TRIAZOLE ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BENZYL ELEMENT

Abstract: Substituted triazoles attached through a methylene bridge to novel substituted phenyl derivatives of formula (I) are useful as angiotensin II antagonists.

Description: ϊ/ - 1 - 10 TITLE OF THE INVENTION TRIAZOLE ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BENZYL ELEMENT 15 BACKGROUND OF THE INVENTION The present application is a continuation in part of Serial No 479,779 filed on Febuary 13, 1990. The Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood 2o 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 25 converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin- angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting 3 0 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 [M. Antonaccio. C-IJH- Eap- Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. - Handbook of Hypertension. Clinical Pharmacology of Antihvpertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984]. Recently, several substituted imidazoles 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; and 4,880,804 in European Patent Applications 028,834; 245,637; 253,310; 291,969; and 324,377 and in articles by A.T. Chiu, et al. rEur. J. Pharm- SSP- Therap, lϋZ, 13-21 (1988)] and by p.c. Wong, ≤t ΔI. [J- Pharm- Exp* I sins., 2__1, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro- 2H-imidazo[4,5-£.]-pyridine-6-carboxylic acid and analogs thereof as antihvpertensive agents. The compounds disclosed within this application have not been identified in any US Patents, European Applications or articles. The compounds of the present invention are substituted triazoles which are bonded through a methylene bridge to a novel substituted phenyl element. DuPont also has filed a European Application (EPO 0,323,841) covering substituted pyrroles, pyrazoles and triazoles . The present invention covers novel antagonists which incorporate a novel substituted benzyl element linked to the triazole moiety. The above cited applications are hereby incorporated by reference, serving as an information source as to the preparation of substituted triazoles. A pending Merck application, Serial No. 382,138, discloses other novel triazoles and the synthetic routes to these triazoles are described in the Schemes 1-1 through 1-14 and the incorporation of the sustituted benzyl element is described in Schemes 1-15 through 1-30. The compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states. In addition, these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia. The compounds of this invention are especially useful in the treatment of these conditions in patients who are also hypertensive or have a congestive heart failure condition. DETAILED DESCRIPTION OF THE INVENTION This invention relates to compounds of Formula I: Wherein R is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C2-C )-alk nyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: 1) Cl, Br, I, F, 2) (C 1 -C 4 )-alkyl, 3) (C 1 -C )-alkoxy, 4) N0 2 5) CF 3 6) S0 2 NR 2a R 2a , 7) (C 1 -C 4 )-alkylthio, 8) hydroxy, 9) amino, 10) C3*-C7)-cycloalkyl, 11) C3-Cιø)-aIkenyl; a ^ ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, or iv) C00R 2 , vi) -CH 2 CF 3 ; and b) perfluoro-(C ] _-C 4 )-alkyl, or (c) (C3-C£)-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consisting of: (C 1 -C 4 )-alkoxy, (Cι-C 4 )-alkyl- thio, perfluoro-(Ci~C 4 )-alkyl, hydroxy, or F, Cl, Br, I; and B is: (a) a single bond, (b) -S(0) n (CH 2 ) s -, or (c) -0-;and n is 0 to 2; and s is 0 to 5; and (a) H, or (b) (C 1 -C 6 )-alkyl; and ,2a s : (a) R 2 , (b) CH 2 -aryl , or (c) aryl ; and (d) when R 2 and R 2a are alkyl substituents on the same nitrogen they can be joined to form a ring; and wherein there is more than one R 2a group in the definition of a structure of Formula I they may be the same or different; and R 9 and R 10 are independently: (a) H, (b) (C-^-Cg^alkyl, unsubstituted or substituted with (C 3 -C 7 )-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, < f > (C 1 -C 6 )-alkoxyl, (g) when R 9 and R* 0 are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(Cι-C 6 )-alkyl, (i) C3~C7)-cycloalkyl, unsubstituted or substituted with (Cι-C 6 )-alkyl, (j) aryl; and X is: (a) -0-, (b) -S(0) n -, (c) -NR 13 - (d) -CH 7 0-, (e) -CH 2 S(0) n -, (f) -CH 2 NR 13 -, (g) -0CH 2 -, (h) -NR 13 CH 2 -, (i) -S(0) n CH 2 -, (j) -CH 2 -, (k) -(CH 2 ) 2 -, (1) single bond, or (m) -CH=, wherein Y and R 12 are absent forming a -C=C- bridge to the carbon bearing Z and R 11 ; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO, S0 2 ). RU and 2 are independently: (a) H, (b) (C 1 -C 6 )-alkyl unsubstituted or substituted with: (i) aryl, or (ϋ (C 3 -C 7 )-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 εubstitutents selected from the group consisting of: i) Cl, Br, I, F, ϋ) (C 1 -C 4 )-alkyl, iii). [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (Cι~C 4 )-alkoxy, or vi) (Cι-C )-alkylthio, and (d) aryl-(Ci~C 2 )-alkyl, wherein the aryl group is unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, (e) -C0NH-S0 2 -aryl, (f) -C0NH-S0 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen from the group consisting of: -OH, -SH, -0(Ci~C )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(Cι-C 4 )-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 ; and (g) -C0NH-S0 2 -perfluoro-(C-L-C )-alkyl, (h) -CONH-S0 2 -heteroaryl, or (i) -C0NHS0 2 NR 2a R 2a ; and (j) -S0 2 NHC0-aryl, (k) -S0 2 NHC0-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen from the group consisting of: -OH, -SH, -0(C 1 -C 4 )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(C 1 -C 4 )-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 ; and (1) -S0 2 NHCO-(C 1 -C )-perfluoroalkyl, (m) -S0 NHC0-heteroaryl, or (n) -S0 2 NHC0NR 2a R 2a ; and T is -S(0) n -, -0-, -NΞCH 2 -, -NHC(=0)-, -C(=0)N(R 20 )-, or -N(R 20 )-; and b is 0 or 1; and Rl5 is (a) H, (b) (C 1 -C 6 )-alkyl, (c) phenyl, or (d) benzyl; and is (a) (C 1 -C 10 )-alkyl; (b) substituted (Cι-Cιø)-alkyl in whicl1 one or more substituent(s) is selected from (1). I, Br, Cl, F, (2) hydroxy, (3) (C 1 -C 10 )-alkoxy, (4) (Cι-C5)-alkoxycarbonyl, (5) (C 1 -C 5 )-acyloxy, (6) (C 3 -C 8 )-cycloalkyl, (7) aryl, (8) substituted aryl in which the substituents are V and W, (9) (C 1 -C 10 )-alkyl-S(0) n , (10) (C 3 -C 8 )-cycloalkyl-S(0) n , (11) phenyl-S(0) n , (12) substituted phenyl-S(0) n in which the substituents are V and W, (13) oxo, (1 carboxy, (15) NR 2 R 2a , (16) (Cι-C5)-alkylaminocarbonyl, (17) di(Cι-C5)-alkylaminocarbonyl, or (18) cyano, (c) perfluoro-(Ci~C 4 )-alkyl, (d) (C 2 -C 10 )-alkenyl, (e) (C 2 -C 10 )-alkynyl, (f) (C 3 -C 8 )-cycloalkyl, (g) substituted (C 3 -C )-cycloalkyl in which the substituent is selected from: (1) (C 1 -C 5 )-alkyl, or (2) (Ci-Cs^alkoxy, (3) (Cι-C5)-alkoxycarbonyl, (4) (C 1 -C 5 )-acyloxy, (5) <C 1 -C 5 )-acyl, (6) hydroxy, (7) Br, Cl, F, I, (8) (C 3 ^C 8 )-cycloalkyl, (9) aryl, (10) substituted aryl in which the substituents are V and W, (ID (C 1 -C 10 )-alkyl-S(O) n , (12) (C 3 -C 8 )-cycloalkyl-S(0) n , (13) phenyl-S(0) n , (14) substituted phenyl-S(0) n in which the substituents are V and W, (15) oxo, (16) carboxy, (17) NR 2 R 2a , (18) (C2-C5)-alkylaminocarbonyl, (19) di(Cι-C5)-alkylaminocarbonyl, or < 20 > cyano, (h) C0 2 R 2a , (i) aryl, (j) substituted aryl in which the substituents are V and W, (k) aryl-(CH 2 ) r -(M 1 ) 2 -(CH 2 ) t - (1) substituted aryl-(CH 2 ) r -(M 1 ) 2 -(CH 2 ) t - in which the aryl group is substituted with V and W, (rn V-(Q)-CCH 2 ) r -CM I ) 2 --(CH 2 ) t - Cn) :CH 2 ) r —<M,) S :CH 2 ) t —, i C tr V P) J Γ -CM 1 ) Z —(CH 2 ) t - or Mi is 0, S, -N(R 15 )-, or -C(0)-; and z is 0 or 1; and r and t are 0 to 2; and V and W are each independently selected from: (a) H, (b) (C 1 -C 5 )-alkoxy, (c) (C 1 -C 5 )-alkyl, (d) hydroxy, (e) ((C 1 -C 5 )-alkyl)S(0) n , R iδ is: (a) phenyl, unsubstituted or substituted with: V and , (b) . (C 1 -C 4 )-alkyl, or (c) perfluoro-(C^-C )-alkyl; and R 20 is (a) H, (b) (C 1 -C 6 )-alkyl (c) allyl, (d) (C 3 -C 6 )-cycloalkyl, (e) (C 1 -C 4 )-acyl, (f) benzyl, or (g) phenyl; and 2 ^ groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C 7 )-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[<C 1 -C )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylthio, (C 1 -C )-acyl, or C(=0)NH 2 , (c) aryl, unsubstituted or substituted with V or W, (d) aryl-(Cι-C )-alkyl, unsubstituted or substituted with V or , R 25 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, or (d) aryl-(C 1 -C 5 )-alkyl; and the pharmaceutically acceptable salts thereof. 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 are 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 methlene 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 aryl substituent recited above represents phenyl or naphthyl. 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, and thiazolyl. The preferred compounds of this invention are: 3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]- methyl]-5-(4-nitrobenzylthio)-4S-l,2,4-triazole. 3-Buty1-4-[[4-(1-carboxy-l-phenylmethoxy)phenyl] methyl]-5-(4-nitrobenzylsulfinyl)-41-l,2, -triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-4I-l,2,4- triazole. 3-Buty1-4-[[4-[1-carboxy-l-(2-methylphenyl)methoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-41-l,2,4- triazole. 3-Butyl-4-[[4-(1-carboxy-l-phenylmethoxy)pheny1]- methyl]-5-(4-methoxybenzylthio)-4S-l,2,4-triazole. 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)phenyl]- methyl]-5-(4-methoxybenzylsulfinyl)-4S-l,2,4-triazole, 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-methoxybenzylthio)-4S-l,2,4- triazole. 3-Buty1-4-[[4-[1-carboxy-l-(2-methylphenyl)methoxy]- phenyl]methyl]-5-(4-methoxybenzylthio)-4H-l,2,4- triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(1-carboxy-l- phenylmethoxy)phenyl]methyl-4I-l,2,4-triazole. 3-Buty1-5-(2-carboxybenzylthio)-4-[[4-[1-carboxy-1-(2- chlorophenyl)methoxy]phenyl]methyl]-4H-l,2,4-triazole 3-Butyl-5-(2-carboxybenzylthio)-4-[[ -[1-carboxy-1-(2- methylphenyl)methoxy]phenyl]methyl]-4E-l,2,4-triazole 3-Butyl-4-[[4-[l-carboxy-l-phenylmethoxy]phenyl]- methyl]-5-(4-chlorobenzylthio)-4S-l,2,4-triazole. 3-Butyl-4-[[4-[1-carboxy-l-(2-methylphenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4E-l,2,4- triazole. 3-Butyl-4-[[4-[1-carboxy-l-phenylmethoxy]phenyl]- methyl]-5-(4-methylbenzylthio)-4E-l,2,4-triazole. 3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-methylbenzylthio)-4I-l,2,4- triazole. 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[l-phenyl-l- (5-tetrazolyl)methoxy]phenyl]methyl]-4S-l,2,4- triazole. 3-Butyl-4-[[4-[l-phenyl-l-(5-tetrazolyl)methoxy]- phenyl]methyl]-5-(4-nitrobenzylsulfiny1)-4B-1,2,4- triazole. 3-Butyl-4-[[4-[l-(2-chlorophenyl)-l-(5-tetrazolyl)- methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4g- 1,2,4-triazole. 3-Butyl-5-(4-methoxybenzylthio)-4-[[4-[l-ρhenyl-l-(5- tetrazolyl)methoxy]phenyl]methyl]-4S-l,2, -triazole. 3-Butyl-5-(4-methoxybenzylthio)-4-[[4-[l-(2-chloro- phenyl)-l-(5-tetrazolyl)methoxy] henyl]methyl]-4g- 1,2,4-triazole. 3-Buty1-5-(4-methoxybenzylthio)-4-[[4-[1-(2-methyl- phenyl)-l-(5-tetrazolyl)methoxy]phenyl]methyl]-4H- 1,2,4-triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[l-phenyl-l-(5- tetrazolyl)methoxy]phenyl]methyl]-4g-l,2,4-triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[l-(2-chloro- phenyl)-l-(5-tetrazolyl)methoxy]phenyl]methyl-4I- 1,2,4-triazole. 3-Butyl-5-(4-chlorobenzylthio)-4-[[4-[l-phenyl-l-(5- tetrazolyl)methoxy]phenyl]methyl]-41-1,2,4-triazole. 3-Butyl-5-(4-chlorobenzylthio)-4-[[4-[l-(2-chloro- phenyl)-l-(5-tetrazolyl)methoxy]phenyl]methyl]-4g- 1,2,4-triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2,6-dichlorophenyl)- methoxy]phenyl]methyl]-5-(4-methoxybenzylthio)-4S-l,2. 4-triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2-methoxyphenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4g-l,2,4- triazole. - 19 - 18059IA 3-Butyl-4-[[4-[(l-carboxy-l-phenylmethyl)amino]- phenyl]methyl]-5-(4-methoxybenzylthio)-4E-l,2,4- triazole. ' 3-Buty1-4-[[4-[[1-carboxy-l-(2-chlorophenyl)methyl]- amino]phenyl]methyl]-5-(4-nitrobenzylthio)-4S-l,2,4- triazole. 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)phenyl]- 0 methyl]-5-(4-chlorobenzylsulfinyl)-4g-l,2,4-triazole, 3-Butyl-4-[[4-[1-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4E-l,2,4- triazole. 5 3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylsulfinyl)-4E-l,2,4- triazole. o 3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3- propylphenyl]methyl]-5-phenyl-4E-l,2,4-triazole. 3-Butyl-4-[[4-(1-carboxy-l-phenylmethoxy)-3- propylphenyl]methyl]-5-(4-chlorobenzylthio)-4E- 5 1,2,4-triazole. 3-Butyl-4-[[4-(l-carboxy-l-ρhenylmethoxy)-3- propylpheny1]methyl]-5-(4-methoxybenzylthio)-4E- 1,2,4-triazole. 