PT97861A - Process for the preparation of N-substituted 1,2,4- triazoline compounds for the treatment of cardiovascular diseases - Google Patents

Abstract

The present invention relates to a process for the preparation of N-substituted 1,2,4-triazolines with the formula <IMAGE> in which R1 is for example 2-oxo-2- (tricyclo[3.3.1.13.7]dec-2-yl)-ethyl, R2 is for example ethyl, and R3 and R11 are for example hydrogen. Said compounds can be prepared by the reaction of a compound of the formula <IMAGE> with a base, followed by a reaction with a compound of the formula <IMAGE> These compounds are particularly useful in the treatment or control of hypertension and congestive heart failure.

Description

Related order

This application is a continuation-in-part of U.S. Patent Application Ser. No. 7,529,979, filed May 25, 1990, which is incorporated herein by reference in its entirety.

1, 2 * 4-1 riazo 1 -one N-substituted non-peptidic compounds are described for use in the treatment of cardiovascular disorders such as hypertension and congestive heart failure. Of particular interest are the angiotensin-11 antagonist compounds provided by 1 triazoles having a biphenylmethyl moiety attached to the nitrogen atom in the fourth position of 1,2,4-

BACKGROUND OF THE INVENTION The renin-angiotensin system is one of the hormonal mechanisms involved in the regulation of pressure / volume homeostasis in the expression of hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the just-quadratic kidney and culminating apparatus in the formation of angiotensin II? the primary active species of this system. * This actapeptide, angiotensin 11f is a potent vasopressor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium retention and fluid retention, inhibiting renin secretion, systemic nervous system, increase secretion vasopressin, provoke positive cardiac inotropic effect modulation of other hormonal systems *

The

Previous studies have shown that antagonizing angiotensin II in its recaptures is a viable method to inhibit the renin-angiotensin system, giving the key role of this octapeptide which elicits the actions of the renin-angiotensin system through the intersection with various tissue receptors. There are a number of angiotensin II antagonists, many of which are of a peptidic nature. Such peptidic compounds are of limited use because of their lack of ara bioavailability or their short duration of action. Also, commercial angiotensin II peptidic antagonists are available for example , Saralasin) is a significant residual agonist activity which furthermore limits its application to tsrap@uti.ca. Non-psyllium compounds with angiotensin-antagonistic properties are known. For example, the sodium salt of 2-n-furoyl-4-chloro-1- (2-chlorohexyl) imidazol-5- acetic acid has specific competitive angiotensin II antagonist activity as if in a series of binding experiments, practical assays are in vivo tests CP, C, Wong st al, 3, Pharmacol Exp, Thr, 24% (1), 1- 7 (1988). Also, the sodium salt of 2-butyl-4-chloro-1- (2-nitrobenzyl) imidazole-S-acetic acid has competitive angiotensin II antagonistic activity as seen in the series of bonding experiments, practical tests and live tests CA.T. Chiu et al, European 3 = Pharmacol, 157, 1321 (1988). A family of 1-benzimidazole-5-acetate derivatives have been shown to have competitive properties of angiotensin II antagonists EA, I, Chiu et al, , Exp, Ther ... 2Q (v (3), 867-874 (1939).) U.S. Patent No. 4,316,433 to Blankley et al discloses a 4,5,6,7-tetrahydro derivatives (4,5-c) -tetrahydropyridine useful as antihypertensive agents * some of which are referred to as antagonizing the binding of labeled angiotensin II to the rat adrenal receptor preparation in this way causes a significant decrease in i

mean arterial pressure in conscious hypertensive rats, A E "F '. Nd. 253, 310, issued January 2, 1988, discloses series of aralkyimidazole compounds. including a particular family of biphenylmethyl-substituted imidazole, as antagonists to the receptor antagonist II. EP No. 323,841 published on July 12, 1989 discloses four classes of angiophoresin II antagonists, namely, biphenylmethylpyrroles, hyalenyl pyrazoles, biphenylmethyl- 1,2,3-triazols and 4H-1,2,3,4-tetrahydropyridines. including the compound 3545-dibutyl-4-t-2'-carbobiphenyl-4-ylmethyl] -4H-1,2,4-triazol-1-one. Mo 4,38® 588 by Cardin et al. Describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in the treatment of hypertension and congestive heart failure. antiulcer,

There are several other families of known compounds having one or two substituents on the triazole ring. For example, East German Patent No. 16,444, issued August 3, 1983 describes a family of compounds 1,2,4 -tri-azolin-S-one, specifically 2,4-dihydro-4,5-heptylmethyl) -3H-1,2,4-triazol-3-one. to be used as herbicide. Belgian Patent No. 806,146 published October 16, 1972 describes a family of triazolazine compounds, including the compound &lt; 3 &lt; 4-m-chlorophenyl-1-piperazinyl> -propyl-3,4-diethoxy-2,4,4-triazo-n-b-one, having tranquilizing, hypotensive and analgesic activities. Belgian Patent No. 631,842 published February 28, 1986 describes a 1,2,4-triazolone family having hypotonic, tranquilizing, narcotic, sedative and analgesic activities, which include a class of 4-N-aralkoxy- 1,2,4-triazol-1-one, EP 7.18, issued June 15, 1978 describes a family of 1,2-disubstituted-4-allyl, 2,4-triazoline-3 , 5-dione has a wide variety of activities such as activities

bronchodilatation inhibitors, which include antihypertensive antiarrhythmic activities, inhibition of platelet and smooth muscle aggregation. EP # 238,310 published on March 18, 1987 describes a family of derivatives

of N &quot; diarylmethyl-N'-aminoalkyl-diaaheterocyclic acid for the treatment of cerebral and ischemic vascular diseases and for protection against anoxia. Fig.

A class of N-substituted biphenylalkyl compounds useful in the treatment of cardiovascular circulatory disorders is defined by Formula I-N-

(I)

The RV Λ N \ in which m is a number from one to four inclusive; wherein R3 is selected from the polycycloalkylD8 polycycloalkylalkyl, 3-phenylpropyl, 2-benzoyl-2-phenylethyl, β-benzoyl-2-phenylacetyl, 1,1-dimethylethylcarbonylethylmethyl, Hexyl, silylbutyl, 3-naphthalenylmethyl, 2-cyclohexylmethylthiophenyl, 2-cyclohexylmethyl, 2-phenylethyl substituted carbymethoxyethyl, 3,5,5-trimethoxy, C2 -phenylmethyl, N-ethenylmethyl, ?

2-oxobutyl-2-oxobutyl) -2,5-dimethoxyphenyl) -2-oxoethyl, 2-naphthyl-2- (phenylmethoxy) 2-naphthylsilylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted by benzoyl, 1-benzoyl-1-methylsethyl, i-pentaacetic acid, cyclopropylmethyl, arylalkenyl alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, aralkylcarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl, sulfinyl, aralkylsulfonyl and radicals of the formula

R12

-CN

R131. wherein each of H * '&amp; R3 are independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and wherein R3 and R4 taken together may form a heterocyclic group -cyclic ring having from five to seven ring members including the nitrogen atom to said amino or amido radical and which heterocyclic group may additionally contain one or more ring heteroatoms selected from oxygen atoms, nitrogen s sulfur atoms in which the heterocyclic group may be saturated or partially unsaturated wherein each of R4 and R4 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said radical amino or amido and which aromatic heterocyclic group may additionally contain one or more heteroatoms as well as ring atoms selected from oxygen, nitrogen and sulfur atoms with condition that when X is oxygen atom, then R'1 & Rx 'may not be selected from hydrogen at alkyl

wherein each of R1 to R11 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl; alkoxycarbonylalkoxyalkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkyl, aralkoxysilane, aralkenyl, cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, aralkoxycarbonyl, aralkoxycarbonyl and aralkoxycarbonyl groups. Alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkenyl, alkenyl, alkynyl, cyano, nitrile, carboxyl, araxylsilyl, alkylcarbonyloxy, mercaptocarbonyl, methylacetylcarbonyloxy, alkoxycarbonyloxy, alkylthio, alkylthiocarbanyl, alkylcarfoonylthio, alkylthiocarbonylthio, alkylthiocarbonylthio, alkylthiocarbonylthio, -fciotiocarhoníla, alquilfciatioearboniltio, ariitio, ari1tiocsrho-No, arylcarbonylthio, ariltiocarboniloxi, ari1tiocarboniitio, ariltiotiocarbonilo, ariltiotiocarboniltio "aralkylthio, aralkyl-quiltiocarbonilo, aralquiIcarboni1 thio, aralquiltiocarbonilcxi, aralquiltiocarboniitio, alkylthiocarbonyl, aralquiltiocarboniitio, mercapto, alkylsulfinyl, alkylsulfonyl, Nile ~ aralquilsulfi- arylsulfonyl, arylsulfonyl, arylsulfonyl, betarazolyl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino acid amides of the formulas &gt; X 1, X 1,

Wherein X is an oxygen atom or sulfur atom wherein each of R 1, R 1, R 2, R 2, R 3, R1, R2 and R19 are independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R &quot; s R '' taken as a set, R ~ e i * 7 1 ρ ·? W*

Taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms in which the heterocyclic group may be unsaturated or partially unsaturated, wherein each of R4 and R4 taken together are each R4, R &quot; &quot; taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may additionally contain one or more hetero atoms as well as ring atoms selected from oxygen atoms, nitrogen and sulfur, -, - 1, and in which each R "to R" &quot; may additionally be independently from hydroxy to acidic moieties of the formula; wherein n is a number selected from zero to three, inclusive, and wherein A is an acyclic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acyclic moieties ; wherein é is a spacer group optionally selected from one or more of alkyl, cycloalkyl, cycloalkylalkylalkenyl, alkynyl, aryl, aralkyl, s heteroaryl having one or more ring atoms selected from the hydrogen atoms, sulfur, and nitrogen

The groups V and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, alkoxy, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxy, msrcap &quot; alkylsulfonyl, aralkylsulphonyl, aralkylsulfonyl, arylsulfinyl, arylsulphonyl, heteroaryl, having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula

X-R 2, R 3, -N

Is A24 mn where X is an oxygen atom or sulfur atom? - 2u in which H &quot; alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR ', and /

-NH wherein D is selected from an oxygen atom and an atom; and is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl &quot; aryl

R 1, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 3 and R 4 are each independently selected from hydrogen, alkyl. cycloalkyl is selected.

cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, carboxy, alkylsulfinyl, alkylsulfonyl, arylsulphenyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, aralkyl and aryl, and wherein each R ' ? η * &quot; * &quot; 5 R'1 &quot; ',' '*' 's R &quot; ~ w s R * &quot; is additionally independently selected from amino and amido radicals of the formula ## STR4 ## wherein R 1, R 2, R 3, s-MC-R '&quot; J-

R X is

X is an oxygen atom or an atom of sulfur, in which each R 'is hydrogen, R' ', R' ', R' 'and R' '' '; is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, cycloalkylalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, araalkyl, aryl, s in each of R4 and R4 taken together and each of R1 '' '' R &quot; taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino or starch radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms, nitrogen and sulfur whose heterocyclic group may be saturated or partially unsaturated. Each R "" is taken together and each R "w and R" taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen atoms, azeste ? and sulfur

or a tautomer or a pharmaceutically acceptable salt thereof.

Compounds of Formula 1 are useful in the treatment of a variety of circulatory disorders including cardiovascular disorders, such as hypertension, congestive heart failure and atherosclerosis, to treat other disorders such as glaucoma. These compounds are also useful as supplemental therapies. For example compounds of the formula I may be used in combination with other drugs, such as a diuretic, to treat hypertension. Also, the compounds of Formula I may be used in conjunction with certain surgical procedures For example, these compounds may be used to prevent post-angioplasty restenosis. Compounds of Formula 1 are therapeutically effective in treating cardiovascular disorders due to acting as compared to angiotensin reuptake blockers ΣΙ <AII> Comp Compounds of Formula I and are therapeutically effective in the treatment of the above-mentioned cardiovascular circulatory disorders or may be precursors or prodrugs of ethically effective compounds. The phrase "acidic group selected to contain at least one acidic hydrogen atom" as used for T i -I define the -YA link at any of the positions k'j through RAA of Formula 1, gives the compound of Formula I an acidic character. "Acidic character &quot; means proton data capacity, i.e., the ability of the compound of Formula I to be a proton donor in the presence of a proton receptor substance such as water. Typically, the acidic group should be selected to have proton donor capacity such that the product of the compound of Formula I has a pK in a range of about one to about twelve. Typically, the compound of Formula I should have a pK in a range of from about two to about seven ; IS **

example of an acidic group containing at least one acidic hydrogen atom is a carboxylic group (COOH), wherein n is sero and A is -COOH, in the -Y-A moiety, such carboxyl group is bound directly to one of the positions of R &quot; The compound of Formula I may have a -Ynft moiety attached to one of the R &quot;

i.e. to R 5, or may have a plurality of such -? ']'? Are more than one of the positions of R '&quot; up to 5% to a maximum of 9% of such moieties. There are many examples of acidic groups other than the carbamyl group, because they contain at least one acidic hydrogen atom. Such other acidic groups would be referred to collectively as &quot; carboxylic acid biaisosters &quot; or referred to as &quot; acid bioisosters. &quot; Specific examples of such acidic bioisosters are described below. Compounds of Formula I having the -Y 4 A moiety attached to one of the positions R 1 Ru% R 'and E &quot; they are expected to have

= 5 &quot; CJ do you want? while bonding to R 2 'is more preferred. Compounds of Formula I may have one or more acidic protons, which may have one or more preferable values, wherein at least one of these pK values of the compound of Formula 1 as conferred by the -Y-A moiety is in the range of from about sixty to seven, the -YA moiety may be attached to one of the positions of R '&quot; to R 2 through any portion of the -Y 2 A moiety which results in a relatively stable compound of Formula I, also having a labile or acidic proton to satisfy the above criterion for example 1, wherein the acidic moiety -Y-A-tetrazole, the tetrazole is attached to the ring carbon atom,

