US 5,017,568 AGranted

Steriod 5-alpha-reductase inhibitors

AssigneeSmithKline Beecham Corporation

InventorsDennis A. Holt, Conrad J. Kowalski, Mark A. Levy, Brian W. Metcalf, Ann M. Tickner

Life of this patent

Estimating the term…

Abstract

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

Claims68

Dependent claims

A compound represented by the formula:

##STR46## 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 rings and the B-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.sup.3 represents two substituents or a divalent substituent;
M is O or S;
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 H 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;
R.sup.10 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
(a) ##STR47## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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.4 or .dbd.CH--W--OR.sup.8, where W is a bond or C.sub.1-12 alkyl and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 -alkylcarbonyl;
(3) ##STR48## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or a pharmaceutically acceptable salt thereof;
except compounds in which:
The A ring has a C.sub.3 -C.sub.4 double bond, the B ring has a C.sub.5 -C.sub.6 double double bond, R.sup.1 is CH.sub.3, and R.sup.3 is keto;
The A ring has a C.sub.3 -C.sub.4 double bond, the B ring has a C.sub.5 -C.sub.6 double bond and the D ring has a C.sub.16 -C.sub.17 double bond, R.sup.1 is CH.sub.3, and
R.sup.3 is COOCH.sub.3 ;
and
The B ring has a C.sub.5 -C.sub.6 double bond, R.sup.1 is CH.sub.3, and R.sup.3 is COCH.sub.3.

39 more elements

A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound of the formula:

##STR50## 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 the A-B rings and the B-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.sup.3 represents two substituents or a divalent substituent;
M is O or S;
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 H;
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.10 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
(a) ##STR51## where W is a bond or C.sub.1-12 alkyl and R.sup.4 is
(i) hydrogen,
(ii) hydroxyl,
(iii) C.sub.18 alkyl,
(iv) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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.4 or .dbd.CH--W-OR.sup.8, where W is a bond or C.sub.1-12 alkyl, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR52## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or a pharmaceutically acceptable salt thereof.

34 more elements

A method of inhibiting steroid 5-.alpha.-reductase activity in mammals that comprises administering to a subject an effective amount of a compound of the formula:

##STR53## 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 rings and the B-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.sup.3 represents two substituents or a divalent substituent;
M is O or S;
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 H 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;
R.sup.10 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
(a) ##STR54## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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.4 or .dbd.CH--W--OR.sup.8, where W is a bond or C.sub.1-12 alkyl, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR55## where the dashed bond replaces the 17.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or
pharmaceutically acceptable salt thereof.

35 more elements

A method of reducing or maintaining prostate size in a mammal that comprises administering to a subject an effective amount of a compound of the Formula:

##STR56## 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 rings and the B-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.sup.3 represents two substituents or a divalent substituent;
M is O or S;
Z is CH.sub.2 or, when part of a double bond, CH;
X is H, Cl, Br, F, 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 H;
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.10 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 acetoxy and/or
(a) ##STR57## where W is a bond or C.sub.1-12 alkyl, an R.sup.4 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) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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--Alk--CO--R.sup.4 or .dbd.CH--Alk--OR.sup.8, where Alk is present or absent, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR58## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or a pharmaceutically acceptable salt thereof.

32 more elements

A compound of the formula:

##STR59## 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 rings and the B-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.sup.14 represents two substituents or a divalent substituent;
Z is CH.sub.2 or, when part of a double bond, CH;
X is H, Cl, Br, F, 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.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 doubled bonded;
R.sup.10 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.14 is
(1) .alpha.-hydrogen, .dbd.-hydroxyl, or acetoxy and/or
(a) ##STR60## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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 ad nitrogen, or
(vii) OR.sup.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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--Alk--CO--R.sup.4 or .dbd.CH--Alk--OR.sup.8, where Alk is present or absent, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR61## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or moieties which can be chemically converted to moieties (1) through (7);
except compounds in which:
the A ring has a C.sub.3 -C.sub.4 double bond, and B ring has a C.sub.5 -C.sub.6 double bond, and R.sup.14 is keto;
and the B ring has a C.sub.5 -C.sub.6 double bond and R.sup.14 is COCH.sub.3.

33 more elements

A compound of the formula ##STR62## in which X.sup.1 is bromo, chloro, fluoro, or iodo;

R.sup.2 is absent or present as H or CH.sub.3 ;
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;
and
R.sup.14 is
(1) .alpha.-hydrogen, .alpha.-hydroxyl, or acetoxy and/or
(a) ##STR63## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1 -18alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is
C.sub.1-12 alkyl, and R.sup.8 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--Alk--CO--R.sup.4 or .dbd.CH--Alk--OR.sup.8, where Alk is present or absent, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR64## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or moieties which can be chemically converted to moieties (1) through (7);
except compounds in which:
X.sup.1 is Cl and R.sup.14 is .beta.-CH.sub.3 CO;
X.sup.1 is Cl and R.sup.14 is .beta.-OH and .alpha.-CH.sub.3 CO.sub.2 ;
and
X.sup.1 is Br and R.sup.14 is .beta.-OH and .alpha.-CH.sub.3 CO.sub.2.

