GB2264710A - Quinoline and azaquinoline angiotensin ii antagonists incorporating a substituted biphenyl element - Google Patents

Abstract

Substituted quinolines and azaquinolines (1,5-naphthridines) attached through an alkoxy bridge to novel substituted biphenyl derivatives of the formula I, are useful as angiotensin II antagonists. <IMAGE> In particular they are useful in the treatment of hypertension, cognitive dysfunction, anxiety, depression and schizophrenia.

Description

TITLE OF THE INVENTION QUINOLINE AND AZAQUINOLINE ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BIPHENYL ELEMENT BACKGROUND OF THE INVENTION The Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other 4 organs. It is the end product of the reninangiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.

One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption EM. Antonaccio. Clin. Exp.

Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. - Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed.

A. E. Doyle, Vol. 5., pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].

Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847 in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A.T. Chiu, metal. EEur. J. Pharm. Exp. Therap, 151, 13-21 (1988)) and by P.C. Wong, et 1. [J. Pharm. Exp.

Therap, 247, 1-7(1988)). European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro2H-imidazo[4,5-c]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents. Recent publications EP 412,848 and WO 91/07404 describe quinoline and azaquinoline derivatives, respectively, as AII antagonists.

None of the compounds disclosed within this application have been claimed or disclosed in any published patents or articles, including the abovementioned publications.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel substituted quinoline and azaquinoline compounds which are useful as angiotensin II antagonists, as antihypertensives, in the treatment of congestive heart failure, and in the treatment of elevated intraocular pressure. The compounds of this invention have the general Formula I:

or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) Cl-C8-alkl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl,.

(e) C1-C8-perfluoroalkyl, (f) phenyl, or (g) phenyl-C1-C4-alkyl; and R2 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) CO2R10, (f) C1-C4-alkoxycarbonyl, (g) CN, (h) NO2, (i) phenyl, or (j) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a > H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: () aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R12, (iv) morpholin-4-yl, (v) OH, (vi) CO2R10, or - (vii) CON(R10)2, (c) C1-C6-alkoxy, (d) C1-C4-perfluoroalkoxy, (e) C1, Br, F, I, (f) CF3, (g) CN, (h) NO2, (i) OH, (j) NH2, (k) NH[C1-C6-alkyl], (1) NEC1-C6-alkyl]2, (m) N(CH2CH2)2O, (n) N(CH2CH2)2NCOR10, (o) N(CH2CH2)2NR10, (p) CO2R10, (q) C1-C4-alkoxycarbonyl, (r) CONH2, (s) CONH[C1-C7-alkyl], (t) CON[C1-C7-alkyl]2, (u) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group;; R5 is (a) H, (b) C1, Br, I, or F, (c) C1-C6-alkyl, (d) C1-C6-alkoxy, or (e) C1-C6-alkoxyalkyl; R6 is (a) H (b) C1, Br, I, or F, (c) NO2, (d) C1-C6-alkyl, (e) C1-C6-acyloxy, (f) C3-C7-cycloalkyl., (g) C1-C6-alkoxy, (h) -NHSO2R, (i) hydroxy(C1-C4-alkyl), (j) aryl(C1-C4-alkyl), (k) C1-C4-alkylthio, (1) Cl-C4-alkyl sulfinyl, (m) Cl-C4-alkyl sulfonyl, (n) NH2, (o) C1-C4-alkylamino, (p) di(C1-C4-alkyl)amino, (q) fluoro-C1-C4-alkyl-, (r) -SO2-NHR, (s) aryl, (t) furyl, (u) CF3, (v) C2-C6-alkenyl, or (w).C2-C6-alkynyl; R7 is (a) H, (b) C1, Br, I, or F, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di(C1-C4-alkyl)amino, (g) SO2NHR, (h) CF3, Ci) C1-C6-alkyl, (j) C1-C6-alkoxy, (k) C1-C6-alkyl-S-, (l) C2-C6-alkenyl, (m) C2-C6-alkynyl; (n) aryl, (o) aryl(Cl-C4-alkyl), or (p) C3-C7-cycloalkyl; wherein aryl is phenyl or naphthyl, or a substituted phenyl or naphthyl with one or two substituents selected from the group consisting of C1, Br, I, F, N(R)2, CO2R11, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, -SO2NR12R13, C3-C7-cycloalkyl, C3-C10-alkenyl, or S(O)x(C1-C4-alkyl);; R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R22,

(e) -SO2NHCN, (f) -SO2NHCO2R,

(h) -NHSO2NHSO2R22,

(v) - NHSO2R, (w) SO2NHRȃ, (x) SO2NHCOR, (y) SO2NHCONRȃR, (z) CH2SO2NHCOR22, (aa) CH2SO2N@CONHRȃ, (bb) CH2CONHS02R22, (cc) NHCONHSO2R, (dd) NHSO2NHCOR22, or (ee) CONHNHSO2R22; wherein Y is O or S; Z is O, S(O)x or NR14; R9 is: (a) H, or (b) C1-C6-alkyl; R10 is: (a) R9, (b) CH2-aryl, or (c) aryl; Rll is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or di substituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, -CF3, C1, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl;; R14 is H, C1-C6-alkyl, C1-C4-alkenyl, C1-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NHZ, -OH or -OCH3; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted or substituted with: i) NH2, ii) NH[C1-C4-alkyl], iii) N[C1-C4-alkyl]2, iv) CO2H, v) C02-C1-C4-alkyl, vi) OH, vii) S03H, or viii) SO2NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl, -OH, -SH1 C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, Cl, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NR12COR22a, -P03H2, -PO(OH)(O C1-C$-alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-alkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6 alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C$-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NR12COR22, -PO3H2, -PO(OH)(O-C1-C4 alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (f) perfluoro-C1-C4-alkyl; R23 is (a) H, (b) aryl as defined above, or (c) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, or CF3;; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C$-alkyl)2, CF3, -COOR10, or CN, (c) -OCH(R11)-O-CO-R16, (d) -OH, or (e) -O-C1-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, or (c) F, C1, Br; x is 0 to 2; and u is 1 to 3.

The alkyl substitutents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl., ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.

The alkenyl and alkynyl substituents denote alkyl groups as described above which ar modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.

Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each which may be substituted or unsubstitued with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.

The alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.

The heteroaryl substituent recited above represents any 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl, imidazolyl, pyrimidyl, oxazolyl, oxadiazolyl, oxathiadiazolyl and thiazolyl.

One embodiment of this invention is represented by the compounds of the formula (I), or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) Cl-C8-alkyl, Cc) C3-C8-cycloalkyl, (d) phenyl, or (e) phenyl-C1-C4-alkyl; and R2 is: (a) H, (b) C1-C8-alkyl, (c) CO2R10, (d) C1-C4-alkoxycarbonyl, (e) CN, (f) NO2, (g) phenyl, or (h) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a) H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R, (iv) morpholin-4-yl, (i) OH, (vi) CO2R10, or (vii) CON(R10)2, (c) C1-C6-alkoxy, (d) C1 or F, (e) CF3, (f) CN, (g) NO2, (h) OH, (i) NH2, (j) NH[C1-C6-alkyl], (k) N[C1-C6-alkyl]2, (l) N(CH2CH2)2O, (m) N(CR2CH2)2NCOR10, (n) N(CH2CH2)2NR10, (o) CO2R10, (p) C1-C4-alkoxycarbonyl, (q) CONH2, (r) CONH[C1-C7-alkyl], (s) CONEC1-C7-alkyl)2, or (t) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group; R5 is H;; R6 is H, F, C1, CF3, NO2, C1-C4-alkyl, C5-C6-cycloalkyl, -NHSO2CH3, NH2, C1-C4-alkylamino, di(C1-C4-alkyl)amino, -SO2-NHCH3, C2-C6-alkenyl, or C2-C6-alkynyl; R7 is H, F, C1, CF3, NO2, C1-C4-alkyl, aryl as defined hereinabove, C2-C6-alkenyl, or C2-C6-alkynyl; R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R,

(d) -SO2NHCN, (e) -SO2NHCO2R,

(g) -NHSO2NHSO2R,

(n) -NHSO2R, (o) SO2NHRȃ, (p) SO2NHCOR22, (q) SO2NHCONR22aR22, (r) CH2S02NHCOR22, (s) CH2SO2NHCONHRȃ (t) CH2CONHSO2R, (u) NHCONHSO2R, (v) NES02NHCOR22, or (w) CONHNHSO2R22; wherein Y is O or S; Z is O, S(O)x or NR14; R9 is: : (a) H, or (b) C1-C6-alkyl; R10 is: (a) R9, (b) CH2-aryl, or (c) aryl; R is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, -CF3, C1, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl; R14 is H, C1-C6-alkyl, C1-C4-alkenyl, C1-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NH2, -OH or -OCH3;; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R21 is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted or substituted with: i) NH2, ii) NH[C1-C4-alkyl], iii) N[C1-C4-alkyl]2, iv) CO2H, v) CO2-C1-C4-alkyl, vi) OH, vii) SO3H, or viii) SO2NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C$-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCORȃ, -PO3H2, -PO(OH)(O C1-C4-alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-alkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6 alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(Cl-C4-alkyl), -SCC1-C4-alkyl), -CF3 C1, Br, F, I, -NO2, -CO2H, CO2-CC1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCOR, -PO3H2, -PO(OH)(O-C1-C4 alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperaz-inyl, or (f) perfluoro-C1-C4-alkyl; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F.C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, (c) -OCH(R)-O-CO-R16, (d) -OH, or (e) -O-C1-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, or (c) F, C1, Br; x is 0 to 2; and u is 1.