A preferred class of compounds consists of the compounds of Formula I wherein m is an amide which is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy- 2-phenyl- dimethylsilyloxysulfonyl, hexyl,

ethoxycarbonylmethyl, carboxymethyl, naphthalenylmethyl, 2-cyclohexylsyl, pentyl, ethoxycarbonylmethoxyethyl substituted by phenyl, substituted phenylsulfonyl, 3,3,3-trimethoxyphenyl, 2-f 1-methoxyethyl) -1- (phenylmethyl) -HE-ethenyl, 1-benzoyl-2-phenylstil, 1-oxobutyl, 2- (2,5- 2-phenyl-2-phenylmethoxy) ethyl, 2 - ((2-dimethoxyphenyl) -2-hydroxymethyl, 2-naphthalenylmethyl, methoxycarbonylmethyl, benzoyl substituted benzoyl, benzoyl- i-methylstil, i-penta-nicanic, cyclopropylmethyl, silylalkenyl, acetonitrile. Cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbanyl, aralkylsulfonyl and radicals of the formula XR 12,

-CN

wherein X is an atom of the hydrogen atom or sulfurμ 1 &quot; wherein each of R2 and R3 is independently sequestered from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is a oxygen atom, then R3 is -13 K &quot; can not be selected from hydrogen and alkyl; Wherein R1 is selected from hydrogen, alkyl, hydroxy-alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, arylaxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkylD, carfooxyalkyl, alkoxy carbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkyl, aroxalkyl, aralkoxyalkyl, alkenyl, alkoxy, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, arylalkyl, Accordingly,

alkyloxycarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonyloxy, arylthiothiocarbonyl, arylthiocarbonyloxy, arylthiocarbonyloxy, arylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonyl, uterecapto, alkylsulfonyloxy, aralkylsulfonyloxy, arylsulfonyls having one or more ring atoms selected from oxygen atoms, sulfur and nitrogen; 11 sm each of K &quot; up until. R 2 'is selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxycarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, the amino acid amide radicals of the formula R 1 and R 4 are as defined above. /, -CN, -CH2 -CH

Wherein X is an oxygen atom or sulfur atom

wherein each of R '' R ', w' R &quot; 5 &quot; *, R1 '&quot; and R '' is independently selected from alkyl, cycloalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl; wherein each R 2 through R 3 may be further independently selected from the acidic moieties of formula

-YA n wherein n is a number selected from zero to trts including 5 wherein A is an amino group selected from acids containing one or more atoms selected from oxygen, phosphorus and nitrogen atoms, wherein said acidic group is selected to contain an acidic hydrogen atom and amide, ester and salt derivatives of said acidic moieties wherein Y is a leaving group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenylop alkynyl, aryl, aralkyl and heteroaryl groups having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, wherein any of the foregoing groups R "to R", Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo ,. haloalkyl, οκο, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbamoyl, carboxyl, cyano, nitro, alkylsulfonyl,

aryl, aralkyl, mercaptocarfoonyl, alkylthiocarbonyl, alkylthiocarbonyl, and amine-amido radicals of formula 5; C-R '' ', N' '> 1 FT &quot; Wherein X is an oxygen atom or sulfur atom 1 &lt; 5 wherein H &quot; is selected from hydrogen, alkyl, alkoxyalkyl, Câ, -Câ, â, ‡ alkoxyquinazoline, aralquio, ania DR

Wherein D is selected from an oxygen atom and a sulfur atom and R "'' is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; 4 A Ύ 7 where each of H &quot; &quot; ? R 2, R 3, R 4, R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, arboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer or pharmaceutically acceptable salt thereof.

A class of more preferred compounds consists of the compounds of Formula I wherein m is an integer from 1 to 5, and R 1 is selected from the group consisting of polycycloalkyl, polycycloalkyl, 3-phenylpropyl, 2-a-2-phenyl ethyl, 2-hydroxy-2-methylsilyl, 1,1-difluylethyloxycarbonylsilyl, hexyl.

Carboxymethyl, N-naphthalenyl, 2-cycloheenylethyl, penyl, ethoxycarbonylmethyl, phenyl substituted by phenyl, carbamoylmethyl substituted by phenyl, 3,5,5-trimethylhexy, ( 2-phenylmethoxy) -1- &lt; 2-phenyl-2-phenylethyl, 2-phenylethyl, 2-phenylethyl, 2-phenylethyl, 2-phenylethyl, 2-phenylethyl, 2-phenylethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonyl-ethyl substituted by benzoyl, isothiazolyl, naphthalene, cyclopropyl-ethyl, arachinyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula

Wherein each of R1 and R3 is independently selected from cyclic alkyl, cyano, cyano, cyano, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and arylsulfonyl, wherein R1- &quot; is selected from hydrogen, alkyl, hydroxy-alkyl, halo; haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, arylalkyl, aralkylalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aryloxy, aralkoxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, arylaminoalkyl, aroyloxyalkyl, cycloalkenyl, cycloalkenyl, cycloalkynyl, carboxyloxycarbonyl, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl,

each of I- &lt; &quot; to R3 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, naphthyl, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryl, aralkyl, alkoxycarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkoxy, cyano-9-nitro- alkoxycarbonyl, alkoxycarbonyl, alkylthio, arylthio, aralkylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl groups and amino and amido radicals of the formula R 1, R 2, R 3 and R 4 are as defined above. Wherein each of R * R &quot; 'J &quot; RJ'WS RA9 and R &quot; "Is independently saturated from the hydroxyl, alkyl, cycloalkyloxy, amino, monoalkylaminoalkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl" wherein each Hâ,ƒ to Hâ, "may be a further optionally independently selected from the aryl moieties of the formula wherein n is a number selected from up to three inclusive; in which A is selected from the carboxylic acid of the carboxylic acid biosynthesis selected from the group consisting of hydrogen, halogen, independently from the oxygen atom, sulfur atom and NR '', wherein each RR '&quot; M &quot; 5 &quot; R &quot; is independently hydrogen, selected from hydrogen ,; alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbanyl, cycloalkyl, cycloalkylalkyl, aryl and the like. &quot; - &quot; 5 &quot;; í. -T in which each of FΓ ': * R' &quot; * R '&quot; and R '' may be further independently selected from the radical of the formula -OH, -SH, Η

W

W-NR34, -C-WH, -3-WH * -S-WH, - w

R 4Θ &quot; .Q, 3.1 &quot; in each R '&quot; and R &quot; is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and wherein R 4 and R 5 taken together may form a heterocyclic group having from seven to seven ring members including the nitrogen atom of said radical, which heterocyclic group may additionally contain one or more ring members selected from oxygen, nitrogen and sulfur whose heterocyclic group may be saturated or partially insatiable *

R5 and R5 taken together may form an aromatic heterocyclic group having five ring members including nitrogen atom of said amino radical, which aromatic heterocyclic group may additionally contain one or more heteroatoms starting from the oxygen, nitrogen and sulfur atoms wherein each of Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, ... Râ, sralcoxys and the amide derivatives? ester salts of said acidifying groups wherein said carboxylic acid bioisosters may further be selected from heterocyclic acydic groups consisting of heterocyclic rings of from four to about nine ring members. wherein the heterocyclic ring contains at least one heteroatom selected from oxygen, sulfur and nitrogen atoms, the beterocyclic ring of which may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached in a single position. * | selected from R '&quot;' to R &quot; or may be attached to any two adjacent positions supported from R 1 through R 2 to form a ring system fused to one of the phenyl rings of formula Is and the amide ester and salt derivatives of said groups heterocyclic acycides: wherein Y is a spacer group inde- pendently selected from one or more of C1-8 alkyl, cycloalkylalkyl, alkenyl, aryl and aryls

A groups having a substitutional position may be substituted by one or more groups selected from hydroxy, alkyl, alkynyl, aralkyl, hydroxyalkyl, Alkoxycarbonyl, carboxy, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio, ethoxycarbonyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl, aralkyl, aralkyl, aralkyl, alkylaminocarbonyl, silynine and amido radicals of the formula X 1 R * &quot;X1; • 7-Amino-N- [ Wherein X is selected from an oxygen atom or a sulfur atom; • "-0 on qus R · 5 &quot; ' alkoxy, alkoxy, cycloalkylalkyl, aralkyl, aryl, aryl, aryl, aryl, aryl, aryl, and r26

07 R /

Wherein D is selected from an oxygen atom and a sulfur atom. in which R &quot; &quot; ' is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryls; &quot; -f - * r ** "? Rfc-T, Rfc-T, Rfc-T, Rfc-T, Rfc-T, and Rfc-T? R 2 and R 3 are as defined above. is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl, aryl,

or a tautomer thereof or a pharmaceutically acceptable salt thereof

An even more preferred class of compounds consists of those compounds of Formula I wherein R'1 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-phenyl-2-phenyl-2 2-phenylethyl, 2-phenylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 5-ylmethyl-2-phenylethyl, 1-oxobutyl, 2-C2,5-dimethoxyphenyl) -2-oxoheptyl, 2-phenethylmethoxy, 2-phenyl-2- (2,2-dimethoxyphenyl) -2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, benzyloxycarbonyl-substituted, benzoyl-1-methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, arachisulphonyl and radicals of the formula ## STR4 ##

-CW

12 i. if each of R &quot; and Hâ,ƒ is independently selected from the group consisting of cyano, amino, nonoalkylamino, dialkylamino, hydroxyalkylalkyl, cycloalkylalkyl, alkoxyalkyl, alkynyl and aryl groups; and is selected from hydrogen, alkyl, polycycloalkyl, polycyclalkylalkyl, aryloxyalkyl, 2-hydroxy-2-ara-1-oxy, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, arakoxyacyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, , balo5 haioalquila? cycloalkyl, alkoxy, aralkyl, aryl, aryl, aryl, aryl, aryl, aryl, alkoxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, aryloxyalkyl, alkynyl, cidoaicenilG :; alkynyl, carboxyalkyl, alkylcarbonyl, alkylthio, arylthioalkylthio, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, arylsulfonyl, until it is selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aryl, aryl, aryl, aralkyl, aralkoxy, alkoxyalkyl, alkyloxycarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylthio, arylalkylthio, and mercapto and each R ' to FC &quot; may be an optionally acid addition moiety independently selected from the acidic moieties of the formula wherein n is a number selected from up to and including 3; wherein A is selected from carboxylic acid and carboxy acid biosorbate selected from

w ll ε --P - WH

Wherein each W is independently selected from the group consisting of oxygen, sulfur atom, sulfur atom, sulfur atom, sulfur atom,

~% ύ tcp where each R ' R 3 'is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulphonyl, haloalkylcarboxonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyls wherein each of R 3, R 4, may be further selected independently from a phenyl radical of the formula R39 /

-N X R40 "where each Ff 'and R' &quot; is independently selected from hydrogen, alkyl, cyloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, and R 's taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms, nitrogen and sulfur atoms whose heterocyclic group may be saturated or partially unsaturated in which R 2 and R 3 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said radical and which aromatic heterocyclic group may additionally contain one or more heteroaryl- As ring atoms selected from the oxygen atoms, nitrogen and sulfur: the amide, ester and salt derivatives of said s acydi groups

wherein said carboxylic acid bioisostere can additionally be selected from heterocyclic acid groups consisting of heterocyclic rings of from four to about nine ring members 9 whose ring contains at least one heteroatom selected from oxygen atoms , sulfur and nitrogen, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 1 to R 1, or may be attached to either adjacent positions selected from R '&quot; in order to form a ring system fused to one of the phenyl rings of formula In and the amide, ester and leaving derivatives of said acidic heterocyclic groups; wherein Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkylglyc;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwhere each R to R '', may be substituted at any substitutable position by one or more groups selected from alkyl, hydroxyl, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy groups; or a pharmaceutically acceptable tautomer or a pharmaceutically acceptable salt thereof.

