1-8 -alkyl,
- (2).dbd.CH--W--COR.sup.4 or .dbd.CH--W--OR.sup.7, where W is a bond or C.sub.1-12 alkylidene, R.sup.4 and R.sup.7. have the same meaning as above and R.sup.7 also is hydrogen or C.sub.1-20 -alkylcarbonyl;
- (3) ##STR25## where the dashed bond replaces the 17.alpha.-hydrogen, (4) .alpha.-hydrogen and NHCOR.sup.8 where R.sup.8 is C.sub.1-12 alkyl or N(R.sup.5).sub.2 where R.sup.5 has the same meaning as above,
- (5) .alpha.-hydrogen and cyano,
- (6) .alpha.-hydrogen and tetrazolyl, or
- (7) keto;
- or a pharmaceutically acceptable salt thereof.
30 more elements
A compound of claim 4 wherein the A ring has a C.sub.3 -C.sub.4 double bond.
A compound represented by the formula:
- ##STR27## in which:
- The A ring has up to 2 double bonds;
- The B, C, and D rings have optional double bonds where indicated by the broken lines, provided that the A, B, and C rings do not have the adjacent double bonds;
- M is C.sub.1-8 alkyl;
- R is hydrogen or C.sub.1-4 alkyl;
- Z is CH.sub.2 or, when part of a double bond, CH.
- X is H, F, Cl, Br, I, CF3, or C.sub.1-6 alkyl;
- Y is H, F, Cl, CF3, or CH.sub.3, provided that Y is H when there is no C.sub.5 -C.sub.6 double bond;
- R.sup.2 is absent or present as H or CH.sub.3, provided R.sup.2 is absent when the carbon to which it is attached is double bonded;
- R.sup.1 is absent when there is a C.sub.4 -C.sub.5, C.sub.5 -C.sub.6, or C.sub.5 -C.sub.10 double bond, or present as an alpha hydrogen;
- and
- R.sup.3 is
- (1) .alpha.-hydrogen, %-hydroxyl, or %-acetoxy and/or
- (a) ##STR28## where W is a bond or C.sub.1-12 alkYl and R.sup.4 is (i) hydrogen,
- (ii) hydroxyl,
- (iii) C.sub.1-8 alkyl,
- (iv) C.sub.1-8 alkoxy,
- (v) N*(R.sup.5).sub.2, where each R.sup.5 is independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
- or taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or
- (vi) OR.sup.6, where R.sup.6 is hydrogen, alkali metal, C.sub.1-18 -alkyl, benzyl, or
- (b) Alk-OR.sup.7, where Alk is C.sub.1-12 -alkyl, and R.sup.7 is
- (i) Phenyl-C.sub.1-6 alkylcarbonyl,
- C.sub.5-10 -cycloalkylcarbonyl,
- (iii) benzoyl,
- (iv) C.sub.1-8 -alkoxycarbonyl,
- (v) aminocarbonyl, or C.sub.1-8 -alkyl substituted aminocarbonyl
- (vi) hydrogen, or
- (vii) C.sub.1-8 -alkyl,
- (2).dbd.CH--W--CO--R.sup.4 or .dbd.CH--W--OR.sup.7, where W is a the same meaning as above and R.sup.7 also is hydrogen or C.sub.1-20 -alkylcarbonyl;
- (3) ##STR29## where the dashed bond replaces the 17.alpha.-hydrogen, .alpha.-hydrogen and NHCOR.sup.8 where R.sup.8 iS C.sub.1-12 alkyl or N(R.sup.5).sub.2 where R.sup.5 has the same meaning as above,
- (5) .alpha.-hydrogen and cyano,
- (6) .alpha.-hydrogen and tetrazolyl, or
- (7) keto;
- or a pharmaceutically acceptable salt thereof.
31 more elements
Dependencies are inferred from the claim text.