3-Butyl-4-[[4-[1-carboxy-l-(2-chlorophenyl)methoxy]■ 3-propylphenyl]methyl]-5-(4-chlorobenzylthio)-4E- 1,2,4-triazole. - 20 - 18059IA 3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]- 3-propylphenyl]methyl]-5-(4-methoxybenzylthio)-4E- 1,2,4-triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2-methylphenyl)methoxy]- 3-chlorophenyl]methyl]-5-(4-chlorobenzylthio)-4E- 1,2,4-triazole. 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3,5- dipropylphenyl]methyl]-5-(4-chlorobenzylthio)-4E- 1,2,4-triazole. 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3,5- dipropylphenyl]methyl]-5- ( 4-methoxybenzylthio)-4E- 1,2,4-triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2,5-dibromo-3,4- dimethoxyphenyl)methoxy]phenyl]methyl]-5-(4-chloro- benzylthio)-4g-l,2,4-triazole. 3-Butyl-4-[[4-[l-carboxy-l-(2,5-dibromo-3,4- dimethoxyphenyl)methoxy]pheny1]methy1]-5-( -methoxy- benzylthio)-4E-l,2,4-triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(l-carboxy-l- phenylmethoxy)-3-propylphenyl]methyl]-4fi-l,2,4- triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(l-carboxy-l- ( 2-chloroρhenyl ) methoxy]-3-propylρhenyl]methyl]-4E- 1,2,4-triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(l-carboxy-l- (2-methylphenyl)methoxy]-3-chlorophenyl]methyl]-4E- 1,2,4-triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(l-carboxy-l- phenylmethoxy)-3,5-dipropylphenyl]methyl]-4H-l,2,4- triazole. 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[1-carboxy-l- (2,5-dibromo-3,4-dimethoxyphenyl)methoxy]phenyl]- methyl]-4E-l,2,4-triazole. 4-[[[N-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]- phenyl]methyl]-3-butyl-5-(4-chlorobenzylthio)-4E- 1,2,4-triazole 4-[[[N-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]- phenyl]methyl]-3-butyl-5-(4-methoxybenzylthio)-4E- 1,2,4-triazole 4-[[[N-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]- phenyl]methyl]-3-butyl-5-(2-carboxybenzylthio)-4E- 1,2,4-triazole 2-Butyl-4-[ I[N-[(1-carboxy-1-phenyl)methyl]-N- ethylamino]phenyl]methyl]-5-(4-chlorobenzylthio)- 4E-1,2, -triazole Preparation of 3,4,5-trisubstituted-l,2,4- riazoies (Formula I) The compounds of Formula I can be prepared by a variety of methods typified by those described below. General synthetic methods for 3,4,5-trisub- stituted 1,2,4-triazoleε are discussed in books or review articles such as: (1) C. Temple and J.A. Montgomery, "Triazoles: 1,2,4" (Vol. 37 of "The Chemistry of Heterocyclic Compounds", A. Weissberger and E.C. Taylor, eds.), iley-Interscience, New York, 1981. (2) J.B. Polya, in "Comprehensive Heterocyclic Chemistry. The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds", A.R. atritzky and C.W. Rees, eds., Vol. 5, Pergamon Press, Oxford, 1984, PP- 733-790. (3) J.H. Boyer, in "Heterocyclic Compounds", R.C. Elderfield, ed., Vol. 7, John Wiley & Sons, New York, 1961, pp. 384-461. In general, the compounds of Formula I are constructed in such a way that N 1 and N 2 of the triazole ring are derived from hydrazine or a hydrazine derivative, while N^ of the triazole and the 4-(arylmethyl) substituent are derived directly or indirectly from a suitably substituted benzylamine, Although the reaction schemes described below are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of Formula I may render the molecule incompatible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagents, solvent, temperature, and time, should be chosen so that they are consistent with the nature of the functionality present in the molecule. The Reaction Schemes below have been generalized for simplicity. It is to be understood that the "ArCH 2 " substituent present at N of the triazole derivatives or in their precursors is any substituted arylmethyl moiety consistent with the definition of the N^ substituent in Formula I or which may be transformed to such a grouping either before or after the assembly of the triazole ring system. Such transformations may involve protection and/or deprotection as shown in Formula I, or other modifications. It is also to be understood that in most of the Reaction Schemes, the "ArCH 2 " (Ar = aryl) substituent is consistent with the definition of Formula I. Abbreviations used in the schemes and examples below are listed in Table 1. ΪΔ23U- Reagents NBS N-bromosuccinimide AIBN Azobis(isobutyronitrile) DDQ Dichlorodicyanoquinone Ac 2 0 acetic anhydride TEA triethylamine DMAP 4-dimethylaminopyridine PPh 3 triphenylphosphine TFA trifluoroacetic acid TMS-C1 trimethylsilyl chloride Im imidazole AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid Solvents DMF dimethylformamide HOAc (AcOH) acetic acid EtOAc (EtAc) ethyl acetate Hex hexane THF tetrahydrofuran DMSO dimethylsuIfoxide MeOH methanol iPrOH isopropanol _0j_J_£££: rt room temperature TBDMS t-butyldimethylsilyl OTf OS0 CF 3 Ph phenyl FAB-MS Fast atom bombardment mass spectroscopy NOE Nuclear Overhauser Effect Si0 2 silica gel trityl triphenylmethyl The compounds of the present invention may be resolved using the techniques known in the art. The diastereomeric salts and esters of the enantiomers are separated and the desired compound is the more active εtereoisomer. The invention is intended to include individual stereoisomers as well as racemic mixtures. The compounds of this invention, their pharmaceutically acceptable salts and their prodrug forms are included within the scope of this invention. It is further to be understood that in the generalized schemes below, unless specified more narrowly in the text, the groups R* and R*6 represent functionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, and the like. The moiety R 16 Q represents an alkylating agent in which i6 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or p-toluenesulfonate. SCHEME 1-1 AΓC R 1 B Q, base N— N l-Ar Scheme 1-1 outlines some of the most widely applicable routes to compounds of Formula X in which either the 3- or 5-substituent is substituted thio. Thus an appropriate benzylamine 1 may be converted to dithiocarbamate ester 2. in a one-pot two-step sequence involving treatment with carbon disulfide in the presence of a base such-as triethylamine followed by alkylation with ' methyl iodide. Treatment of 2 with hydrazine (preferably in excess) affords the 4-εubstituted thiosemicarbazide ___. This is also readily obtained upon reaction of hydrazine with the isothiocyanate 4, which in turn is prepared from amine 1 [for example, via an intermediate carbethoxy dithiocarbamate (J.E. Hodgkins and M.G. Ettlinger, J. Org. Chem.. 21, 404 (1956)) or by one of the other methods known in the literature]. The acylthiosemi- carbazide 5. may be prepared either by reaction of 2 with the appropriate acid chloride or anhydride or by addition of an acid hydrazide (readily obtained from the corresponding ester) to the isothiocyanate 4. As described in G.F. Duffin, J.D. Kendall, and H.R.J. Waddington, J. Chem. Soc.. 3799 (1959), S.M. El-Khawass and N.S. Habib, ___. Heterocyclic Chem.. 26, 177 (1989), and numerous other papers, acylthiosemi- carbazides related to 5. can by cyclized in the presence of hydroxide or alkoxide to the mercapto- triazoles (best represented as triazolinethiones) corresponding to £. Compounds of type 6 can also be prepared by direct reaction of the thiosemicarbazide derivative 2 with an appropriate acid derivative. For example, reaction of 2 with a trimethyl orthoester at elevated temperature in a suitable solvent (such as 2-methoxyethanol at reflux) yields f_. Similar syntheses of mercaptotriazoles have been reported by G.A. Reynolds and J.A. Van Allan, J___ Org. Chem.. 2i, 1478 (1959). Other acid derivatives such as esters [in the presence of alkoxide: M. Pesson, G. Polmanss, and S. Dupin, Compt. _____,. , 248, 1677 (1959)] and selenoesters [V.I. Cohen, ___ Heterocyclic Chem.. 15, 237, (1978)] have also been reported to react with 4-εubstituted thiosemicarbazideε to give mercaptotriazoles analogous to £. In certain instances the carboxylic acid itself may be used. Thus, 4-substituted thiosemicarbazides have been reacted with trifluoroacetic acid at elevated temperature to give mercaptotriazoles analogous to £ (R=CF 3 ) [T. Cebalo, U.S. Patent 3,625,951 (1971) and E.I. Aoyagi, U.S. Patent 4,477,459 (1984)]. The S-alkylated mercaptotriazoles of structure 2 are obtained by treatment of the triazolinethione £ with an appropriate alkylating agent R 6 Q in which R 6 is functionalized or unfunctionalized alkyl, aralkyl, heterocyclyl, or the like, and Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or p-tolueneεulfonate. This alkylation is conducted in any of a variety of solvents (including methanol, ethanol, 2-methoxy- ethanol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane and water, depending on the properties of the particular substituents) in the presence of a base (such as a trialkylamine, alkoxide, or hydroxide). Triazolinethiones (mercaptotriazoleε) are known to give the S-alkylated derivatives predominantly if not exclusively under basic conditions (see, for examples, C. Temple and J.A. Montgomery, "Triazoles: 1,2,4", Wiley-Interscience, New York, 1981, pp. 251-258).The alkylation reaction iε generally run at a temperature of from 0 β C to 125 β C, depending on the reactivity of the alkylating agent. The triazolinethiones f_ may be prepared by alternative, routes. In the method of F. Malbec, R. Milcent, and G. Barbier fJ. Heterocvcl. Chem.. 21, 1689 (1984)] (Scheme 1-2), the imidate hydrochloride £ is reacted with thiosemicarbazide at ambient temperature to give the ester thiose icarbazone 3- The conversion of 3 to the triazolinethione £ can be effected by heating with amine 1 in DMF at reflux. Similarly, an N^-substituted ester thiosemicarbazone 9a. which is obtained by reaction of 2 with 2. can be cyclized to _•_ by heating in the presence of a base, e.g., l,8-diazabicyclo{5.4.Q}undec-7-ene (DBU), in a solvent such as tetrahydrofuran. SCHEME 1-2 5 NH'HCl | | II NNHCNH- r JCLLOEr * t H,LNHCNH, * R n COEt DMF 8 -wv- For triazolinethiones of type £ where R^aryl, the method of T. Radha Vakula, V. Ranga Rao, and V.R. Srinivasan fin ian J. Chem.. 2, 577 (1969)](Scheme 1-3) is applicable. Thus the thiosemicarbazide derivative 2 iε condensed with an aromatic aldehyde Ifi to give the thiosemicarbazone 11- Upon treatment of 11 with bromine in acetic acid. ' the triazolinethione 1 is formed. SCHEME 1-3 s s II , _ II ArCI^NHCNH H. + ∞ -— — ΛrCHa-OCNHIfcCHR 1 3 10 11 R^aryl H N-N Br, AoOH L_Ar 12 Following the method of . Strzemecka [ " Polish J. Chem.. _1561 (1983)] (Scheme 1-4), reaction of an amidrazone 12 with the isothiocyanate 4 in ethanol at reflux giveε triazolinethione _>.. SCHEME 1-4 H NNH ∑ , ' , 1 1 EtOH , JT 1 ? R 1 CNH 2 « HCl + ArCH 2 NCS — * R 1 ~ ^^ t 1 3 4 LAΓ rr rtΛ. **wvv- o Certain S-substituted mercaptotriazoleε of formula 2 which may not be accessible by the reactions of Scheme 1-1 (especially R 16 = aryl) can be prepared by an alternative route (Scheme 1-5) involving diεplacement of a leaving group on the triazole by an appropriate thiol. Treatment of the triazolinethione ii . with chlorine under anhydrous conditions in a solvent such as chloroform or dichloromethane gives as a major product the chlorotriazole 14 [D.S. Deshpande, T.G. Surendra Nath, and V.R. Srinivasan, Indian J. Chem.. 13, 852 (1975)]. In addition, the synthesis of chlorotriazoles by POCI3/PCI5 treatment of the corresponding triazolinone has been reported [S. Naqui and V.R. Srinivasan, J. Sci. Industr. Res. τ 21E, 195 (1962)]. Reaction of 14 with a thiophenol or other thiol in the presence of a base such as N,N-diisopropylethylamine at elevated temperature (for example, in DMF at reflux) gives ∑. Similar reactions have been reported by H. Becker and K. ehner, British Patent 1,157,256 (1969). Alternatively, the methylthiotriazole li may be prepared (by alkylation of f_ with methyl iodide) and SCBEME 1-5 H N-N _v \ * _ cι 2 JΠΪ R* 1 β SSHH N - N 'Ar A. r • A. r 1 4 1 5 1 6 then oxidized to the methylsulfone 16. using hydrogen peroxide. Displacement of the methanesulfonyl group of li, like the chloro group of 14., by R 16 SH in the presence of a base affords 2, especially for R* 6 = aryl. The preparation of a methanesulfonyltriazole analogous to ___ and its nucleophilic displacement have been reported by E.B. Akerblom and D.E.S. Campbell, J. Med. Chem.. }__, 312 (1973). SCEEME 1-6 7 I? C0 3 H 1 7 1 8 The S-subεtituted mercaptotriazoles 2 can be converted to the corresponding sulfoxides 1Z and/or sulfones 12 by oxidation with various reagents such as hydrogen peroxide in acetic acid or a suitable peracid. Reactions of this type have been described by E.B. Akerblom and D.E.S. Campbell (see reference above). Whether 12 or 12 iε the primary or excluεive product depends on the stoichiometry of the reagents, reaction time, and temperature. SCHEME 1-7 O MH--HC1 o II II II ArCHjNH. COEt R^CNHNH-, 1 R'COEC — E OH Δ R 1 '<^>→ ,t 19 & The method of R. Kraft, H. Paul, and G. Hilgetag rchem. Ber.. 121, 2028 (1968)] (Scheme 1-7) is useful for preparing triazoleε of εtructure 22 in which R 16 iε aryl or heterocyclic. Treatment of the imidate hydrochloride 2 with an appropriate hydrazide (typically at -10° to 5*C.) giveε the adduct 12, which can be reacted with the amine 1 and cyclized to the triazole 22 upon heating in ethanol. By use of the adaption of M. Pesεon and M. Antoine l " Bull. Soc. Chim. Fr.. 1590 (1970)], triazoleε of type 22 in which R 6 iε a εubstituted carboxamide group are obtained by employing a subεtituted oxamic acid hydrazide in Scheme 1-7. SCHEME 1-8 ArCHjNCS 2L 22 ArC H_AΓ S4L 25. Aminotriazoleε of formula 24. where B iε a single bond, can be prepared as shown in Scheme 1-8. An analogous route has been reported by E. Akerblom, Acta Chem. Scand.. 