A preferred class of compounds of Formula I are those compounds wherein m is wherein R4 is selected from polycycloalkyl,

cycloalkylalkyl; 2-methyl-2-phenyl-2-phenylethyl, 2-hydroxy-2- 1-methyl-2-cyclohexylsilyl, pentyl, 5-ethoxycarbonylmatoxyethyl substituted by phenyl, carboxymethoxyethyl substituted by phenyl, 3,5-dihydroxy-5-ethylhexylsilyl, 2-yl) -benzoyl-1-benzoyl-1-phenylethyl] dimethoxyphenyl) -2-cyanoethyl) -2-hydroxy-2-oxomethoxy) ethyl] -2,2,5,5- imidazol-2-yl) -2-hydrazide; 2-naphthenylmethyl, methoxycarbonylbutyl, benzoyl-substituted-thioxycarbonyl, 1-benzoyl-methylethyls, 1-pentanoic acid, cyclopropylmethyl, aralkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula 1 or R '&quot; 51 /

- CN

i wherein each of H &quot; and R &quot; &quot; is independently selected from cycloalkyl, cyano, amino, halooxyalkyl, acyloxy-alkyl, phenalkyl and phenyl,

wherein R1 is selected from hydrogen, alkyl, hydroxy-alkyl, halo, haloalkyl, eeloylalkyl, polycycloalkyl, polycyloalkylalkyl, arylalkyl, 2-hydroxy-2-arylsulfonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl , aralkyl, aryloxy, aryloxy, alkoxyalkyl, alkyletaryl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, aryl, aralkyl, arylalkyl, aralkoxy, aralkoxy, , aralkylthio and arylsulfonyl, wherein each of Râ, "is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cyanoalkyl, alkoxy, cyano, nitro, carboxyl, alkylthio, and mercaptofine in which each R 'is hydrogen, alkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, to K &quot; may be an added acidic portion &quot; independently selected from the acidic moieties of the formula wherein n is a number selected from zero to two inclusive; wherein A is selected from carboxylic acid and biosynthetic resins of carboxylic acid selected from

HW W W

I 5 ' 55 H +, β

-HH, -S-WH, and -PH-NR ', wherein each W is independently selected from the group consisting of Oxygen, sulfur atom and NH4;

Each R ', R' 'and R' ', is independently selected from hydrogen, alkyl, haloalkyl and haloalkylsulfonyl, haloalkylcarboxonyl, cycloalkyl, phenyl and isopropyl; &quot; -7-sis that each of R &quot; ', And H' may be further independently selected from the amino radical of the formula R39 /

-N \

&quot; yes each R '~' b 9. &quot; '' is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzenesulfonyl and the amide, ester and salt derivatives of said acidic groups: wherein said carboxylic acid bioassay may further be selected from heterocyclic acyclic groups consisting of heterocyclic rings of from four to about nine ring members, the ring of which contains at least one hetero ring selected from hydrogen, sulfur and ascat whose heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring is -5; may be attached in a single position selected from R '' to R '' or may be attached to any two adjacent positions selected from R '' to TC '' as well as to form a ring system condensed with one of phenyl rings of formula I? the amide, ester and salt derivatives of said heterocyclic acid groups in which Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenenyl and aralkyl; in which each of RJ 'to R &quot; 'R' 'to R' 'and the others may be substituted at any position replaceable by one or more groups selected from alkyl, cycloalkylalkyl, cycloalkylalkyl, hydroxy, halo, omo alkoxy, aryloxy, aralkoxy, aralkoxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, or a pharmaceutically acceptable salt thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof,

A still further preferred class of compounds consists of the compounds of Formula I wherein m is a? in which R 2 'is selected from the group consisting of benzenesulfonyl, adamantylalkyl, 3-phenylpropyl, 2-methylsulfonyl, 2-phenylsilyloxy, di-methylethyloxycarbonylmethyl, halo, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenesylmethyl, 2-hexylsilyl, pentyl, ethoxycarbonylmethoxy-substituted phenyl, carbonyloxyethyl substituted with phenyl, 3? 2-phenylmethoxy) -1-phenylmethyl) -E-ethenyl, 1-benzoyl-2-phenylthiazole, 1-oxobutyl, 2- (2,5-dimethoxyphenyl) -2-oxyethyl-2- -2 - &lt; 2-naphthalenylmethyl, methoxycarbonylbutyl, benzoyl-substituted ethoxycarbonylethyl, 1-bentoyl-1-bentoyl-1-propenyl, 2-naphthalenylmethyl, 2- (2,5-dimethoxyphenyl) -2- methylethyl, I-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitrile in which R is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adansantyl, adamantylalkyl, arylalkyl, 2-hydroxy-2-aralkyl alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylXalkoxyalkyl, carboxyloxyalkyl, aryloxyalkyl, aroylalkyl, aralkoxyalkyl, aralkyl, cyanoalkyl, baloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, alkylthio , phenyl and phenylandylthioalkyl which are each Hâ,ƒ to Râ, " is selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkenyl, chloro, nitro, carboxyl, alkylthio, ΐα 5

scidic additive 1-n- · of pcreoss acia i cas SH, RiV-t, "ΜΗΒΟ, Χ-F- ,, ... 'J- \ Λ. W CONHOD-L, CONHDw-L., O '

I _ &quot; ξ 11 and in which each R &quot; until R ...... claims to be a part independently selected from conc.Lcii.ndc sff. ΟΟ, Η, CO CH CH₂-CH₂-CH₂-CH₂-CH₂-CH SH, Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ Λ. CH3 OH, CH2 OH, NH2 OH, NH2 OH

from H =; Cl, CN, NO 2, CF 3,

L-Di-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H-C H- -CH 2 CH 3 CH-F w; . CO-

4 wherein Z is selected from the group consisting of hydrogen, CH 2, and CH 2 CH 3, wherein R 4 is selected from the group consisting of hydrogen, may be a heterocyclic acidic group attached to any two adjacent positions of R 1 to R 2 in order to form a ring system fused to one of the phenyl ring of the hyphenyl moiety of Formula I, said ring system being biphenyl selected from

Is the esters, amides and salts of said acidic moieties? or a tautomer or a pharmaceutically acceptable salt thereof =

J

A class of compounds of particular interest consists of the compounds of Formula I wherein m is aq

wherein R 2 is selected from adamantyl, adamantylmethyl, adamantyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenyl-2-hydroxy-2-phenylethyl; 1? i-dimethylethylcarbonyloxy, hexyl, ethanedicarbhamylmethyl, carbamoyl, 1-naphthalenemethyl, 2-cyclohexylmethyl, pentyl, substituted phenylcarbonyloxyethyl, carboxymethoxyethyl substituted by 3Î ±, 5β, 5-trimethylsilyl, 2- (I) - (-) - 1-yl) -E-ethenyl, 1-benzo-i. 1-β-isothiocyanate; obu t i 1 ο, Ξ- < 2,5-d i. 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-dimethoxyphenyl) -2- methoxycarbonylsilyl, ethoxycarbonyl-ethyl substituted with benzenesulfonyl; methylbenzoic acid, isopropylic acid, cyclopropylmethyl acid, 3-phenyl-2E-propanesyl acetonitrile. wherein R ': &quot; is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-pentyl, isopentyl, neopenyl, adamantyl, adamantylmethyl, adamamethylpropyl, 3-phenyloxypropyl, 2-amino-2-phenylethyl, 2-isopropyl, 1-naphthalenylmethyl, 2-cyclohexylmethyl, pentyl, ethoxycarbonylmethoxyethylc substituted by phenyl, carboxymethoxyethyl substituted by phenyl, 3,5,5-trimethylhexyl, 1-naphthalenylmethyl, 1-naphthalenylmethyl, (2-phenyl-2-oxoethyl) -2- (2,5-dimethylphenyl) -2-phenylethylglyoxylate, 2- (2,5-dimethylphenyl) (2-phenylmethoxyethyl) -2- (2,5-dimethylaminophenyl) -2-hydroxystyrene-2-naphthalenecarboxylate i-benzoyl-1-methylstil, cyclopropylmethyl, 3-phenyl-ZE-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, ethoxycarbonylethyl, , 1-oxoethyl, 1-oxopropyl-1-oxobutyl, 1-chlorophenyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyaphthyl,

difluoropropyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R '' Rw5 R &quot; and R 'is an acidic moiety selected from COOH,  € ƒâ € ƒâ € ƒSOâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒHNMR (CDCl3): .delta. ♦ *

Η H

4? Wherein each of R 2 and R 3 is independently selected from Cl, CN, CH 2, CH 2, CH 3, and CH 2, (i.e. . Or its pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof.

A class of compounds of more particular interest consists of those compounds of Formula I wherein m is a compound of formula I wherein R 2 is selected from 2-amino-2- (tricyclo3.3.1.1.1, 2-yl-2-phenylethyl, 2-hydroxy-2-phenylethyl, isoxymethyl, methylcarbonylmethyl, hydroxyethyl, carboxymethyl, 1-naphthalenylmethyl, 2- phenylsulfonyloxycarbonylsilyloxy, phenylsulfonyloxycarbonylsilyloxy, phenylsulfonyloxycarbonylsilyloxy, phenylsulfonyloxycarbonylsilyloxy, phenylsulfonyloxycarbonylsilyloxy, phenylsulfonyloxyphenylsulfonyloxy, phenylsulfonylphenyl, 2-carboxylic acid 2-phenyl-2-phenyl-2-phenylethylmethyl-2-phenylethyl] -2- (2-methoxyphenyl) 2-naphthalenylmethyl, methoxycarbonylbutyl, benzoyl-substituted ethoxycarbonyleyl, 1-benzyl-1-methylsiloxy, 1-pentanoic acid, cyclopropylmethyl, 3-phenylethyl, 2-naphthalenylmethyl, 2E-propenyl and 1-cyanobutyl groups;

wherein R3 is selected from ethyl, n-propyl, isopropyl, n-butyl " ssc-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neoperitiyl, 1-cyanobutyl, propylthio and butylthio; wherein at least one of R &quot; f R1 &quot; ? R 1 and R 2 are an acyl group selected from CO 2 H, CH 2 PO 4, SO 2, CONHNHSO, CF,, OH,

a. R 2, R 3 and R 4 are independently selected from Cl, CN, NO 2, CF 3, CH 2 CH 2, and SO 2 CF 3; . or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.

A class of compounds of even more particular interest consists of compounds of Formula I wherein m is one in which R 2 is selected from the group consisting of α, α, α 2-C 1 -C 3 -cycloalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenoxy, 1,1-dimethylsethyloxycarbonylsilyl, hexyl, ethoxycarbonylmethyl , carboxymethyl, naphthalenesulfinyl, 2-cyclohexylethyl, pentyl, phenylethylcarbonyloxyethylsilyl, substituted phenylcarbonyloxyethyl, 3,5,5-tri-fistyl-heptyl, and 3-C2-phenyl 1-benzyl-2-phenylethyl) -1-oxobutyl, 2- (2,5-dimethylphenyl) -2-oxoethyl, 2-phenyl 1-2-Cienyl. 1. ) ethyl, 2- &lt; 1,2-dihydroxy-2-naphtho-1-naphtho, methoxycarbonylbutyl, ethoxycarbonyl-stilcs substituted by hanzoyl, 1-benzoyl-1-methylethyl,

i --psn ian o i c ο, e i c 1 ο ρ ro ρ i sis t i 1 ο? butyl; And R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4- methylpentyl, 1-cyanobutyl, propylthio and butyllithium; R 4, R 4, R 4, R 4, R 4, R 4, R 4, R 4, R 4, R 4, R 4, and R &quot; is hydrogen; wherein one of R1 and R2; is hydrogen and the other of R 'and R' is an acidic group selected from CG "H s

H

N-N

or a tautomer thereof or a pharmaceutically acceptable salt thereof.

A family of specific compounds of particular interest within Formula I consists of compounds and their pharmaceutically acceptable salts of the group of compounds consisting of 4-E &lt; 3-dibutyl-4,5-dihydro-5 - [[1- (4-methoxyphenyl) -2-methyl- 5-butyl-2,4-dihydro-2-C2-oxy-2-tricyclic C3.3.1. 13β-1,2,4-Tetrasol-5-yl) -1-biphenyl-4'-ylmethyl] -3H-1,2,4-tetrazolyl] 3-one;

5-butyl-2,4-dihydro-2- (3-phenylpropyl) -4- [2- (1H-tetrazol-5-yl)] -1 '-biphenyl-4-yl] -1,24-triazol-3-one;

5-Buti-2 ' 1- (2-oxo-2-phenylethyl) -4- (2-methoxy-5-methoxy- Biphenyl-4-ylmethyl] -3H-imidazol-3-yl] 5-butyl-2- (4-dihydro-2- (2-hydroxy-2-phenylethyl) -4- (2-hydroxyphenyl) -1- 11-ylmethyl] -3H-1 (2S) -triene-3α-3-one Î ± 1-acetate of 3-butyl- 4,5-dihydro-5-oxa-4 - [(4-methoxyphenyl) -3-methylphenyl] -4- -1H-tetrazol-5-yl) -1 H -biphenyl-3-ylmethyl] -3 H -1,2,4-triasol -3-one-4-carboxylic acid ethyl ester 3-butyl-4,5-dihydro-5-oxo-4-2- (1H-tetrazol-5-yl) 3-butyl-4,5-dihydro-5-DMD-4-L2 '- (1H-tetrahydro-1H-indol-3-yl) -biphenyl- 4-dihydro-2- (1-naphthalen-1-ylmethyl) -1H-imidazo [1,2-a] 4-ylmethyl] -3 H -1,2,4-triazol-3-one 5-butoxy-2- (4-methoxyphenyl) (2-cyclohexyl-ethyl) -2 ', 4'-dihydro-4-E 2' - [1H-tetrazo] -5- (E) -1,1'-biphenyl-4-ylmethyl] -3 H -1,2,4- 3-one-5-butyl] -2,4-dihydro-2-methylpropyl) -4- [2- (1H-tetrazol-5-yl) triazol-1-yl-3-one

C2 -C3 -butyl-4 ', 5-dihydro-5' '- ethyl acetate, 4-methyl-2' - &lt; (4-methoxyphenyl) -1H-imidazol-3-ylmethyl] -1H-imidazol-3-yl]

I

 € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ 1-biphenyl-4-ylmethyl] -1H-1,2,4-triazol-1-yl] -1-phenylethyl] acetic acid 5-butyl] -2S-4-dihydro- -yl) and 1? 1'-biphenyl-3-4-yl) -ethyl] -2- (3,5,5-trichlorophenyl) -3H-indole. -phenyl-2-phenylethynyl-3- (4-methoxyphenyl) -phenyl] -4- [2- (4-methoxyphenyl) - (1H-tetrazol-5-yl) -5β-biphenyl-4-ylmethyl] -3H-1,2,4-triazolo-3-one 2- Dihydro-4-C2- (C1-C4) -tetrahydrofuran-5-yl] -1,2-biphenyl-3- 3-anis-5-butyl-2,4-dihydro-2-chloro-4-oxobutyl) -4- [2 H -1-tetrasoyl] -1H- 5 '' - biphenyl-4-ylmethyl-3 H -1,2,4-triazal-3-one; 5-butyl-2,4-dihydro-2-E2- (2S, 5-dimethylamino) -2-oxoethyl 3-4-2- (1-H-tetrazol- i. 5-butyl-2,4-dihydro-2-E-2-phenyl-2-phenylethyl) -3-hydroxyethyl] -3- (4-methylphenyl) -4-methyl-4-methyl-3- (1H-1,2,3,4-tetrahydro- 4-triazol-3-one 5-butyl-2,4-dihydro-2- (2-S) -ethoxyphenyl) -2-hydroxyethyl- istrazol-5-yl &gt; C1. biphenyl-4-yl-ethyl] -3H-1? 2 5 4-thiols 3 &quot;2apos; -naphthalene-4-carboxylic acid (2-naphthalen-1-yl) -4- 1) 3-Butyl-4,5-dihydro-5-Î ± -α-4-C2apos; -dimethyl-1Î ±, 3apos; -biphenyl-4-ylmethyl] -3 H -1,2,4- 1 H -tetrazol-5-yl] C 15-1 '-biphenyl-4-ylmethyl] -1 H -benzyrate;