A class of this embodiment is represented by the compounds of the formula (I), or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are each independently: (a) H, (b) C1-C6-alkyl, (c) C1 or F, (d) NO2, (e) C1-C6-alkoxy, (f) NH2, (g) NH[C1-C6-alkyl], (h) N[C1-C6-alkyl]2, (i) N(CH2CH2)2O, (j) N(CH2CH2)2NCOR10, (k) N(CH2CH2)2NR10, (l) CO2R10, (m) C1-C4-alkoxycarbonyl, (n) CONH2, (o) CONH[C1-C7-alkyl], (p) CON[C1-C7-alkyl]2, or (q) R3 and R4 may optionally together form a C1-C4-alkylenedioxy -group; R6 and R7 are each independently:H, F, C1, CF3, NO2, C1-C4-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl; R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R,

(d) -SO2NHCN, (e) -SO2NHCO2R,

(g) -NHSO2NHSO2R,

(n) -NHSO2R, (o) SO2NHRȃ, (p) SO2NHCOR, (q) SO2NHCONRȃR (r) CH2SO2NHCOR, (s) CH2SO2NHCONHRȃ, (t ) CH2CONHSO2R22, (u) NHCONHSO2R, (v) NHSO2NHCOR22, or (w) CONHNHSO2R; wherein Y is O or S; and Z is 0, S(O)x or NR14.

Another embodiment of this invention is represented by the compounds of the formula (I), or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) C1-C8-perfluoroalkyl, (f) phenyl, or (g) phenyl-C1-C4-alkyl; and R2 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) CO2R10, (f) C1-C4-alkoxycarbonyl, (g) CN, (h) NO2, gi) phenyl, or (j) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a) H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R12, (iv) morpholin-4-yl, (v) OH, (vi) CO2R10, or (vii) CON(R10)2, (c) C1-C6-alkoxy, (d) C1-C4-perfluoroalkoxy, (e) C1, Br, F, I, (f) CF3, (g) CN, (h) NO2, (i) OH, (j) NH2, (k) NH[C1-C6-alkyl], (l) N[C1-C6-alkyl]2, (m) N(CH2CH2)2O, (n) N(CH2CH2)2NCOR10, (o) N(CH2CH2)2NR10, (p) CO2R10, (q) C1-C4-alkoxycarbonyl, (r) CONH2, (s) CONH[C1-C7-alkyl], (t) CON[C1-C7-alkyl]2, (u) r and R4 may optionally together form a C1-C4-alkylenedioxy group; R5 is (a) H, (b) C1, Br, I, or F, (c) C1-C6-alkyl, (d) C1-C6-alkyl, or (e) C1-C6-alkoxyalkyl;; R6 is (a) H (b) C1, Br, I, or F, (c) NO2, (d) C1-C6-alkyl, (e) C1-C6-acyloxy, (f) C3-C7-cycloalkyl, (g) C1-C6-alkoxy, (h) -NHSO2R, (i) hydroxy(C1-C4-alkyl), (j) aryl(C1-C4-alkyl), (k) C1-C4-alkylthio, (l) C1-C4-alkyl sulfinyl, (m) C1-C4-alkyl sulfonyl, (n) NH2, (o) C1-C4-alkylamino, (p) di(C1-C4-alkyl)amino, (q) fluoro-C1-C4-alkyl-, (r) -SO2-NHR, (s) aryl, (t) furyl, (u) CF3, (v) C2-C6-alkenyl, or (w) C2-C6-alkynyl; R7 is (a) H, (b) C1, Br, I, or F, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di(C1-C4-alkyl)amino, (g) S02NHR12, (h) CF3, (i) C1-C6-alkyl, (j) C1-C6-alkoxy, (k) C1-C6-alkyl-S-, (1) C2-C6-alkenyl, (m) C2-C6-alkynyl; (n) aryl, (o) aryl(C1-C4-alkyl), or (p) C3-C7-cycloalkyl; 4 wherein aryl is phenyl or naphthyl, or a substituted phenyl or naphthyl with one or two substituents selected from the group consisting of Cl, Br, I, F, N(R)2, CO2R, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3.

C1-C4-alkylthio, OH, -SO2NRR C3-C7-cycloalkyl, C3-C10-alkenyl, or S(O)x(C1-C4-alkyl); R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -S02NHS02R22,

(e) -SO2NHCN, (f) -SO2NHCO2R,

(h) -NHSO2NHSO2R,

(v) -NHSO2R wherein Y is O or S; Z is O, S(O)x or NR14; R9 is: (a) H, or (b) C1-C6-alkyl; R10 is:: (a) R9, (b) CH2-aryl, or (c) aryl; Rll is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or di substituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, -CF3, Cl, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl;; R14 is H, C1-C6-alkyl, C1-C4-alkenyl, Ci-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NH2, -OH or -OCH3; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R21 is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted or substituted with: i) NH2, ii) NH[C1-C4-alkyl], iii) N[C1-C4-alkyl]2, iv) CO2H, V) C02-C1-C4-alkyl, vi). OH, vii) SO3H, or viii) SO2NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCORȃ, -PO3H2, -PO(OH)(O C1-C4-alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-alkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6 alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCOR, -PO3H2, -PO(OH)(O-C1-C4 alkyl), -POCOR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (f) perfluoro-C1-C4-alkyl; R23 is (a) H, (b) aryl as defined above, or (c) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OR, -NH2, -NH(C1-C4-alkyl).

-N(C1-C4-alkyl)2, or CF3; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -NCC1-C4-alkyl)2, CF3, -COOR10, or CN, (c) -OCH(R)-O-CO-R16, (d) -OR, or (e) -O-C1-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NR(C1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, or (c) F, Cl, Br; x is O to 2; and u is 1 to 3.

GENERAL METHODS FOR PREPARATION OF COMPOUNDS OF GENERAL FORMULA I: The methods described below illustrate the preparation of angiotensin II antagonists of Formula I. There are several general approaches to the synthesis of antagonists of Formula I, and it is taken as a general principle that one or another method may be more readily applicable for the preparation of a given antagonist; some of the approaches illustrated below may not be readily applicable for the preparation of certain antagonists of Formula I.

It should be recognized that antagonists of Formula I consist of a heterocyclic component designated by Formula 1 and a substituted methyl biphenyl substituent which is attached to the heterocyclic component through an oxygen atom. Thus, two generally applicable approaches to antagonists of formula I are these: A substituted quinolone or azaquinolone of formula 1 is prepared as described below in Part I.

The uinolone o azaquinolone is then alkylated at the oxygen atom with a substituted biphenylmethyl halide.or pseudohalde giving an O-alkylated quinoline or azaquinoline as described in the Schemes below, this alkylating agent is.often designated as "ArCH2-Q where Q is a halide (-Cl,3r,I) or pseudohalide (-OMs, OTs, OTf). In some cases, alkylation may take place at both the oxygen and nitrogen atoms of the pyridine ring, and in these cases, separation by fractional crystallization or by chromotographic methods may be necessary for isolation of the desired product.In some cases, the alkylation step produces a fully-assembled antagonist of Formula I, except that functional groups on the alkylating agent or on the quinoline or azaquinoline moiety may be present in protected form and require deprotection steps to be carried out to complete the synthesis. In other cases, the alkylation of the heterocycle is carried out with a substituted biphenylmethyl halide or pseudohalide ("ArCH2-Q"), but here the alkylation step is followed by subsequent steps which are required to assemble the functional groups on the biphenyl moiety of the antagonist of Formula I. The alkylation steps and subsequent steps used to prepare antagonists of formula I, are described below.

In cases where the biphenylmethyl halides and pseudohalides are not commercially available, they are prepared as described below or by standard methods of organic synthesis. Subsequent steps which may be required to complete the synthesis of antagonists of Formula I are described below.

The compounds of this invention, their pharmaceutically acceptable salts and their prod rug forms are included within the scope of this invention.

Abreviations used in schemes and examples are listed in Table 1.

TABLE 1 Reagents.

NBS N-bromosuccinimide AIBN Azo(bis)isobutyronitrile DDQ Dichlorodicyanoquinone Ac2O acetic anhydride TEA tr iethylamine DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine TFA trifluroacetic acid TMS-C1 trimethylsilyl chloride Im imidazole AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid DIPEA Diisopropylethylamine TBS-C1 Tributylsilyl chloride TBAF tetrabutylammonium fluoride TMSCN trimethylsilyl cyanide Solvents: DMF dimethylformamide HOAc (AcOH) acetic acid EtOAc (EtAc) ethyl acetate Hex hexane THF tetrahydrofuran DMSO dimethylsulfoxide MeOH methanol iPrOH isopropanol hexamethylphosphoramide Others:: Phe phenylalanine rt room temperature TBDMS t-butyldimethylsilyl OTf OSO2CF3 Ph phenyl FAB-MS (FSBMS) Fast atom bombardment mass spectroscopy NOE Nuclear Overhauser Effect SiO2 silica ge-l trityl triphenylmethyl Bn benzyl PART I: Preparation of the guinol-4-ones and 1,5-azaquinol-4-ones of Formula 1

E = CH or N The compounds of Formula 1 can be prepared using the synthetic routes shown below in Schemes I-1 and I-2. Scheme I-1 describes the Conrad -Limpach synthesis EChem.Ber, A2, 523 (1988)] a straight forward route to quinol-4-ones.The 1,5-azaquinol4-ones can be prepared by an analogous route as shown in Scheme I-2. Recent EPO and PCT publications, EP 412,848 and WO 91/07404, by ICI describe the preparation of the quinol-4-ones and 1,5-azaquinol-4-ones, respectively.

SCHEME I-1

SCHEME I-2

PART II:- Preparation of substituted benzyl derivatives of the general Formula I The synthesis of Angiotensin II Antagonists of Formula I may be accomplished as shown in Scheme II-. Treatment of the appropriate quinolone or azaquinolone (l) with a biphenylmethyl compound (2) bearing a good leaving group and appropriate substituents such as R7 and R8a, in the presence of an appropriate base, may provide a precursor compound The R8a-group may then be transformed into appropriate R8 functional groups to provide desired antagonists of the formula I.

SCHEME II-1

The biphenylmethyl halides (2) can be prepa d as described in European Patent Applications 253,310 and 291,969 and the references cited therein. However, a preferred method to prepare the biphenyl precursors 7a, 7b and 7c, using Ni (O) or Pd(O) catalyzed cross-coupling reaction (E. Negishi, T. Takahashi, and A. O. King, Org Synthesis, 66, 67 (1987)], is outlined in Scheme II-2. As shown in Scheme II-2, treatment of 4-bromotoluene (4) with t-BuLi, followed by the addition of a solution of ZnCl2, produces the organo-zinc compound (5).

