US 5,308,846 AGranted

Quinazolinones

AssigneesMerck & Co., Inc., E. I. Du Pont de Nemours and Company

InventorsEric E. Allen, Richard E. Olson

Life of this patent

Estimating the term…

Abstract

Substituted quinazolinones and pyridopyrimidines of structural formula 1 ##STR1## are angiotensin II antagonists useful in the treatment of disorders related to the renin-angiotensin system (RAS) such as hypertension, congestive heart failure, ocular hypertension and certain CNS disorders.

Claims9

Dependent claims

A compound of structural formula:

##STR167## or a pharmaceutically acceptable salt thereof, wherein:
G is
(1) R.sup.1, or
(2) ##STR168## E is (1) a single bond,
(2) --CH(OH)--,
(3) --O--,
(4) --CO--,
(5) --S(O).sub.x (CH.sub.2).sub.s --wherein x is 0, 1, or 2, and s is 0-5, or
(6) --NR.sup.3 (CH.sub.2).sub.s --wherein R.sup.3 is
(a) --H,
(b) C.sub.2-4 alkanoyl,
(c) C.sub.1-6 alkyl,
(d) C.sub.2-6 alkenyl,
(e) C.sub.3-7 cycloalkyl,
(f) phenyl, or
(g) benzyl;
R is
(1) aryl,
(2) heteroaryl,
(3) C.sub.3-7 cycloalkyl,
(4) polyfluoro-C.sub.1-4 alkyl,
(5) --H,
(6) C.sub.2-6 alkenyl,
(7) C.sub.2-6 alkynyl,
(8) C.sub.1-6 alkyl, either unsubstituted or substituted with:
(a) aryl,
(b) C.sub.3-7 cycloalkyl,
(c) halo,
(d) --NH.sub.2,
(e) --NH(C.sub.1-4 alkyl),
(f) --N(C.sub.1-4 alkyl).sub.2,
(g) --OR.sup.4, wherein R.sup.4 is
(i) --H,
(ii) aryl,
(iii) heteroaryl,
(iv) C.sub.1-6 alkyl,
(v) aryl-C.sub.1-6 alkyl, or
(vi) C.sub.3-7 cycloalkyl;
(h) --COOR.sup.4,
(i) --NHSO.sub.2 R.sup.4, or
(j) --SO.sub.2 NHR.sup.5, wherein R.sup.5 is
(i) --H,
(ii) C.sub.1-5 alkyl,
(iii) aryl, or
(iv) --CH.sub.2 -aryl;
R.sup.1 is
(1) --SO.sub.2 NHCO.sub.2 R.sup.7, wherein R.sup.7 is
(a) --H,
(b) aryl,
(c) heteroaryl,
(d) C.sub.3-7 cycloalkyl,
(e) polyfluoro-C.sub.1-4 alkyl, or
(f) C.sub.1-10 alkyl, either unsubstituted or substituted with:
(i) aryl,
(ii) heteroaryl,
(iii) --OH,
(iv) --SH,
(v) C.sub.1-4 alkoxy,
(vi) C.sub.1-4 alkylthio,
(vii) halo,
(viii) --NO.sub.2,
(ix) --CO.sub.2 R.sup.11, wherein R.sup.11 is --H or C.sub.1-4 alkyl,
(x) --NH.sub.2,
(xi) --NH(C.sub.1-4 alkyl),
(xii) --N(C.sub.1-4 alkyl).sub.2,
(xiii) --PO.sub.3 H.sub.2,
(xiv) --P(O)(OH)(OC.sub.1-4 alkyl), or
(xv) --P(O)(OR.sup.4)(R.sup.8), wherein R.sup.8 is
(a) --H,
(b) --C.sub.1-5 alkyl,
(c) --aryl,
(d) --CH.sub.2 -aryl, or
(xvi) C.sub.3-7 cycloalkyl;
R.sup.9 is
(a) --H,
(b) C.sub.1-6 alkyl,
(c) C.sub.2-4 alkenyl,
(d) C.sub.1-4 alkoxy-C.sub.1-4 alkyl
(e) benzyl, either unsubstituted or substituted with
(i) --NO.sub.2,
(ii) --NH.sub.2,
(iii) --OH, or