B-benzoyl-3-butyl-4,5-dihydro-b-oxa-4 '- (2 H -tetrazol-5-yl) -1 H -biphenyl-3- benzyl-1-methyl-ethyl-5-butyl-2,4-dihydro-4-C2 '-H-1,2,4- tetrazol-5-yl) Z19 -biphenyl-4-ylmethyl] -3 H -1,2,4-triazol-3-ones

3-Butyl-4,5-dihydro-5 '' - (4-C2 '- (1H-tetrazol-5-yl) -biphenyl-3-yl] -1H-imidazo [4,5-c] [1,4] diazabicyclo [2.2.1] heptadecahydro- (1H-tetrazol-5-yl) [13β-biguanyl] -4-methyl-3- (1H-tetrazol-3-one, 5-butynyl-2,4-dihvdro 3-phenyl-2E-propyl] -4-methyl-1H-tetrazole-5-yl) -biphenyl-4-ylethyl] -3H- dihydro-5-oxo-α-propyl-4 '- (2'H-tetrazol-5-yl) -1,1'-biphenyl-3'- in i 13-3-i-methyl 3 -1 -1 -1; 2 p 4 -1. 1-ene-3-carboxylic acid. The term quot; hydrogenquot; denotes a single hydrogen atom. This hydrogen group may be attached, for example, to an oxygen atom to form a hydroxyl group, or as another example, a hydrogen may be attached to a carbon atom to form a C-? or, as another example, two hydrogen atoms may be attached to a carbon atom to form a -CH 2 - group wherein the term &quot; alkyl &quot; is used, alone or within other terms such as &quot; haloalkyl &quot;, and &quot;hydrokineticquot; &quot; The term &quot; alkyl &quot; embraces linear or branched radicals having one to twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are only radicals &quot; lower alkyl &quot; having one to about ten carbon atoms. More preferred are lower alkyl radicals

having one to about one and two carbon atoms = the term &quot; alkyl &quot; alkyl &quot; encompasses cyclic radicals having three to about ten ring carbon atoms, preferably up to about six carbon atoms, such as cyclopropyl, cyclohexyl, cyclopentyl and cyclohexyl. The term &quot; polycycloalkyl &quot; denotes a radical having two or more cycloalkyl rings; for example, two cycloalkyl rings may share one atom to form a spiro system, such as a dicyclohexyl ring system; or a lower alkyl group or a methylene radical may link a cycloalkyl ring to form, for example, an adamantyl group. Preferred polyocycloalkyl groups include up to about 2 carbon atoms, the term &quot; halcalkyl &quot; embraces radicals in which any one or more of the carbon atoms of the alkyl group is substituted by one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically encompassed by the term &quot; haloalkyl-1, &quot; are the monoalkyl, the dihaloalkyl and the polyhaloalkyl groups. A roonohaalkyl group, for example, may have a bromine atom, a chlorine atom, or a fluorine atom within the group.

Dihaloalkyl and polyhaloalkyl groups may be substituted by two or more of the roeso groups halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluorine atoms, such as difluorooroethyl and difluoroethyl groups, two chlorine atoms, such as a chlorooroethyl group, or a fluorine atom to a chlorine atom such as a croup fluoro-chloromethyl. Examples of polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3-tetrafluoropropyl, the term &quot; difluoroalkyl &quot; encompasses alkyl groups having two fluorine atoms

substituted on any one or two carbon atoms of the alkyl group. The terms &quot; alkanyl &quot; and &quot; hydroxyalkyl &quot; encompasses linear or branched alkyl groups having one to about two carbon atoms, any of which may be substituted by one or more hydroxy groups. The term "alkenyl" embraces linear or branched radicals having two to about twenty atoms of carbon, preferably tris to carbon atoms, and containing at least one carbon-carbon double bond: which may have either cis or trains geometry within the alkenyl moiety. The term &quot; alkynyl &quot; embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about two carbon atoms, and containing at least one triple bond of carbon atoms, the term &quot; cycloalkenyl &quot; embraces cyclic radicals having three to about ds ds ds carbon atoms in the ring including one or more double bonds involving adjacent ring carnones. The terms "alkoxy" and "alkali metal" include straight or branched oxo radicals each having alkyl portions of up to about one carbon atoms, such as the methoxy group, the term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, i.e., to form monoalkoxyalkoxyalkoxyalkyl, the radicals &quot; alkoxy &quot; or &quot; alkoxyalkyl &quot; may be further substituted by one or more halo atoms, such as fluoro, chloro or bromo, to bear on haloalkoxy or haloalkoxyalkyl groups, &quot; alkylthio &quot; embraces radicals containing a linear or branched group, from one to about one carbon atoms attached to a divalent sulfur atom, such as a methylthio group. Preferred carbocycles are those consisting of one, two or three benservo rings. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl and biphenyl, the term &quot; aralkyl &quot; embraces alkyl substituted aryl radicals such as bensyl, diphenylmethyl, triphenylmethyl, phenylmethyl, phenylbutyl and diphenylstil. The terms &quot; benzyl &quot; s

&quot; fsnylmethyl &quot; are iniermutávsis * The fakes &quot; ariloxx &quot; s "sr.11 uncle &quot; are each independently of the radical, aryl groups having an oxygen and sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio, the &quot; sulfinyl &quot; &quot; sulfonyl &quot; linked to other terms, denote respective divalent radicals SO and SCU, the term &quot; aralkyloxy &quot;, or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy, the term &quot; acyl &quot; whether used alone or within a term such as acyloxy, denotes a radical provided by the residue after removal of the hydroxyl from an organic acid, examples of such radicals being acetyl and benzoyl. &quot; Lower alkanoyl &quot; is an example of a more preferred acyl sub-class: The term &quot; amido &quot; denotes a radical consisting of a nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. bonded to the nucleus of the compound of the invention through the carbonyl moiety or through the nitrogen atom of the amino radical the term &quot; alkanyl. lai kilo &quot; denotes a radical having an unsaturated double bond position between two carbons or may be further substituted with alkyl groups which may optionally contain an additional unsaturated double bond. The term &quot; heteroaryl &quot; encompasses aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five to six members, examples of which are thienyl, fursyl, pyridinyl, thiazolyl, pyrimidinyl, isoxazolyl. Such a heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached via a carbon atom of a moiety replacing a member carbon of the heteroaryl ring, for example, through the methylene substitutions of the imidazolesmethyl moiety. Such a beteroaryl may also be attached

A nitrogen atom to the ring provided that the aromati fi cates of the heteroaryl moiety is preserved after the bonding. For any of the foregoing defined radicals, the preferred radicals are those containing from one to about one hundred carbon atoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl, n-butyl, serotonyl, isobutyl, tert-butyl, n-methyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have an unsaturated bond such as an allyl group, or may have a plurality of unsaturated bonds, such a plurality of beads being either adjacent, such as alloys, or conjugated, or separated by several saturated carbons,

It has been found that Formula I compounds inhibit the action of angiotensin II in mammals. Angiotensin II is a vasoconstrictor and participates in the formation of aldosterone which regulates sodium balance of water in mammals. Thus, compounds of Formula I are therapeutically useful in methods for the treatment of hypertension by administering to a hypertensive patient a therapeutically effective amount of a compound of Formula 1A phrase "hypertensive patient" means in this context a mammalian subject suffering from or suffering from the effects of hypertension susceptible to hypertension disease if not treated to prevent or control such hypertension.

Also included in the family of compounds of formula I are the optical isomeric forms including diastereoisomers. Also included in this invention are the stereoisomers of the compounds of Formula I, for example, compounds having the biphenylalkyl moiety exchanged with the substituent R1 on the nitrogen of the triasols ring shown in Formula I Also included in this invention are the pharmaceutically acceptable salts

acceptable salts of the compounds of Formula I. The term &quot; acceptable pharmaceutically acceptable salts &quot; include salts thereof used to form alkali metal salts to form salts with the addition of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of The compounds of formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydrohalic, nitric, carbonic, sulfuric and phosphoric acid. Suitable organic acids may be selected from the aromatic, cycloaliphatic, aromatic, aromatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are thermal, acetic, popionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic * aspartic, glutamic, benzoic, anthranilic, p-hydroxy, benzyl, salicylic, phenylacetic, methyl naphthalic, , methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, bensenesulfonic, toluenesulfonic, sulfanilic, mesylic * cyclobenzylaminosulfonic * stearic, alginic, bicyclic, malonic, galactaric and galacturonic. Suitable pharmaceutically acceptable base addition salts of compounds of Formula I include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N, M'-dibenzylethylenediamine, chloroprocaine , choline, diethanolamine, ethylenediamine, methanol CN-methyl glucamine) and procaine. All these salts can be prepared by conventional means from the corresponding compounds of Formula X by reacting, for example, the appropriate acid or the base with the compound of Formula 1 "

General synthetic processes

The compounds of the invention may be synthesized according to the following procedures of Scheme 1, wherein each of the substituents R is as defined for Formula (I) and wherein (I)

=?

I

s C02Et

S = C = hT 2

C02Et3 HNO2NHR15

1

Synthetic Scheme I shows the preparation of 152S4-triamasolone i. from 2-isothiocyanate 2 via W-stovicarbonate 1 thioamide 3 according to the general procedure outlined for Papadopoulos, E = P = and Beerge, B., et al., Chem .; In the first step 3 N-ethoxycarbonylthioamides 3 can be prepared from ethoxyKetosyl isothiocyanate 2 and the corresponding organometallic 4-N-ethoxycarbonylthioamide 3 can be converted into triasal -one by the action of the corresponding hydrazines 5 as described in the reference given above *

I

ch3 CH2Br Γίxx NBS, AIBN CCI4

V

7 6 t

XX

Synthetic Scheme 11 shows the preparation of agent 6 of the corresponding precursor 7. When Ru is the same as can be purchased from Chamo Dynamics Inc, i ΙΑ Τ ch3 2 CH 3 V 7 R 5 = CO 2 CH 3

hH 1. 1. NaOH / HCl 2. (COCl) 2 3. NH 3 4. SOCI 2

V 9

CN

Me3SnN3

8

Synthetic Scheme shows the preparation of the precursor alkylating agent / wherein R &quot; The corresponding methyl ester is (7) in step 1, the methyl ester is converted to the corresponding acid (R) = CH₂H) by the sodium hydroxide / hydrochloric acid salt. In step 29 the acid is converted to the corresponding acid chloride &lt; R -C0C1. In step 35 the acid chloride is converted into the corresponding primary amine CR? = CONH &gt; by ammonium action. In phase 4? the amide is converted to the corresponding nitrile by the action of the thionyl chloride at reflux. The nitrile 9 is reacted with trimethyltin azide in toluene at reflux to give the corresponding protected tetrazols trimethoxysedate by deprotection with acetic acid / water, with triphenylmethyl chloride / triethylamine gives N-trityl tetrazol-7 &lt; RTI ID = 0.0 &gt; CCC, &lt; / RTI &gt; 6:

I

I

R1

R

KOC (CH3) 3-1 DMF

N-N

13

Synthetic Scheme XV shows the reaction of 1α, 2β, 4-triazole 1 with the appropriate alkylating reagent and subsequent conversion to the compounds of the invention. In the first step, is treated with base 5 such as potassium t-butoxide to generate the corresponding anil 10, Q is anyl, θ is reacted with an alkylating agent 6 to give the product 11, A 1, = 2 = 4 ---- triasolone trisubst. may subsequently be converted to the corresponding acid 12 or tetracolole 13 by treatment with one of the appropriate reagents as shown in Scheme IV. Alternatively the compounds of the invention may be synthesized according to the following procedures of Scheme V and v Σ =

CH 2 Br 1 N NaN 3 CH 2 N 3

σ R5 1 7 6 R 5 = CN or CO 2 C (CH 3) 3

H2, Pd / C

JJ

Synthetic Scheme V shows the preparation of semicarbacids 14. from bromide Î'= Semicarbazide 14 may be prepared from aminomethylbiphenyl 15 and the corresponding thiadiazolines can be obtained by treating its ester precursor with hydrazine. The amine 1.5 can be prepared by hydrogenation of the corresponding compound 17, which can be obtained from its precursor bromide 6 by treatment with sodium azide = π2Α .nv ° R2 ΝΗ [, Ν Η

Ν-Ν &quot; r 2A χ 0 NaOMe, CHgOH R ν υ Η reflux

R 14 = CN or CO 2 C (CH 3) 3

n-n'r 'Λ Θ Ν-Ν R Ν R1X 20 CH2

R2 Ν 0 CH2

Synthetic Scheme VI shows the cyclisation of 1 4 to 18 and subsequent alkylation to 1: 1 In the first step, the triasolone 11 can be prepared by dehydration of semicartea citrate in alcohol with a catalyst base such as sodium methoxide Then the triacoione 18 is treated with a base such as potassium t-butoxide to give the corresponding anion 18, the anion 19 is reacted with a 2-positioning agent to give the alkylated product. which may be converted to the corresponding acid 12 or tetraoleol by treatment with one of the appropriate reagents as shown in Scheme IV.