19, 1135 (1965). Reaction of the isothiocyanate 4 with an appropriate amine gives the thiourea 21. which is alkylated with methyl iodide to give the isothiourea hydriodide 22- The acylaminoguanidine 22, obtained by reaction of 22 with a hydrazide in the presence of base, can be thermally cyclized to ___, which is separated from the isomeric byproduct 22- Modest yieldε of aminotriazoleε analogouε to 4 have alεo been obtained by direct thermal reaction of intermediates analogouε to 22 with a hydrazide [L. Carey, B.J. Price, J.W. Clitherow, J. Bradεhaw, M. Martin-Smith, D.E. Bays, and P. Blatcher, U.S. Patent 4,481,199 (1984)]. SCHEME 1-9 NR 1 ' m" II Δ " F'CO J H N-N AΓCI^NH, ♦ H,røOC9Mi ' H,NNHCre K,Ar — • R' -^ ^-JJHR 1 ' ( +2 5) 2 ■ a In another route is shown in Scheme 1-9 following a sequence reported by . Carey, ___ ___ . . , U.S. Patent 4,481,199 (1984), amine 1 is heated with the S-methyl thiosemicarbazide derivative 26 to give the aminoguanidine 21- Heating 22 with an appropriate carboxylic acid provides the aminotriazole ___, which iε separated from the isomer 22 if present. Similar chemistry has been reported by C.F. Kroger, G. Schoknecht, and H. Beyer, Chem. Ber.. 31, 396 (1964), R.G.W. Spickett and S.H.B. Wright, British Patent 1,070,243 (1967), and G.J. Dυrant, G.M. Smith, R.G.W. Spickett, and S.H.B. Wright, J. Med. Chem.. 2, 22 (1966). This last paper also describeε the synthesis of aminoguanidines analogous to 2Z by hydrazine treatment of isothioureaε correεponding to 22 (εee Scheme 1-8). SCBEME I-1P N-N β ιo,- t _- N-N „._„ N-N ^ ^ ^ E2. £9 ^ 3 R 1 β =aryl A uεeful route to certain N-(arylmethyl) aminotriazoleε 22 is shown in Scheme 1-10. The aminotriazole 22 (equivalent to 24, R'=H), which can be prepared by Scheme 1-8 or Scheme 1-9 iε condenεed with an aromatic aldehyde to give the Schiff baεe 29. Reduction of 23 with a suitable reducing agent such as sodium borohydride gives 22- Related syntheses of benzylaminotriazoles have been reported by Reiter [J. Reiter, T. Somorai, P. Dvortsak, and Gy. Bujtas, J__ Heterocvcl. Chem.. 22, 385 (1985) and J. Reiter, L. Pongo, and P. Dvortsak, J. Heterocvcl. Chem.. 24. 127 (1987)]. SCHEME 1-11 2B 31 32 0 Following the methodε of R.G. Harriεon, W.B. Jamison, W.J. Ross, and J.C. Saunders, Australian Patent Specification 518,316, aminotriazoles of structure 23. can be heated with an acid anhydride to give the acylaminotriazoles 21- These can be reduced 5 with lithium aluminum hydride to give the N-εubεtituted aminotriazoleε of formula 32. SCHEME 1-12 0 • S I * 24 1 6 Aminotriazoleε of εtructure 24 can alεo be obtained by heating a chlorotriazole 14 or a methaneεulfonyltriazole 12 with an amine. Amine displacements on chlorotriazoles have been reported by H.G.O. Becker and V. Eisenεchmidt, ____________ 2, 105 (1968) and H. Becker and K. Wehner, Britiεh Patent 1,157,256 (1969). SCHEME 1-13 E ιι 8 KH IΓ-H H-WOCHH, H II otr er oκf ΛS _ι* . _krCH_ICβ — i- UrCHjlOCWlOCMH, ■ ^ 34 R'Q 'S-^ ^NH, tfOP K'S- ^-tfcCHR 1 * NtBH. "^" -1 NK.H.R basa . i i ι 35 36 37 Aminomercaptotriazoles of εtructure 2Z can be prepared aε outlined in Scheme 1-13, which utilizeε the chemiεtry of L.E. Godfrey and F. Kurzer, ___________ ____. 5137 (1961), J. Reiter, T. Somorai, P. Dvortsak, and Gy. Bujtas, J. Heterocvcl. Chem.. 22, 385 (1985), and J. Reiter, L. Pongo, and P. Dvortεak, J. Heterocyclic Chem.. 24, 127 (1987). Reaction of the iεothiocyanate 4 with aminoguanidine giveε 22, which can be cyclized in the preεence of baεe to the aminotriazolinethione 24- Alkylation of 24 in the preεence of baεe yieldε the 5-substituted derivative 3_2. Further transformations to the Schiff baεe 22 and then to 22 are as in Scheme 1-10. SCHEME 1-14 14 38 16 Alkoxy and aryloxytriazoles of formula 22 can be prepared by heating a chlorotriazole 14 or a methaneεulfonyl triazole 12 with the appropriate alkoxide or phenoxide anion. Such a tranεformation haε been described by E.B. Akerblom and D.E.S. Campbell, J. Med. Chem.. 12, 312 (1973). - 39 - 47 C0 2 H In Scheme 1-15, p-hydroxybenzylamine 23 iε treated first at room temperature with carbon disulfide in the presence of triethylamine and then at -10 to +20 # C with iodo ethane to give the dithiocarbamate derivative ML. Upon heating with excess hydrazine in ethanol, this is transformed to the thiosemicarbazide ___. Reaction of __l with an imidate ___ in N,N-dimethylformamide (DMF) at room temperature gives the substituted ester thiosemicarbazone 42, which cyclizes to the triazolinethione ___ upon heating with a baεe such as l,8-diazabicyclo{5.4.0>undec-7-ene (DBU) in a suitable solvent such as anhydrous tetrahydrofuran (THF). Next, treatment of 44 with an alkylating agent (e.g., an alkyl or aralkyl bromide) in the presence of a tertiary amine base, preferably N,N-disopropylethylamine, in a solvent such as 2-methoxyethanol generally affordε the S-alkylated derivative 42 aε the primary or excluεive product. Thiε reaction iε typically carried out at 20-100 β C, depending on the reactivity of the alkylating agent. Treatment of 42 with the appropriate σ-bromophenylacetic acid eεter __f_ in the preεence of a baεe such aε anhydrous sodium carbonate or sodium hydride in DMF or dimethyl sulfoxide (DMSO) gives an O-alkylated product which is next saponified to the acid 47. The last step iε accompliεhed by treatment of the intermediate eεter with exceεε εodium or potaεεium hydroxide in aqueouε methanol followed by acidification. A similar sequence may be carried out starting with a ring-εubεtituted 4-hydroxybenzylamine (analog of 22). The triazolinethione ____ may be prepared by alternative methods (Scheme 1-16). In one of these, the thiosemicarbazide ___, iε reacted with a trimethyl orthoester, preferably in 2-methoxyethanol at reflux. In another method, __1 is treated with an acid chloride or anhydride to give the acyl derivative 42- Heating 4.2 with a base such as sodium ethoxide or hydroxide in an alcoholic or aqueous solvent results in ring closure to 44 (and also removes any phenolic 0-acyl group that may be present as a by-product of the synthesis of 48) . It should be noted that a compound of structure 47 may also be oxidized to the corresponding sulfoxide or εulfone by treatment with hydrogen peroxide in acetic acid or with a suitable peracid as described for Scheme 1-6. The oxidation may be carried out either before or after the ester hydrolysiε of Scheme 1-15. Aε shown in Scheme 1-17, the intermediate ester - prepared as in Scheme 1-15, may be converted to a primary amide by treatment with methanolic ammonia. Dehydration of the amide with phosphoruε oxychloride in the preεence of triethylamine at 0 β C giveε the cyano derivative 22- Reaction of 22 with trimethyltin azide in toluene at reflux, followed by removal of the trimethyltin moiety by treatment with acid and/or εilica gel, yieldε the correεponding tetrazole 21- SCHEME 1-16 20 25 30 - 43 - 18059IA SCSEME 1-17 49 50 51 As shown in Scheme 1-18, 4-(aminomethyl)- benzoic acid i___) can be reduced with lithium aluminum hydride or diborane to the corresponding benzyl alcohol 22. which is converted to a triazole 54 by methods previously described. When 24 is subjected to Swern oxidation conditions, the aldehyde 55 results, and this can be used to reductively alkylate phenylalanine methyl ester in the presence of sodium cyanoborohydride. The resulting product 56 may be acylated to yield 2Z, which is then saponified to the free acid 22- Intermediate 22 may also be saponified, affording 22- SCBSME 1-18 25 * D- or* L- configuration SCHEME 1-19 sncα. In Scheme 1-19, 4-nitrobenzylamine (££) iε transformed to the triazole £1 by previously described methods. Stannous chloride reduction of the nitro group provides the amine ___, which can be alkylated with the α-bromophenylacetic ester i__ to give ___.. Acylation of f_3. to give and then saponification to ___. proceed under normal conditions. Intermediate £2. may also be directly saponified to give 66. SCHEME 1-20 The aldehyde 5 may also be reacted with benzylamine and trimethylsilyl cyanide to give the adduct _J_ (Scheme 1-20). Treatment of f_l with an acid chloride in the presence of triethylamine yields the acyl derivative &$. Finally, transformation of the cyano group to tetrazole by heating with trimethyltin azide affords the target __l. SCHEME 1-21 In Scheme 1-21, 4-methylbenzophenone (_Z__ ) ) iε α-brominated with N-bromosuccinimide in the presence of a radical initiator such as benzoyl peroxide or azobis(isobutyronitrile). The resulting bromo derivative 21 is converted to the azide ___, which is then reduced with triphenylphosphine to the amine 73. By previously described methods, 2 is transformed to the triazole lA- Treatment of 24 with a trimethylsilyl cyanide-potassium cyanide mixture in the presence of a crown ether yields the protected cyanohydrin 1__ . Upon heating 25. with excess trimethyltin azide, followed by acid treatment, the α-hydroxy tetrazole ___. is obtained. SCBEME 1-22 30 Schemeε 1-22 and 1-23 illustrate a typical synthesis in which the 4-(α-carboxybenzyloxy)benzyl side chain (see also Schemes 1-15 and 1-16) iε fully constructed before formation of the triazole ring. First, the appropriate phenylacetic acid 22 is converted to its t-butyl ester 23. by reaction with iεobutylene in the presence of concentrated sulfuric acid, in a pressure vessel. Reaction of 13 with bromine under controlled conditions yields the α-brominated product ∑3- p-Cresol (SJ iε converted to its anion (for example, with potassium hydride or potassium t-butoxide in the presence of 18-crown-6 or with anhydrous potassium carbonate in DMF) and treated with 21 to give ___. Bromination with N-bromosuccinimide in the preεence of azobis(isobutyronitrile) (AIBN) or benzoyl peroxide provides 3Z, which is readily converted to the azide derivative 32. (for example, with lithium azide in DMSO). Using the methodology of 0. Tεuge, S. anemasa, and K. Matsuda Γ . Org. Chem.. 49. 2688 (1984)], the azide 31 may be converted directly to the isothiocyanate £4 by reaction with triphenylphosphine and carbon disulfide. Reaction of 84. which may be used without purification, with hydrazine at room temperature in a solvent such as THF or ethanol affords the thiosemicarbazide 31. The ring closure of 31 with trimethyl orthoformate to give _£f_ . and the subsequent alkylation of £& to give 87 proceed as described for Schemes 1-16 and 1-15, respectively. Finally, the t-butyl protecting group in £2 is removed with trifluoroacetic acid at room temperature, and the free acid 33 is thus obtained. - 51 - In a variation of Scheme 1-22 analogous to a sequence in Scheme 1-21, intermediate 31 is reduced directly to a primary amine and then converted to a triazole by one of the previously described methods. SCHEME 1-23 Compounds of formula I where Z is -CONHSO2R 18 may be prepared from the corresponding carboxylic acid derivatives (I) aε outlined in Scheme 1-24. The carboxylic acid (I) can be converted into the corresponding acid chloride by treatment with refluxing thionyl chloride or preferably with oxalylchloride and a catalytic amount of dimethylformamide at low temperature [A. . Burgstahler, L. 0. eigel, and C. G. Shaefer Synthesis. 767,(1976)]. The acid chloride then can be treated with the alkali metal salt of R 18 S0 2 NH 2 to form the desired acylεulfonamide 33. Alternatively, these acylεulfonamides may be also prepared from the carboxylic acids using N,N-diphenylcarbamoyl anhydride intermediates [F. J. Brown et al - European Patent Application. EP 100543: K. L. Shepard and W. Halczenko- J. Het. Chem.. ___,, 321 (1979)]. Preferably the carboxylic acids can be converted into acyl-imidazole intermediates, which then can be treated with an appropriate aryl or alkylsulfonamide and diazabicycloundecene (DBU) to give the desired acylsulfonamide fi [J. T. Drummond and G. Johnson - Tetrahedron Lett.