Compound (5) is then coupled with ii or 6b in the presence of Ni(PPh3)2C12 catalyst to produce the desired biphenyl compound 7a or 7b. Similarily, l-iodo-2-nitro-benzene (6c) is coupled with organo-zinc compound 5 in the presence of Pd(PPh3)4 catalyst Prepared by treating C12Pd(PPh3)2 with (i-Bu)2AlE (2 equiv.)] to give the biphenyl compound 7c. These precursors, 7a, 7b and 7c,-are then transformed into halomethylbiphenyl derivatives ti, 8b and 8c, respectively, according to procedures described in European Patent Applications 253,310 and 291,969.

SCHEME 11-2

When there are additional substituents on the second phenyl ring, the preferred method to prepare the bihenyl precursors 7d and 7e, using the Pd(O) catalyzed cross-coupling reaction [J. K.

Stille, Angew Chem. Int. Ed. Engl., 25, 508 (1986)), is outlined in reaction Scheme II-3. As shown in Scheme II-3, p-tolyltrimethyltin (e) is coupled with 6d or 6e in refluxing toluene in the presence of 5 mole.% of Pd(PPh3)4 to produce the desired biphenyl compounds 7d and 7e. Compounds 7d (R7 = NO2) and 7e (R7 = NO2) could be converted to their respective chlorides by catalytic hydrogenation, diazotization and treatment with copper (I) chloride. The biphenyl fluorides which could not be obtained by direct coupling to a fluoro arylbromide were prepared from 7d (R7 = NO2) and 7e (R7 = NO2) via reduction, formation of the diazonium tetrafluoroborate salt and thermal decomposition.These precursors 7d (R7 = NO2 or F or C1) and 7e (R7 = NO2 or F or C1) are then transformed into the halomethyl biphenyl derivatives 8d and 8e, respectively according to the procedures described in European Patent Applications 253,310 and 292,969.

REACTION SCHEME 11-3

Compounds of formula I where R8 is S02NECOR22 may be prepared as outlined in Scheme II-4. The nitro compound, for example 7c (prepared as described in Scheme 11-2), can be reduced to the corresponding amino compound and converted into aromatic diazonium chloride salt, which then can be reacted with sulfur-dioxide in the presence of a copper (II) salt to form the corresponding arylsulfonyl chloride 10 [R. Meerwein, G. Dittmar, R.

Gollner, K. Hafner, F. Mensch and 0. Steifort, Chem.

Ber., 90, 841 (1957); A.J. Prinsen and H. Cerfontain, Recueil, 84 24 (1965); E.E. Gilbert, Synthesis, .3 (1969) and references cited therein). The sulfonyl chloride can be reacted with ammonia in aqueous solution or in an inert organic solvent [F.H. Bergheim and W. Baker, J.Amer. Chem.Soc., 66, (1944), 1459), or with dry powdered ammonium carbonate, [E.H.

Huntress and J.S. Autenrieth, j. Amer. Chem. Soc., 63 (1941), 3446; E.H. Huntress and F.H. Carten, J.Amer.

Chem. Soc., 62, (1940), 511) to form the sulfonamide 11. The sulfonamide must then be protected preferably with. the triphenylmethyl group by reaction with triphenylmethylchloride and triethylamine to give 12. The benzyl bromide 13 may be prepared from the sulfonamide 12 as outlined in Scheme II-2, and then can be reacted with an alkali metal salt of an appropriate quinolinone or azaquinolinone compound to form the key sulfonamide 14. The sulfonamide 14 may then be acylated under appropriate conditions to give 15.

SCHEME II-4

SCHEME II-4 (CONT'D) a. (i) H2/Pd-C, (ii) NaN02-HCl, (iii) SO2, AcOH, CuCl2 b. NR3 or (NH4)2CO3 c. (C6H5)3CC1, Et3N, CH2C12, 25 C d. N-Bromosuccinimide e. R22COC1 or R22CO-Im or other acylating agents.

The biaryl sulfonamides 21 and 12 (described in Scheme 11-4) can be prepared alternatively using palladium(0) catalyzed cross-coupling reactions of appropriate aryl-organotin precursors [J.K. Stille, Pure Appl. Chem., 51, 1771 (1985); T.R. Baiely, Tetrahedron Lett., 27, 4407 (1986); D.A. Widdowson and Y.Z. Zhang, Tetrahedron, 42, 2111 (1986)], as outlined in Scheme II-5. The organotin compound 17 ES.M. Moerlein, J. Organometallic Chem., 319, 29 (1987)], obtained from the aromatic precursor 16, may be coupled with aryl sulfonamide 19 and 20 using Pd(PPh3)4 or (PPh3)2PdC12 as catalysts to give biaryl sulfonamide 21 and 13, respectively.Similarly, the benzyl bromides 26a and 26b may be alternatively prepared from the appropriate organotin precursor 24 using the Pd(0) catalyzed cross-coupling reaction as outlined in Scheme II-7.

SCHEME II-5

a. (i) t-BuLi/ether, -78 C or Mg, ether; (ii) Me3SnCl b. (i) NaNO2/HCl (ii) SO2, CuCl2 c. Pd(PPh3)4, toluene, reflux or (PPh3)2PdC12, DMF, 90 C.

SCHEME II-6

a. t-BuMe2Si-Ci/imidazole, DMF b. t-BuLi, -780C, Me3SnCl c. tetrabutylammonium fluoride d. CBr4/Ph3P The compounds bearing R8 as SO2NHRȃ (where R228 is heteroaryl) may be prepared from the sulfonamide 14 as outlined in Scheme II-7.

SCHEME II-7

ER = 2-pyridinyl, 2-pyrimidinyl, 3-isooxazoyl, 3-isothiazolyl, 2-oxazoyl or 2-thiazoyl.] Treatment of 14 with appropriate heteroaryl sulfone (27) may provide the desired sulfonamides 28.

The heteroaryl sulk one (27) may be prepared from the corresponding heterocyclic amine 2 as outlined in Scheme II-7.

SCHEME II-8

a. Imidazole, CH2C12 b. Pd(PPh3)2Cl2, DMF, 80 C-120 C c. RNH2, THF or DMF d. (C6H5)3C-Cl, Et3N e. tetrabutylammonium fluoride f. CBr4/PPh3 or CH3SO2-C1, Et3N Alternatively, compounds 28 may be prepared by the alkylation of appropriate quinolinone or azaquinolinones (1) with the alkylbromide 37a or 37b, The synthesis of alkylating agents 37a and 37b may be accomplished as outlined in Scheme 11-8. The sulfonylimidazole 33 prepared from 32, can be subjected to Pd(O) mediated biaryl cross-coupling reaction to provide 34, which then can be reacted with an appropriate heterocyclic amine to yield the sulfonamide 35.Protection of the sulfonamido group may provide 36, which upon desilylation and further treatment with either CBr4/Ph3P or CH3SO2Cl may give desired alkylating agents 37a and 37b, respectively.

Compounds bearing R8= -CH2SO2NHCOR22 and -CH2SO2NHR may be prepared as outlined in Scheme II-9. The key precursor aryl-methanesulfonyl chloride 43 may be prepared either from the reaction of arylmethylmagnesium chloride 42, obtained from the corresponding benzyl chloride Al and magnesium, or.by oxidation of the aryl-methylthioacetate 41 (prepared from the benzyl bromide 40 with chlorine in presence of trace amount of water) (3agnay and Dransch, Chem.

Ber., 93, 784 (1960)]. Alternatively, the aryl-methylthioacetate 41 can be oxidized with sulfuryl chloride in presence of acetic anhydride to form arylmethylsulfinyl chloride (S. Thea and G.

Cevasco, Tet. Lett., 28, 5193 (1987)), which can be further oxidized with appropriate oxidizing agents to give the sulfonyl chloride 43. The compounds 44 and 45 can be obtained by reacting the sulfonyl chloride 43 with appropriate amines.

SCHEME 11-9

SCHEME II-9 (CONT'D) a. (i) EtOCOCl/Et3N, THF, 0 C (ii) NaBH4 (iii) CCl4 or CBr4/PPh3 b. AcSK c. S02C12 d. C12, AcOH, H20 or, (i) SO2Cl2 (ii) oxidation e. RyNH2 or, (i) NR3 (ii) acylation.

Compounds 49 where R8= -NHSO2NHR may be prepared by the reaction of appropriate primary amines with the sulfamide 48 (S.D. McDermott and W.J.

Spillane, Synthesis, 192 (1983)), as described in Scheme II-10. The compound 48 may be obtained from the corresponding N-t-butylsulfamide 47 after treatment with anhydrous trifluoroacetic acid EJ.D.

Catt and W.L. Matier, J. Org. Chem., 39, 566 (1974)]. The N-t-butylsulfamide 47 may be prepared by the reaction of the aromatic amine 46 (prepared as 4 in Scheme II-1) with t-butylsulfamoyl chloride [W.L.

Matier, W.T. Comer and D. Deitchman, J. Med. Chem., ii, 538 (1972)].

SCHEME II-10

SCHEME II-ll

Alternatively, the amine 50 may be converted into the sulfamoyl chloride 51, which upon further reaction with the amine 46 may provide the desired antagonists 49 (Scheme II-11).

Compounds of formula I where R8 is

may be prepared from the corresponding carboxylic acid derivatives C) (prepared from the corresponding derivative 3 described in Scheme II-1) as outlined in Scheme II-12. The carboxylic acid (52) can be converted into the corresponding amide by treatment with carbonyldiimidazole and then with ammonia. The resulting amide then can be treated with sodium hydride or n-butyllithium in TRF at -20 C followed by an appropriately substituted phosphonyl or phosphinyl halide to form the desired compounds (53).