The following Examples: are detailed descriptions of the methods of preparation of the compounds of Formula I. These detailed preparations are within the scope of the invention and serve to exemplify the foregoing description of the Oenal Synthetic Processes which are presented for illustrative purposes only and are not to be construed as a restriction Scope of the invention 'All parts are parts by weight unless otherwise indicated'

EXAMPLE # 1

4'-E (1,3-dibutyl-4,5-dihydro-5-o-t-1,2,4-triazol-3-yl) -L-1,3,4-triazol-1-yl] ... of ... v- &lt; p-tolyl) benzoic acid

A mixture of methyl 2-Cp-octyl-115-osmonate (Chemo Dynamics Inc.) and 100 ml of a solution of 2.5% aqueous sodium hydroxide solution 1 ml of methanol was stirred at room temperature for about 6 h, then at reflux for 1 h. The resulting solution was concentrated in vacuo to half its original volume. The aqueous solution was acidified with 3M hydrochloric acid to about pH 3 s extracted with methylene chloride. The extracts were dried (MgSO)) and concentrated in vacuo to give 48.7 g (99%) of 2-β-tolyl-benoic acid. as a white solid 10.4-11.4 1 H NMR (CDCl 3) δ 2.4 (s, 3H, 7.00-8.05 (m, 1H)

Clarke s, 1H &gt;.

Fasos 2s Prgparaclp ....., de ... terç-butyl. 2- (p-tolyl) benzoate

For 4S q &lt; 0.22 is mol &gt; of the Phase II 2-β-tolyl) benzoic acid and 5 ml of the concentrated sulfuric acid in 1 ml of anhydrous ether cooled in a dry acetone-ice bath were transferred to 2 ml of 2-methylpropanone. stirred in a Parr apparatus at room temperature for 15 hours, and excess methylpropene was allowed to evaporate at ambient temperature. The ether solution was neutralized with a 2.5 N aqueous sodium hydroxide solution and extracted with dichloromethane The combined extracts were dried (MgSOâ, ") and concentrated in vacuo to give 57.2 g (94%) of tert -butyl 2-p-tolyl) benzoate as a 1: 1 solids (COClx), 1.29 (0.9H), 2540 (s, 3H), 7.2 (s, 4H), 7.25-7.55 (m, 3H), 7.7-7.8 (m, 1H) (1), (2), (3), (4) and (4). A mixture of tert-butyl (57 g, 213 mol) of tert-butyldimethylsilyl- N-bromosuccinimide (NBS) (36.4 g C2.4 mol) of N-bromosuccinimide (NBS) at -65 ° C was added, The resulting solution was stirred at reflux for about 12 h followed by the addition of 1.7 g (9.6 mmol) of N-bromosuccinimide and 1, 2, 3, 4-dimethyl- g &lt; Θ, 6 romol) from AIBN. The mixture was stirred at reflux for an additional 13 hours, and concentrated in vacuo, the residue was dissolved in ethyl acetate-hexane (1%), filtered through a pad of silica gel, eluted with ethyl acetate-hexane &lt; ) to give 79 g (quantitative) of a sample containing much of the desired product, 4-bromo-meta-2-tert-butoxycarbonylbiphenyl, with a small amount of the product starting from the starting material. Further purification was performed using additional purification, which was used directly in a subsequent procedure for 1 H NMR &lt; RTI ID = 0.0 &gt; 8 1.26 (1H, 9H), 4.56 (s, 2H &gt;, 7.2-7.9 (m, 8H). (0.632 mole) of 4-foromethyl-2'-tert-butoxycarbonyl-biphenyl-2-carboxylic acid was prepared as a white solid. Step 3: 4.6 g (0.071 mol) of sodium azide in 42 ml of dimethylformamide and 4.2 ml of water was stirred at room temperature for about 24 hours and concentrated in vacuo. The residue was extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give 4 g (quantitative) of 4-azidomethyl-2'-tert-butoxycarbonylbiphenyl as a yellow oil.1 H NMR (CDCl3) (S, 9H), 4.38 (s, 2H), 7.2-7.9 (m, 8H).

E] -2- (4-tert-butoxycarbonyl) biphenyl-

A suspension of 16 g of palladium on charcoal (16 g) in absolute ethanol (30 ml) was stirred in a Parr apparatus under a hydrogen atmosphere at 40 psi for about The mixture was filtered through a pad of celite and concentrated in vacuo to give 9.2 (quantitative) of 4-aminomethyl-2 "-tert -butoxycarbonylbiphenyl as a yellow oil (2 H) &quot; H NMR (S, 2H), 3.92 (s, 7.2-7.9 (m, 8H)), 1.71 (br.

Step & 8 Preparation of ....... tert-butyl ____ 4 &quot;1-OHP-3-methoxy-2-methyl-2-methyl-3-methyl-; To 6.4 ml of the phosgene (1: 1) (6.4 mmol) in toluene and 5 ml of toluene was added dropwise a solution of Ι Θ g (3.53 mmol) of 4-aminomethyl-2'-t-butoxycarbonylphenyl chloride in methylene chloride along with a dropwise addition of 1.5 ml &lt; 18.5 mmol &gt; of pyridine. The resulting mixture was stirred at 0 ° C for about 3 minutes, at ambient temperature for about 1.5 hours, the phosgene layer was removed under a stream of nitrogen. 6.9 mmol) of valeric acid hydrazide (Lances ter Synthesis), 1.0 mL (12.3 mmol) of pyridine and 2 mL of ether, and the resulting mixture was stirred at room temperature for about 2.5 The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluted with isopropanol-beige, to give 78 mg (52%) of the semicarbazide as a white solid.1 H NMR (CDCl3): Î'(t, J = 7.2 Hz, 3H), 1.28 &lt; 9H &gt;, 1.20 (Q, 2H), 1.50 (quintet, J = 7.2 Hz, 2H), 2.2 (t, J = 7.5 Hz, 2H), 4.538 (d, J = 6 Hz, 2H) ), 6.27 (broad t, 1H), 7.2-7.5 (m, 7H), 7.76 <dd, <3 = 7.5, 1.0 Hz, 1H &gt; 7.59 -8.05 (m, 1H), 8.85 (broad s, 1H); 13.7, 22.3, 27.4, 27.7, 33, é, 43.7, 127.0, 128.8, 128.7, 130.7, 132.7, 127.7, 14 Î', 7, 141.7, 158.3, 167.9, 173.0,

E2SS-Z * gmpar_acIo. in . tert-butyl] -4 '-1 (5-butyl-4,5-dihydro-5-propionyl) -2-carbobenzyloxy) benzaldehyde To 50 mg (1.13 mmol) in l &

methanol in 5 ml of toluene was added 126 mg (2.33 mmol) of sodium methoxide and the resulting mixture was stirred under vigorous reflux for about 48 hours with a water siphon? (molecular sieve? 3ft) bound between a condenser and the reaction vessel. The mixture was acidified with acetic acid to concentrated in vacuo. The residue was dissolved in chloroform and washed with water, saturated sodium bicarbonate and brine. The residue was chromatographed on silica gel (eluted with ethyl acetate-hexane: 2: 1) to give 48 mg (9%) of 3-butyl-1,2,4- (T, J = 7.2 Hz, 3H), 1.24 (s, 9H), 1.30 --- 1.45 (s, 3H)

(2H, m), 1.62 (quintet, J = 7.8 Hz, 2H); 2.43 (t, J = 7.5 Hz, 2H), 4.87 (s, 2H), 7.2-7.55 (m, 7H), 7.78 (d, J = , 2Hz, 1H). ......... 4 &quot; -L (1,3-dibutyl) -1,4-difluoropropane.

Cl, 1 &quot; -bl. 2-carboxylate To 226 mq (0.555 mmol) 3-butyl-1,2,4-triazole of Step 7 in 5 ml of N, N-dimethylformamide at about 5 ° C was added 0.66 ml (0.66 mmol) of potassium tert-butoxide in tetrahydrofuran. The resulting solution was stirred at about 5Â ° C for 2 minutes, followed by the addition of 2Âμl (1.76 mmol ) of i-isobutane. The mixture was stirred at room temperature for 30 minutes, quenched with acetic acid and concentrated in vacuo. The residue was chromatographed (eluted with ethyl acetate-hexane, 1: 2) to give 21 mg ( (S, 9H), 1.24 (s, 9H), 1.24 (s, 9H), 1.24 (s, 9H) 1.45 (m, 4H), 1.5-1.68 (m, 2H), 1.68-1.8 (m, 2H), 2.41 (t, J = 7.5 Hz). 2H), 3.80 (t, J = 7.2 Hz, 7.28), 5H3, 7.35-7.55 (m,

2H), 7.20-7.34 (m, 2H), 7.78 (d, J = 7.5, 1.2 Hz, 1H); ΞΗ) 5 4.86 &lt; s,

Mass spectrum (FAB) m / e (relative intensity) 470 (46), 414C100) Preparation of 4apos; -E (1,3-dibutyl-4,5-dihydro- To 165 mg (6.356 mmol) of Step 8 tert-butyl ester in 2 ml of chloroform was added 1 ml of chloroform mmol) of trifluoroacetic acid (7FA). The solution solution was stirred at room temperature for about 15 hours, and concentrated in vacuo. The residue was chromatographed on silica gel (ethyl acetate-methanol-acetic acid, 85 g 10: 5) to give 152 mg (quantitative) of the compound of the product of Example 1 as a solid

Mass spectum (FAB) m / e (relative intensity) 408 (33), 390 (20), 211 (160)

Hi everyone

N-N

2,5-b] [1,4] diazepine-4-carboxylic acid [3 H-4-tr 3-Qa

95 ml 2M butylmagnesium &gt; 19.4 mol) in tetrahydrofuran and 55 ml of anhydrous ether at about -6Â ° C (chloroform-dry ice) was added dropwise 24.4 g. C, 162 mmol. of isothiocyanate in 205 ml of anhydrous ether over a period of 2 hours. The solvent was decanted and the solid was washed with four 50 ml portions of ether. The solid was partitioned between ether (50 ml) and ether (50 ml). Of saturated ammonium chloride. The aqueous layer was washed with water. extracted with two 50 ml portions of ether & the combined extracts were dried (Na2 SO4) and concentrated in vacuo. The red oily residue was distilled under reduced pressure to give 58 g of N-ethoxycarbonyl thienyl amide as a yellow oil, mp 89 DEG- 1.5 torr 5

1 H NMR (CDCl 3): 0.90 (t, J = 7 Hz, 3H), 1.20-1.5 (111.5H), 1.65-1.8 (m, 2H), 3.20 (t , J = 7.5 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 9.2 (br s, 1H).

A solution of 5-butyl-2n4-dlhydro-β-1,2,4-triazol-3-one To 567 mg (3 mmol) of thawed M-ethoxycarbonyl in 6 ml of absolute ethanol at room temperature was added The resulting solution was stirred at about 84Â ° C for 30 minutes, and was concentrated in vacuo, and the resulting solid was rinsed with ether-hexane (10 mL) , is collected by filtration to give 32 mg (76%) & 5-butyl-triacal-3-one as a white solid.1H NMR (CDCl3) δ 0.85 (t, 3H), 1.2 (s, 3H), 1.2-1.4 &lt; m, 2H &gt; , 0.5-3.0 (m, 2H), 2.0-3.0 (m, 2H), 2.38 (m, 2H), 3.83 (m, 2H), 1.11 , 1H),

Step 3a preparation of N - (triphenylmethyl) -5- [2- (4-bromomethylbiphenyl) -2-yl] ethanol (A sample 542.5 mg (2.4 mol) of 2- ( (Chemo Dynamics Inc) was dissolved in 5.5 l of ethanol and treated with 3 L (7.5 mol) of 2.5% sodium hydroxide. The reaction was stirred overnight at r.t. The solution was cooled in ice and acidified to ρ 1 with hydrochloric acid and the residue was cooled to 0 ° C. which caused the product precipitate from filtration and drying in vacuo gave 51% of crude 2-Cp-tolyl) benzoic acid, mp 145.0-147.5 ° C.

RnM (CDCU) 5 2.4® < 3H &gt;, 7.17-7.28 (m, 4H), 7.35-7.45 (m, 1H), 7.59-7.58 (m, 1H). The crude acid was suspended in 10 ml of toluene and treated with 4 g (3.15 mol) of sodium chloride under nitrogen, whereupon the resulting solution was stirred at room temperature for 4.5 hours. concentrated in vacuo to remove the oxalyl chloride solution. The residue was redissolved in Ξ 1

of toluene and treated with 92.8 g (5.46 mol) in anhydrous ammonia. The reaction was filtered and the filtrate was concentrated in vacuo yielding 424 g (84%) of 2β-tolyl) -benzamides mp 128 -1H-NMR (CDCl3): 2.40 (s, 3H), 5.28 (s, 1H), 5.77 (br., 1H), 7.21-

-7.53 (m, 7H), 7.76-7.83 (m, 1H). The crude amide was treated with 142 ml (19.5 mol) of thionyl chloride in reflux for 3.5 h. filtered, and the thionyl chloride was removed in vacuo, the residue was dissolved in 8 ml of toluene and concentrated in vacuo. The crystals were collected and washed with hexane to give 296 g (64%) of 2- (p-tolyl) benzenitriles, mp 50.5-52.0%.

J

NMR (CDCl3) δ 2.42 (s, 3H), 7.22-7.34 (m, 2H), 7.37-7.52 (m, 3H), 7.58-7.66 (m, 1H), 7.72-7.78 (m, 1H).

A sample (286 g, 1.48 mol) of crude nitrile was dissolved in 163 ml of toluene and treated with 377 g (1.8 mol) of trimethyltin acetate in reflux for 24 hours. The reaction was cooled to 0 ° C. N-trimethylstannyl-5-E2- (4apos; -methylbiphen-2-yl) -tetrazolines mp 271-272 ° C.

