Quinazolinone and pyridopyrimidine a-II antagonists

• US 5,202,322 A
• Filed: 09/25/1991
• Issued: 04/13/1993
• Est. Priority Date: 09/25/1991
• Status: Expired due to Fees

• Current Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.), Merck & Co., Inc.
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.), Merck & Co., Inc.
• Inventors: Olson, Richard E., Allen, Eric E.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US07/765,626
• Time in Patent Office: 566 Days
• Field of Search: 544/284, 544/285, 544/58.6, 544/57, 544/116, 544/287, 514/255, 514/259, 514/260, 514/234.5, 514/228.2
• US Class Current: 514/228.2
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 239/96 Two oxygen atoms

Abstract

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

Claims

1. A compound of structural formula:

##STR107## or a pharmaceutically acceptable salt thereof, wherein;

G is

(1) R¹ or ##STR108## E is (1) a single bond,

(2) --CH(OH)--,

(3) --O--,

(4) --CO--,

(5) --S(O)_x (CH₂)_s --wherein x is 0, 1, or 2, and s is 0-5, or

(6) --NR³ (CH₂)_s -- wherein R³ is

(a) --H,

(b) C_2-4 alkanoyl,

(c) C_1-6 alkyl,

(d) C_2-6 alkenyl,

(e) C_3-7 cycloalkyl,

(f) phenyl, or

(g) benzyl;

R is

(1) aryl,

(2) heteroaryl,

(3) C_3-7 cycloalkyl,

(4) polyfluoro-C_1-4 alkyl,

(5) --H,

(6) C_2-6 alkenyl,

(7) C_2-6 alkynyl,

(8) C_1-6 alkyl, either unsubstituted or substituted with;

(a) aryl,

(b) C_3-7 cycloalkyl,

(c) halo,

(d) --NH₂,

(e) --NH(C_1-4 alkyl),

(f) --N(C_1-4 alkyl)₂,

(g) --OR⁴, wherein R⁴ is

(i) --H,

(ii) aryl,

(iii) heteroaryl,

(iv) C_1-6 alkyl, or

(v) aryl-C_1-6 alkyl;

(h) --COOR⁴,

(i) --NHSO₂ R⁴, or

(j) --SO₂ NHR⁵, wherein R⁵ is

(i) --H

(ii) C_1-5 alkyl,

(iii) aryl or

(iv) --CH₂ --aryl;

R¹ is

(1) --CO₂ R⁴

(2) --SO₃ R⁶, wherein R⁶ is

(a)--H

(b)--CH(R⁴)--O--CO--R^4a wherein R^4a is

(i) C_1-6 alkyl,

(ii) aryl or

(iii) --CH₂ --aryl;

(3) --P(O)(OR⁶)₂,

(4) --CONHNHSO₂ CF₃,

(5) --SO₂ NHCN,

(6) --P(O)(OR⁶)(OR⁴),

(7) --SO₂ NHR⁷, wherein R⁷ is

(a) --H

(b) aryl,

(c) heteroaryl,

(d) C_3-7 cycloalkyl,

(e) polyfluoro-C_1-4 alkyl, or

(f) C_1-10 alkyl, either unsubstituted or substituted with;

(i) aryl,

(ii) heteroaryl,

(iii) --OH,

(iv) --SH,

(v) C_1-4 alkoxy,

(vi) C_1-4 alkylthio

(vii) halo

(viii) --NO₂

(ix) --CO₂ R¹¹, wherein R¹¹ is --H or C_1-4 alkyl,

(x) --NH₂,

(xi) --NH(C_1-4 alkyl)