- 21, 1653 (1988)]. SCHEME 1-24 I 69 *Alternative Methods a) (i) S0C1 2 , reflux (ii) R 18 S0 2 NH-M + (where M is Na or Li) b) (i) (C0C1) 2 , DiF, -20 β C; (ii) R 18 S0 2 NH"M + c) (i) N-(N,N-Diphenylcarbamoyl)pyridinium chloride, aq. NaOH; (ii) R 18 S0 2 NH"M + Intermediate ring-subεtituted methyl α-bromo- phenylacetates ___, aε used in Scheme 1-15, may be prepared as shown in Scheme 1-25. A phenylacetic acid derivative 22. bearing one or more ring εubεtituents, may be reacted under Hell-Volhard-Zelinsky conditions with bromine and thionyl chloride, followed by treatment with methanol to give 4&* Alternatively, a substituted benzaldehyde 32. is reacted with trimethylsilyl cyanide in the presence of potassium cyanide and 18- crown-6 to give the cyanohydrin 31- Treatment of 31 with anhydrous HCl in methanol provides the α-hydroxy ester 21. Finally, reaction of 21 with carbon tetrabromide and triphenylphosphine gives the α-bromo ester 46. SCHEME 1-25 An approach to compounds of Formula I having a 3-substituent on the benzyl portion is illustrated in Scheme 1-26. A 2-substituted phenol such as 2- ethylphenol (92) can be selectively carboxylated upon heating at reflux with carbon tetrachloride, 507. aqueous sodium hydroxide, and copper powder according to EP 193,853, to give the substituted 4-hydroxy- benzoic acid 31- Esterification of the acid followed by silylation of the phenol and lithium aluminum hydride reduction of the eεter yields the benzyl alcohol 24- This may be converted to the benzyl bromide with carbon tetrabromide and triphenylphosphine and then to the azide 31 with lithium azide in DMSO. Triphenylphosphine reduction of the azide and then desilylation with tetrabutyl- ammonium fluoride gives the substituted 4-hydroxy- benzylamine derivative 31, which may be converted by the methods of Scheme 1-15 to a triazole of type 22- SCHEME 1-26 Et \^^ Et ^^CO j H OMBOU H J SO* Jf j CC1 4 , 50% NaOH f 2)t-Bιώfe 2 SiCl. HO HO ' 92_ Cu, Δ , 93_ DMΛP. CH 2 C1 2 3)LiAlH», THF Y N 3_. BU 4 .rF- 9 6 Scheme 1-15 The Claisen rearrangement of allyl phenyl ethers is another useful route to intermediates for incorporation of certain alkyl or alkenyl substituents (R 9 or R 10 ) at the 3-position of the benzyl moiety in compounds of Formula I. As an example (Scheme 1-27), methyl 4-hydroxybenzoate (98) iε alkylated under standard conditions with allyl bromide. The product 33. undergoeε Claiεen rearrangement to 100 by heating at 185*C in o_- dichlorobenzene. Silylation of the phenol, followed by hydrogenation of the allyl group in the preεence of a catalyεt such as rhodium on carbon, giveε the n- propyl derivative 101. Lithium aluminum hydride reduction of the eεter then affordε 102. By the methods described for Scheme 1-26, this is converted to the εubεtituted 4-hydroxybenzylamine derivative 103. By employing the methods of Scheme 1-15, 103 may be transformed to a triazole of structure 1Q4. SCHEME 1-27 THF Sυcceεεive Claisen rearrangements may be used to introduce two m-alkyl or alkenyl substituents (R 9 and R °) into the benzyl moiety of a compound of Formula I. Thus, the allyl phenol 100 from Scheme 1-27 is converted to an allyl ether and then subjected to a second Claisen rearrangement to give the diallyl phenol 111 (Scheme 1-28). By the methods described for earlier schemes, 105 may be transformed to the 4-hydroxybenzylamine derivative 106 and then to a triazole of structure 107. SCBEME i- 2 g Another example of incorporation of a m-alkyl substituent (R 9 or R 10 ) on the benzyl group of a compound of Formula I is shown in Scheme 1-29. This route iε uεeful for the preparation of triazoles wherein the group ?- iε aryl or heterocyclyl and iε directly attached to the triazole ring (see also Scheme 1-7). Intermediate 102 (from Scheme 1-27) may be desilylated with tetrabutylammonium fluoride and then alkylated with methyl α-bromophenylacetate (46) in the presence of a baεe εuch aε potaεsium carbonate to give 108. Analogous to previously described schemes, the benzylic alcohol of 108 may be replaced by bromide and then azide. Triphenylphosphine reduction of the azido group affords the benzylamine derivative 109. Reaction of 109 with the ester acylhydrazone 12 (from Scheme 1-7) in ethanol at elevated temperature gives the triazole 110. Finally, the methyl ester iε saponified to yield HI. SCHEME 1-29 The synthesis of compounds of Formula I wherein X=NR (R=alkyl, alkenyl, and the like) is illustrated in Scheme 1-30. The r»-aminobenzyl triazole ___ (from Scheme 1-19) can be protected as the tert-butoxycarbonvl (Boc) derivative 112. The carbamoylated NH may be deprotonated using a strong baεe such as sodium hydride and then alkylated with an appropriate alkyl (or allyl, etc.) halide. Subεequent removal of the Boc group with trifluoroacetic acid yieldε the monoalkylated aniline 113. The aniline NH may be deprotonated again with εodium hydride and alkylated with the α-bromo eεter 46 to give 114. • Alternatively, 114 may be prepared from the intermediate 31 (from Scheme 1-19) by deprotonation with a strong base such as lithium " bis(trimethylsilyl)amide followed by treatment with the alkylating agent RBr . Upon saponification of the methyl ester of 114. the target compound 115. is obtained. SCHEME 1-30 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, alkai metal salts like sodium and potasεium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine salts, salts with ami o acids like arginine, lysine, and the like. Alεo, εalts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H2SO4, H3PO4, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorεulfonic. The non-toxic, phyεiologically, acceptable εaltε 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 iε insoluble, or in a solvent εuch aε water which iε then removed in vacuo or by reeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin. Angiotensin II (All) is a powerful arterial vaεoconεtrictor, 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 All at the receptors. In order to identify All antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established. Receptor binding asεay uεing rabbit aortae membrane preparation Three frozen rabbit aortae (obtained from Pel-Freeze Biologicalε) were suspended in 5 mM Triε-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 4*C. The pellet thus obtained was resuspended in 30 mL of 50 mM Triε-5 mM M Cl2 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL Bacitracin and the suspenεion was used for 100 asεay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 125 I-Sar 1 Ile 8 - angiotensin II [obtained from New England Nuclear] (10 mL; 20,000 cpm) with or without the test sample and the mixture was incubated at 37 C C for 90 minutes. The mixture was then diluted with ice-cold 50 mM Tris-0.97. NaCl, pH 7.4 (4 mL) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in εcintillation cocktail (10 mL) and counted for radioactivity uεing Packard 2660 Tricarb liquid εcintillation counter. The inhibitory concentration (IC5 Q ) of potential All antagonist which gives 50% displacement of the total specifically bound 125I-Sar 1 Ile 8 -angiotensin II was presented aε a measure of the efficacy of such compounds as All antagonists. Receptor assay using Bovine adrenal cortex preparation Bovine adrenal cortex was selected as the source of All receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate waε centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na 2 HPθ (10 mM)-NaCl (120 mM)-disodium EDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1 mM)]. (For screening of compounds, generally " duplicates of tubes are used). To the membrane preparation (0.5 mL) there was added 3H-angiotensin II (50 mM) (10 mL) with or without the test sample and the mixture was incubated at 37'C for 1 hour. The mixture was then diluted with Tris buffer (4 mL) 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 potential All antagonist which gives 507. displacement of the total specifically bound -angiotensin II was presented as a measure of the efficacy of such compounds as All antagonists. The potential antihvpertensive effects of the compounds described in the present invention may be evaluated using the methodology deεcribed below: Male Charleε River Sprague-Dawley ratε (300-375 gm) were aneεthetized with methohexital (Brevital; 50 mg/kg i.p.) and the trachea was cannulated with PE 205 tubing. A εtainless εteel pithing rod (1.5 mm thick, 150 mm long) waε 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 strokeε per minute, volume - 1.1 cc per 100 gramε body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for dr.ug administration, and body 0 temperature was maintained at 37 β C by a thermostati¬ cally controlled heating pad which received input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later 5 angiotensin II or other agonists were administered intravenously at 30 minute intervals and the increase in the diastolic blood presεure was recorded before and after drug or vehicle administration. Using the methodology described above, o representative compounds of the invention were evaluated and found to exhibit an activity of at least IC50 < 50 mM thereby demonstrating and confirming the utility of the compounds of the invention as effective All antagonists. Thus, the compoundε of the invention are uεeful in treating hypertenεion. They are alεo of value in the management of acute and chronic congeεtive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteroniεm, primary and εecondary pulmonary hypertenεion, renal failure and renal vascular hypertension, and in the management of vascular disorders such as migraine or Raynaud's diεease. The application of the compounds of this invention for these and similar disorderε will be apparent to thoεe εkilled in the art. 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 0 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 5 about 0.17. to 157. by weight, and preferably 0.5% to 2.07. 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 o as tablets, capsuleε or elixirε for oral administra¬ tion, suppoεitorieε for rectal administration, sterile solutions or suεpenεionε for parenteral or intramuεcular adminiεtration, and the like. The compoundε of thiε invention can be adminiεtered to 5 patientε (animalε and human) in need of such treatment in dosageε that will provide optimal pharmaceutical efficacy. Although the doεe will vary from patient to patient depending upon the nature and εeverity 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 doseε. Perferably, the doεage 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 compoundε of thiε invention can alεo be adminiεtered in combination with other antihyperten- sives 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 compoundε as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydro¬ chloride, minoxidil, pargyline hydrochloride, polythiazide, prazoεin, propranolol, rauwolfia serpentina, rescinnamine, reεerpine, sodium nitroprusside, εpironolactone, timolol maleate, trichlormethiazide, trimethophan camεylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furoεemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, liεinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admixtures and combinationε 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 the 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 mg) plus miloride (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 angiotenεin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood preεεure in hypertenεive patientε. 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 compositionε as discussed below. About 1 to 100 mg of compound or mixture of compounds of Formula I or a physiologically acceptable 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 εuch that a εuitable 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 εtarch or gelatin; an excipient εuch as microcryεtalline celluloεe; a diεintegrating agent εuch aε corn εtarch, pregelatinized εtarch, alginic acid and the like; a lubricant εuch aε magneεiυm εtearate; a sweetening agent such as sucroεe, 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 materialε of the above type, a liquid carrier εuch 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 preservativeε, 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 εuch as water for injection, a naturally occurring vegetable oil like εeεame oil, coconut oil, peanut oil, cottonεeed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Bufferε, preεervativeε, antioxidantε 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 εuch 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 0.17. 