NMR DWS0-d6) Î', 3.beta., J = 34Hz) 9H), 2.24 (3H, g), 6.89-7.06 (m, 4H), 7.35-7.55 (m, , 44. The crude triethylsilane triethylsilane was suspended in 4270 ml of talan and 287 ml of anhydrous tetrahydrofuran (THF) and treated with 63.4 g (173 mol) of anhydrous hydrogen chloride at room temperature under nitrogen with stirring. The reaction was allowed to stand overnight and filtered through recrystallization from toluene gave 217 g (62%) of 5- [2- (4-methylbiphen-2-yl) -tetrazole as a solid mp 149-152 (S, 3H), 6.94-7.02 (m, 2H), 7.08-7.15 (m, 2H), 7.50-7.40 (m, (M, 2H), 7.62-7.72 (m, 2H).

A sample of 2.8 g (6.85 mole) of tsirazole was suspended in 3.3 L of dichloromethane and treated with 262 g (θ, 91%) of triphenylmethyl chloride and 1 ml (1 mole) gave The reaction was stirred at reflux for 3 hours under nitrogen, washed with water, dried (MgSO 4) and concentrated in vacuo. Recrystallization gave 338 g (83%) of N-triphenylmethyl-5- [2- 2-yl) -1-thiazole as a colorless solid. mp 70-73 ° C. NMR (CDCl 3): δ 2.27 (s, 3H), 6.86-6.96 (m, 1H), 6.98-7.04 (m, 2H), 7.09-7.52 (m, 12H ), 7.86-7.94 (m, 1H). N-Triphenylmethyl tetrazole was dissolved in 426 ml of carbon tetrachloride and treated with 126.4 g (0.11 mol) of N-bromosuccinimide (MBS) and 11.9 g (49 mmol) of benzoyl peroxide were added dropwise over 3.5 hours. The reaction was filtered and the solvent was removed in vacuo. Rrystallization from toluene provided 277 g (59%) of N 5-C4 '-forocnomethyl-biphen-2-yl) -tetrazole as an colorless solid mp 140 DEG-142 DEG C.

NMR (CDCl3) δ 4.39 &lt; s ? 2H), 6.85-6.95 (m, 7H), 7.86-7.15 (m, 4H), 7.22-7.43 (m, 9H), 7.45-7.55 (m, 2H &gt;, 7.94-8.01, 1H &gt;. The R 1 N indicated that this material had 85% puresa; it contained 7% dibromo compound (86.50%) and 8% maturity. However, no further purification attempts have been made and this mixture has been used in all of the subsequent alkylation reactions of the preparation of the compound of the formula (II): ## STR1 ## in which R 1 and R 2 are as defined above. -1H-tetrazol-5-11- 1-methyl-3-3H-1,2,4-triazol-3-one To 247 mg (1.75 mmol) of 5-butyl- 3-one from Step 2 in 17 ml of N, N-dimethylformamide was added dropwise 1.8 ml of 1M potassium tetrabuthoxide in tetrahydrofuran. The resulting clear brown solution was stirred at room temperature for 10 minutes, followed by the addition of 952 mg Cl, 7 mmol &gt; of Step 3 M-triphenylmethyl-2- (4-bromomethylbiphen-2-yl) 3-tetrazole in two portions, 38 min = indentations. The resulting solution was stirred at room temperature for about 1 hour, acetic acid and concentrated in vacuo, the residue was chromatographed (eluted with isopropanol-hexane, 7: 1) to give 29 mg (27%) of N-substituted triazolone as a solids: 1 H NMR (CDCl3):? S, 0.85 (t, 3H), 1.28 (septet, J = 7.5 Hz, 2H), 1.53 (d, J = 7.7 Hz, 2H), 2.29 (d, J = 7 Hz) , 3Hz, 2H &gt; J = 7 Hz, 6H), 7.01 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 85 Hz, 2H), 7.9 (M, 2H), 7.9-8.0 (m, 1H), 9.0 (m, 1H), 7.4-7.8

Mass spectrum (S-AB) m / e (relative intensity) 624 (22), 568 (4), 388 < 3, 382 (185, 339, 1005).

3-methyl-3 H -1,2,4-oxadiazol-2-ol (24 mg, 389 mmol) of M-substituted trisolone from Step 4 in 4.5 ml of N, N- dimethylformamide. was added potassium tert -butoxide to 5N in tetrahydrofuran. The resulting solution was stirred at room temperature for 10 minutes, followed by the addition of 150 μl (1.32 mmol) of 1-iodohutane. The mixture was stirred at room temperature for about 1 hour, quenched with acetic acid and concentrated in vacuo. The residue was filtered through a pad of silica gel (eluted with ethyl acetate-hexane, to afford Ξ55 mg (97%) of N, N'-disubstituted triazolone as an oil (1 H NMR (CDClâ,ƒ) Î', 84 (t, Î ±, 7.3 Hz, 3H), Î', 96 (t, , 3H), 1.27 (t, 3H), 1.27 (t, J = 7.9 Hz, 2H), 1.75 (quintet (t, J = 7.5 Hz, 2H), 2.28 (t, J = 5.8 Hz, 2H), 3.80 6.96 7.01 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 7.20-7.40 (m, 1H), 7.4Â ° -7.53 (m, 2H), 7.88-7.95 (m, 1H);

Mass spectrum (FAB) m / e (relative intensity) 680 (20), 444 (25), 410 (20), 395 (10®), 381 (15) =

Step 5: Preparation of 2-S-dibutyl- (4-dihydroxy-4-C-2- (1H-tetrazol- QDa.

A solution of 245 mg &lt; 0.364 mmol) of the N5 N'-disubstituted triasolane from Step 5 in 4 ml of acetic acid and 0.4 ml of water was stirred at ambient temperature for about 17 hours and the residue was concentrated in vacuo The aqueous layer was acidified to about pH 3 with 3N hydrochloric acid and extracted with chloroform and ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The combined extracts were dried (MgSOâ, ") and concentrated in vacuo to give 150 mg (quantitative) of the compound of example product as a solids.1 H NMR (CDClâ,ƒ) Î'0.85 â € ƒâ € ƒâ € ƒ7.1, 6H ), 1.15-1.42 (m, 4H), 1.42-177010 (with two quintets at 1.50 and J = 7S4 and 7.3Hz> 4H>, 2.34 (t, J = = 735 Hz, 2H), 3.64 (t, J = 7.2 Hz, 2H), 4.69 (s, 2H), 7.06 (q, J = 8.1 Hz, 4H) (D, J = 7.2 Hz, 1H), 7.45-7.65 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H)

Mass spectrum (FAB) m / ε (relative intensity) 432 (20), 277 (Î'05) 178 (25)? HRMS = calc'd for M + H + 432.2512 .. Found 432.2510 =

A process for the preparation of Triasolone with Reagent............... Tritil ....... I'll bring you

Step 4. A solution of 2-amino-2- (4-methyl- To a solution of 0.4-0.5 mmol of 5-butyl-2,4-dihydro-4-C2 '' - (1-trifluoromethyl) -1H- (prepared in Example 2 Step 4): â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ (1.0 M in tetrahydrofuran) was added dropwise, the resulting yellow solution was stirred at room temperature for 1 minute. , 5 equivalent of an appropriate alkylating reagent dropwise (or in portions, if it is solid). The resulting solution was stirred at room temperature for 1.5 h and concentrated in vacuo, the crude product could be purified by silica gel chromatography, eluting with ethyl acetate / hexane to give pure alkylated product. In most cases the crude mixture was purely pure, and was used directly for deprotection in Step (E). Step 2: The product of Step 1 was dissolved in dichloromethane in 12 ml of glacial acetic acid and 1.2 ml of water. The resulting solution was stirred at room temperature for 2 hours and concentrated in vacuo. The solid residue was stirred with 5 ml of saturated sodium bicarbonate and 16 ml of ether for 1 minutes. The ether layer was removed and the aqueous layer was washed two

times with fresh ether. The resulting aqueous layer was acidified with 3 W hydrochloric acid to about pH 3 S and extracted with three portions of chloroform. The combined extracts were dried (Na2 SO4) and concentrated in vacuo. oil of the resulting foam solidified upon standing to give the desired tetrazolylbis-5-disubstituted triazacin. mm &amp;amp;amp;amp;amp;

dihydro-1H-imidazol-4-yl] -amide; -1H-tatrazol-5-yl &gt; 1,1'-biphenyl-4-ylmethyl] -1H-benzimidazo [1,2-a] pyridine.

Following the general procedure for reacting a threonone with alkylating agent (described later), 3â € ²-methoxy-5â € ²-methyl-5â € ²-butyl-3,4-dihydro- 3-ylmethyl-3 H -1,2,4-triazole-3-one in 4.5 ml of N, N-dimethylformamide was made to react with Î ±, 574 mmol of potassium tert-butoxide in tetrahydrofuran (150 mg, 0.584 mmol) of i-adamantane. bromomethyl cstone. The alkylated product was deprotected following Serial Procedure step 2 and the resulting solid was re-crystallized from ethyl acetate / hexane to afford 18 mg (67%) of the desired product compound as a white solid

1 H nm &lt; DMSO-d6 &gt; δ ® 77 (t, 3 = 7.25Ha, 3Η), 1322 <m9 '2Η>, 1.38 (quin ceiling 9 3 = 7.26, 2Η> 3 1.67 (br s, 6Η), 1 , 80 (br s, 3H &gt;, 2.37 (t, J = 7.25H2, 2H), 4.76 (br s, 2H), 4.81 (br s, 2H), 6.87 &lt; (M, 2H), 7.60-7.72 (m, 2H), 7.48-7.6 (m, 2H), 7.60-7.75 (m, 2H)

Mass spectrometry (FAB) m / e (relative intensity) 552 (35), 207 (100), 178 (40) HRMS, Calcd for: ,

π3. ~ d I- b t.d r Q &quot; 2 to 5: 1 to 2: 1 to 2: 1 to 2: 1 to 2: 1 to 2: 4 H -1,2,4-triazol-5-one

Following the general practice to provide a triazole-lones with an alkylating agent (described above), 3.00 mg (0.48 mmol) of 5-butyl-2,4-dihydro-4-E2 '- <i-trifysni 1-yl) -1,1,1-biphenyl] -4-methyl-3 H -1,2,4-triazol-3-one in 4.5 was reacted with 2574 mmol of potassium tert -butoxide in tetrahydrofuran and 89 pL (0.583 mmol) of 1-bromo-3-alanyl pragan. The alkylated product was deprotected following the procedure described in Example 1. The title compound was obtained as a white solid.1 H NMR (CDCl3) δ 0.82 (1 H, 7.25 Hz, 3H), 1.27 (t, J = 7.0 Hz, 25 Hz, 2H), 1.50 (quintet, J = 7.25 Hz, 2H), 2.01 (quintet, 7.1.25H, 2H), 2.33 (t, J = 7, 6 Hz, 2H &gt; , 2.59 (t, J = 6.65Hz, 2H), 3.75 (t, J = 6.85Hz, 2H), 4.71 (br s, 2H), 6.95-7.30 (m, 9H), 7.30-7.60 (m, 3H), 7.68 (d, J = 7.25 Hz, 1H)

Mass spectrum, Î ± (FAB) m / e (relative intensity): 494 (32), 207 (300), 178 (45) 5 HRMS e Calc. for Hâ,,Hrs: 494.2266, Found: 494.2673,

(1H-tetrazol-5-yl) -1,1-biphenyl-3-yl] methyl] -5H-1 , 2 "-4-triazol-5-ana

Following the general procedure for reacting a triazole with an alkylating agent (described below), 55%): 5-butyl-4,4-dihydro-4 - [(1 ', 2'-triphenylmethoxy) 5-yl) -1,1-biphenyl-4-ylmethyl] -3 H -1,2,4-triazal-3-one in 9 ml of N, N -dimethylformamide was reacted with 1, 14 mmol of potassium lerc-butoxide in tetrahydrofuran and 2 mg (1.88 mmol) of 2-bromo-D-octanoacetate. A portion of the alkylated product (22 mg mg, 229 mmol) was deprotected following General Procedure step 2 to give 127 (80%) of the desired product compound as a white solid. 2H), 1.51 (quintet, d = 7326Hz, 2H), 2.36 (br, J = 7.66Hz, 2H), 4.74 (br s, 2H) (Br s, 4H), 7.30-7.65 (m, 6H), 7.79 (d, J = 7.25Hz, 1H), 7.86 (br s, (d, J = 7.25Hz, 2H)

Mass spectrum (FAB) m / e (relative intensity) 494 (175, 451 (3), 376 (8), 2β7 (1α);

Found: 494.250Â ° C, HR11Sâ € ¢ CaClâ,ƒ for M + H + 494.2304.