(xii) --N(C_1-4 alkyl)₂

(xiii) --PO₃ H₂,

(xiv) --P(O)(OH)(OC_1-4 alkyl), or

(xv) --P(O)(OR⁴)(R⁸) wherein R⁸ is

(a) --H

(b) --C_1-5 alkyl,

(c) -aryl or

(d) --CH₂ --aryl,

(8) --NHSO₂ R⁷,

(9) --SO₂ NHCOR⁷,

(10) --CH₂ SO₂ NHCOR⁷,

(11) --CONHSO₂ R⁷,

(12) --CH₂ CONHSO₂ R⁷,

(13) --NHSO₂ NHCOR⁷,

(14) --NHCONHSO₂ R⁷,

(15) --SO₂ NHCONR⁴ R⁷,

(16) --CH₂ SO₂ NHR⁷,

(17) --C(OH)(R⁸)--P(O)(OR⁶)₂,

(18) --P(O)(R⁸)(OR⁶),

(19) tetrazol-5-yl, substituted with R⁹ wherein R⁹ is

(a) --H,

(b) C_1-6 alkyl,

(c) C_2-4 alkenyl,

(d) C_1-4 alkoxy-C_1-4 alkyl

(e) benzyl, either unsubstituted or substituted with

(i) --NO₂,

(ii) --NH₂,

(iii) --OH, or

(iv) --OCH₃,

(20) --CH₂ -tetrazol-5-yl substituted with R⁹,

(21) --CONH-tetrazol-5-yl substituted with R⁹,

(22) --1,3,4-triazol-2-yl substituted with R¹⁰ wherein R¹⁰ is

(a) --CN,

(b) --NO₂,

(c) --CF₃ or

(d) --CO₂ R⁴ ;

(23) 1,2,3-triazol-4-yl substituted with R¹⁰,

(24) --SO₂ NHSO₂ R⁷,

(25) --OH or ##STR109## R² is;

(1) --H,

(2) --CO-aryl,

(3) C_3-7 cycloalkyl,

(4) halo,

(5) --OH,

(6) --OR⁷

(7) polyfluoro-C_1-4 alkyl,

(8) --S(O)_x R⁷,

(9) --COOR⁴,

(10) --SO₂ H,

(11) --NR⁴ R⁷,

(12) --NHCOR⁷,

(13) --NHCO₂ R⁷

(14) --SO₂ NR⁸ R¹¹, wherein R¹¹ is

(a) --H or

(b) C_1-4 alkyl,

(15) --NO₂

(16) --NHSO₂ R⁷

(17) --NHCONR⁴ R⁷,

(18) --OCONR⁷ R⁸,

(19) aryl,

(20) heteroaryl,

(21) --NHSO₂ polyfluorophenyl,

(22) --SO₂ NH--heteroaryl,

(23) --SO₂ NHCOR⁷,

(24) --CONHSO₂ R⁷,

(25) --PO(OR⁴)₂,

(26) --PO(OR⁴)R⁸,

(27) tetrazol-5-yl,

(28) --CONH(tetrazol-5-yl),

(29) --COR⁴

(30) --SO₂ NHCN,

(31) --CO--heteroaryl,

(32) --NHSO₂ NR⁷ R⁸, or

(33) C_1-6 alkyl, either unsubstituted or substituted with

(a) --OH,

(b) --guanidino,

(c) --C_1-4 alkoxy,

(d) --N(R⁴)₂,

(e) --CO₂ R⁴,

(f) --CON(R⁴)₂,

(g) --O--COR⁴

(h) -aryl,

(i) -heteroaryl,

(j) --S(O)_x R⁷

(k) -tetrazol-5-yl,

(l) --CONHSO₂ R⁷,

(m) --SO₂ NH--heteroaryl,

(n) --SO₂ NHCOR⁷,

(o) --PO(OR⁴)₂,

(p) --PO(OR4)R⁹,

(q) --SO₂,NHCN,

(r) --NR¹¹ COOR⁷,

(s) -morpholino,

(t) --N(C_1-6 alkyl)piperazine or

(u) --COR⁴, with the proviso that the R² groups can be the same or different;

or two R² groups joined to the same carbon taken together represent

(a) =O

(b) =S or

(c) --[(CH₂)_2-6 ]--;

R^2a, R^2b, R^3a and R^3b independently represent

(1) C_1-5 alkyl,

(2) polyfluoro-C_1-5 alkyl,

(3) halo;

(4) hydroxy or

(5) C_1-5 alkoxy;

U, V and W are --CH═

or

Z is;

(1) --O--,

(2) --S(O)_x --

(3) --N(R¹²)-- wherein R¹² is

(a) --H or

(b) --R¹³ wherein R¹³ is

(i) C_1-4 alkyl,

(ii) C_3-7 cycloalkyl

(iii) aryl,

(iv) heteroaryl,

(v) polyfluoro-C_1-4 alkyl,

(vi) polyfluoro-C_3-7 cycloalkyl, or

(vii) polyfluorophenyl;