(iv) --OCH.sub.3,
R.sup.10 is
(a) --CN,
(b) --NO.sub.2,
(c) --CF.sub.3 or
(d) --CO.sub.2 R.sup.4 ;
R.sup.2 is:
(1) --H,
(2) --CO-aryl,
(3) C.sub.3-7 cycloalkyl,
(4) halo,
(5) --OH,
(6) --OR.sup.7
(7) polyfluoro-C.sub.1-4 alkyl,
(8) --S(O).sub.x R.sup.7,
(9) --COOR.sup.4,
(10) --SO.sub.2 H,
(11) --NR.sup.4 R.sup.7,
(12) --NHCOR.sup.7,
(13) --NHCO.sub.2 R.sup.7
(14) --SO.sub.2 NR.sup.8 R.sup.11, wherein R.sup.11 is
(a) --H or
(b) C.sub.1-4 alkyl,
(15) --NO.sub.2
(16) --NHSO.sub.2 R.sup.7
(17) --NHCONR.sup.4 R.sup.7,
(18) --OCONR.sup.7 R.sup.8,
(19) aryl,
(20) heteroaryl,
(21) --NHSO.sub.2 polyfluorophenyl,
(22) --SO.sub.2 NH-heteroaryl,
(23) --SO.sub.2 NHCOR.sup.7,
(24) --CONHSO.sub.2 R.sup.7,
(25) --PO(OR.sup.4).sub.2,
(26) --PO(OR.sup.4)R.sup.8,
(27) tetrazol-5-yl,
(28) --CONH(tetrazol-5-yl),
(29) --COR.sup.4
(30) --SO.sub.2 NHCN,
(31) --CO-heteroaryl,
(32) --NHSO.sub.2 NR.sup.7 R.sup.8,
(33) --CON(R.sup.5).sub.2 wherein the R.sup.5 groups are the same or different or
(34) C.sub.1-6 alkyl, either unsubstituted or substituted with
(a) --OH,
(b) -guanidino,
(c) --C.sub.1-4 alkoxy,
(d) --N(R.sup.4).sub.2,
(e) --CO.sub.2 R.sup.4,
(f) --CON(R.sup.4).sub.2,
(g) --O--COR.sup.4
(h) -aryl,
(i) -heteroaryl,
(j) --S(O).sub.x R.sup.7
(k) -tetrazol-5-yl,
(l) --CONHSO.sub.2 R.sup.7,
(m) --SO.sub.2 NH-heteroaryl,
(n) --SO.sub.2 NHCOR.sup.7,
(o) --PO(OR.sup.4).sub.2,
(p) --PO(OR4)R.sup.9,
(q) --SO.sub.2,NHCN,
(r) --NR.sup.11 COOR.sup.7,
(s) -morpholino,
(t) --N(C.sub.1-6 alkyl)piperazine or
(u) --COR.sup.4,
with the proviso that the R.sup.2 groups can be the same or different;
or two R.sup.2 groups joined to the same carbon taken together represent
(a)=O,
(b)=S, or
(c) --[(CH.sub.2).sub.2-6 ]--;
R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b independently represent
(1) C.sub.1-5 alkyl,
(2) polyfluoro-C.sub.1-5 alkyl,
(3) halo,
(4) hydroxy,
(5) C.sub.1-5 alkoxy,
(6) hydrogen or
(7) COOH;
U, V and W are each --CH.dbd.;
Z is:
(1) --O--,
(2) --S(O).sub.x --,
(3) --N(R.sup.12)--, wherein R.sup.12 is
(a) --H, or
(b) --R.sup.13, wherein R.sup.13 is
(i) C.sub.1-4 alkyl,
(ii) C.sub.3-7 cycloalkyl,
(iii) aryl,
(iv) heteroaryl,
(v) polyfluoro-C.sub.1-4 alkyl,
(vi) polyfluoro-C.sub.3-7 cycloalkyl, or
(vii) polyfluoro-phenyl;
(4) --N(COR.sup.13)--,
(5) --N(CONHR.sup.13)--,
(6) --N(CON(R.sup.13).sub.2)--,
(7) --N(CO.sub.2 R.sup.13)--,
(8) --N(SO.sub.2 NHR.sup.13)--,
(9) --N(SO.sub.2 N(R.sup.13).sub.2)--,
(10) --N(SO.sub.2 R.sup.13)--, or
X is
(1) a single bond,
(4) --C(R.sup.2).sub.2 --,
Y is
(3) --C(R.sup.2).sub.2 --.