5-butyl-2,4-dihydro-2- 2-hydroxy-2-phthalazin-4-yl) -2-hydroxyethyl] -5- Fig. 4-yl) -3H-1,2,4-triaza-gum To a solution of 4-methoxybenzylammonium bromide of Example 5 in methanol 4 ml of methanol and 2 ml of tetrahydrofuran at  ° C was added sodium borohydride (25 mg, mmol) in portions. The resulting solution was stirred at 0 ° C for 2 hours, quenched with saturated ammonium chlorate. Volatiles were The aqueous layer was extracted with chloroform, dried (MgSO 4) and concentrated in vacuo to give 38 mg (95%) of the desired alcohol. Following the general process step 2? (27 mg) of the alcohol obtained from the process described above was deprotected, the resulting solid was recrystallized to give 102 mg (76%) of the desired product compound as a white solid

1 H NMR (CDCl 3, δ): 0.77 (t, J = 7.25 Hz, 3H), 1.10-1.28 (m, 2H), 1.28-1.545 (m, 2H), 2.34 = 7.65Hz, 2H), 3.73 <dd, O =: 13.7, 6.0Hz, 1H), 3.85 <dd, 05 = 13.7, 7.7Hz, 1H &gt; , 4.74 (br s, 2H), 4.88 (q, 3 = 6 Hz, 1H), 5.54 (d, 0.8 Hz, 1H), 6.97 (d, J = 2H), 7.04 (d, J = 8.4Hz, 2H), 7.10-7.40 ({is, 5H &gt;, 7.45-7.60 &lt; m, 2H), 7.60- 7.7 &gt;2H);

Mass spectrum (FAB) m / a (relative intensity) 496 (5), 478 (12), 435 (3, 207 (100) ¾ HRH8 Calc'd for M + H: 496.2461 Found 496, 2501,

3-Butoxy-2,4-dibromo-5-p-tolyl-4-

Following the general procedure for reacting a threonine with an alkylating agent (described above), 45 mg (0.728 mg) of 5-butyl-2,4-dihydro-4 - [[2 '- [1-triphenylmethyl- 5-yl) -1,1'-biphenyl-3-4-ylmethyl] -3,4-diisopropyl-3-one in 8 ml of N3 N -dimethylformamide was reacted with 0.87 mmol of potassium tert -butoside in tetrahydrofuran and 141 μl, 37 mmol) of tert -butyl bromoacetate. A portion of the alkylated product (24 mg, 0.328 mmol) was deprotected following General Procedure step 2 to give 161 mg &lt; 7% &gt; of the desired product compound bed a white solid Ή-! 1 H-NMR (CDCl3): Î'0.88 (3H, d, J = 7.25Hz, 3H), 1.35 (m, 2H), Î'.59 (quintet, , J = 7.25Hz, δ), 4.43 &lt; s, 2H &gt; , 4.78 <s, 2H), 7.18 <AB quartet, J = S, 5Hz, 4H), 7.41 (d, J = 7.7Hz, 1H), 7.48-7.05 (m, 2H, &gt;; 7.8 (2H, d, J 7.7, 1.2 Hz); (FAB) su / s (relative intensity) 496 (39), 440 (60), 412 (45), 397 (25), 235 (22), 207 (10)), 192 (4)), 178 (60), Calc'd for C 20 H 26 N 3 O 4,

W.

JiPLU # 8 i

5-butyl-2,4-dihydro-2-hexy-4-C2 '- (1H-tetrazol-5-yl) -biphenyl-4-yl] 5-one

Following the general procedure for reacting a trisulmonone with an alkylating agent (described below), 250 mq (&gt; 486 mmol) of 5-butyral-2,4-dihydro-4-L 2 ' 5-yl) -1,1'-biphenyl-4-ylethyl 3-3H-15 2,4-triazol-3-ana in 4 ml of N, N- -dimethylformamide was reacted with 0.58 mmol of potassium tert-butoxide in tetrabrofuran and 145 μl of the alkylated product was deprotected following the general procedure step 2, the solid resulting was (57%) of the desired product compound as a white solid: 1 H NMR (DMSO-d6) δ 0.7-0.9 (111: 1 H), 1.15-1 J = 7.25Hz, 2H), 1.5-1.7 (s, 2H &gt;, 2.37 (t, J = 7.26Hz, 2H) (D, J = 8.6Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.64 (d, 2H), 7.45-7.60 (m, 2H), 7.60-7.70 (m, 2H) HRMS = Calc'd for M + H 460.2825. Found 46.4.220 EXPL. "2.

3-fluoro-3,4,5-trimethoxy-3,4-dihydro-1H-indole

Following the general procedure to react a zirconia with an alkylating agent (described above), 50 mg (0.81 mmol) of 5-butyl-2,4-dihydro-4 - [[2- &lt; 1 &gt; -triphenylmethyl-lB-tetrazol-5-yl) was dissolved in 7 ml of N, N-dimethylformamide was reacted with 1.62 mmol of potassium tert-butoxide in tetrahydrofuran and 147 μl. (1.33 mmol) of ethyl bromoacetate The alkylated product was deprotected following the Sarai Procedure step 2 to give 336 mg (90%) of the desired product compound as a white solid: 1 H NMR (DMSO-d 6): 0.77 (1, J = 7.65Hz, 3H), 1.10-1.3 (Em t = 1.17, J = 6.85Hz), 5H 3, 1.41 (quintet, J = 7.25Hz, 2H), 2.39 (t, J = 7.65Hz, 2H), 4.12 (q, J = 6.9Hz, 2H), 4.55 (s, 2H &gt; (D, J = 8.4 Hz, 2H), 7.45-7.75 (m, 4H), 7.6 (d,

Mass spectrum (FAB) m / e (relative intensity) 402 (85), 446 (10), 235 (1.5), 207 (100), 192 (18) ¾ HRMS. Calc'd for P + Hs 462.2254, Found 462.2267,

EXAMPLE # 10 n-n-co2h

(&gt; 12

N-S-butyl-4,5-dihydro-5-oxo-4- [2- (1H-tetrazol-5-yl] t, 11-Methyl-

A mixture of 17.4 mg &lt; 0.368 mmol) of the ethyl ester of Example 9 in 3.4 ml of tetrahydrofuran and 3.4 ml of 2 W aqueous lithium hydroxide was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The aqueous layer was partitioned with 4 ml of ether and acidified with 3N hydrochloric acid to about pH3. The mixture was filtered, and the solution was washed with water. The solid was dried in vacuo to give 1 &amp; 637) of the desired product compound. The filtrate was extracted with chloroform, dried (MgSOâ, "), concentrated in vacuo and triturated with ether to give an additional 5 mg of &lt; 3.1% &gt; of the desired product compound as a white solid; 2 H NMR (DMSO-d 6) δ 8.28 (d, 3 = 7.25H, 3H), 1.17-1.32 (m, 2H), 1.32-1.5 # 2H), 4.82 (s, 2H), 7.36 (d, J = 8, 6 Hz, 2H), 2.39 (t, J27.26 Hz, , 7.13 (m, 2H), 7.58-7.7 (m, 2H), 7.45-7.6 (m, 2H)

Mass spectrum (FAB) m / s (relative intensity) 440 (25), 429 (12); HRMS. Calc'd for M + Hs 434.1941 Found 434.1977

5-butyl &lt; / RTI &gt; 2, f4-dihydro- &quot; 2 &quot; (naphthalenyl) 4R: &lt; / RTI &gt; 4-ylmethyl] -3 H -1,2,3-a] -triazol-5-one

Following the general procedure for reacting a fructopolol with an alkylating agent (described above), 25 mg (6.4æ5 mmol) of 5-butyl-2,4-dihydro-4- [2 '- &lt; 1-triphenylmethyl-1H-israzol-5-yl) -1H-biphenyl-4-ylmethyl-3 H -1,2,4-triazol-3-one in 4 ml of N -dimethylformamide was reacted with 6.5 g of potassium tert-butoxide in tetrahydrofuran and 34 mg (0.606 mmol) of 1- (bromoethylethyl) naphthalene. The alkylated product was deprotected following General Procedure step 2 to give 159 mg &lt; 76%) of the desired product compound as a white solid 1H NMR (DMSO-d 6): 6.73 (t, J = 7.25 Hz, 3H), 1.1-1.0 25C, 2H) 1.25-1.4Cm3 2H), 2.34 <t, J = 7.66Hz, 2H), 4.84 (5, 2H), 5.31C, 2H &gt;, 7.65 (D, J = 7.6 Hz, 2H), 7.36 (d, J = 8 Hz, 1H), 7.4-7.7 (m, 7H &gt;, 7.80-8.0 (m, 2H), 8.18-8.3 (m, 1H); HKT »Calo» for H-f-Hs 516,2512 »Found 516,2534»

1 ΙΚξ / Àfr ~~

I

5-butyl-2- (2-cyclohexylethyl) -2,4-dihydro-4-methyl-1H-imidazo [1,2-

Following the general procedure for reacting a tris-zalone with an alkylating agent (described above), δ50 mg <0.405 mmol) of 5-butyl-2,4-dihydro-4-L2 ' triphenylmethyl-1H-tetrazol-5-yl) -1,1'-diphenylmethyl] -1,3,4,11,11,11,12-triazol-3-one 3 ml of N, N-dimethylformamide was reacted with 0.53 mmol of potassium tert-butoxide in tetrahydrofuran and 10 mg (0.523 mmol) of 2-cyclohexyl ethylbromide. The alkylated product was deprotected following General Procedure step 2 to give 165 mg (84%) of the desired product compound as a white solid. 1H NMR (DMSO-d6): δ 0.77 (t, J = 7.25Hz, 3H) 0.8-0.95 (m, 2H) 1.0-6H), 1.3-1.8 (m, 9H, 2.37 &lt; t, J = 7.65Hz, 2H), 3.67 (t, J = = 7.26Hz, 2H), 5.47 (s, 2H), 7.07 (d, 0.8.46Hz, 2H), 7.80 (s, 2H), 7.45-7, 60 Cm, 2H), 7.60-7.70 (m, 2H). Calc'd for M + H + 488, 29 Si. Found: 486.3012.

&lt; 1 H-tetragecylsilanate: 1: 1: 2:

Following the general procedure for reacting a triplet with an alkylating agent (described above), 5-furo-2,4-dihydro-4-E2 '- &lt; 1-triphenylmethyl-1H-tetrazol-5-yl) -1,1'-fiphenyl] -4-yl] -1H-benzimidazol-3-one and 3 ml of N, N-dimethylformamide was reacted with 53 mmol of potassium tert -butoxide in tetrahydrofuran, 7 mg (0.354 mmol) of 1-iodopethane. The alkylated product was deprotected following General Procedure step 2 to give 11% (mg) of the desired product compound as a white solid (DMBQ-d6): 0.7-0.9 <m / e; (quintet, J = 7.2 Hz, 2H), 1561 (quintet, J = 6.9 Hz, 21-1 ', 2537 (t, J = 7.2 Hz). = 7.7Hz, 2H), 3.64 (t, J = 6.8Hz, 2H), 4.79 (s, 2H), 7.05 <d, -8.46Hz, 2H> 7 (M, 2H), 7.66-7.7 (m, 2H), 7.45-7.6 (m, 2H);

Mass spectrum (FAB): n / e (relative intensity) 44 & C6B), 235C1®) E 207 (100), 192 (20), 178 (20). Found: 446.2705,

1-yl) methyl] -1H-1,3-f] [1,4] diazabicyclo [2.2.1] hept-3-yl] To a solution of 16Θ mg (0.121 mmol) of the hydroxymethylstrityltetracholylbiphenyl triazolone obtained from Example 4 in 4 ml of dry tetrahydrofuran was added 18 mg (6.45 mmol) of sodium hydroxide (16%) in oil one portion, and the resulting suspension was stirred at room temperature for 1 minute. After evolution of the gas was complete, 76 μmol (5.06 mmol) of methyl bromoacetate was added. The resulting solution was stirred at room temperature for 4 hours, and quenched with saturated ammonium chlorate. The aqueous layer was extracted with three 10 mL portions of chloroform, the combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude alkylated product, Following the General Procedure step 2 the alkylated product was deprotected to give 165 mg (83%) of the desired product of the desired product as a white solid

1 H NMR (DMSO-d 6) δ 0.75 (t, J = 7.66Hz, 3H), 1.06-1.46 (m, 1H); J = 7.65Hz, 2H &gt;, 3.70-4.20 (m, 5H), 4.73 (5, ΞΗ) 4.82 (d, J = 5.5Hz, 1H), 6.91 (d, J = 8.05Hz, 2H), 6.95-7.20 (with da 7.01, α = 8, 3H), 7.20-7.4 (m, 5 H), 7.45-7.77 (m, 4)

Mass spectrum (FAB) m / e (relative intensity) 582 <1e>, 478 (13), 235 (15), 2 7 (1), 192 (48), 178 (28); HRMS. Calc'd for M + H + 582.2829. Found: 582.2832. ; 8-

Example Am.

C02H N i CHa

H

2-[(3-butyl-4,4-dihydro-5-propyl] -2- (1H-tetrazol-3-yl)

Li 2 O + = Z + Z + Z + Z

A mixture of 8 mg (ñ = 138 mmol) of the ester from example 14 in j. 57 ml of tetrahydrofuran and 1 ml of 1: 1 lithium hydroxide was stirred at room temperature for 3 hours. The volatiles were removed in vacuo, and the aqueous solution was washed with three portions of ether. The resulting aqueous solution was acidified with 3% hydrochloric acid extracted with chloroform (dried (MgSO ^) and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate / hexane to give 72 mg (94%) of the title compound of the desired product as a white solid

Mass spectrum (FAB) m / s (relative intensity) 054 (3). 478 (12), 450 (5), 235 (10), 207 (100), 192 (30), 178 (25). Ualc. to 554.2516. Found: 554 =, 2536.

Hi

* 2., AT ^ Mzvi = sna

Following the general procedure to react a trialkylone with an alkylating agent (described hereinbefore), 25 mg (0.05 mmol) of 5-butyl-2,4-dihydro-4- [2'-yl 4-methyl-1H-1,2,4-triazol-3-one, 2.5 ml of N, N-dimethylformamide was reacted with 0.43 mmol of potassium tert.-butyl ester in tetrahydrofuran (50 mg, 483 mmol) of 3 S, 4 S -dimethyl-1-bromohexane. The alkylated product was deprotected following the procedure of Beral step 2 to give 176 mg (S7%) of the desired product compound as a solid (0.25 g, (dd, J = 13.2, 5.7Hz, 1B>, 1, CDCl3, Î'= 13.2, 2.8Hz, 1H), 1.29 (t, -1.6 &lt; m, 4H), 1.60-1.77 &lt; m, 1H), 2.36 &lt; t, E = 8.06Hz, 2H), 3.55-3.75 , 2H), 4.68 (br s, 2H &gt; , 7.7 CAB quartet, = = 7.7Hz, 41-1), 0,,, Η Η Η Η Η Η

LH)

In; the mass bspsctra (intensity rsla · 'ί-ή'-τ ZZ / 40.