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 εecondary 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 εystem (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 asεay in which cholinomimeticε εuch 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 of the muscarinic antagonist scopolamine which diεruptε 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 ratε who have been εubjected to thiε training and who have been treated only with control vehicle take longer to re-enter the dark chamber than teεt 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 εcopolamine produces. Typically, compounds of this invention should be efficacious, in this pasεive 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) asεay. Diazepam iε a clinically uεeful anxiolytic which iε 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 seεsions. All animalε 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 L1D1L2D2L3 sequence. During both periodε (L or D), preεsing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presεeε alεo elicit mild footεhock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 secondε. Lever preεεing iε suppresεed during the dark periodε reflecting the formation of a conditioned emotional reεponεe (CER). Drug teεting in thiε paradigm iε carried out under extinction conditionε. During extinction, animalε learn that reεponding for food in the dark is no longer punished by shock. Therefore, responεe rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increaεe in reεponεe 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 antidepresεant 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 desipra ine. The method iε baεed on the obεervations that a mouse suεpended 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 εtereotypy model. A clinically uεeful antipεychotic drug that iε uεed aε a positive control in this assay is haloperidol. The asεay method iε baεed upon the obεervation that εtimulation of the dopaminergic εyεtem in ratε produceε stereo- typed motor behavior. There is a strong correlation between the effectiveneεε of claεεical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent εchizophrenic symptomε. Stereotyped behavior induced by apomorphine, with and without pretreatment with teεt compoundε, is recorded using a keypad linked to a microcomputer. Compounds of the inven¬ tion should be efficacious in this asεay 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 compoεitionε εuch as tablets, capεules or elixirs for oral administration, suppositories for rectal administration, sterile εolutions or suεpen- εionε for parenteral or intramuεcular adminiεtration, and the like. The compoundε of thiε 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 diseaεe, the patient'ε 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. Preferably, 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 agentε. Theεe include acetylcholineεterase inhibitors εuch aε heptylphyεoεtigmine and tetrahydroacridine (THA; tacrine), muεcarinic agonists such as oxotremorine, inhibitors of angiotensin-converting enzyme such aε octylramipril, captopril, ceranapril, enalapril, liεinopril, foεinopril and zofenopril, centrally-acting calcium channel blockerε such as nimodipine, and nootropic agents εuch as piracetam. In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other anxiolytic agentε such as alprazolam, lorazepam, diazepam, and buspirone. In order to achieve optimal antidepreεεant activity, combinations of the compounds of this invention with other antidepresεantε are of uεe. 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 εuch aε promethazine, fluphenazine and haloperidol. The following exampleε illuεtrate the preparation of the compoundε of Formula I and their incorporation into pharmaceutical compoεitionε and as εuch are not to be conεidered aε limiting the invention εet forth in the claimε appended hereto. 3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]- methvn-5-(4-nitrobenzvlthio , )-4H-l.2.4-triazole Step A: Methvl N-(4-Hvdroxvbenzvl)dithiocarbamate To a solution of 8.4 g (33 mmol) of 4-hydroxybenzylamine hydriodide [M. Tiffeneau, Su . Soc. Chim. Fr.. 3, 819 (1911)] and 10.1 ml (7.3 g, 73 mmol) of triethylamine in 32 ml of MeOH stirred under N 2 at ambient temperature was added gradually a solution of 2.2 ml (2.8 g, 38 mmol) of carbon disulfide in 12 ml of MeOH. After 1 hour, the resulting solution was cooled to -10°C and treated gradually with a εolution of 2 ml (4.7 g, 33 mmol) of iodomethane in 6 ml of MeOH. The εolution waε then stirred at room temperature for 2 hours. Next, the solution was concentrated to small volume and partitioned between ether and 0.2 N. HCl. The ethereal phase was waεhed further with 0.2 H HCl followed by saturated NaCl. The ether solution was dried (MgSO^, filtered, and concentrated to an oil, which gradually solidified, affording 5.98 g. (85%), mp 90-91 β C; homogeneous by TLC in 2:1 hexane-EtOAc. Mass Spectrum (FAB): 214 (M+l). Analysis (Cg^- ] ^^ calculated: C, 50.67; H, 5.20; N, 6.57 and found: C, 50.76; H, 5.24; N, 6.41. 1H NMR (CDC1 3 , 300 MHz, ppm): δ 2.64 (s,3H), 4.81 (d,2H), 6.80 (d,2H), 6.99 (br ε, 1H), 7.20 (d, 2H). Step B: 4-('4-Hvdroxvbenzvl , )-3-thiosemicarbazide A mixture of 5.98 g (28 mmol) of methyl N-(4-hydroxybenzyl)dithiocarbamate (product of Example 1, Step A), 27 ml (560 mmol) of hydrazine hydrate, and 72 ml of absolute EtOH was stirred at reflux for 1 hour. The εolution waε purged with N2 and then concentrated. The reεidual oil waε treated with 100 ml of CH2CI2, 100 ml of ethyl acetate, and 100 ml of H2O, The solid which separated was washed first with H2O and then with ether. This material was recrystallized twice from absolute EtOH to give 2.74 g (50%) of solid, mp 179-179.5"C; homogeneous by TLC in 19:1 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 198 (M+l). Analysis: {CgH- ^OS • 0.1 C 2 H 6 0 (EtOH)} calculated: C, 48.78; H, 5.79; N, 20.82 found: C, 48.73; H, 5.52; N, 20.65. •i-H NMR (DMS0-d 6 , 300 MHz, ppm): δ 4.47 (s,2H), 4.56 (d,2H), 6.68 (d,2H), 7.13 (d,2H), 8.09 (br S,1H), 8.67 (s,lH), 9.25 (ε,lH). Step C: Ethyl Valerate 4-(4-Hydroxybenzyl)-3- hiosemicarbazone A mixture of 2.67 g (13.6 mmol) of 4-(4-hydfoxybenzyl)-3-thiosemicarbazide (Example 1, Step B), 3.2 g (19 mmol) of ethyl valerimidate hydrochloride [A.J. Hill and I Rabinowitz, J. Am t Chem. Soc. 4&, 734 (1926)], and 30 ml of dry N,N-dimethylformamide (DMF) was stirred overnight at room temperature under N2. It was then concentrated to small volume (oil pump, 50°C) and partitioned between ethyl acetate and H2O. The organic phase was washed with H2O followed by saturated NaCl. The organic solution was dried (MgSO^s, filtered, and concentrated to give a foam, which was chromatographed on a εilica gel column (initial elution with CH 2 C1 2 , followed by 0.5% MeOH in CH2CI2). Evaporation of the pooled product fractions yielded 928 mg (22%) of a εticky white foam; homogeneous by TLC in " 19:l NMR indicated a mixture of εyn and anti iεomers. Mass Spectrum (FAB): 310 (M+l). Analysis (C15H23N3O2S): calculated: C, 58.22; H, 7.49; N, 13.58 and found: C, 58.11; H, 7.41; N, 13.34. •^H NMR (CDCI3, 300 MHz, ppm): δ 0.89 (q,3H), 1.2-1.4 (m,5H), 1.50 (m,2H), 2.27 (m,2H), 3.94,4.07 (minor and major q, total 2 H), 4.80 (d,2H), 6.80 (d,2H), 7.22 (d,2H), 7.40 (br t.lH), 7.93, 8.91 (minor and major ε, total 1H). Step D: 5-Butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3E- 1.2.4-triazole-3-thione A solution of 788 mg (2.55 mmol) of ethyl valerate 4-(4-hydroxybenzyl)-3-thiosemicarbazone • (Step C) and 761 μl (775 mg, 5.10 mmol) of l,8-diazabicyclo{5.4.0}undec-7-ene (DBU) in 8 ml of dry tetrahydrofuran (THF) waε stirred at reflux under N 2 for 24 hourε. During thiε time heavy precipitation occurred. The cooled mixture was filtered, and the solid waε washed with THF followed by ether. The. solid (DBU εalt of the product) was partitioned between EtOAc and 0.2 fi HCl. The EtOAc phase was washed with additional 0.2 fi HCl and then with saturated NaCl. The EtOAc solution was dried over gSU , filtered, and concentrated to give 229 mg (34%) of a white solid, mp 156-157 * C; homogeneous by TLC in 19:1 CH 2 Cl 2 :MeOH. Mass Spectrum (FAB): 264 (M+l)- Analysis (C 13 H 17 N 3 OS): calculated: C, 59.29; H, 6.51; N, 15.96 and found: C, 59.20; H, 6.54; N, 15.59 ±E NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.78 (t,3H), 1.23 (m,2H), 1.41 (m,2H), 2.49 (t,2H), 5.11 (s,2H), 6.72 (d,2H), 7.12 (d,2H), 9.45 (ε.lH). Step E : 3-Butyl-4-(4-hydroxybenzyl )-5-(4-nitro- benzvlthio^H-l .2.4-tr iazole A εolution of 215 mg (0.82 mmol) of 5-butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3S-l,2,4- triazole-3-thione (Step D) in 3 ml of 2-methoxy- ethanol waε treated with 143 ml (106 mg, 0.82 mmol) of N,N-diiεopropylethylamine and then with 177 mg (0.82 mmol) of 4-nitrobenzyl bromide. The solution was εtirred at room temperature in a stoppered flaεk. Heavy precipitation began within 30 minutes. After 2.5 hours, the mixture was partitioned between 100 ml of EtOAc pluε 10 ml of MeOH and 100 ml of 0.2ϋ HCl. The EtOAc layer waε washed further with 0.2H HCl and then with saturated NaCl. The organic phase was dried ( gSθ4), filtered, and concentrated. After drying in vacuo (oil pump) at 50 * C, there was obtained 327 mg (100%) of a solid, mp 132-133 °C ~' homogeneous by TLC in 97:3 CHCl3-iPr0H. Mass Spectrum (FAB): 399 <M+I>- •IH NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.80 (t,3H), 1.25 (m,2H) 1.48 (m,2H), 2.62 (t,2H), 4.45 (s,2H), 4.93 (s,2H), 6.67 (d,2H), 6.83 (d,2H), 7.57 (d,2H), 8.15 (d,2H), 9.53 (br ε, 1 H) . Step F: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-phenyl- methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)- 4H-1.2.4-triazole A mixture of 322 mg (0.81 mmol) of 3-butyl- 4-(4-hydroxybenzyl)-5-(4-nitrobenzylthio)-4g-l,2,4- triazole (Example 1, Step E), 278 mg (1.21 mmol) of methyl α-bromophenylacetate, 168 mg (1.22 mmol) of anhydrous K2CO3, and 3 ml of dry DMF was εtirred under N 2 at 60°C for 24 hourε. The mixture was concentrated is vacuo (oil pump,.50 β C), and the residue was partitioned between EtOAc and H θ. The organic εolution was dried (M SU4), filtered, and concentrated. The residual oil was chromatographed on a column of silica gel (elution with a gradient of 0.5-10% MeOH in CH 2 C1 2 ). TLC (97:3 CHCl 3 -iPrOH and 98:2 CH 2 Cl2-MeOH) and NMR were used to identify the appropriate product fractions, which were combined and concentrated to give the product as a gum. Mass Spectrum (FAB): 441 (M+l). 1H NMR (CDC1 3 , 300 MHz, ppm): δ 0.84 (t,3H), 1.31 (m,2H), 1.61 (m,2H), 2.55 (t,2H), 3.71 (s,3H), 4.40 (s,2H) 4.80 (s,2H), 5.57 (ε.lH), 6.82 (ε,4H), 7.25-7.55 (m,7H), 8.10 (d,2H). Step G: 3-Butyl-4-[[4-[l-carboxy-l-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)- 4H-1.2.4-triazole A εolution of 16 mg (0.03 mmol) of 3-butyl- 4-[[4-[l-(carbomethoxy)-l-phenylmethoxy]phenyl]- methyl]-5-(4-nitrobenzylthio)-4H-l,2,4-triazole (Example 1, Step F) in 240 μl of CH3OH was treated with 120 μl (0.3 mmol) of 2.5N NaOH. After 15 minutes of stirring at room temperature, TLC indicated complete conversion of starting material to a lower Rf product. The εolution waε acidified to pH 1.5 by addition of 0.2N HCl. The precipitated εolid was collected on a filter, washed with H 2 0 then with ether, and dried in vacuo over P2O5 to give 9.5 mg (60%) of the product as a εolid, mp 105-106 β C (preliminary softening); homogeneous by TLC in 90:10:1 C^C^C^OHJC^^H. Mass Spectrum (FAB): 533 (M+l). Analysis ■ 0.25H 2 0-0.25C 4 H 10 0 (ether)]: calculated: C, 62.68; H, 5.62; N, 10.09 and • found: C, 63.05; H, 5.23; N, 9.68. 1H NMR (CDC1 3 , 300 MHz, ppm): δ 0.75 (t,3H), 1.20 (m,2H), 1,49 (m,2H), 2,57 (t,2H), 4.37 (s, 2H), 4.81 (ABq,2H), 5.61 (ε,lH), 6.86 (ABq,4H), 7.2-7.65 (m,7H), 8.07 (d,2H). EXAMPLE 2 3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]- methyl1-5-(4-nitrobenzvlsulfinvl)-4H-1.2.4-triazole Step A: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-phenyl- methoxy]phenyl]methyl]-5-(4-nitrobenzyl- sulf inyl 4H-1.2.4-triazole A εolution of 3-butyl-4-[[4-[l-(carbo- methoxy)-l-phenylmethoxy]phenyl]methyl]-5-(4-nitro- benzylthio)-4g-l,2,4-triazole (from Example 1, Step F) in dry CH2CI2 is treated with E-chloroperoxy- benzoic acid (1 equivalent), and the resulting mixture is stirred at room temperature for about 30 minutes or until TLC indicates complete reaction. At this point the mixture is partitioned between ethyl acetate and saturated NaHC03 εolution. The organic phase is washed repeatedly with saturated NaHCU3, then dried over MgSU4, filtered, and concentrated. The residue may be purified by chromatography on silica gel to give the title compound. Step B: 3-Butyl-4-[[4-[l-carboxy-l-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylsulfiny1)-4H- 1,2-4-triasole By the procedure of Example 1, Step G, 3-buty1-4-[[4-[1-(carbornethoxy)-1-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylεulfinyl)-4B-l,2,4-tri- azole (from Example 2, Step A) iε converted to the title compound. EXAMPLE 3 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[l-phenyl-l- (tetrazol-5-yl)methoxy]phenyl]methyl]-4H-l,2,4- triazole Step A: 3-Butyl-4-[[4-[1-carbamoyl-1-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-4H- 1,2-4-triagple . A solution of 3-butyl-4-[[4-[l-(carbo- methoxy)-l-phenylmethoxy]phenyl]methyl]-5-(4-nitro- benzylthio)-41-l,2,4-triazole (from Example 1, Step F) in methanol is saturated with gaseous ammonia at 0° and then εtirred at that temperature in a εtoppered veεεel for about 6 hours or until TLC indicates complete reaction. The mixture is then concentrated to dryneεε to yield the title compound. Step B: 3-Butyl-4-[[4-[1-cyano-l-phenylmethoxy]- phenyl]methyl]-5-(4-nitrobenzylthio)-4H- 1.2.4-triazole A εuεpenεion of 3-butyl-4-[[4-[l-carbamoyl- l-phenylmethoxy]ρhenyl]methyl]-5-(4-nitrobenzylthio)- 4H-l,2,4-triazole (from