32 more elements

A process for preparing compounds of the formula:

##STR65## in which X.sup.1 is bromo, chloro, or iodo;
R.sup.2 is absent or present as H or CH.sub.3,
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;
and
R.sup.14 is
(1) .alpha.-hydrogen, .alpha.-hydroxyl, or acetoxy and/or
(a) ##STR66## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 -alkyl, C.sub.3-6 -cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal,
C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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--Alk--CO-R.sup.4 or .dbd.CH--Alk--OR.sup.8, where Alk is present or absent, and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 alkylcarbonyl;
(3) ##STR67## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto or moieties which can be chemically converted to moieties (1) through (7);
that comprises treating with a carboxylic acid halide or phosphorous polyhalide a compound of the formula:
##STR68## in which R.sup.2, R.sup.14, X and Y are as defined above, provided that X and Y do not include any such moities that render inoperative the above process;
except compounds in which:
R.sup.2 is CH.sub.3 and R.sup.14 is keto;
and
R.sup.2 is CH.sub.3 and R.sup.14 is .beta.-OH and .alpha.-CH.sub.3 CO.sub.2.

33 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/499,244Filed 23 Mar 1990 · continuation in part
Priority: 29 Apr 1987
Granted: 21 May 1991
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07J 1/0011
Androstane derivatives: substituted in position 17 by a keto group
C07J 1/0022
Substituted in position 17 beta, not substituted in position 17 alfa: the substituent being an OH group free esterified or etherified
C07J 1/007
Substituted in position 17 beta not substituted in position 17 alfa: the substituent being an OH group free esterified or etherified
C07J 3/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17

Family

Serial43,773Parent of this continuation-in-part · filed 29 Apr 1987
Serial127,147Parent of this continuation-in-part · filed 1 Dec 1987
Serial182,828Parent of this continuation-in-part · filed 18 Apr 1988
US 4,910,226 AParent of this continuation-in-part
US 5,017,568 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound represented by the formula:

##STR46## 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 rings and the B-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.sup.3 represents two substituents or a divalent substituent;
M is O or S;
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 H 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;
R.sup.10 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
(a) ##STR47## 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) hydroxy C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6 cycloalkyl, phenyl;
or R.sup.5 and R.sup.6 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.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-18 alkyl, benzyl, or
(b) .beta.-Alk-OR.sup.8, where Alk is C.sub.1-12 alkyl, and R.sup.8 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.4 or .dbd.CH--W--OR.sup.8, where W is a bond or C.sub.1-12 alkyl and R.sup.4 and R.sup.8 have the same meaning as above and R.sup.8 also is hydrogen or C.sub.1-20 -alkylcarbonyl;
(3) ##STR48## where the dashed bond replaces the 17-.alpha.-hydrogen, (4) .alpha.-hydrogen and .beta.-NHCOR.sup.9 where R.sup.9 is C.sub.1-12 alkyl or .beta.-NR.sup.5 R.sup.6 where R.sup.5 and R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and .beta.-cyano,
(6) .alpha.-hydrogen and .beta.-tetrazolyl, or
(7) keto;
or a pharmaceutically acceptable salt thereof;
except compounds in which:
The A ring has a C.sub.3 -C.sub.4 double bond, the B ring has a C.sub.5 -C.sub.6 double double bond, R.sup.1 is CH.sub.3, and R.sup.3 is keto;
The A ring has a C.sub.3 -C.sub.4 double bond, the B ring has a C.sub.5 -C.sub.6 double bond and the D ring has a C.sub.16 -C.sub.17 double bond, R.sup.1 is CH.sub.3, and
R.sup.3 is COOCH.sub.3 ;
and
The B ring has a C.sub.5 -C.sub.6 double bond, R.sup.1 is CH.sub.3, and R.sup.3 is COCH.sub.3.

39 more elements

Facts

Application

07/499,244Filed 23 Mar 1990 · continuation in part

Priority

29 Apr 1987

Granted

21 May 1991

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07J 1/0011
Androstane derivatives: substituted in position 17 by a keto group
C07J 1/0022
Substituted in position 17 beta, not substituted in position 17 alfa: the substituent being an OH group free esterified or etherified
C07J 1/007
Substituted in position 17 beta not substituted in position 17 alfa: the substituent being an OH group free esterified or etherified
C07J 3/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17

Family

Serial43,773Parent of this continuation-in-part · filed 29 Apr 1987

Serial127,147Parent of this continuation-in-part · filed 1 Dec 1987

Serial182,828Parent of this continuation-in-part · filed 18 Apr 1988

US 4,910,226 AParent of this continuation-in-part

US 5,017,568 AThis patent

From the US filing history. Foreign family members aren’t listed.