(4) --N(COR¹³)--,

(5) --N(CONHR¹³)--,

(6) --N(CON(R¹³)₂)--,

(7) --N(CO₂ R¹³)--,

(8) --N(SO₂ NHR¹³)--,

(9) --N(SO₂ N(R¹³)₂)--,

(10) --N(SO₂ R¹³)--, or

(11) --C(R²)₂ --,

X is

(1) a single bond

(2) --SO₂ --

(3) --O--

(4) --C(R²)₂ --

(5) --N(R¹²)--

(6) --N(COR¹³)--

(7) --N(CONHR¹³)--

(8) --N(CON(R¹³)₂)--

(9) --N(CO₂ R¹³)--

(10) --N(SO₂ NHR¹³)--

(11) --N(SO₂ N(R¹³)²)--

(12) --N(SO₂ R¹³)--

Y is

(1) --O--

(2) --S(O)_x -- where x is 0, 1, or 2,

(3) --C(R²)₂ --

(4) --N(R¹²)--

(5) --N(COR¹³)--

(6) --N(CONHR¹³)--

(7) --N(CON(R¹³)₂)--

(8) --N(CO₂ R¹³)--

(9) --N(SO₂ NHR¹³)--

(10) --N(SO₂ N(R¹³)₂)--

(11) --N(SO₂ R¹³)--.

2. The compound of claim 1 wherein G is ##STR110##

3. The compound of claim 2 wherein:

E is

(1) a single bond,

(2) --O-- or

(3) --S--;

R is

(1) C_1-6 alkyl, either unsubstituted or substituted with;

(a) C_3-5 cycloalkyl,

(b) --Cl,

(c) --CF₃,

(d) --OCH₃,

(e) --OC₂ H₅,

(f) --SCH₃,

(g) --SC₂ H₅

(h) --F, or

(i) phenyl;

(2) C_2-5 alkenyl,

(3) C_2-5 alkynyl, or

(4) C_3-5 cycloalkyl;

R¹ is

(1) --CO₂ H,

(2) tetrazol-5-yl,

(3) --NHSO₂ R⁷,

(4) --SO₂ NH--heteroaryl,

(5) --CH₂ SO₂ NH-heteroaryl,

(6) --SO₂ NHCOR⁷,

(7) --CH₂ SO₂ NHCOR⁷,

(8) --CONHSO₂ R⁷,

(9) --CH₂ CONHSO₂ R⁷

(10) --₂ NHSO₂ NHCOR⁷ or

(11) --NHCONHSO₂ R⁷

(12) --SO₂ NHCON(R⁴)R⁷

(13) --SO₂ NHCON Z

R² is;

(1) H,

(2) C_1-4 alkyl, either unsubstituted or substituted with;

(a) --CO₂ R⁴,

(b) --OCOR^4a,

(c) --OH, or

(d) --aryl;

(3) C_2-4 alkenyl,

(4) --OH,

(5) -NO₂,

(6) -NHCOR⁷,

(7) --C_1-4 alkoxy,

(8) --NHCO₂ R⁷,

(9) --NR⁴ R⁷ or

(10) --Cl, --F, or --Br;

or two R² groups on the same carbon taken together represent ═

O or --(CH₂)_2-5 --; and

X is

(1) --C(R²)₂ -- or

(2) a single bond;

Y is

(1) --C(R²)₂ -- or

(2) --N(R¹²)₂ --;

Z is

(1) --N(R¹²)--,

(2) --N(COR¹³)--,

(3) --N(CONHR¹³)--, or

(4) --N(CON(R¹³)₂)--,

(5) --O--

(6) --S--.