SCHEME II-12

Compounds of formula I where R8 is -S02NE502R22 may be prepared from the key sulfonamide intermediate 54 as outlined in Scheme II-13. The intermediate 54 may be prepared by the alkylation of appropriate heterocycles with the alkylating agent 26b as outlined in Scheme II-1. Treatment of 54 with trifluoroacetic acid followed by sulfonylation of the resulting sulfonamide 14 with appropriate sulfonyl chlorides may produce the desired compounds (55).

SCHEME 11-13

a. i) NaH/THF or DMF (ii) RSO2Cl b. RSO2Cl, DBU, THF Compounds of Formula (I) wherein R8 is -SO2NHCO2R may be prepared by reacting an appropriate chloroformate with the sulfonamide (14) in pyridine or in the presence of DBU in THF to afford the desired compound (56), as outlined in Scheme II-14.

SCHEME II-14

pyridine or DBU, THF Compounds of Formula (I) wherein R8 is

may be prepared by treating sulfonamide (14) with n-butyllithium in THF followed by the treatment of the resulting anion with an appropriately substituted phosphonyl or phosphinyl halide to form the desired compounds (57). (Scheme II-15) SCHEME II-15

a. BuLi, -2O0C in

Compounds of Formula (I) wherein R8 is SO2NRSO2N(R11)(R12) or

may also be prepared from sulfonamide (14) as outlined in Scheme II-16. Treatment of 14 with n-butyllithium in THF at -25 C and then with an appropriate sulfamoyl halide may produce the desired product (58) or (59).

SCHEME 11-16

a. nBuLi, -250C in THF b- R*-SO2Cl Compounds of Formula (I) wherein R8 is -NHS02NES02R22 or

may be prepared from the protected amino sulfonamide (47), as outlined in Scheme II-17. The amino sulfonamide (48) obtained after removal of the t-butyl protecting group may then be reacted with an appropriate acylating agent in the presence of a base such as pyridine or DBU in an organic solvent such as THF or DMF to form the desired products (60) or (61).

Compounds of the Formula (I) wherein R1 is -NHS02R22 may be prepared by the reaction of an appropriate sulfonyl halide (R22S02C1) or sulfonyl imidazole derivative with the aryl amine 46 in the presence of an appropriate base such as pyridine, triethylamine or DBU.

SCHEME 11-17

Compounds of Formula (I) where R8 is SO2NHCN may be prepared, as outlined in Scheme II-18.

SCHEME 11-18

a. NaN(SiMe3)2, THF b. BrCN Compounds 66 of Formula (I) and the benzyl halides of the formula (55) wherein R8 is 1,2,3,5oxathiadiazole-2-oxide may be prepared from the corresponding cyano derivative (63) or cyano precursor (8b) as outlined in Schemes II -19 and II-20, respectively utilizing procedures described in U.S. Patent 4,910,019. The cyano derivatives (63), obtained as described in Scheme II-2, can be converted into the corresponding amidoxime (64) by treatment with hydroxylamine hydrochloride and sodium methoxide in an organic solvent, such as methanol or DMSO.The amidoxime (64) then can be treated with base and thionyl chloride in an aprotic solvent to form the desired 1,2,3,5-oxathiadiazole-2-oxide (65). Similarly, the oxathiadiazole-2,2-dioxide iS can be prepared by treatment of amidoxime 64 with a base and sulfuryl chloride. As shown in Scheme II-20, the cyano precursor (8a) may be converted into the desired 1,2,3,5-oxathiadiazole (68) which is then protected with the trityl group prior to the formation of the desired benzyl halide (69). The protecting group is removed subsequent to the alkylation of heterocycle 1 to give the desired (product (65).

SCHEME II-19

SCHEME 11-20

Compounds of Formula (I) and the benzyl halides of the formula (3) wherein R8 is 1,2,3,5-thiatriazole-l-oxide may be prepared from the corresponding precursors 70 or 75 as outlined in Schemes II-21 and II-22, respectively. Intermediate 75 may be prepared from the biphenyl 8a according to the scheme illustrated (see procedures described in U.S.

Patent No. 4,870,186). Intermediates (71) and (76) can be treated with SOCl2 (see procedures described in: Ber. Deutsch. Chem. Ges. 1971, 104 pp 639) td give intermediates, 72 and 77. Bromination of the N-protected compounds 72 and 77 provides intermediates 74 and 78 respectively. After alkylation with an appropriate heterocycle, the trityl group of the intermediate derived from 74 is removed with protic acid and the cyanoethyl group of the intermediate derived from 78 is removed upon treatment with hydroxide. Alternatively, 74 and 78 may be prepared as shown in Scheme 11-23 and II-24.

Treatment of 79 with SOCl2 (see procedures in: Ber.

Deutsch. Chem. Ges. 1971, 104 pp 639) provides 80, which under mild hydrolytic conditions provides 72.

The conversion of 72 to 74 is as described for Schemer II-24. Alkylation of the trityl protected analog 81 by treatment with a base such as NaH and an alkyl halide would provide 73, which then may be converted to 78 as previously described.

SCHEME II-22

SCHEME 11-22

SCHEME 11-23

SCHEME II-24

Compounds of Formula (I) and the benzyl halides of formula (3) wherein R8 is 1,2,3,5-thiatriazole-l,l-dioxide-4-yl may be prepared using procedures described in Nonatsh. Chem., 1985, 116, pp 1321 and described herein. Sequential treatment of intermediates such as 75 or 71 with n-BuLi and S02F2 will provide the 1,2,3,5-thiatriazol-l,l-dioxide analogs of 72 and 76. Further elaboration of the afore mentioned analogs by the methods described for the conversion of 72 to 74 in Scheme II-21 and the methods described for the conversion of 76 to 78 in Scheme II-22 would give the benzyl halides of formula (Ç) wherein R8 is 2-triphenylmethyl-1,2,3,5- thiatriazole-l,l-dioxide-4-yl and 5-triphenylmethyl 1,2,3,5-thiatriazole-l,l-dioxide-4-yl, respectively.

Compound of Formula (I) wherein R8 is 3-oxo-1,2,4-thiadiazolidine-1,1-dioxide may be prepared from the nitro derivative C) as outlined in Scheme II-24. The amino compound 82 obtained from 8c may be reacted with t-butyl sulfamoylchloride to form the intermediate 83, which then can be alkylated with an appropriate bromoacetic acid derivative to give 84. Treatment of 84 with trifluoroacetic acid followed by the treatment with an appropriate base such as sodium or potassium alkoxide may produce the desired compound 8f, which can be elaborated further to give the key alkylating agent 87 as outline in the scheme. Alkylation of an appropriate heterocyclic compound with 87 may then furnish the desired antagonist.

SCHEME II-24

Compound of Formula (I) wherein R8 is 5-aminosulfonyl-1,2,4-oxadiazole may be prepared using the bromomethyl biphenyl derivative 91 and an appropriate heterocyclic compound. The synthesis of 91 can be accomplished as outlined in Scheme II-25.

The amidoxime 67 may be reacted with S-methylisothiourea to form the 5-amino-1,2,4-oxadiazole 88, which can be then treated with an appropriate sulfonylchloride to give the corresponding 5-aminosulfonyl-1,2,4-oxadiazole 89. The appropriately protected derivative W0 then can be brominated to form the desired alkylating agent al.

SCHEME II-25

Compounds of Formula (I) wherein R8 is 3-aminosulfonyl-1r2,4-oxadiazole can be prepared starting from the carboxylate derivative (8a) as outlined in Scheme II-26. The ester derivative 92 obtained from 8a is treated with N-hydroxy guanidine sulfate in the presence of an alkoxide base to form the 3-amino-1,2,4-oxadiazole derivative 93, which may be reacted with an appropriate sulfonyl chloride to give the 3-aminosulfonyl-1,2,4-oxadiazole compound 94.

The compound 95 can be prepared from 94 as outlined in Scheme II-26.

SCHEME II-26

Compounds of Formula (I) and the benzyl halides of formula (X) wherein R8 is 1,2,3-ox@th@azin- 4(3H)-one-2,2-dioxide-6-yl may be prepared as outlined in Scheme 11-27. As shown and according to procedures in Anaew. Chem, Int. Edn., (1973), 12, pp 869, the betaketoester (97) is treated with fluorosulphonyl isocyante, heated to extrude CO2 and iso-butene, then treated with base such as KOH to form the oxathiazolinone dioxide intermediate (98).

Treatment of (98) with triphenylmethyl chloride and triethylamine in CH2Cl2 gives been which in turn is converted to benzyl halide (100) by treatment with N-bromosuccinimide, AIBN, in CCl4 at reflux.

SCHEME 11-27

Compounds of Formula (I) wherein R8 is oxamic acid may be prepared utilizing procedures described in J. Med. Chem., 1981, 24, pp 742-748 and as outlined in Scheme II-28. The amine (46) is reacted with ethyl oxalyl chloride in the presence of a base such as pyridine or triethylamine and a solvent such as CH2Cl2 to form the intermediate oxalyl ester which is subsequently saponified with hydroxide to form oxamic acid (101).

SCHEME II-28

Compounds of Formula (I) wherein R8 is -SO2NR22aOR22a may be prepared as outlined in Scheme 11-29. The key intermediate 103 is prepared by the reaction of an appropriate heterocyclic compound (2), preferably as an alkali metal salt, with the alkylating agent 102 (prepared from 36). The compound 105, prepared from the sulfonyl chloride 104 and O-t-butylhydroxylamine, is then reacted with 103 in the presence of a Pd(0) catalyst to give 106.

Removal of the t-butyl protecting group produces the desired N-hydroxy sulfonamide 107.

SCHEME II-29

It will be appreciated by those skilled in the art that functional group transformations can be conducted on aryl and heterocyclic rings to afford desired analogs. For example, esters may be converted to amides by heating them with amines and an amide nitrogen if present in the heterocycle may be alkylated using bases such as sodium hydride in DMF with the appropriate alkyl halide. Functional group protection throughout these syntheses will be chosen to be compatible with subsequent reaction conditions. Ultimately such protecting groups will be removed to generate the desired optimally active compounds of Formula I.

The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.

Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H2SO4, H3PO4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.

The non-toxfc, physiologically, acceptable salts are preferred, although other salts are also useful; e.g., in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.