Example 3, Step A) in phoεphorus oxychloride (25-30 equivalents) iε εtirred at 0 β C under N 2 as triethylamine (2.2 equivalents) is added dropwise over about 1 hour. After the addition is complete, the mixture is gradually warmed to room temperature and then heated to reflux for about 45 minutes or until TLC indicates complete reaction. The cooled mixture is concentrated n vacuo. and the residue iε partitioned between ice-water and an organic solvent, such as ether, ethyl acetate, or toluene. The organic phase is washed with dilute NaOH and then with H2O. The organic solution iε dried over MgSU4, filtered, and concentrated to give the title compound, which is used directly or may be purified by chromatography on silica gel. Step C: 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[l- phenyl-l-(tetrazol-5-yl)methoxy]phenyl]- methyl1-4H-l.2.4-triazole A mixture of 3-butyl-4-[[4-[l-cyano-l- phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)- 4H-1,2,4-triazole (from Example 3, Step B), trimethyltin azide (3.5 equivalents), and toluene is stirred at reflux for about 2 days. The mixture is then cooled and concentrated in vacuo. The residue is partitioned between 0.5 E HCl and ethyl acetate. The ethyl acetate phase iε dried (MgSU4), filtered, and concentrated. The reεidue iε taken up in methanol and εtirred with εilica gel (4-5 g per mmol of cyano starting material) for about 1 hour. The mixture is then evaporated in vacuo to give a dry powder, which is layered on top of a column of silica gel packed in CH 2 Cl2- Elution of the column with a gradient of methanol in CH2CI2 affords the title compound. EXAMPLE 4 3-Butyl-5-(4-nitrobenzylsulfinyl)-4-[[4-[l-phenyl-l- (tetrazol-5-yl)methoxy]phenyl]methyl]-4H-l,2,4- triazole , To a εtirred εolution of 3-Butyl-4-[[4-[l- phenyl-l-(tetrazol-5-yl)methoxy]phenyl]methyl]-5-(4- nitrobenzylthio)-4H-l,2,4-triazole (from Example 3, Step C) in glacial acetic acid iε added gradually an equal volume of 307. hydrogen peroxide (aqueouε). The resulting solution is εtirred at room temperature in a stoppered flask for about 15-20 hours, until TLC and/or NMR (fτom work-up of an aliquot) indicates complete reaction. The reaction mixture is then partitioned between ethyl acetate and dilute HCl. The ethyl acetate phase is dried (MgS04), filtered, and concentrated in vacuo. The residue iε triturated with ether to give the title compound aε a εolid, which iε collected on a filter and waεhed further with ether. EXAMPLE 5 3-Buty1-4-[[4-(1-carboxy-l-phenylmethoxy)phenyl]- methvl1-5-(4-chlorobenzvlthio)-4H-1.2.4-triazole Step A: 3-Butyl-5-(4-chlorobenzylthio)-4-(4-hydroxy- benzvl)-4H-l.2.4-triazole A εolution of 500 mg (1.9 mmol) of 5-butyl- 2,4-dihydro-4-(4-hydroxybenzyl)-3E-l,2,4-triazole-3- thione (from Example 1, Step D) in 4 ml of 2-methoxy- ethanol was treated with 330 μl (245 mg; 1.9 mmol) of N.N-diiεopropylethylamine and 306 mg (1.9 mmol) of 4-chlorobenzyl chloride. The mixture waε stirred at room temperature in a stoppered flask for 5 hours and then concentrated in vacuo to small volume. The residue was partitioned between 50 ml of ItOAc and 50 ml of 0.2 H HCl. The organic layer was washed with an additional 50 ml of 0.2 fi HCl followed by 50 ml of saturated NaCl. The EtOAc solution was dried over gS04, filtered, and concentrated. The residue was chromatographed on a column of silica gel (elution with a gradient of 1 to 3% isopropanol in CH2CI2) to give 411 mg (56%) of the product aε a white εolid, mp 149-150 β C; homogeneouε by TLC in 97:3 CH 2 Cl -iPr0H. Mass Spectrum (FAB): 388 (M+l). Analysis (C 2Q H22C1N 3 0S): calculated: C, 61.92; H, 5.72; N, 10.83 and found: C, 62.21; H, 5.79; N, 10.96 X H NMR (DMS0-d 6 , 300 MHz, ppm) δ 0.81 (t, 3H), 1.26 ( , 2H), 1.48 (m, 2H), 2.57 (t, 2H), 4.30 (s, 2H), 4.89 (ε, 2H), 6.68 (d, 2H), 6.78 (d, 2H), 7.33 (ABq, 4H), 9.50 (s, 1H). Step B: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-phenyl- methoxy]phenyl]methyl]-5-(4-chlorobenzyl- thio)-4g-1.2,4-triasple A solution of 200 mg (0.52 mmol) of 3-butyl- 5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl)-4I-l,2,4- triazole (from Step A) in 2 ml of dry DMF was treated with 21 mg (0.52 mmol) of sodium hydride (607. in oil), and the mixture was stirred under N2 at room temperature for a few minutes until H 2 evolution had ceased and a clear solution had resulted. To this waε added 119 mg (0.52 mmol) of methyl α-bromo- phenylacetate, and εtirring waε continued under N2 at room temperature for 10 minutes and then at 65*C for 6 hours. The cooled mixture was treated with 1 ml of MeOH and then concentrated in vacup. The residue waε partitioned between 25 ml of EtOAc and 30 ml of H2O. The EtOAc phaεe was washed with 2 x 25 ml of H2O and then with 25 ml of saturated NaCl. The organic solution was dried over MgS04, filtered, and concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.75-1.2% MeOH in CH 2 Cl2) yielded 191 mg (69%) of the title compound as a glass; homogeneous by TLC in 97:3 CH 2 Cl2- eOH. Mass Spectrum (FAB): 535 (M + ). Analysis calculated: C, 64.97; H, 5.64; N, 7.84 and found: C, 64.80; H, 5.79; N, 7.69. X H NMR (CDCI3, 300 MHz, ppm) δ 0.84 (t, 3H), 1.30 (m, 2H), 1.59 (m, 2H), 2.52 (t, 2H), 3.71 (s, 3H), 4.27 (ε, 2H), 4.75 (ε, 2H), 5.58 (ε, 1H), 6.80 (ABq, 4H), 7.15-7.55 (m, 9H). Step C: 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)- phenyl]methyl]-5-(4-chlorobenzylthio)-4E- 1,2 -triazole To a εolution of 165 mg (0.31 mmol) of 3-butyl-4-[[4-[l-(carbomethoxy)-l-phenylmethoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4H-l,2,4- triazole (from Step B) in 2.5 ml of MeOH waε added 1.23 ml (3.1 mmol) of 2.5 ϋ NaOH. The reεulting solution was stirred at room temperature in a stoppered flask for 1 hour and then adjusted to pH 2 by addition of dilute HCl. The mixture was concentrated in vacuo to give a white solid, which waε waεhed thoroughly with dilute HCl (pH 2) and then dried. After further washing with Et2θ and vacuum-drying over P2O5. 133 mg (79%) of the title compound was obtained as a white solid, mp 66-67*C; homogeneous by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH. Mass Spectrum (FAB): 522 (M+l). Anal y sis (C28H28 C N 3°3 S#0 - 2 H 2 0«0.25 C4H 10 0 (Et 2 0)): calculated: C, 64.00; H, 5.72; N, 7.72 and found: C, 63.69; H, 5.67; N, 7.77 *H NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.80 (t, 3H), 1.24 (m, 2H), 1.48 (m, 2H), 2.59 (t, 2H), 4.30 (s, 2H), 4.96 (s, 2H), 5.81 (s, 1H), 6.90 (apparent s, 4H), 7.25-7.55 (m, 9H). EXAMPLE 6 3-Butyl-4-[ [4-(l-carboxy-l-phenylmethoxy)phenyl]- methvπ-5-(4-chlorobenzvlsulf invl)-4H-l .2.4-tr iazole To a εtirred εolution of 60 mg (0.11 mmol) of 3-butyl-4-[[4-[l-carboxy-l-phenylmethoxy]phenyl]- methyl]-5-(4-chlorobenzylthio)-4g-l,2,4-triazole (from Example 5) in 0.75 ml of glacial acetic acid was added gradually 0.75 ml of 3iθ% hydrogen peroxide in H2O. The solution became turbid during the addition but largely clarified within a few minutes. After adding an additional 4 drops of acetic acid, the mixture was stirred at room temperature in a stoppered flask for 16 hours. It was then diluted with 50 ml of EtOAc and shaken with 50 ml of dilute HC1 (pH 2.5). The aqueous phase was extracted with an additional 3 portions of EtOAc. The combined EtOAc fractions were washed once with dilute HCl (pH 2), then dried ( SU4), filtered, and concentrated. Trituration of the residue with Et2θ gave a gum. Upon decantation of the Et2θ and drying in vacuo. 31 mg (51%) of the title compound was obtained as a stiff foam, mp 76-78'C dec. Mass Spectrum (FAB): 538 (M+l). Anal y sis (C 2 8H28 c l N 3 0 4 s *°-5 H 2 0 « 0.1 C 4 H 1 . 0 0 (Et 2 0)): calculated: C, 61.52; H, 5.45; N, 7.58 and found: C, 61.56; H, 5.40; N, 7.52. •IH NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.80 (m, 3H), 1.24 (m, 2H), 1.47 (m, 2H), 2.62 (m, 2H), 4.72 (ABq, 2H), 5.23, (ABq, 2H), 5.81 (s, 1H), 6.90 (m, 4H), 7.25-7.55 (m, 9H). EXAMPLE 7 3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]- methvn-5-(4-methoxvbenzvlthio')-4g-l.2.4-triazole Step A: 3-Butyl-4-(4-hydroxybenzyl)-5-(4-methoxy- benzvlthio)-4ft-l.2.4-triazole Reaction of 5-butyl-2,4-dihydro-4-(4-hydroxy- benzyl)-32-l,2,4-triazole-3-thione (from Example 1, Step D) with 4-methoxybenzyl chloride according to the procedure of Example 5, Step A, gave a 707. yield of the title compound as a εolid, mp 130-131 β C; homogeneouε by TLC in 95:5 CH 2 Cl2-MeOH. Mass Spectrum (FAB): 384 (M+l) Analysis (C21H25N3O2S): calculated: C, 65.77; H, 6.57; N, 10.96 and found: C, 65.89; H, 6.56; N, 10.77 J-H NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.81 (t, 3H), 1.26 (m, 2H), 1.48 (m, 2H), 2.57 (t, 2H), 3.73 (s, 3H), 4.24 (s, 2H), 4.87 (s, 2H), 6.67, 6.79, 6.85, 7.20 (d, each 2H), 9.48 (s, 1H). Step B: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-phenyl- methoxy]phenyl]methyl]-5-(4-methoxybenzyl- thio)-4B-1.2.4-triazole The product from Step A waε converted to the title compound by the procedure of Example 5, Step B. The material waε obtained in 67% yield aε a gum; homogeneous by TLC in 97:3 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 532 (M+l) Analysis (C 30 H 33 N 3 θ 4 S): calculated: C, 67.77; H, 6.26; N, 7.91 and found: C, 67.68; H, 6.41; N, 7.75 • H NMR (CDC1 3 , 400 MHz, ppm): δ 0.83 (t, 3H), 1.30 (m, 2H), 1.59 (m, 2H), 2.62 (t, 2H), 3.70, 3.77 (s, each 3H), 4.34 (s, 2H), 4.78 (s, 2H), 5.57 (s, 1H), 6.78 (d, 2H), 6.81 (ABq, 4H), 7.18 (d, 2H), 7.3-7.55 (m, 5H). Step C: 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)- phenyl]methyl]-5-(4-methoxybenzylthio)-4g- 1.2.4-triazole The product from Step B was converted to the title compound according to the procedure of Example 5, Step C. The material was obtained in 85% yield as a white solid, mp 78-79*C; homogeneous by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH. Mass Spectrum (FAB): 518 (M+l) Analysis (C 2 9H 31 N3θ4S-»0.5 H 2 0): calculated: C, 66.13; H, 6.12; N, 7.98 and found: C, 65.96; H, 6.10; N, 7.97. 1 g_UME (DMS0-d 6 , 300 MHz, ppm): δ 0.81 (t, 3H), 1.25 (m, 2H), 1.49 (m, 2H), 2.61 (t, 2H), 3.73 (s, 3H), 4.26 (8, 2H), 4.96 (ε, 2H), 5.81 (s, 1H), 6.8-7.7 (m, 13H). 0 EXAMPLE 8 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)phenyl]- methyll-5-(4-methoxvbenzvlsulfinvl 4g-1.2.4-triazole By the procedure of Example 6, the title 5 compound was prepared from 3-butyl-4-[[4-(l-carboxy- l-phenylmethoxy)phenyl]methyl]-5-(4-methoxybenzyl- thio)-4g-l,2,4-triazole (Example 7). The material was obtained in 657. yield as a stiff foam, mp 74-75 β C, Mass Spectrum (FAB): 534 (M+l) o Anal y sis C 4 H 10 0 (Et 2 0)): calculated: C, 63.16; H, 6.13; N, 7.52 and found: C, 63.37; H. 6.05; N, 7.42. •1-H NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.80 (t, 3H), 1.23 (m, 2H), 1.48 (m, 2H), 2.60 (m, 2H), 3.75 (s, 5 3H), 4.64 (ABq, 2H), 5.18 (ABq, 2H), 5.80 (ε, 1H), 6.8-7.6 (m, 13H). EXAMPLE 9 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4g-l,2,4- triazole Step A: Preparation of methyl 2-bromo-2-(2-chloro- henvDacetate A mixture of 2-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.25 eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes. The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature. Methanol (30 mL, 25 eq) was then added slowly, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5% NaHSU3, dried ( gSU4), filtered, and concentrated in vacuo. The residue waε purified on a silica gel flash chromatography column (170 x 45 mm) eluted with 15% ethyl acetate/hexane to yield 2.13 g (28%) of the title compound. -3-H NMR (300 MHz, CDC1 3 , ppm): δ 3.8 (ε, 3H), 5.95 (ε, 1H), 7.25-7.45 (m, 3H), 7.7-7.8 (m, 1H) . Step B: 3-Butyl-4-[[4-[l-carbomethoxy)-l-(2-chloro- phenyl)methoxy]phenyl]methyl]-5-(4-chloro- benzylthio)-4β-l.2.4-triazole Reaction of 3-butyl-5-(4-chlorobenzylthio)-4- (4-hydroxybenzyl)-4g-l,2,4-triazole (from Example 5, Step A) with methyl 2-bromo-2-(2-chlorophenyl)acetate, from Step A, according to the procedure of Example 5, Step B, provided a 75% yield of the title compound as a glass; homogeneous by TLC in 97:3 C^C^-MeOH. Mass Spectrum (FAB): 570 (M+l) Analysis (C29H29CI2N3O3S): calculated: C, 61.05; H, 5.12; N, 7.37 and found: C, 60.87; H, 5.33; N, 7.45. - H NMR (CDCI3, 300 MHz, ppm): δ 0.84 (t, 3H), 1.29 (m, 2H), 1.58 (m, 2H), 2.51 (t, 2H), 3.74 (s, 3H); 4.27 (s, 2H), 4.75 (s, 2H), 6.09 (ε, 1H), 6.81 (ABq, 4H), 7.15-7.6 (m, 8H). Step C: 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)- methoxy]phenyl]methyl]-5-(4-chlorobenzyl- thio^-4g-1.2.4-triazole The product from Step B waε converted to the title compound according to the procedure of Example 5, Step C. The material waε obtained in 85% yield as a white solid, mp 100-102 # C, homogeneous by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH. Mass Spectrum (FAB): 556 (M+l) (high resolution FAB): calculated: 555.1150 and found: 555.1239 JH NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.79 (t, 3H) 1.23 (m, 2H), 1.47 (m, 2H), 2.62 (t, 2H), 4.32 (s, 2H), 5.00 (s, 2H), 6.04 (s, 1H), 6.91 (m, 4H), 7.25-7.55 (m, 8H). EXAMPLE 10 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4- " chlorobenzylεulfinyl)-4g-l,2,4- triazole The title compound waε prepared from 3-butyl- 4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]phenyl]- methyl]-5-(4-chlorobenzylthio)-4g-l,2,4-triazole (Example 9) according to the method of Example 6. The material was obtained in 71% yield as a stiff foam, mp 89-90 β C dec. (preliminary softening). Mass Spectrum (FAB): 572 (M+l) Analysis (C28H27Cl 2 3θ4S » H 2 0): calculated: C, 56.95; H, 4.95; N, 7.12 and found: C, 56.71; H, 4.91; N, 7.00 ^ -IBffi (DMS0-d 6 , 300 MHz, ppm): δ 0.78 (m, 3H), 1.21 (m, 2H), 1.45 (m, 2H), 2.60 (m, 2H), 4.72 (ABq, 2H), 5.23 (ABq, 2H), 6.04 (s, 1H), 6.90 (m, 4H), 7.2-7.6 (m, 8H). EXAMPLE 11 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-methoxybenzylthio)-4g-l,2,4- triasole Step A: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-(2-chloro- phenyl)methoxy]phenyl]methyl]-5-(4-methoxy- benzylthio)-4ff-l■2.4-triazole Reaction of 3-butyl-4-(4-hydroxybenzyl)-5- (4-methoxybenzylthio)-4g-l,2,4-triazole (from Example 7, Step A) with methyl 2-bromo-2-(2-chlorophenyl)- acetate, as prepared in Example 9, Step A, according to the procedure of Example 5, Step B, gave a 62% yield of the title compound as a glass; homogeneous by TLC in 97:3 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 566 (M+l). Analysis (C 30 H32C1N 3 04S-»0.2 H 2 0): calculated: C, 63,24; H, 5.73; N, 7.38 found: C, 63.08; H, 5.81; N, 7.47 IH NMR (CDC1 3 , 300 MHz, ppm): δ 0.83 (t, 3H), 1.29 (m, 2H), 1.57 ( , 2H), 2.51 (t, 2H), 3.74, 3.77 (s, each 3H),.4.25 (ε, 2H), 4.72 (ε, 2H), 6.08 (ε, 1H), 6.77 (d, 2H), 6.81 (ABq, 4H), 7.15 (d, 2H), 7.2-7.6 (m, 4H). Step B: 3-Butyl-4-[[4-[l-carboxy-l-(2-chlorophenyl)- methoxy]phenyl]methyl]-5-(4-methoxybenzy1- thio^-4g-1.2.4-triazole The product from Step A was converted to the title compound by the method of Example 5, Step C. The material waε obtained in 797. yield aε a white εolid, mp 84-86*C; homogeneouε by TLC in 90:10:1 CH 2 Cl 2 -MeOH-AcOH. Mass Spectrum (FAB): 552 (M+l) Analvsis (C29H3 0 C1N 3 0 4 S-»0.5 H 2 0): calculated: C, 62.07; H, 5.57; N, 7.49 and found: C, 62.30; H, 5.70; N, 7.43. 1 H NMR (DMS0-d 6 , 300 MHz, ppm): δ 0.79 (t, 3H), 1.24 (m, 2H), 1.47 (m, 2H), 2.60 (t, 2H), 3.73 (s, 0 3H), 4.25 (ε, 2H), 4.95 (s, 2H), 6.04 (s, 1H), 6.8-6.95 (m, 6H), 7.20 (d, 2H), 7.40 (m, 2H), 7.53 (m, 2H). EXAMPLE 12 5 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl- phenyl1methyl1-5-phenvl-4g-1.2.4-triazole Step A: Preparation of methyl 4-(2-propen-l-yloxy)- o bensoate A 2 L flask was equipped with a mechanical stirrer, a reflux condenser and a stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydroxy- benzoate, 960 mL of acetone, 22.50 g (1.625 mol) of 5 anhydrous potassium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the mixture was stirred and refluxed for 14 hours. The mixture was cooled to room temperature, filtered and concentrated to an oil. The residual oil was purified by distillation (97'C @ 0.03 mm Hg) to afford 53.52 g (867.) of the title compound. - H NMR (300 MHz, CDCI3, ppm): δ 3.84 (s, 3H), 4.56 (d, J=7 Hz, 2H), 5.28 (dd, J=3,12 Hz, IH), 5.40 (dd, J=3,19Hz, IH), 5.96-6.10 (m, IH), 6.90 (d, J=10 Hz, 2H), 7.96 (d, J=10 Hz, 2H). FAB-MS: m/e 193 (M+l). Step B: Preparation of methyl 4-hydroxy-3-(2-prop- en-l-yl)benzoate A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically stirred' and refluxed (183 β C) under an argon atmosphere, for 18 hours. At this point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25% ethyl acetate-hexane to separate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractions were concentrated in vacuo and the residual oil was crystallized from hexane to afford 13.70 g (91%) of the title compound. J-H NMR (300 MHz, CDCI3, ppm): δ 3.42 (d, J=8 Hz, 2H), 3.88 (s, 3Ξ), 5.14-5.20 (m, 2H), 5.48 (s, IH), 5.94-6.06 (m, IH), 6.82 (d, J=12 Hz, IH), 7.80-7.85 (m, 2H). FAB-MS: m/e 193 (M+l). Step C: Preparation of methyl 4-(tert-butyldimethyl- silvloxv)-3-(2-propen-l-vl)benzoate To a solution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g (2.95 mmol) of tert-butyldimethylchloroεilane,0.100 g of 4-dimethylaminopyridine, and the reaction mixture waε εtirred at room temperature for 2 hourε. The mixture was then diluted with 50 mL dichloromethane, washed with 100 mL 1 N hydrochloric acid, dried (M SU4), filtered and- evaporated. The residual oil (7.993 g, 97%) was used in the next εtep without further purification. 1H NMR (300 MHz, CDCI3, ppm): δ 0.24 (s, 6H), 1.02 (s, 9H), 3.36 (d, J=8 Hz, 2H), 3.84 (s, 3H), 4.98-5.08 (m, 2H), 5.88-6.03 (m, IH), 6.78 (d, J=ll Hz, IH), 7.76-8.40 (m, 2H) . FAB-MS: m/e 307 (M+l). Step D: Preparation of 4-(tert-butyldimethyl- silvloxv)-3-(2-propen-l-vl)benzvl alcohol To a magnetically stirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous THF was added 15.0 mL of a 1.0 M solution of lithium aluminum hydride in THF, and the reaction mixture was stirred under a nitrogen atmosphere for 2 hours. At this point, the reaction was quenched by cautious addition of 10 mL water, the resulting precipitate was dissolved by addition of 1.0 N hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was separated, dried (MgSU4), filtered and evaporated in vacuo to afford 7.258 g (937.) of the title compound. •Is NMR (300 MHz, CDCI3, ppm): δ 0.20 (ε, 6H), 1.00 (ε, 9H), 3.34 (d, J=8 Hz, 2H), 3.84 (s, IH), 4.57 (ε, 2H), 4.97-5.07 (m, 2H), 5.88-6.03 (m, IH), 6.86 (d, J=10 Hz, IH), 7.05-7.14 (m, 2H). FAB-MS: m/e 279, 261 (M+l). Step E: Preparation of 4-hydroxy-3-(2-propen-l-yl)- benzyl alcohol To a solution of approximately 7.26 g (2.6 mmol) of crude 4-tert-butyldimethylsilyloxy-3-(2- propen-l-yl)benzyl alcohol, from Step D, dissolved in 50 mL of anhydrous THF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the residual oil was purified on a silica gel flash • chromatography column eluted with 57. methanol/chloro¬ form to afford 3.386 g (79%) of the title compound as a colorless oil. -IH NMR (300 MHz, CDCI3, ppm): δ 2.12 (br s, IH), 3.35 (d, J=8 Hz, 2H), 4.54 (ε, 3H), 5.05-5.15 (m, 2H), 5.90 (br s, IH), 5.90-6.05 (m, IH), 6.70 (d, J=10 Hz, IH), 7.02-7.10 (m, 2H). FAB-MS : in/e 165 (M+l) . Step F: Preparation of 4-hydroxy-3-propylbenzyl alcohol To a solution of 0.370 g (2.25 mmol) of the .product of Step E disεolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyεt and the mixture waε εhaken under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound. •JH NMR (300 MHz, CDCI3, ppm): δ 0.95 (t, J=8 Hz, 3H), 1.55-1.68 (m, 2H), 2.22 (br ε, IH), 2.57 (t, J=8 Hz, 2H), 4.56 (8, 2H), 5.93 (br s, 1), 6.66 (d, J=10 Hz, IH), 7.00 (dd, J=2, 10 Hz, IH), 7.08 (d, J=2 Hz, IH). FAB-MS: m/e 167 (M+l). Step G: Preparation of methyl 2-(4-hydroxymethyl-2- ropylphenoχy)-2-phenvlacetate To a solution of 0.484 g (2.91 mmol) of the product of Step F dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromo-2-phenyl- acetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux-for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The. residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound. 1H NMR (300 MHz, CDCI3, ppm): δ 0.95 (t, J=8 Hz, 3H), 1.58 (br s, IH), 1.60-1.75 (m, 2H), 2.70 (t, J=8 Hz, 2H), 3.68 (s, 3H), 4.57 (m, 2H), 5.62 (ε, IH), 6.68 (d, J=10 Hz, IH), 7.07 (dd, J=2, 10 Hz, IH), 7.16 (d, J=2 Hz, IH), 7.32-7.44 ( , 3H), 7.55-7.60 (m, 2H). FAB-MS: m/e 315 (M+l). Step H: Methyl 2-(4-bromomethyl-2-propylphenoxy)-2- henvlacetate A solution of 402 mg (1.28 mmol) of methyl 2-(4-hydroxymethyl-2-propylphenoxy)-2-phenylacetate, from Step G, in 4 ml of CH 2 Cl2 was treated with 510 mg (1.54 mmol) of carbon tetrabromide. The solution was stirred vigorously under N2 at room temperature as 403 mg (1.54 mmole) of triphenylphosphine was added portionwise. The mixture was diluted with an additional 2 ml of CH 2 Cl2 and stirred at room temperature for 2 hours. Next, the mixture was filtered through Celite, and the filtrate was concentrated in vacuo. Flash chromatography of the residue on silica gel (gradient elution with 2.5-107. EtoAc in hexane) afforded 184 mg (38%) of the product as a gum; satisfactory purity by TLC in 98:2 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 378 (M+l) X H NMR (CDC1 3 , 400 MHz, ppm): δ 0.96 (t, 3H), 1.68 (m, 2H), 2.69 (m, 2H), 3.70 (s, 3H), 4.45 (s, 2H), 5.63 (s, IH), 6.65 (d, IH), 7.1-7.6 (m, 7H). Step I: Methyl 2-(4-azidomethyl-2-propylphenoxy)-2- phenvlacetate To a solution of 45 mg (0.12 mmol) of the product from Step H in 0.37 ml of dry DMSO was added 7.3 mg (0.15 mmol) of lithium azide- The solution was εtirred at room temperature under N2 for 4.5 hourε. After flash chromatography on silica gel (elution with 10:1 hexane-EtOAc), 33 mg (83%) of the title compound was obtained as a gum; εatisfactory purity by TLC in 4:1 hexane-EtOAc. Mass Spectrum (FAB): 340 (M+l) 1 H NMR (CDCI3, 400 MHz, ppm): δ 0.96 (t, 3H), 1.68 (m, 2H), 2.71 (t, 2H), 3.70 (ε, 3H), 4.22 (ε, 2H), 5.64 (ε, IH), 6.70 (d, IH), 7.03 (dd, IH), 7.10 (fine d, IH), 7.35-7.45 (m, 3H), 7.57 (dd, 2H). Step J: Methyl 2-(4-aminomethyl-2-propylphenoxy)-2- henvlacetate A solution of 185 mg (0.546 mmol) of the product from step I in 1.36 ml of THF waε treated portionwise with 179 mg (0.682 mmol) of triphenyl¬ phosphine. The solution was stirred at 40*C for 2 hours. Then 19.6 μl of H 2 0 was added, and the solution was stirred at room temperature under N 2 overnight. The solution was concentrated in vacuo. and the residue was re-concentrated from CH2CI2- Column chromatography on silica gel (elution with a gradient of 1.5-107. MeOH in CH2CI2 afforded 160 mg (94%) of the product as a colorless oil; satisfactory purity by TLC in 95:5 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 314 (M+l) 1H NMR (.CDCI3, 400 MHz, ppm): δ 0.94 (t, 3H), 1.67 (m, 2H), 2.03 (br m, 2H), 2.68 (t, 2H), 3.43 (s, 2H), 3.68 (s, 3H), 5.61 (s, IH), 6.6-7.6 (m, 8H). Step K: Ethyl valerate benzovlhvdrazone A solution of 2.2 g (15.9 mmol) of benzoic hydrazide in 50 ml of dry EtOH was stirred under N 2 at -10*C as a solution of 2.5 g (15.1 mmol) of ethyl valerimidate hydrochloride [prepared by method of A.J. Hill and I. Rabinowitz, J. Am. Chem. Soc. _+£- 734 (1926)] in 50 ml of dry EtOH waε added dropwiεe over about 15 minutes. Stirring was continued at -10'C for 3 hours, during which time a white precipitate separated. The cold mixture waε filtered through Celite, and the filtrate was co-evaporated with CHCI3 at 10 e C. The residue was chromatographed twice on εilica gel columns (gradient elution with 963 -102- 0.3-5% MeOH in CH 2 C1 2 ) to give 951 mg (257.) of the title compound as a cream-colored semi-solid, suitable for use without further purification (TLC in 97:3 CH 2 Cl 2 -MeOH). λ E NMR (CDC1 3 , 400 MHz) was complex, suggesting that the product is a mixture of syn- and anti-iεomers. Mass Spectrum (FAB): 249 (M+l) Step L: 3-Butyl-4-[[4-[l-(carbomethoxy)-l-phenyl- methoxy]-3-propylphenyl]methyl]-5-phenyl-4g- 1.2.4-triazole To a solution of 43.2 mg (0.175 mmol) of ethyl valerate benzoylhydrazone (from Step ) in 0.2 ml of ethanol was added a solution of 82 mg (0.262 mmol) of methyl 2-(4-aminomethyl-2-propylphenoxy)-2- phenylacetate (from Step J) in 0.2 ml of ethanol. The resulting solution was stirred under N2 at 50 β C for 5.5 hours. After dilution with 0.4 ml of ethanol, the solution was then εtirred at 70 β C under a condenεer for 13 hourε. Next, the εolution was co-evaporated with CHCI3. The residue was chromatographed twice on silica gel columns (gradient elution, first with 0.5-3% and then with 0.3-2% MeOH in CHC1 2 ) to give 32 mg (37%) of the title compound as a white glass; homogeneous by TLC in 9:1 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 498 (M+l) ^H NMR (CDCI3, 400 MHz, ppm): δ 0.86, 0.90 (t, each 3H), 1.35, 1.60, 1.72 (m, each 2H), 2.64 (m, 4H), 3.69 (s, 3H), 5.08 (ε, 2H), 5.60 (ε, IH), 6.6-7.6 (m, 13H). Step M : 3-Butyl-4-[ [4-( l-carboxy-l-phenylmethoxy)-3- propylphenyl]methyl]-5-phenyl-4g-l , 2 , 4-tri- azole To a solution of 32 mg (0.064 mmol) of the product from Step L in 320 μl of THF was added 320 μl (0.32 mmol) of lfi NaOH in MeOH. The εolution waε εtirred under N2 at room temperature overnight and then concentrated. The reεidue was disεolved in 1 ml of MeOH and acidified to pH 1.5 by addition of IE HCl in MeOH. This was then concentrated, and the residue was leached with CHCi3- The CHCI3 extract waε dried over anhydrous Na 2 SU4, filtered through Celite, and evaporated in vacuo. The residue was chromatographed on a silica gel column (gradient elution with 2-15% MeOH in CH 2 C1 2 ) to yield 25 mg (72%) of the title compound as a white glass; satisfactory purity by TLC in 9:1 CH 2 Cl 2 -MeOH. Mass Spectrum (FAB): 484 (M+l) Analysis (C 30 H33N 3 θ3'»2/3 CH 2 C1 2 ) calculated: C, 68.20; H, 6.50; N, 7.78 and found: C, 68.31; H, 6.30; N, 7.93 X H NMR (CD3OD, 400 MHz, ppm): δ 0.8-0.95 (m, 6H), 1.42, 1.59, 1.73, 2.63, 2.97 (m, each 2H), 5.40 (s, 2H), 5.71 (8, IH), 6.8-7.7 (m, 13H).