4. The compound of claim 3 of structural formula:

##STR111## or a pharmaceutically acceptable salt thereof selected from the group of compounds consisting of those in the following table;

space="preserve" listing-type="tabular">______________________________________ RE R.sup.1 Z ______________________________________ n-C.sub.4 H.sub.9 ##STR112## O n-C.sub.4 H.sub.9 ##STR113## ##STR114## n-C.sub.3 H.sub.7 ##STR115## ##STR116## n-C.sub.3 H.sub.7 ##STR117## ##STR118## n-C.sub.3 H.sub.7 ##STR119## ##STR120## n-C.sub.4 H.sub.9 ##STR121## ##STR122## ______________________________________

5. The compound of claim 1 wherein G is R¹.

6. The compound of claim 5 wherein:

E is

(1) a single bond,

(2) --O-- or

(3) --S--;

R is

(1) C_1-6 alkyl, either unsubstituted or substituted with;

(a) C_3-5 cycloalkyl,

(b) --Cl,

(c) --CF₃,

(d) --OCH₃,

(e) --OC₂ H₅,

(f) --SCH₃,

(g) --SC₂ H₅

(h) --F, or

(i) phenyl;

(2) C_2-5 alkenyl,

(3) C_2-5 alkynyl, or

(4) C_3-5 cycloalkyl;

R¹ is

(1) --CO₂ H,

(2) tetrazol-5-yl,

(3) --NHSO₂ R⁷,

(4) --SO₂ NH-heteroaryl,

(5) --CH₂ SO₂ NH-heteroaryl,

(6) --SO₂ NHCOR⁷,

(7) --CH₂ SO₂ NHCOR⁷,

(8) --CONHSO₂ R⁷,

(9) --CH₂ CONHSO₂ R⁷

(10) --₂ NHSO₂ NHCOR⁷ or

(11) --NHCONHSO₂ R⁷

(12) --SO₂ NHCON(R⁴)R⁷

(13) --SO₂ NHCON Z

R² is;

(1) H,

(2) C_1-4 alkyl, either unsubstituted or substituted with;

(a) --CO₂ R⁴,

(b) --OCOR^4a,

(c) --OH, or

(d) -aryl;

(3) C_2-4 alkenyl,

(4) --OH,

(5) --NO₂,

(6) --NHCOR⁷,

(7) --C_1-4 alkoxy,

(8) --NHCO₂ R⁷,

(9) --NR⁴ R⁷ or

(10) --Cl, --F, or --Br;

or two R² groups on the same carbon taken together represent ═

O; and

X is

(1) --C(R²)₂ -- or

(2) a single bond;

Y is

(1) --C(R²)₂ -- or

(2) --N(R¹²)₂ --;

Z is

(1) --N(R¹²)--,

(2) --N(COR¹³)--,

(3) --N(CONHR¹³)--, or

(4) --N(CON(R¹³)₂)--,

(5) --O--

(6) --S--.

7. The compound of claim 6 wherein E-R is ##STR123##

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

9. The composition of claim 8 which includes another antihypertensive selected from a diuretic selected from hydrochlorothiazide, chlorothiazide, chlorthalidone, methyclothiazide, furosemide, ethacrynic acid, triamterene, amiloride, atriopeptin and spironolactone;

a calcium channel blocker, selected from diltiazem, felodipine, nifedipine, amlodipine, rumodipine, isradapine, nitrendipine and verapamil;

a β

-adrenergic antagonist selected from timolol, atenolol, metoprolol, propanolol, nadolol and pindolol;

an angiotensin converting enzyme inhibitor selected from enalapril, lisinopril, captopril, ramipril, quinapril and zofenopril;

a renin inhibitor selected from A-69729, FK-906 and FK-744;

an α

-adrenergic antagonist selected from prazosin, doxazosin, and terazosin;

a sympatholytic agent selected from methyldopa, clonidine and guanabenz;

the atriopeptadase inhibitor UK-79300 (alone or with ANP);

the serotonin antagonist, ketanserin;

the A₂ -adenosine receptor agonist CGS 22492C;

a potassium channel agonist selected from pinacidil and cromakalim;

another antihypertensive drug selected from reserpine, minoxidil, guanethidine, hydralazine, hydrochloride and sodium nitroprusside;

a cardiac stimulant selected from dobutamine and xamoterol;

a phosphodiesterase inhibitor selected from amrinone and milrinone or combinations of the above-named drugs.

10. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim 1.

11. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim 1.

12. A method of treating ocular hypertension comprising administering to a patient in need of such treatment an effective ocular antihypertensive amount of a compound of claim 1.