182 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/096,125Filed 22 Jul 1993 · continuation
Priority: 25 Sep 1991
Granted: 3 May 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 239/91
Oxygen atoms: with aryl or aralkyl radicals attached in position 2 or 3
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents

Family

Serial765,626Parent of this continuation-in-part · filed 25 Sep 1991
Serial923,273Parent of this continuation · filed 31 Jul 1992
US 5,256,667 AParent of this continuation
US 5,202,322 AParent of this continuation-in-part
US 5,308,846 AThis patent

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

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of structural formula:

##STR167## or a pharmaceutically acceptable salt thereof, wherein:
G is
(1) R.sup.1, or
(2) ##STR168## E is (1) a single bond,
(2) --CH(OH)--,
(3) --O--,
(4) --CO--,
(5) --S(O).sub.x (CH.sub.2).sub.s --wherein x is 0, 1, or 2, and s is 0-5, or
(6) --NR.sup.3 (CH.sub.2).sub.s --wherein R.sup.3 is
(a) --H,
(b) C.sub.2-4 alkanoyl,
(c) C.sub.1-6 alkyl,
(d) C.sub.2-6 alkenyl,
(e) C.sub.3-7 cycloalkyl,
(f) phenyl, or
(g) benzyl;
R is
(1) aryl,
(2) heteroaryl,
(3) C.sub.3-7 cycloalkyl,
(4) polyfluoro-C.sub.1-4 alkyl,
(5) --H,
(6) C.sub.2-6 alkenyl,
(7) C.sub.2-6 alkynyl,
(8) C.sub.1-6 alkyl, either unsubstituted or substituted with:
(a) aryl,
(b) C.sub.3-7 cycloalkyl,
(c) halo,
(d) --NH.sub.2,
(e) --NH(C.sub.1-4 alkyl),
(f) --N(C.sub.1-4 alkyl).sub.2,
(g) --OR.sup.4, wherein R.sup.4 is
(i) --H,
(ii) aryl,
(iii) heteroaryl,
(iv) C.sub.1-6 alkyl,
(v) aryl-C.sub.1-6 alkyl, or
(vi) C.sub.3-7 cycloalkyl;
(h) --COOR.sup.4,
(i) --NHSO.sub.2 R.sup.4, or
(j) --SO.sub.2 NHR.sup.5, wherein R.sup.5 is
(i) --H,
(ii) C.sub.1-5 alkyl,
(iii) aryl, or
(iv) --CH.sub.2 -aryl;
R.sup.1 is
(1) --SO.sub.2 NHCO.sub.2 R.sup.7, wherein R.sup.7 is
(a) --H,
(b) aryl,
(c) heteroaryl,
(d) C.sub.3-7 cycloalkyl,
(e) polyfluoro-C.sub.1-4 alkyl, or
(f) C.sub.1-10 alkyl, either unsubstituted or substituted with:
(i) aryl,
(ii) heteroaryl,
(iii) --OH,
(iv) --SH,
(v) C.sub.1-4 alkoxy,
(vi) C.sub.1-4 alkylthio,
(vii) halo,
(viii) --NO.sub.2,
(ix) --CO.sub.2 R.sup.11, wherein R.sup.11 is --H or C.sub.1-4 alkyl,
(x) --NH.sub.2,
(xi) --NH(C.sub.1-4 alkyl),
(xii) --N(C.sub.1-4 alkyl).sub.2,
(xiii) --PO.sub.3 H.sub.2,
(xiv) --P(O)(OH)(OC.sub.1-4 alkyl), or
(xv) --P(O)(OR.sup.4)(R.sup.8), wherein R.sup.8 is
(a) --H,
(b) --C.sub.1-5 alkyl,
(c) --aryl,
(d) --CH.sub.2 -aryl, or
(xvi) C.sub.3-7 cycloalkyl;
R.sup.9 is
(a) --H,
(b) C.sub.1-6 alkyl,
(c) C.sub.2-4 alkenyl,
(d) C.sub.1-4 alkoxy-C.sub.1-4 alkyl
(e) benzyl, either unsubstituted or substituted with
(i) --NO.sub.2,
(ii) --NH.sub.2,
(iii) --OH, or
(iv) --OCH.sub.3,
R.sup.10 is
(a) --CN,
(b) --NO.sub.2,
(c) --CF.sub.3 or
(d) --CO.sub.2 R.sup.4 ;
R.sup.2 is:
(1) --H,
(2) --CO-aryl,
(3) C.sub.3-7 cycloalkyl,
(4) halo,
(5) --OH,
(6) --OR.sup.7
(7) polyfluoro-C.sub.1-4 alkyl,
(8) --S(O).sub.x R.sup.7,
(9) --COOR.sup.4,
(10) --SO.sub.2 H,