Claims: HAT IS CLAIMED IS: 1 . A compound of Formula I wherein : FORMULA I or a pharmaceutically acceptable salt thereof wherein: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C6)-alkynyl each of which is unsubεtituted or εubstituted with one or more substituents selected from the group conεisting of: i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubεtituted or εubstituted with 1 or 2 substituentε εelected from the group consisting of: 1) Cl, Br, I, F, 2) (C 1 -C )-alkyl, 3) (Ci-C4)-alkoxy, 4) N0 2 , 5) CF 3 , 6) S0 2 NR 2a R 2a , 7) (C 1 -C 4 )-alkylthio, 8) hydroxy, 9) amino, 10) (C3-C7)-cycloal yl, 11) (C 3 -C-Lo*~ a ken y ! an<3 ii) (C 3 -C 7 cycloalkyl, iii) Cl, Br, I, F, or iv) C00R 2 , v) -CF 2 CF 3 , or (b) perfluoro-(Cι-C4)-alkyl, or (c) (C3-C )-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consisting of: (C!-C4)-alkoxy, (C 1 -C4)-alkyl- thio, perfluoro-(Cι-C4)-alkyl, hydroxy, or halogen (F,Cl,Br,I); and B is: (a) a single bond, (b) -S(0) n (CH 2 ) g -, or (c) -0-;and n is 0 to 2; and s is 0 to 5; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and -106- (a) R 2 , (b ) CH 2 -aryl , or (c ) aryl ; and (d) when R 2 and R 2a are alkyl substituentε on the same nitrogen they can be joined to form a ring; and wherein there is more than one R 2a group in the definition of a structure of Formula I they may be the same or different; and R 9 and R!° are independently: (a) H, (b) (C^-Cg)-alkyl, unsubεtituted or εubstituted with (C 3 -C7)-cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, < f > (C!-C 6 )-alkoxyl, (g) when R 9 and R^-^ are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(C -C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubεtituted or εubstituted with (C^-Cg)-alkyl, (j) aryl; and (e) -CH 2 S(0) n -, (f) -CH 2 NR 13 -, (g) -0CH 2 -, (h) -NR 13 CH 2 -, (i) -S(0) n CH 2 -, (j) -CH 2 -, (k) -(CH 2 ) 2 -, (1) single bond, or (m) -CH=, wherein Y and R 2 are absent forming a -C=C*- bridge to the carbon bearing 2 and R 11 ; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneouεly iε bonded to two heteroatoms (0, N, S, SO, S0 2 ). R 1 and R 12 are independently: (a) H, (b) (Cι-C 6 )-alkyl unsubstituted or substituted with: (i) aryl, or (ii) (C 3 -C 7 )-cycloalkyl, (c) aryl, unsubstituted or subεtituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, -108- ii) (C 1 -C 4 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (Cι~C4)- l oxy, or vi) (Cι~C4)-alkylthio, and (d) aryl-(C-^-C 2 )-alkyl, wherein the aryl group is unsubεtituted or substituted with 1 to 5 substitutentε εelected from the group conεisting of: i) Cl, Br, I, F, ii) (C 1 -C )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (Cι-C4)-alkoxy, or (e) (C3-C7)-cycloalkyl; and (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C=0)-, (e) (C 1 -C 6 )-alkyl-(C=0)-, (f) C(C 2 -C 5 )-alkenyl]CH 2 -, (g) [(C 2 -C 5 )-alkynyl]CH 2 -, or (h) aryl-CH 2 -, and Z iε: (a) -C0 2 H, (b) -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-S0 2 -aryl, -109- (f) -C0NH-S0 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubεtituted or εubstituted with a substituent chosen rom the group consisting of: -OH, -SH, -0(Cι-C4)-alkyl, -S-(Cι-C )- lkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -CO2H, -Cθ2~ Cι-C )-alkyl, -NH 2 , -NH[(C 1 -C4)-alkyl], -N[(C 1 -C4)-alkyl] 2 ; and (g) -C0NH-S0 2 -perfluoro-(C-L~C )-alkyl, (h) -C0NH-S0 -heteroaryl, or (i) -C0NHS0 2 NR 2a R 2a ; and (j) -S0 2 NHC0-aryl, (k) -S0 2 NHC0-(Cι-C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a subεtituent chosen from the group consiεting of: -OH, -SH, -0(Cι-C4)-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(C 1 -C4)-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 ; and (1) -S0 2 NHC0-(C 1 -C4)-perfluoroalkyl, On) -S0 2 NHCO-heteroaryl, or (n) -S0 2 NHC0NR 2a R 2a ; and T is -S(0) n -, -0-, -NHCH 2 -, -NHC(=0)-, -C(=0)N(R 20 )-, or -N(R 20 )-; and b is 0 or 1; and R" is (a) H, (b) (C 1 -C 6 )-alkyl 1 (c) phenyl, or (d) benzyl; and is (a) (C 1 -C 10 )-alkyl; (b) subεtituted (Cι-Cιø)-alkyl in which one or more substituent(ε) is selected from (1) I, Br, Cl, F, (2) hydroxy, (3) (C 1 -C 10 )-alkoxy, (4). (C 1 -C5)-alkoxycarbonyl, (5) (C 1 -C 5 )-acyloxy, (6) (C 3 -C 8 )-cycloalkyl, (7) aryl, (8) substituted aryl in which the substituents are V and W, (9) (C 1 -C 10 )-alkyl-S(0) n , (10) (C 3 -C 8 )-cycloalkyl-S(0) n , (11) phenyl-S(0) n , (12) substituted phenyl-S(0) n in which the substituents are V and W, < 13 > oxo » (14) carboxy, (15) NR 2 R 2a , (16) (Cι-C5)-alkylaminocarbonyl, (17) di(Cι-C5)-alkylaminocarbonyl, or (18) cyano, (c) perfluoro-(Ci~C4)-alkyl, (d) (C 2 -C 10 )-alkenyl, (e) (C 2 -C 10 )-alkynyl, (f) (C 3 -C 8 )-cycloalkyl, (g) substituted (C3-Cg)-cycloalkyl in which the substituent is selected from: (1) or (2) (C 1 -C 5 )-alkoxy, (3) (Cι-C5)-alkoxycarbonyl, (4) (C 1 -C 5 )-acyloxy, (5) ( -C^-acyl, (6) hydroxy, (7) Br, Cl, F, I, (8) (C 3 -C 8 )-cycloalkyl, (9) aryl, (10) substituted aryl in which the substituents are V and , (11) (C 1 -C 10 )-alkyl-S(0) n , (12) (C 3 -C 8 )-cycloalkyl-S(0) n , (13) phenyl-S(0) n , (14) substituted phenyl-S(0) n in which the subεtituents are V and W, (15) oxo, (16) carboxy, (17) NR 2 R 2a , (18) (Cι-C5)-alkylaminocarbonyl, (19) di(C -C5)-alkylaminocarbonyl, or (20) cyano, (h) C0 2 R 2a , (i) aryl, (j) substituted aryl in which the substituents are V and W, (k) aryl-(CH 2 ) r -(M 1 ) 2 -(CH 2 ) t - (1) subεtituted aryl-(CH 2 ) r -(M 1 ) 2 -(CH 2 ) t - in which the aryl group iε substituted with V and W, M x is 0, S, -N(R 15 )-, or -C(0)-; and z is 0 or 1; and r and t are 0 to 2; and V and are each independently selected from: phenyl, unsubstituted or εubstituted with: V and W, (Cι-C )-alkyl, or perfluoro-(Ci~C4)-alkyl; and >20 IS (a) H, (b) (C 1 -C 6 )-alkyl, (c) allyl, (d) (C 3 -C 6 )-cycloalkyl, (e) (C 1 -C )-acyl, (f) benzyl, or (g) phenyl; and R 2 groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C£)-alkynyl each of which is unsubεtituted or εubstituted with a substituent selected from the group consisting of (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NHC(C 1 -C 4 )-alkyl], -N[(C 1 -C )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C 1 -C4)-alkoxyl, (C 1 -C4)-alkylthio, (c) aryl, unsubstituted or substituted with V or , (d) aryl-(Ci~C4)-alkyl, unsubstituted or substituted with V or W, R 25 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, or (d) aryl-(Ci-Cs)-alkyl. 2. A compound which is or a pharmaceutically acceptable εalt thereof wherein: R! is: (a) (Cι-C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C£)-alkynyl, each of which iε unεubstituted with a εubεtituent selected from the group consisting of: ϋ) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, or iv) C00R 2 , v) -CF 2 CF 3 , or vi) -CH 2 CF 3 ; and (b) perfluσro-(Cι-C4)-alkyl, or (c) (C3-Cg)-cycloalkyl; and R 2 is: H, or (C 1 -C 6 )-alkyl; and R2a i s: R2^ benzyl, or phenyl; and when R 2 and R 2a are alkyl substituents on the same nitrogen they can be joined to form a ring; R 9 and R!° are independently: H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, Cl, Br, F, I, (Cχ-C )-alkoxy, aryl, or R 9 and R 10 join to form a phenyl ring; and X and Y are: -CH -, -0-, -S-, -NR 13 -, single bond, or -CH=, which is double bonded to the carbon bearing Z and R-^, except that X and Y are not defined in such a way that the carbon atom to which Z is attached alεo simultaneouεly bonded to two heteroatoms (0, N, or S(0) n ); and Z is: (a) -C0 2 H, (b -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -C0-NH(tetrazol-5-yl) (e) -C0NH-S0 2 -aryl, (f) -CONH-S0 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubεtituted or subεtituted with a εubstituent εelected from the group conεisting of: -OH, -SH, -0(C 1 -C 4 )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(C 1 -C 4 )-alkyl J -NH 2 , -NH[(C 1 -C 4 )-alkyl] , -N[(C 1 -C4)-alkyl] 2 ; and (g) -C0NH-S0 2 -perfluoro-(Cι-C4)-alkyl, (h) -C0NH-S0 2 -heteroaryl, or (i) -C0NHS0 2 NR 2 R 2a ; and R 11 and R 2 are independently: H, (C -C5)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of: Br, I, Cl, F, (Cχ-C4)-alkyl, (C 2 -C4)-alkenyl, (C 2 -C4)-alkynyl, (Cι-C4)-alko yl, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio; hydroxyl, -NR 2a R 2a ; and > 13 is : (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, wherein aryl is unsubstituted or substituted with 1 or 2 subεtituents εelected from the group conεiεting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, (C 1 -C4)-alkoxy, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C )-alkylthio, hydroxy, -NR 2a R 2a , (c) [(C 2 -C 5 )-alkenyl]CH 2 -, (d) [(C 2 -C 5 )-alkynyl]CH 2 -, (e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubεtituted or substituted with 1 or 2 substituents εelected from the group consisting of: Cl, Br, I, F, (C 1 -C4)-alkyl, (Cι-C )-alkoxyl, N0 2 , CF3, S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl or (G3-Cιo)-al enyl, (f) aryl[(C 1 -C 6 )-alkyl]CO-, or (g) [(C 1 -C 6 )-alkyl]C0-; and T is -S(0)n-, -0-, -NHCH 2 -, -NHC(=0)-, -C(=0)NR 20 , or -N(R 20 )-; and b is 0 or 1; and R 16 is (a) (C^-C^ Q )-alkyl in which one or more subεtituent(ε) is selected from the group consisting of: hydroxy, oxo, carboxy, (Cι-C5)-alkox - carbonyl, (C3-C 8 )-cycloalkyl, aryl, or subεtituted aryl in which the εubstituents are V and W, and (b) aryl, unsubεtituted or εubstituted in which the εubstituents are V and ; and W are each independently selected from: (a) H,- (b) (C-L-C5)-alkoxy, (c) (C 1 -C 5 )-alkyl, (d) hydroxy, (e) ((C 1 -C 5 )-alkyl)S(0) n , (f) -CN, (g) -N0 2 , (h) -NR 2 R 2a , (i) [(C 1 -C 5 )-alkyl]CO-NR 2 R 2a , (j) -C0 2 R 2a , (k) [(C 1 -C 5 )-alkyl]C0-, (1) CF 3 , (m) I, Br, Cl, F, (n) hydroxy-(Cι-C4)-alkyl-, -119- (p) -tetrazol-5-yl, (q) -NH-S0 2 CF 3 , (r) aryl, (s) -0-C0NR 2 R 2a , (t) NR 2a -C0 2 R 2a , (u) -NR 2a -C0NR 2a R 2a , (v) -NR 2a -C0N(CH 2 CH 2 ) 2 Q, (w) -0C0N(CH 2 CH 2 ) 2 Q, or (x) -C0NR 2 R 2a ; and Q is: 0, S(0) n , or NR 2a ; and R ,^2 υ 0 is: H or (C 1 -C 6 )-alkyl. A compound which is or a pharmaceutically acceptable εalt thereof wherein: R 1 is (C 1 -C 6 )-alkyl; and T is S, or S(=0); and R 9 and R 10 are: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C 1 -C 6 )-alkynyl, (C 1 -C 4 )-alkoxyl, (C 3 -C 8 )-cycloalkyl, Cl, Br, I, F, or aryl; and X is -CH -, 0 or -NR 13 -; and R 1 is phenyl, unsubstituted or substituted with 1 to 5 subεtituents selected from the group consisting of: Br, Cl, F, I, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxyl, CF 3 , N0 2 , (C 1 -C4)-alkylthio, OH or NR 2a R 2a ; and R 13 is: H, (Ci-Ce)-alkyl, [(C 2 -C 5 )-alkenyl]CH 2 -, C(C2-C5)-alkynyl]CH 2 - or aryl; and Z iε carboxyl, Cθ2-(Cι~C )-alkyl or tetrazol-5-yl; and R!6 ig benzyl, unsubstituted or substituted in the.2-position or in the 4-position with a εubstitueήt εelected from the group consisting of: carboxyl, (C1-C )-alkyl, Br, Cl, F, or I, methoxy or nitro. 4. A compound which is or a pharmaceutically acceptable salt thereof, wherein: V is: H, 4-C1, 4-Br, 4-1, 4-F, 4-N0 2 , 4-0CH 3 , 4-CH 3 , 2-C0 2 H; and R 9 and R!0 are independently: H, Cl, Br, F, I, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 1 -C4)-alkoxyl, (C3-C7)-cycloalkyl, and R 11 is: phenyl, unsubstituted or substituted with subεtitutents εelected from the group conεisting of: H, Cl, Br, F, I, CH3, or X is: 0 or -NR 13 -; and R 13 is: H, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, or (C -Cg)-alkynyl; and Z is: carboxyl, C0 2 -(Cι-C )-alkyl or tetrazol-5-yl; and 5. The compound of claim 1 wherein said compound or its pharmaceutically acceptable salt iε εelected from the group conεisting of: 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)phenyl]- methyl]-5-(4-chlorobenzylthio)-4E-l,2,4-triazole; 3-Butyl-4-[[4-[1-carboxy-l-phenylmethoxy]phenyl]- methyl]-5-( -methoxybenzylthio)-4S-l,2,4-triazole; 0 3-Buty1-4-(1-carboxy-1-phenylmethoxy)phenyl]methyl]-5- (4-nitrobenzylthio)-4E-l,2,4-triazole; 3-Butyl-4-[[4-[1-carboxy-l-(2-chlorophenyl)methoxy]- 5 phenyl]methyl]-5-(4-methoxybenzylthio)-4g-l,2,4- triazole; 3-Butyl-4-[[-4-[1-carboxy-l-(2-chlorophenyl)methoxy]- phenyl]methyl]-5-(4-chlorobenzylthio)-4H-l,2,4- o triazole; 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(1-carboxy-l- phenylmethoxy)phenyl]methyl]-4S-l,2,4-triazole; 5 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[l-phenyl-l- (tetrazol-5-yl)methoxy]phenyl]methyl]-4S-l,2,4- triazole; 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl- phenyl]methyl-5-(4-chlorobenzylthio)-4S-l,2,4- triazole; 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl- pheny1]methy1-5-(4-methoxybenzy11hio)-42-1,2,4- triazole; 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3,5- dipropylphenyl]methyl]-5-(4-chlorobenzylthio)-42- 1,2,4-triazole; 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3,5- dipropylphenyl]methyl]-5-(4-methoxybenzylthio)-42- 1,2,4-triazole; 3-Butyl-4-[[4-[l-carboxy-l-(2,5-dibromo-3,4-dimethoxy¬ phenyl)methoxy]phenyl]methyl]-5-(4-chlorobenzylthio)- 4H-1,2,4-triazole; 3-Butyl-4-[[4-[l-carboxy-l-(2,5-dibromo-3,4-dimethoxy- pheny1)methoxy]phenyl]methyl]-5-(4-methoxybenzy1thio)- 42-1,2,4-triazole; 4-[[[N-ally1-N-[(1-carboxy-1-phenyl)methyl]amino]- pheny1]methyl]-3-butyl-5-(4-chlorobenzylthio)-42- 1,2,4-triazole; 3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl- phenyl]methyl]-5-phenyl-4g-l,2,4-triazole; 4-[[[N-allyl-N-[(1-carboxy-l-phenyl)methyl]amino]- phenyl]methyl]-3-butyl-5-(4-methoxybenzylthio)-42- 1,2,4-triazole; or 3-Butyl-4-[[[N-[(1-carboxy-1-phenyl)methyl]-N-ethy1- amino]phenyl]methyl]-5-(4-chlorobenzylthio)-42- 1,2,4-triazole. 6. A pharmaceutical composition useful in the treatment of hypertenεion which compriεeε 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 εelected from a diuretic, an angiotensin converting enzyme inhibitor a calcium channel blocker and a β-blocker which are members selected from the group consisting of: amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates , deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina. reεcinna ine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan ca εylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, etftacrynic acid, furosemide, merethoxylline procaine, εodiυm ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, difluniεal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, aε well as admixtures and combinations thereof. 8. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Claim 1. 9. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of Claim 1. 10. A method of treating ocular hypertenεion compriεing topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of Claim 1. 11. A method of treating cognitive dysfunction, anxiety, or depresεion comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of Claim 1.

Inventors: ASHTON WALLACE, DHANOA DALJIT S, FITCH KENNETH J, GREENLEE WILLIAM J, HANGAUER DAVID, PATCHETT ARTHUR A, RIVERO RALPH A, WALSH THOMAS, ASHTON, WALLACE, DHANOA, DALJIT, S., FITCH, KENNETH, J., GREENLEE, WILLIAM, J., HANGAUER, DAVID, PATCHETT, ARTHUR, A., RIVERO, RALPH, A., WALSH, THOMAS
Applicants: MERCK & CO INC, MERCK & CO., INC.
Application year: 1991
Main classification: A01N43
IPC codes: A61K31, A61P7, A61P9, A61P43, C07D249, C07D403