It will be further appreciated that the compounds of general Formula I in this invention may be derivatized at functional groups to provide prodrug derivatives which are capable of conversion back to the parent compounds In vivo. The concept of prodrug administration has been extensively reviewed (e.g. A.A. Sinkula in Annual Reports in Medicinal Chemistry, Vol 10, R.V. Heinzelman, Ed., Academic Press, New York London, 1975, Ch. 31, pp. 306-326), H. Ferres, Druas of Tod, Vol.19, 499-538 (1983) and J. Med. Chem., 18, 172 (1975). Examples of such prodrugs include the physiologically acceptable and metabolically labile ester derivatives, such as lower alkyl (e.g. methyl or ethyl esters), aryl (e.g.

5-indanyl esters), alkenyl (e.g. vinyl esters), alkoxyalkyl (e.g. methoxymethyl esters), alkylthioalkyl (e.g. methylthiomethyl esters), alkanoyloxyalkyl (e.g. pivaloyloxymethyl esters), and substituted or unsubstituted aminoethyl esters (e.g.

2-dimethylaminoethyl esters). Additionally, any physiologically acceptable equivaients of the compounds of general Formula I, similar to the metabolically labile' esters, which are capable of producing the parent compounds of general Formula I in vivo, are within the scope of this invention.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as competitive antagonists of AII at the receptors. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established.

Receptor binding assay using rabbit aortae membrane PreDaration: Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5mM Tris-0.25M Sucrose, pH 7.4 buffer (.50 ml) homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4OC.

The pellet thus obtained was resuspended in 30 ml of 50mM Tris-5 mM MgC12 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitration and the suspension was used for 100-assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 ml) there was added l25I-SarlIle8-angiotensin II [obtained from New England Nuclear] (10ml; 20,000 cpm) with or without the test sample and the mixture was incubated at 370C for 90 minutes. The mixture was then diluted with ice-cold 50EM Tris-0.9% NaCl, pH 7.4 (4ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter.The inhibitory concentration (IC50) of potUiltial AII antagonist which gives 50% displacement of the total specifically bound 1251-Sar1Ile8-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.

Preceptor assay using Bovine adrenal cortex presaratio Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HC1 (50mM), pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na2HPO4 (lOmM)-NaCl (120mM)-disodium EDTA (5mM) containing phenylmethane sulfonyl fluoride (PMSF)(O.lmM)I. (For screening of compounds, generally duplicates of tubes are used).

To the membrane preparation (0.5 ml) there was added 3H-angiotensin II (50mM) (lOml) with or without the test sample and the mixture was incubated at 370C for 1 hour. The mixture was then diluted with Tris buffer (4ml) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (lOml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist which gives 50% displacement of the total specifically bound 3H-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.

Using the methodology described above, rePre-ntative compounds of the invention were evaluated and were found to exhibit an activity of at least IC50 < 50mM thereby demonstrating and confirming the utility of the compounds of the invention as effective AII antagonists.

The potential antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 strokes per minute, volumn - 1.1 cc per 100 grams body weight).The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37"C by a thermostatically controlled heating pad which received input from a rectal temperature probe. Atropine (l-mg/kg i.v.) was then administered and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later antagonists of formula I were administered intravenously or orally. Angiotensin II was then typically given at 5, 10, 15, 30, 45 and 60 minute intervals and every half-hour thereafter for as long as the test compound showed activity. The change in the mean arterial blood pressure was recorded for each angiotensin II challenge and the percent inhibition of the angiotensin II response was calculated.

Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure. These compounds may also be expected to be useful in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, end stage renal disease, renal transplant therapy, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinapathy and in the management of vascular disorders such as migraine, Raynaud's disease, luminal hyperclasia, and to minimize the atherosclerotic process. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.

The compounds of this invention are also useful to treat elevated intraocular pressure and to enhance retinal blood flow and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like.

Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.

In the management of hypertension and the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspe-nsions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 1 to 1000 mg.

per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.

The compounds of this invention can also be administered in combination with other antihypertensives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothålidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine', reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan damsylate, benzthiazide, quinethazone, ticrynafan, 'triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.

Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.

To illustrate these combinations, one of 64e angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg) chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg.), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg).In addition, triple drug combinations of hydrochlorothiazide (15-200 mgj plus amiloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients.

Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity-of the disease, weight of patient, special diets and other factors.

Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.

About 1 to 100 mg. of compound or mixture of compounds of Formula I or a physioogisdlly acceptab salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occuring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can, be incorporated as required.

The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound of this invention.

Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders such as migraine or Raynaud's disease. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.

The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY The efficacy of these compounds to enhance cognitive function can be demonstrated in a rat passive avoidance assay in which cholinomimetics such as physostigmine and nootropic agents are known to be active. In this assay, rats are trained to inhibit their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet.The test animals are pretreated with 0.2 mg/kg ofthe muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of. the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.

Upon return to the illuminated chamber, normal young rats who have been subjected to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been exposed to the apparatus but who have not received a shock. Rats treated with scopolamine before training do not show this hesitation when tested 24 hours later. Efficacious test compounds can overcome the disruptive effect on learning which scopolamine produces. Typically, compounds of this invention should be efficacious in this passive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg.

ANXIOLYTIC ASSAY The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful anxiolytic which is active in this assay. In the CER protocol; male Sprague-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed LlDlL2D2L3 sequence.During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presses also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during the dark periods reflecting the formation of a conditioned emotional response (CER).

Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, response rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.

DEPRESSION ASSAY The antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a mouse suspended by the .tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation.

Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity code and to measure latency, duration and frequency of immobile periods.

Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.

SCHIZOPHRENIA ASSAY The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced sterotypy model. A clinicallyuseful antipsychotic drug that is used as a positive oncr 1 in this assay is haloperidol. The assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereotyped motor behavior. There is a strong correlation between the effectiveness of classical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer. Compounds of the invention should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.

In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules- or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg.

per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.

In order to obtain maximal enhancement of cognitive function, the compounds of this invention may be combined with other cognition-enhancing agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (THA; tacrine), muscarinic agonists such as oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.

In order to achieve optimal anxioiytic activity, the compounds of this invention may be combined with other anxiolytic agents such as alprazolam, lorazepam, diazepam, and busipirone.

In order to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepressants are of use.

These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors such as tranylcypromine.

In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.

The following examples illustrate the preparation of the intermediates of compounds of Formula I and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

Example 1 Preparation of 4'-bromomethylbiphenyl-2-tert-butylsulfonamide SteD 1: Preparation of 2-bromobenzene(tert-butyl) sulfonamide To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen'at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 h, then the mixture evaporated to dryness. Flash chromatography (silica gel, 10,15% ethyl acetate-hexane) afforded 2-bromobenzene(tertbutyl)sulfonamide as a white solid; 1H NMR (300 MHz, CDC13) 6 8.18 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.50-7.35 (m, 2H), 5.11 (s, 1H), 1.20 (s, 9H).

Step 2: PreDaration of v-tolvltrimethvltin p-Tolylmagnesium bromide solution (Aldrich) (1.OM solution in diethyl ether) (53 ml, 0.0530 mol)- was added dropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in-tetrahydrofuran (50 ml) under nitrogen at. -10 C. The suspension was allowed to warm slowly to room temperature over 3 h then saturated ammonium chloride solution (10 ml) was added followed by sufficient water to dissolve the precipitate.The solution was extracted three times with.diethyl ether-hexane (1:1). The combined organic phase was washed with brine, dried (magnesium sulfate) and the soivents removed in vacuo .Vacuum distillation of the residue afforded a colorless liquid (39-40 "C, 0.1 mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin as a colorless liquid; 1H NMR (300 MHz, CDCl3) 6 7.40 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 2.34 (s, 3H), 0.30 (s, 9H).

Step 3: Preparation of 4'-methylbiphenyl-2-tert butvlsulfonamide 2-Bromobenzene(tert-butyl)sulfonamide (1.00 g, 3.92 mmol), p-tolyl-trimethyltin (1.95 g, 6.67 mmol), bis(triphenylphosphine)palladium(II) chloride (Aldrich) (165 mg, 0.235 mmol) and dimethylformamide (25 ml) were heated with stirring under nitrogen at 90"C for 5 h. The black suspension was cooled to room temperature, then filtered through a pad of celite which was washed with tetrahydrofuran.The colorless filtrate was evaporated to dryness then chromatographed (silica gel, 8,10% ethyl acetate-hexane) to give 4'-methylbiphenyl-2-tert-butylsulfonamide as a white solid; 1H NMR (300 MHz, CDCl3) 6 8.16 (d, J = 7.9 Hz, 1H), 7.60-7.37 (m; 4H), 7.36-7.24 (m, 3H), 3.57 (s, lH), 2.42 (s, 3H), 0.99 (5,. 9H).

Step 4: Preparation of 4'-bromomethyibiphenyl-2-tert- butylsulfonamide N-Bromosuccinimide (0.387 g, 2.17 mmol), a,a'-azoisobutyronitrile (catalytic), 4'-methylbiphenyl-2-tert-butylsulfonamide (0.55 g, .1.81 mmol) and carbon tetrachloride (50 ml) were heated with stirring at reflux for 3 h. After cooing to room temperature the mixture @/as filtered and the filtrate evaporated to dryness.Flash chromatography (silica gel, 10,20% ethyl acetate-hexane) afforded 4'-bromomethylbiphenyl-2-tert-butylsulfonamide (77% pure (the remainder of the material was 4'-dibromomethylbiphenyl-2-tert-butylsulfonamide)) as a white solid; 1H NMR (300 MHz, CDCl3) # 8.17 (dd, J = 7.5, 1.6 Hz, 1H), 7.68-7.45 (m, 6H), 7.31 (dd, J = 7.5, 1.6 Hz, 1H), 4.55 (s, 2H), 3.52 (s, 1H), 1.00 (s, 9H).