(11) --NR.sup.4 R.sup.7,
(12) --NHCOR.sup.7,
(13) --NHCO.sub.2 R.sup.7
(14) --SO.sub.2 NR.sup.8 R.sup.11, wherein R.sup.11 is
(a) --H or
(b) C.sub.1-4 alkyl,
(15) --NO.sub.2
(16) --NHSO.sub.2 R.sup.7
(17) --NHCONR.sup.4 R.sup.7,
(18) --OCONR.sup.7 R.sup.8,
(19) aryl,
(20) heteroaryl,
(21) --NHSO.sub.2 polyfluorophenyl,
(22) --SO.sub.2 NH-heteroaryl,
(23) --SO.sub.2 NHCOR.sup.7,
(24) --CONHSO.sub.2 R.sup.7,
(25) --PO(OR.sup.4).sub.2,
(26) --PO(OR.sup.4)R.sup.8,
(27) tetrazol-5-yl,
(28) --CONH(tetrazol-5-yl),
(29) --COR.sup.4
(30) --SO.sub.2 NHCN,
(31) --CO-heteroaryl,
(32) --NHSO.sub.2 NR.sup.7 R.sup.8,
(33) --CON(R.sup.5).sub.2 wherein the R.sup.5 groups are the same or different or
(34) C.sub.1-6 alkyl, either unsubstituted or substituted with
(a) --OH,
(b) -guanidino,
(c) --C.sub.1-4 alkoxy,
(d) --N(R.sup.4).sub.2,
(e) --CO.sub.2 R.sup.4,
(f) --CON(R.sup.4).sub.2,
(g) --O--COR.sup.4
(h) -aryl,
(i) -heteroaryl,
(j) --S(O).sub.x R.sup.7
(k) -tetrazol-5-yl,
(l) --CONHSO.sub.2 R.sup.7,
(m) --SO.sub.2 NH-heteroaryl,
(n) --SO.sub.2 NHCOR.sup.7,
(o) --PO(OR.sup.4).sub.2,
(p) --PO(OR4)R.sup.9,
(q) --SO.sub.2,NHCN,
(r) --NR.sup.11 COOR.sup.7,
(s) -morpholino,
(t) --N(C.sub.1-6 alkyl)piperazine or
(u) --COR.sup.4,
with the proviso that the R.sup.2 groups can be the same or different;
or two R.sup.2 groups joined to the same carbon taken together represent
(a)=O,
(b)=S, or
(c) --[(CH.sub.2).sub.2-6 ]--;
R.sup.2a, R.sup.2b, R.sup.3a and R.sup.3b independently represent
(1) C.sub.1-5 alkyl,
(2) polyfluoro-C.sub.1-5 alkyl,
(3) halo,
(4) hydroxy,
(5) C.sub.1-5 alkoxy,
(6) hydrogen or
(7) COOH;
U, V and W are each --CH.dbd.;
Z is:
(1) --O--,
(2) --S(O).sub.x --,
(3) --N(R.sup.12)--, wherein R.sup.12 is
(a) --H, or
(b) --R.sup.13, wherein R.sup.13 is
(i) C.sub.1-4 alkyl,
(ii) C.sub.3-7 cycloalkyl,
(iii) aryl,
(iv) heteroaryl,
(v) polyfluoro-C.sub.1-4 alkyl,
(vi) polyfluoro-C.sub.3-7 cycloalkyl, or
(vii) polyfluoro-phenyl;
(4) --N(COR.sup.13)--,
(5) --N(CONHR.sup.13)--,
(6) --N(CON(R.sup.13).sub.2)--,
(7) --N(CO.sub.2 R.sup.13)--,
(8) --N(SO.sub.2 NHR.sup.13)--,
(9) --N(SO.sub.2 N(R.sup.13).sub.2)--,
(10) --N(SO.sub.2 R.sup.13)--, or
X is
(1) a single bond,
(4) --C(R.sup.2).sub.2 --,
Y is
(3) --C(R.sup.2).sub.2 --.

182 more elements

Facts

Application

08/096,125Filed 22 Jul 1993 · continuation

Priority

25 Sep 1991

Granted

3 May 1994

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 239/91
Oxygen atoms: with aryl or aralkyl radicals attached in position 2 or 3
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/12
Drugs for disorders of the cardiovascular system: antihypertensives
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents

Family

Serial765,626Parent of this continuation-in-part · filed 25 Sep 1991

Serial923,273Parent of this continuation · filed 31 Jul 1992

US 5,256,667 AParent of this continuation

US 5,202,322 AParent of this continuation-in-part

US 5,308,846 AThis patent

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