US 4,946,834 AGranted

Phosphonic acid substituted steroids as steroid 5.alpha.-reductase inhibitors

AssigneeSmithKline Beecham Corporation

InventorsDennis A. Holt, Mark A. Levy, Brian W. Metcalf

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Abstract

Invented are substituted acrylate analogues of steroidal synthetic compounds, pharmaceutical compositions containing the compounds, and methods of using these compounds to inhibit steroid 5.alpha.-reductase. Also invented are intermediates used in preparing these compounds.

Claims24

Dependent claims

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 ring does not have adjacent double bonds and the D ring does not have a C.sub.16 -C.sub.17 double bond when R represents two substituents or a divalent substituent;
Z is CH.sub.2 or, when part of a double bond, CH;
X is H, Cl, F, Br, I, CF.sub.3, or C.sub.1-6 alkyl;
Y is H, CF.sub.3, F, or Cl, CH.sub.3, provided that Y is H when there is no C.sub.5 -C.sub.6 double bond;
R.sup.1 is absent or present as an alpha hydrogen, provided 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;
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, and
R 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.3 is
(i) hydrogen,
(ii) hydroxyl,
(iii) C.sub.1-8 alkyl,
(iv) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) N(R.sup.4).sub.2, where each R.sup.4 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
(vii) OR.sup.5, where R.sup.5 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) --Alk-OR.sup.6, where Alk is C.sub.1-12 alkyl, and R.sup.6 is
(i) phenylC.sub.1-6 alkylcarbonyl,
(ii) 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.3 or .dbd.CH--W--OR.sup.6, where W is a bond or C.sub.1-12 alkylidene, and R.sup.3 and R.sup.6 have the same meaning as above and R.sup.6 also is hydrogen or C.sub.1-20 -alkylcarbonyl;
##STR25## where the dashed bond replaces the 17.alpha.-hydrogen, (4) .alpha.-hydrogen and NHCOR.sup.7 where R.sup.7 is C.sub.1-12 alkyl or N(R.sup.4).sub.2 where R.sup.4 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.

28 more elements

The 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 adjacent double bonds and the D ring does not have a C.sub.16 -C.sub.17 double bond when R represents two substituents or a divalent substituent;
Z is CH.sub.2 or, when part of a double bond, CH;
X is H, Cl, F, Br, I, CF.sub.3, or C.sub.1-6 alkyl;
Y is H, CF.sub.3, F, Cl or CH.sub.3, provided that Y is H when there is no C.sub.5 -C.sub.6 double bond;
one R' is C.sub.1-8 alkyl and the other R' is hydrogen or C.sub.1-8 alkyl;
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;
and
R.sup.1 is absent or present as an alpha hydrogen provided 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;
and
R is
(1) .alpha.-hydrogen, .alpha.-hydroxyl, or .alpha.-acetoxy and/or ##STR28## where W is a bond or C.sub.1-12 alkyl and R.sup.3 is (i) hydrogen,
(ii) hydroxyl,
(iii) C.sub.1-8 alkyl,
(iv) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) N(R.sup.4).sub.2, where each R.sup.4 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
(vii) OR.sup.5, where R.sup.5 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) --Alk--OR.sup.6, where Alk is C.sub.1-12 alkyl, and R.sup.6 is
(i) phenyl C.sub.1-6 alkylcarbonyl,
(ii) 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.3 or .dbd.CH--W--OR.sup.6, where W is a bond or C.sub.1-12 alkylidene, and R.sup.3 and R.sup.6 have the same meaning as above and R.sup.6 also is hydrogen or C.sub.1-20 alkylcarbonyl;
##STR29## where the dashed bond replaces the 17.beta.-hydrogen, (4) .alpha.-hydrogen and NHCOR.sup.7 where R.sup.7 is C.sub.1-12 alkyl or N(R.sup.4).sub.2 where R.sup.4 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

A process for preparing compounds of the formula:

##STR30## 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 and the D rings does not have a C.sub.16 -C.sub.17 double bond when R.sup.10 represents two substituents or a divalent substituent;
M is C.sub.1-8 alkyl;
Z is CH.sub.2 or, when part of a double bond, CH;
X is H, Cl, F, Br, I, CF.sub.3, or C.sub.1-6 alkyl;
Y is H, CF.sub.3, F, or Cl, CH.sub.3, provided that Y is H when there is no C.sub.5 -C.sub.6 double bond;
R.sup.1 is absent or present as an alpha hydrogen produced 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;
and
R.sup.2 is absent or present as H or CH.sup.3, provided R.sup.2 is absent when the carbon to which is attached is double bonded;
are
R.sup.10 is
(1) .alpha.-hydrogen, .alpha.-hydroxyl, or .alpha.-acetoxy and/or ##STR31## where w is a bond or C.sub.1-12 alkyl and R.sup.3 is (i) hydrogen,
(ii) hydroxyl,
(iii) C.sub.1-8 alkyl,
(iv) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) N(R.sup.4).sub.2, where each R.sup.4 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
(vii) OR.sup.5, where R.sup.5 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) --Alk--OR.sup.6, where Alk is C.sub.1-12 alkyl, and R.sup.6 is
(i) phenyl C.sub.1-6 alkylcarbonyl,
(ii) C.sub.5-10 cycloalkylcarbonyl,
(iii) benzoyl,
(iv) C.sub.1-8 alkoxycarbonyl,
(v) amino, or C.sub.1-8 alkyl substituted amino, carbonyl,
(vi) hydrogen, or
(vii) C.sub.1-8 alkyl,
(2) .dbd.CH--W--CO--R.sup.3 or .dbd.CH--W--OR.sup.6, where W is a bond or C.sub.1-12 alkylidene, and R.sup.3 and R.sup.6 have the same meaning as above and R.sup.6 also is hydrogen or C.sub.1-20 alkylcarbonyl;
##STR32## where the dashed bond replaces the 17.alpha.-hydrogen, (4) .alpha.-hydrogen and NHCOR.sup.7 where R.sup.7 is C.sub.1-12 alkyl or N(R.sup.4).sub.2 where R.sup.4 has the same meaning as above,
(5) .alpha.-hydrogen and cyano,
(6) .alpha.-hydrogen and tetrazolyl, or
(7) keto;
or
(8) moieties which can be chemically converted to moieties (1) through (7) above;
or a pharmaceutically acceptable salt thereof which process comprises:
reacting a compound of the Formula:
##STR33## wherein the substituents are as defined above with a posphite and a palladium catalyst in a non-reactive organic solvent to give a 3-phosphonate compound of Formula I;
and thereafter optionally forming a pharmaceutically acceptable salt.

36 more elements

Dependencies are inferred from the claim text.

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