Example 2 Preparation of 2-Methyl-4-(2'-(aminosulfonyl)(l,l' biDhen-4-sl)methoxv)-uinoline Step 1: Preparation of 2-Methyl-4-(2'-((tert-butyl- amino)sulfonyl) (1,1'-biphen-4-yl)methoxy) suinoline 2-Methyl-quinoline-4-(lH)-one (Aldrich) (0.48 g, 3.0 mmol) was stirred with K2C03 anhydrous (0.84 g) in dimethylformamide (10 ml) at room temperature under nitrogen for 15 min. 4'-(bromomethyl)-biphenyl-2-tertbutylsulfonamide (1.18 g, 3.1 mmol) was added as solid in three portions, stirred at room temperature for 15h. The reaction mixture was poured into ice water (150 m) and the precipitated solid was filtered and then dried in vacuo.Flash chromatography (silica gel, ethyl acetate-hexane (1:2)] afforded -2-methyl- 4-(2'-((tert-butylamino)sulfonyl)(l,l'-biphen-4-yl) methoxy)-quinoline as a white solid. 1H NMR (400 MHz, CDCl3) 5 8.18 (dd, J = 7.5, 1.6 Hz; 1H), 7.62 7.32 (m, 9H), 7.09 (d, J = 9.1 Hz, 1H), 6.87 (s, 1H), 5.42 (s, 2H), 1.92 (s, 3H,), 0.95 (s, 9H).

Step 2: Preparation of 2-methyl-4(2'-(aminosulfony1) (1,1'-biphen-4-yl)methoxy)quinoline Anisole (6 drops) was added to a stirred solution of 2-methyl-4-(2'-((tertbutylamino)sulfonyl) (l,l'-biphen-4-yl)methoxy)quinoline (0.264 g, 0.554 mmol) in trifluoroacetic acid (6 ml) under nitrogen at room temperature. After stirring at room temperature for 8 h the solvent was removed in vacuo and the crude product was treated with sat. NaHC03 and extracted into ethyl acetate (60 ml). The organic phase was then washed with water, dried (MgSO4), and concentrated in vacuo to give the crude material as a foam.Flash chromatography silica gel, ethyl acetate-hexane (1:1)] afforded 2-methyl-4-(2'-(aminosulfonyl)(l,l'-biphen-4-yl)methoxy)quinoline as a white solid; 1H NMR (200 MHz, CDC13): 6 8:14 (m, 2H), 7.65-7.25 (m, 7H), 7.0 (d, 1H), 6.92 (s, 1H) 5.45 (s, 2H), 1.95 (s, 3H).

Example 3 Preparation of 2-methyl-4-(2'-((benzoylamino) sulfonyl) (1,1'-biphen-4-yl)methoxy)quinoline To a stirred suspension of NaH (0.01 g, 0.25 mmol) in dry DMF (1.0 ml) under nitrogen at room temperature was added 2-methyl-4-(2'-(aminosulfonyl) (l,l'-biphen-4-yl)methoxy)quinoline (0.08 g, 0.2 mmol). After stirring for 30 minutes at room temperature, benzoylchloride (0.14 ml, 1.0 mmol) was added,. and the resulting mixture was stirred at room temperature for 18h. The reaction mixture was poured into ice water (50 ml), acidified with 5% citric acid solution and extracted with chloroform (15 ml X'3).

The combined organic phase was washed with water and brine, and then dried over MgS04. Removal of the solvent gave the crude product as a foam which was purified by flash-chromatography starting with 5% MeOH-CH2C12 and then with CH2Cl2-MeOH-NH4OH (100:10:1) to give the desired product as a cream colored solid. 1H NMR (200 MHz, CD30D): 8 8.41 (d, J = 8.8, 1H), 8.15 (d, J = 7.9, 1H), 7.71-7.25 (m, 12H), 7.10 (d, 1H), 6.87 (s, 1H), 5.42 (s, 2H), 1.92 (s, 3H).

Example 4 Preparation of 2-ethyl-6-methoxy-4-.(2'-(aminosulfonyl) (1,1'-biphen-4-yl)methoxy-1,5-naphthyridine Step 1: Preparation of 2-ethyl-6-methoxy-4-(2' ((tert-butylamino)sulfonyl) (1,1'-biphen-4-yl) methoxy)-1,5-naphthyridine 2-Ethyl-6-methoxy-1,5-naphthyeridine-4-(1H)one (prepared according to the procedure described in PCT Application WO 91/07404) was alkylated with 4'-(bromomethyl)-biphenyl-2-tert-butyl-sulfonamide, according to the procedure described in Step 1 of Example 2, to provide the titled compound. 1H NMR (400 MHz CDC13):: 6 8.2 (d, J 1 8.8 Hz, 1H), 8.16 (dd, J - 7.9, 1.3 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.55-7.42 (m, 4H), 7.30 (dd, J = 7.5, 1.3 Hz, 1H), 7.15 (d, J = 9.1 Hz, 1H), 6.95 (s, 1H), 5.45 (s, 2H), 4.08 (s, 3H), 2.95 (q, J I 8Hz, 2H), 1.36 (t, J = 8Hz, 3H), 0.97 (s, 9H).

Step 2: Preparation of 2-ethyl-6-methoxy-4-(2'-amino- sulfonyl)(l,l'-biphenyl-4-yl)methoxy) 1,5-naphthyridine The compound obtained in Step 1 above was treated with anhydrous trifluoroacetic acid as described in Step 2 of Example 2 to give the titled compound. 1H NMR (200 MHz CDC13): 6 8.12 (m, 2H), 7.70-7.28 (m, 7H), 7.08 (d, J = 9.0 Hz, 1H), 6.90 (s, 1H), 5.42 (s, 2H), 4.62 (bs, 2H), 4.1 (s, 3H), 2.91 (q, J = 8Hz, 2H), 1.35 (t, J = 8Hz, 3H).

Example 5 Preparation of 2-ethyl-6-methoxy-4-(2'-(benzolylamino- sulfonyl) (1,1'-biphen-4-yl)methoxy)-1,5-naphthyridine A mixture of benzoic acid (0.073 g, 0.6.mmol) and l,l'-carbonyldiimidazole (0.097 g, 0.6 mmol) in dry THF (2 ml) was ref fluxed for lh. The reaction was cooled to room temperature, and a solution of 2-ethyl-6-methoxy-4-(2'-(aminosulfonyl)(l,l'-biphen- 4-yl)methoxy)-1,5-naphthyridine (0.09 g, 0.2 mmol) and DBU (0.073 ml) in dry THF (1 ml) was added to the above reaction mixture. The mixture was stirred at 600C for 3h and then concentrated in vacuo.The crude product thus obtained was purified by flash chromatography [silica gel; CHC13:MeOH:NH40H (80:10:1)) to give the titled compound as an amorphous solid. 1H NMR (200 MHz, CDC13): 6 8.38 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.68-7.28 (m, 12H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 5.46 (s, 2H), 4.1 (s,'3H), 2.92 (q-, J = 9.0 Hz, 2H), 1.38 (t, J = 8Hz, 3H).

Example 6 Preparation of 4'-bromomethylbiphenyl-2-(0-tert butvl ) -N-hvdroxvsulfonamide Step 1: Preparation of 2-bromobenzene(O-tert butvl) -N-hvdroxvsulfonamide To a stirred solution of 2-bromobenzenesulfonyl chloride (Lancaster Synthesis) (1.0 g, 4.0 mmol) in chloroform (10 ml) under nitrogen at 0 C was added O-tert-butylhydroxylamine hydrochloride (Fluka) (0.6g, 4.77 mmol) in three portions. The solution was stirred at room-temperature for 18 h and then diluted with methylene chloride (20 ml).The organic phase was washed successively with 5% citric acid, water and then dried over MgS04. Removal of the solvent in vacuo gave the crude product as white solid, which was then purified by flash chromatography (silica gel, 10% ethyl acetate-hexane) to afford 2-bromobenzene(O-tert-butyl)N-hydroxysulfonamide (1.12 g, 89%) as a white solid; 1H NMR (300 MHz, CDC13) 6 8.15 (dd, J = 7.5, 2.1 Hz, 1H), 7.75 (d, J = 7.6, 1.8 Hz, 1H), .7.55-7.35 (m, 3H), 5.11 (s, 1H), 1.21 (s, 9H). FAB-MS: 309 (M+H).

Step 2: Preparation of 4'-methylbiphenyl-2-(0 tert-butvl)-N-hvdroxv sulfonamide A solution of 2-bromobenzene(O-tert-butyl) N-hydroxysulfonamide (0.31 g, 1.0 mmol), p-tolyltrimethyltin (0:3 g, 1.18 mmol) and bis(triphenylphosphine)palladium(II) chloride (Aldrich) (0.036 g) in dry dimethylformamide (6 ml) was stirred under nitrogen at 90 C for 6 h. The black suspension was cooled to room temperature, then filtered through a pad of celite which was washed with tetrahydrofuran.

The colorless filtrate was evaporated to dryness then purified by flash chromatography (silica gel, 8% ethyl acetate-hexane) to give the titled compound as a semi-solid mass. 1H NMR (300 MHz, CDC13) 6 8.15 (d, J = 7.8, 1.6 Hz, 1H), 7.67-7.50 (m, 2H), 7.36-7.24 (m, 5H), 5.78 (s, 1H), 2.42 (s, 3H), 1.08 (s, 9H).

FAB-MS: 320 (M+H).

Step 3: Preparation of 4'-bromomethylbiphenyl-2 (O-tert-butyl)-N-hydroxysulfonamide A mixture of N-Bromosuccinimide (0.14 g, 0.78 mmol), a,a'-azoisobutyronitrile (10 mg) and 4'-methyl biphenyl-2-(O-tert-butyl)-N-hydroxy sulfonamide (0.25 g, 0.78 mmol) in carbon tetrachloride (10 ml) was refluxed for 7 h. After cooling to room temperature the mixture was filtered and the filtrate evaporated to dryness. Flash chromatography (silica gel, 10% ethyl acetate-hexane) afforded 4'-methylbiphenyl-2 (Otert-butyl)-N-hydroxy sulfonamide as a white solid.

1H NMR (300 MHz,CDC13) 5 8.15 (d, J = 7.8 Hz, 1H), 7.70-7.30 m, 7H), 5.72 (s, 1H), 4.55 (s, 2H), 1.08 (s, 9H). FAB-MS: 398, 400 (M+H).

EXAMPLES A3 TO A17 The compounds of the Formula (II) exemplified in Table A are prepared from the appropriate substituted starting materials utilizing the general procedures outlined in the noted schemes.

TABLE A

Conpound No.

* p6 R1 R2 R( Scherre A3 - S 2 NHS Et M3 Et H s I 11-13 A4 - S02NHS02iPr Et II-l 3 A5 Hz Hz Et H H II-19, II-20 =0 H A6 HN ,N-Ph Et H H II-21, II-22 N~S=O H A7 SO2 Et H H 11-27, II-1 , FNH 0 TABLE A (CON'T)

Conpound No.

* p6 ~~ R4 Schene o II A8 -NH-C-COH Et H H 11-28 II 0 A9 -SO2NHCOiPr Et H H 11-4 0 II AlO -so2NHpOCH2Ph Et H H 11-15 OCH2Ph C rn All -N N-H Et H S 11-24 o o N-O Al 2T\THSO,Ph Et H H 11-25 NO A13 Et II-'19 Awl 4 -SO2NHCOX Et ., H H 11-4 'A1 5 -SO2NHCOX Et H H 11-4 A16 -SO2NH-COt Et H H 11-4 Ai7 -802,NH-OH Et H H 11-29 A18 -SO2NHCOOEt Et H H 11-14 A19 -SO2NKOOt Bu Et. H H II-1 4 EXAMPLES BI TO Bll The compounds of the formula (III) exemplified in Table B are prepared from the appropriately substituted starting material utilizing the general procedures outlined in the noted schemes.

TABLE B

Compound No.

&num; .RB 'S ~~ R I 4 Scherm B1 -S4NM3H Et MbO II-29 + B2 -SO2NHOH Et -O < HzII-29 B3 -SOaNHSOziPr Et -OCH3 II-1 3 B4 -sNHsQPh Et -OCH3 II-13 0 II B5 -SO2NHP-OCHzPh Et -OCH3 II-15 OCH2Ph 0' 11-24 Ed -H gN-H Et -o oo o TABLE B (CON'T)

Conpound No.

R8 PS p1 S Se he rre o B7 -N ,N-H Et OCH3 II-24 0' 0 B8 AN-o Et oCH3 II-25 NHSC2Ph B9 HNE Ph Et -o 11-21, 11-22 H B10 tN-o Et -OCH3 IIIj 11-20 N'-S = O H B1 1 g0-N Et -OS II-25 Y NHSo2CF3 B12 -SO2NHCCOEt Et ONe II-14 B13 -SO2NHCOOEt Et -OiPr 11-14 B14 -SO2NHCOOBu Et -ONe II-14 B15 - SO2NHCOOBu Et -OiPr II-14 216 -SC2NHCOOtBu Et -ONe 11-14 B1 7 -SO2NHCOOt13u Et -OiPr 11-14 FORMULATION EXAMPLES Typical Pharmaceutical Compositions Containing a Compound of the Invention A: Dry Filled Capsules Containing 50 mg of Active Inaredient Per Capsule Inaredient Amount per capsule (ma) Compound A-l 50 Lactose 149 Magnesium stearate 1 Capsule (size No. 1) . 200.

The Compound A-1 (title compound of Example 11) can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry.gelatin capsule.

B: Tablet A typical tablet would contain the Compound A-l (25 mg), pregelatinized starch USP (82 mg), microcrystaline cellulose (82 mg) and magnesium stearate (1 mg).

Claims (11)

WHAT IS CLAIMED IS:

1. A compound of structural formula I

or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) C1-C8-perfiuoroalkyl, (f) phenyl, or (g) phenyl-C1-C4-alkyl; and R2 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) C02R10, (f) C1-C4-alkoxycarbonyl, (g) CN, (h) NO2, (i) phenyl, or.

(j) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a) H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R12, (iv) morpholin-4-yl, (v) OH, (vi) CO2R10, or (vii) CON(R10)2, (c) C1-C6-alkoxy, (d) C1-C4-perfluoroalkoxy, (e) C19 Br, F, I, (f) CF3, (g) CN, (h) NO2, (i) OH, (j) NH2, (k) NH[C1-C6-alkyl], (l) N[C1-C6-alkyl]2, (m) N(CH2CH2)2O, (n) N(CH2CH2)2NCOR10, (o) N(CH2CH2)2NR10, (p) CO2R10, (q) C1-C4-alkoxycarbonyl, (r) CONH2, (s) CONH[C1-C7-alkyl], (t) CON[C1-C7-alkyl]2, (u) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group;; R5 is (a) H, (b) C1, Br, I, or F, (c) C1-C6-alkyl, (d) C1-C6-alkoxy, or (e) C1-C6-alkoxyalkyl; R6 is (a) H (b) C1, Br, I, or F, (c) NO2, (d) C1-C6-alkyl, (e) C1-C6-acyloxy, (f) C3-C7-cycloalkyl, (g) C1-C6-alkoxy, (h) -NHS02R11, (i) hydroxy(C1-C4-alkyl), (j) aryl(C1-C4-alkyl), (k) C1-C4-alkylthio, (1) C1-C4-alkyl sulfinyl, (m) Cl-C4-alkyl sulfonyl, (n) NH2, (o) Cl-C4-alkylamino, (p) di(C1-C4-alkyl)amino, (q) fluoro-C1-C4-alkyl-, (r) -SO2-NHR, (s) aryl, (t) furyl, (u) CF3, (v) C2-C6-alkenyl, or (w) C2-C6-alkynyl;; R7 is (a) H, (b) C1, Br, I, or F, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di(C1-C4-alkyl)amino, (g) SO2NHR, (h) CF3, (i) C1-C6-alkyl, (j) C1-C6-alkoxy, (k) C1-C6-alkyl-S-, (l) C2-C6-alkenyl, (m) C2-C6-alkynyl; (n) aryl, (o) aryl(Cl-C4-alkyl), or (p) C3-C7-cycloalkyl;' wherein aryl is phenyl or naphthyl, or a substituted phenyl or naphthyl with one or two substituents selected from the group consisting of C1, Br, I, F, N(R)2, CO2R11, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, -S02NR12R13, C3-C7-cycloalkyl, C3-C10-alkenyl, or S(O)x(C1-C4-alkyl);; R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R,

(e) -SO2NHCN, (f) -SO2NHCO2R,

(h) -NHSO2NHSO2R,

(v) -NHSO2R, (w) SO2NHRȃ, (x) SO2NHCOR, (y) SO2NHCONRȃR, (z) CH2SO2NHCOR, (aa) CH2SO2NHCONHRȃ, (bb) CH2CONHS02R22, (cc) NHCONHS02R22, (dd) NHSO2NHCOR22, or (ee) CONHNHSO2R22; wherein Y is O or S; Z is 0, S(O)x or NR14; R9 is: (a) H, or (b) C1-C6-alkyl; R10 is:: (a) R9, (b) CH2-aryl, or (c) aryl; Rll is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, -CF3, C1, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl; R14 is H, C1-C6-alkyl, Cl-C4-alkenyl, C1-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NH2, -OH or -OCH3;; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R21 is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted Or substituted with: i) NH2, ii) NH[C1-C4-alkyl], iii) N[C1-C4-alkyl]2, iv) C02H, v) C02-C1-C4-alkyl, vi) OH, vii) SO3H, or viii) S02NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -NCC1-C4-alkyl)2, NRCORȃ, -PO3H2, -PO(OH)(O C1-C4-alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-a'lkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6 alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, C02-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NR12COR22, -P03H2, -PO(OH)(O-C1-C4 alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (f) perfluoro-C1-C4-alkyl; R23 is (a) H, (b) aryl as defined above, or (c) C1-C6-alkyl optionally substituted with aryl, F, Cl, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, or CF3;; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NRCC1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, (c) -OCH(R)-O-CO-R16, (d) -OH, or (e) -O-C1-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, or (c) F, C1, Br; x is O to 2; and u is 1 to 3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) phenyl, or (e) phenyl-C1-C4-alkyl; and R2 is; (a) H, (b) C1-C8-alkyl, Cc) Co2R5a, (d) C1-C4-alkoxycarbonyl, (e) CN, (f) NO2, (g) phenyl, or (h) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a) H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R12, (iv) morpholin-4-yl, (v) OH, (vi) CO2R10, or (vii) CON(R10)2, (c) C1-C6-alkoxy, (d) C1 or F, (e) CF3, (f) CN, (g) NO2, (h) OH, (i) NR2, (j) NH[C1-C6-alkyl], (k) N[C1-C6-alkyl]2, (1) N(CH2CH2)20, (m) N(CH2CH2)2NCOR10, (n) N(CH2CH2)2NR10, (o) CO2R10, (p) C1-C4-alkoxycarbonyl, (q) CONH2, (r) CONH[C1-C7-alkyl], (s) CON[C1-C7-alkyl]2, or (t) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group; R5 is H;; R6 is H, F, C1, CF3, NO2, C1-C4-alkyl, C5-C6-cycloalkyl, -NHSO2CH3, NH2, C1-C4-alkylamino, di(C1-C4-alkyl)amino, -SO2-NHCH , C2-C6-alkenyl, or C2-C6-alkynyl; R7 is H, F, C1, CF3, N02, C1-C4-alkyl, aryl as defined hereinabove, C2-C6-alkenyl, or C2-C6-alkynyl; R8 is (a) -SO2N(Rȃ)-ORȃ,

(d) -S02NHCN, (e) -SO2NHCO2R,

(g) -NHS02NHS02R22,

(n) -NHSO2R, (o) SO2NHRȃ, (p) SO2NHCOR, (q) SO2NHCONRȃR, (r) CH2SO2NHCOR, (s) CH2SO2NHCONHR, (t) CH2CONHSO2R, (u) NHCONHSO2R, (v) NHSO2NHCOR22, or (w) CONHNHSO2R; wherein Y is O or S; Z is 0, S(O)x or NR14; R9 is: (a) H, or (b) C1-C6-alkyl; R10 is: (a) R9, (b) CH2-aryl, or (c) aryl; R11 is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or di substituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SH, C1-C4-alkyl, C1-C4-alkoxy, -CF31 C1, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl;; R14 is H, C1-C6-alkyl, C1-C4-alkenyl, C1-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NH2, -OH or -OCH3; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R21 is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted or substituted with: i) NH2, ii) NH(C1-C4-alkyl], iii) N[C1-C4-alkyl]2, iv) CO2H, v) CO2-C1-C4-alkyl, vi) OH, vii) S03H, or viii) SO2NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl; -OH, -SR,.

C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NHCC1-C4-alkyl), -NCC1-C4-alkyl)2, NRCORȃ, -PO3H2, -PO(OH)(O C1-C4-alkyl), -Po(oR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-alkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6 alkyl with a substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2R, C02-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCOR, -PO3H2, -PO(OH)(O-C1-C4 alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (f) perfluoro-C1-C4-alkyl;; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NHCC1-C4-alkyl), -NCC1-C4-alkyl)2, CF3, -COOR1l, or CN, (c) -OCH(R)-O-CO-R16, (d) -OH, or (e) -O-C1-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, CF3, -COOR10, or CN, or (c) F, C1, Br; x is O to 2; and u is 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are each independently: (a) H, (b) C1-C6-alkyl, (c) C1 or F, (d) N02, (e) C1-C6-alkoxy, (f) NH2, (g) NH[C1-C6-alkyl], (h) N(C1-C6-alkyl]2, (i) N(CH2CH2)2O, (j) N(CH2CH2)2NCOR10, (k) N(CH2CH2)2NR1O, (l) CO2R10, (m) C1-C4-alkoxycarbonyl, (n) CONH2, (o) CONH[C1-C7-alkyl], (p) CON[C1-C7-alkyl]2, or (q) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group; R6 and R7 are each independently:H, F, Cl, CF3, N02, C1-C4-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl; R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R22,

(d) -SO2NHCN, (e) -SO2NHCO2R,

(g) -NHSO2NHSO2R,

(n) -NHSO2R, (o) SO2NHRȃ, (p) S02NHCOR22, (q) SO2NHCONRȃR, (r) CH2S02NHCOR22, (s) CH2SO2NHCONHRȃ, (t) CH2CONHSO2R, (u) NHCONHS02R22, (v) NHS02NHCOR22, or (w) CONHNHS02R22; wherein Y is O or S; and Z is 0, S(O)x or NR14.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: E is CH or N; R1 is: (a) H, (b) C1-C8-alkyl, (c) C3-C8-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) C1-C8-perfluoroalkyl, (f) phenyl, or (g) phenyl-C1-C4-alkyl; and R2 is: (a) H, (b) C1-C8-alkyl, (c) C3-Cg-cycloalkyl, (d) C3-C8-cycloalkyl-C1-C4-alkyl, (e) CO2R10, (f) C1-C4-alkoxycarbonyl, (g) CN, (h) NO2, (i) phenyl, or (j) phenyl-C1-C4-alkyl; and R3 and R4 are independently: (a) H, (b) C1-C6-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, wherein aryl is defined as phenyl or naphthyl, (ii) C3-C7-cycloalkyl, (iii) NR9R12 (iv) morpholin-4-yl, (v) OH, (vi) CO2R10, or (vii) CON(R10)2, (c) Cl-C6-alkoxy, (d) C1-C4-perfluoroalkoxy, (e) C1, Br, F, I, (f) CF3, (g) CN, (h) NO2, (i) OH, (j) NH2, (k) NHEC1-C6-'alkyl], (l) N[C1-C6-alkyl]2, (m) N(CH2CH2)2O, (n) N(CH2CH2)2NCOR10, (o) N(CH2CH2)2NR10, (p) CO2R10, (q) C1-C4-alkoxyca.rbonyl, (r) CONR2, (s) CONH[C1-C7-alkyl], (t) CON[C1-C7-alkyl]2, (u) R3 and R4 may optionally together form a C1-C4-alkylenedioxy group; ; R5 is (a) H, (b) C1, Br, I, or F, (c) C1-C6-alkyl, (d) C1-C6-alkoxy, or (e) C1 C6,-alk9xyalkyl; ,R6 is (a) H (b) C1, Br, I, or F, (c) NO2, (d) C1-C6-alkyl, (e) C1-C6-acyloxy, (f) C3-C7-cycloalkyl, (g) C1-C6-alkoxy, (h) -NHSO2R, (i) hydroxy(C1-C4-alkyl), (j) aryl(C1-C4-alkyl), (k) C1-C4-alkylthio, (1) C1-C4-alkyl sulfinyl, (m) C1-C4-alkyl sulfonyl, (n) NH2, (o) C1-C4-alkylamino, (p) di(C1-C4-alkyl)amino, (q) fluoro-C1-C4-alkyl-, (r) -SO2-NHR, (s) aryi, (t) furyl, (u) CF3, (v) C2-C6-alkenyl, or (w) C2-C6-alkynyl; R7 is (a) H, (b) C1, Br, I, or F, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di(C1-C4-alkyl)amino, (g) SO2NHR, (h) CF3, (i) C1-C6-alkyl, (j) C1-C6-alkoxy, (k) C1-C6-alkyl-S-, (1) C2-C6-alkenyl, (m) C2-C6-alkynyl;; (n) aryl, (o) aryl(C1-C4-alkyl), or (p) C3-C7-cycloalkyl; wherein aryl is phenyl or naphthyl, or a substituted phenyl or naphthyl with one or two substituents selected from the group consisting of Cl Br, I, F, N(R)2, CO2R, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, -SO2NRR , C3-C7-cycloalkyl, C3-C10-alkenyl, or S(O)x(C1-C4-alkyl); R8 is (a) -SO2N(Rȃ)-ORȃ, (b) -SO2NHSO2R,

(e) -SO2NHCN, (f) -SO2NHCO2R,

(h) -NHSO2NHSO2R,

(v) -NHSO2R wherein Y is O or S; Z is O, S(O)x or NR14; R9 is: (a) H, or (b) C1-C6-alkyl; R10 is:: (a) R9, (b) CH2-aryl, or (c) aryl; R is H, aryl, C1-C6 alkyl, or substituted C1-C6 alkyl in which substituent is aryl or heteroaryl, wherein heteroaryl is an unsubstituted, monosubstituted or disubstituted heteroaromatic 5 or 6 membered ring which contains one to three heteroatoms selected from the group consisting of N,.O, and S, and wherein the substituents are members selected from the group consisting of -OH, -SR, C1-C4-alkyl, C1-C4-alkoxy, -CF3, C1, Br, I, F, and NO2; R12 is H, C1-C5-alkyl, aryl or arylmethyl; R13 is H or C1-C4-alkyl;; @ R14 is H, C1-C6-alkyl, Cl-C4-alkenyl, Cl-C4-alkoxy alkyl, C1-C6-alkoxycarbonyl, aryl-C1-C6-alkoxycarbonyl or

R15 is H, -NO2, -NH2, -OH or -OCH3; R16 is aryl, C1-C6-alkyl or aryl-C1-C6-alkyl; R21 is: (a) H, or (b) C1-C4-alkyl, which is unsubstituted or substituted with:: i) NH2, ii) NHEC1-C4-alkyl), iii) N[C1-C4-alkyl]2, iv) C02H, v) CO2-C1-C4-alkyl, vi) OH, vii) SO3H, or viii) S02NH2; and R22 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C8-alkyl or a substituted C1-C6 alkyl with one or two substituents selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NRCORȃ, -PO3H2, -PO(OH)(O C1-C4-alkyl), -PO(0R4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (e) perfluoro-C1-C4-alkyl;; R22a is (a) hydrogen, (b) aryl, (c) heteroaryl, (d) C3-C7-cycloalkyl, (e) C1-C6-alkyl or a substituted C1-C6- alkyl with a 'substituent selected from the group consisting of aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl), -CF3, C1, Br, F, I, -NO2, -CO2H, CO2-(C1-C4-alkyl), -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, NR12COR22, -P03H2, -PO(OH)(O-C1-C4 alkyl), -PO(OR4)R9, morpholinyl or C1-C4alkylpiperazinyl, or (f) perfluoro-C1-C4-alkyl; R23 is (a) H, (b) aryl as defined above, or (c) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2. or CF3;; R24 is (a) aryl as defined above, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NHCC1-C4-alkyl), -N(C1-C4-alkyl)2. CF3, -COOR10, or CN, (c) -OCH(R)-O-CO-R16, (d) -OH, or (e) -O-Cl-C6-alkyl wherein alkyl is as defined in (b); R25 is (a) H, (b) C1-C6-alkyl optionally substituted with aryl, F, C1, Br, -OH, -NH2, -NHCC1-C4-'alkyl), -N(Cl-C4-alkyl)2, CF3, -COOR1O, or CN, or (c) F, C1, Br; x is O to 2; and u is 1 to 3.

5. The compound according to claim 1 which is selected from: 2-methyl-4-(2(-(aminosulfonyl)(l,l'-biphen-4-yl)- methoxy)-quinoline; 2-methyl-4-(2'-((benzoylamino)sulfonyl) (1,1'-biphen-4-yl)methoxy)quinoline; 2-ethyl-6-methoxy-4-(2'-(aminosulfonyl) (l,l'-biphen-4-yl)methoxy)-1,5-naphthyridine; 2-ethyl-6-methoxy-4-(2'-(benzolylaminosulfonyl) (1,1'-biphen-4-yl)methoxy)-1,5-naphthyridine; or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.

7. The composition of Claim 6 which includes another antihypertensive agent selected from a diuretic, an angiotensin converting enzyme inhibitor a calcium channel blocker and a b-blocker which are members selected from the group consisting of: amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.

8. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of hypertension.

9. An ophthalmic formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of Claim 1.

10 The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of ocular hypertension.

11. The use of a compound as claimed in claim 1 for the manufacture of a medicament for the treatment of cognitive dysfunction, anxiety, or depression.