235 C 277 (1)? ΓϋΗΗ:: 1. 1. 1. 1. 1. a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a EXAMPLE # 17

ethylene 11-4-12 '- &lt; To a solution of 0.1 mg (0.136 mmol) of the fersylacetyl trityl-tetramolylphiphenyl-triasolone of Example 5 in 1, 1-methyl- 5 ml of dry terahydrofuran was added 1 mg (0.25 mmol) of sodium hydride (60% in oil) and the resulting suspension was stirred at room temperature for 5 minutes. After evolution of the gas was complete, 3 μM . The resulting mixture was stirred at room temperature for 2 hours, quenched with ammonium chloride, evaporated and worked up in water and chloroform. The crude product was chromatographed on silica gel, eluting with ethyl acetate / hexane, to give 7Θ mg (56%) of the desired trityl protected product product as an oil;

1 H NMR (CDCl 3): δ 7.74 (3H, s), 1.1 (septet, 2.77 Hz, 2H), 1.37 (quintet, J = 7.65 Hz, 2H &gt;, 2.12 (t, J = 7.25Hz, 2H), 3.85 (s, 2H), 4.63 (s, 2H), 4.74 (s, 2H), 6.73 , Δ = 8.06Hz, 2H &gt; 6.80-7.00 (m, 27H), 7.93 (d, J = 2.0Hz, 1H).

Following the work-up of the title compound (2 mg), the resulting product was deprotected. The resulting product was crystallized from ethyl acetate / ether / hexane to give 46 mg (90%) of the title compound. of the desired product compound as a white solid.1H NMR (CDCl3): Î'], 7B (t, J = 7.2 Hz, 3H), 1.18 (sept), 2.76 (m, 3H); ? 1.41 (quintet, J = 7.7 Hz, ΞΗ), 2.24 (1, J = 7.7H2, 2H), 3.67 (s, 2H), 4.50 (s, 2H), 4.55 (brs, 2H), 6.69 (d, J = 8.6Hz, 2H), 6.91 (d, J = 8.46Hz, 2H), 7.76-7.20 (m, 9H), 7.45 (td, 2 = 7.65, 1.2 Hz, 1H), 7.55 (td, 2 = 7.65, 1.2 Hz, 1H), 7.85 (td, J = 7.66, 1.21 Hz , 1H &gt; =

Mass spectrum (FAB) m / e (relative intensity) 674 (15), 582 (8), 554 (3), 325 (5), 297 (20), 235 (8), 207 (100), 192 5), 178 (40) HRMS Calc'd for HHU 674.3243 Found 674.330%

OfeoELQ Jm.

5- &lt; 1-benzyl] -2-phenylethyl, -5-butyl. -5,44-d ihyd rQ = 2 = 121%. To a solution of 0.14 ml (3.2 mmol) of lithium diisopropylamine (1: 5: 1 tetrahydrofuran, Aldrich) at -20 ° C was added a solution of the product (0.143 mole) of triisopropylbenzylphenyl The resulting solution was stirred cold for 1 minute. To the solution was added 25 pL (0.21 mmol) of benzyl bromide and the resulting solution was stirred at room temperature. The reaction is quenched with ammonium chloride. evaporated and worked up in water with methylene chloride. The crude product was chromatographed on silica gel eluting with ethyl acetate / hexanes to give 10 mg (9%) of the desired trityl protected product. Following the usual procedure step 2 the alkylated product was deprotected to give 6- mg &lt; 8%) of the desired product compound as a white solid

1 H NMR (CDCl 3): δ 0.75 (3H, d, J = 7.50Hz, 3H), 1.00-1.45 (m, 4H), 1.83-25.00 (m, 1H), 5.22 = 2.20 (1H, m), 3.36 (dd, J = 13.3,4.4Hz, 1H &gt;

 € ƒâ € ƒâ € ƒ3.85 (t, J = 12.9Hz, 1Hâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ4.99 (dd, J = 10.9, 3.6Hz, 1H), 5.11 (AB quartet, Î'17.7Hz, 2H), 7.0-7.7 (m, 14H), 7.90 (d, J = 7.26 Hz, 4H),

Mass spectrum (FAB) m / s (relative intensity) 584 (15), 325 (60), 260 (100), 207 (10) Calc'd for M + H + 584.2774. Found 584.2794.

I, S3ELS. or

N-N

Following the general procedure for reacting α-zolons with an alkylating agent (described above), 150 mg (0.243 mmol) of S-butyl-α-dihydro-β-β-1-triphenylmethyl- 5-yl) -1,1'-biphenyl-4-ylmethyl] -3 H -1,2,4-triazal-3-one in 1.5 ml of N, N-dimethylformamide was reacted with 0.26 mmol of potassium tert-butoxide in tetrahydrofuran and 6 æl (0.367 mmol) of butyric anhydride. The alkylated product was deprotected following Serial Procedure step 2, the crude product was crystallized from ethyl acetate / hexane to give 92 mg &lt; / RTI &gt; 85% &gt; of the desired product compound as a white solid 1 H NMR &lt; CDC1T &gt; 5, 89 &lt; (M, 2H), 1.55-1.70 (m, 2H), 1.76 (q, J = 7.1 Hz, 3H) 3 Hz, 2H), 2.4 (t, J = 7.6 Hz, 2H), 2: 92 C19 = 7.26 Hz; 2H), 4.84 (s, 2H)

7518-7 = 32 ((51: 2Η), 7.35-7945 &lt; ιβ, 1Η), 7945-7965 &lt; m, 2Η), 8.05-8.0 (1H,

Mass spectrum (FAB) ra / e (Relative Intensity) 4 * 8 (33)., 446 (45), 376 (1.00), 235 (45), 207 (100), 192 (42). HRiiS »Cal for n-t-Hi; 446.2304. = Found 446.2351 = EXAMPLE # 20 OMe

Following the general procedure for reacting a thiazolone with an alkylating agent (described above) to 5-methyl-2,4-dihydro-4 ', 2'- (4-trifluoromethylphenyl) 5-yl) -1H-biphenyl-4-ylmethyl] -1,2,4-triazol-3-one in 6 ml of N, N-dimethylformamide was made The crude product was crystallized from ethyl acetate / ether / hexane to give the title compound as a white solid (0.25 g). The crude product was crystallized from ethyl acetate / ether / dichloromethane to give 750 mg (97%) of the desired trityl protected product.

General process step 2 = 2Θ &amp; mg of the alkylated product was deprotected, and the crude product was re-esterified to provide 11Θ mq (<79%) of the desired product compound as a white solid.

1 H NMR (CDCl 3): δ 0.85 (t, J = 7.65Hz, 3H), 1.32 (s, 3H), 1.55 (s, 3H) , δH (3H, 2B), 3.75 (3, 3H), 5.82 (s, 2H), 5.15 (s, 2H), 6.92 (d, J = 9927Hz, 1H &gt; 1H), 7.15 (d, J = 8.6Hz, 2H), 7.21 <d, 0-8, Θ6, 2H>, 7533-7 (m, , 4H) 7992, d, J = 8.06., 1.2 Hz, 1H &gt;

Mass spectrum (FAB) m / e (relative intensity) 576 (13), 554 (38), 207 (100), 165 (63); HRMS, Calc'd for n-Bis 554.2516. Found: 554.2567,

5-oxo-1,1,1,2,2-tetrahydro-2 H -2-phenyl-2 H -imidazol-4-yl] (0.229 mmol) of trityl tetra-cyclohexylbiphenylhexylhydroxyethyl triscolone of Example 6 in 4 ml of tetrahydrofuran was added 18 mg (9.2 mmol) of N, N-dimethylformamide , 201 mmol) of sodium hydride (~9% in oil), and the resulting suspension was stirred at room temperature for 5 minutes. After the evolution of the gas was complete, 5 μm (9.42 mmol) of benzyl bromide The resulting mixture was stirred at room temperature for 1 hour, quenched with ammonium chloride, and concentrated in vacuo, the residue was processed with water and methylene chloride to give 299 mg of the alkylated crude product. Seral procedure step 2 the alkylated product was stripped to give 12 mg (quantitative) of the desired product compound as a white solid

1 H-NMR (DMSO-d 6): δ 0.75 <t, J = 7.25Hz, 3H), 1.10-1.38 (m, 2H), 1535 <quintet> 3.75Hz, 2H), 2.34 (t, J = = 7.65Hz, 2H), 3577 <dd, y = 14.44Hz, 1H), 4.03 (d, J = 3.07, 8.46Hz, 1H), 4.21 (d, 1H), 4.539 (d, J = 12.1Hz, 1H), 4.70-4.82 (m, 4H), 7.10 (brs, 7.43 &lt; m, 1ΘΗ), 7.43-7.72 (m, 4H &gt;

Mass spectrum <FAB) m / e (relative intensity) S86, 478 (18), 243θθβ)? 207 (88) HRMS: Calc'd for M + H + 5865293; Found; 586.2979.

5-bytyl-2,4-dihydro-2- [2 - [(2,2-dimethoxyphenyl) -2-hydroxyethyl] -4- -1.1) Cl, 1, To a solution of 25.4 mg (0.134 mmol) of trityl protected biphenyl dimethoxyphenacyl triszolone from Example 21 in 3 ml of methanol was added 6 ml of acetonitrile tetrahydrofuran at 0 ° C was added 16 m ((Θ 5423 mi) of sodium borohydride in one portion. The resulting solution was stirred cold for 1 hour, quenched with ammonium chloride and evaporated. The residue was chromatographed on silica gel, Following the procedure of Seral Step 2, 71 mg (0.089 mol) of the alkylated product was deprotected to give 50 mg (quantitative) of the desired trityl product. Compound of the desired product as a white solid

1 H NMR (CDCl3) Î'6.88 (br, 7.4H, e, 3H), 1.25-1.42 (¾, 2Hâ,ƒ, 2H), 2.42 (t, 0.7.4H2, 2H), 3.71 (s, 3H), 3.8 (s, 3H), 430-4.25 (m), 2H), 4.76 (s, 2H), 5.33-5.25 (m, 1H), 6.70-6.83 (m, 2H, 7.65-7.2 (m, 4H), 7.35-7.43 (m, 1H), 7.45-7.65 (m, 2H), 7.96-8.68 (m, 1H);

Mass spectrum CFfiB) ffi / e (relative intensity) 578 (35), 538 &lt; 9Θ), 516 (3), 495 (6), 235 (12), 207 (100), 192 (36), 178 30)? HRMS e Calc'd for M-H -h 566.2672 = Found 556.2691.

N-N

§ = Mtilr2 ^ MM.dro ~ 2, ··· < 2-naphthalene-4-carboxylic acid (2-naphthalen-1-yl) -amide; 4 t rji a ^ l ^ 5zgna

Following the general procedure for reacting a trisulgone with an alkylating agent (described above), mg mg &lt; , 243 mmol) of 5-fluoro-294-dihydro-4-C2 -1-triphenylmethyl-1H-tetradec-S-yl) C15β-biphenyl-3-11- triazol-3-one In 3 ml of N, N-dimethylformamide was reacted with 3.0 mmol of potassium tert -butoxide, tetrahydrofuran and 81 mg (,, 3 x 7 mmol) of 2- <bromomsti1> naphthalene The crude product was deprotected following the procedure of Step 2, the crude product was recrystallized to give 125 mg (quantitative) of the desired product compound as a white solid.1 H NMR (CDCl3) Î'0.81 (t, J = 7.25Hz, 2H), 1.5 (3H), J = 8.0Hz, 2H), 2.34 (t, J = 7.25Hz, , 2H &gt;, 4.69 (s, 2H), 5.5 (m, 4H, 2H), 6.95-7.0

Mass spectrum (FAB) νmax / (relative intensity) 5Î ± (25), 326 (30), 242 (25), 207 (100), 192 (3β), 78 (35), 14β Calc'd for: H-516.2512 = Found::::::::::::::::

(&gt; 0 N I CHa

1 H-NMR (DMSO-d6): Î'(CDClâ,ƒ) Î'(CDClâ,ƒ)

Following the general procedure for reacting a 5-butyl-2,4-dihydro-4-2- (1-triphenylmethyl) -1H-firasol- 3-ylmethyl-3 H -1,2,4-triazol-3-one in 3 ml of N, N-dimethylformamide was reacted with <3.3 g mmol potassium tert -butoxide in tetrahydrofuran and 52 μl (0.3 μmole) of methyl 5-bromoacetate. The crude product was deprotected following General Procedure step 2 to give 1.5 mg (97%) of the desired product compound as a white solid.1 H NMR (CDCl3) δ 0.89 (t, J = 7 Hz, 3H), 1.35 (t, 3H) (M, 4H), 1.75 (quintet, J = 8.5, 4H, 2H), 2.32 (t, 2H,

1.2 Hz, 1H)

Mass spectrum (FAB) m / s (relative intensity) 490 (20), 430 (8), 235 (8), 207 (100), 192 (30), 178 (50). Cf. for rH-H s 4ν0.257 "Found 490.2570 = EXAMPLE_25

benzoyl-2-oxo-3-methyl-1H-benzoyl-

1 ΓΙ 1,5 1,5 1,5 1,5 1,5 1,5 1,5 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 ζΙ · Ll 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 ηρ & ίο. To a solution of diisopropylsilylphosphate dihydroestradiol (5M, Aidrich) at -78 ° C was added a solution of 348mM (0.473 mmol) of phenacyl triti-tetraeo-biphenyl. The triacolons of Example S were dissolved in 2 ml of dry tetrahydrofuran via cannula. The resulting solution was stirred cold for 1 minute. To the solution was added 63 μΙ. (+/- P568 mmoles) of ethyl chloroformate, the resulting solution was stirred cold for 15 minutes, then was heated to -3 DEG C. for a period of 3 minutes. The reaction was quenched with 1M hydrochloric acid, stirred until The crude product was chromatographed on silica gel, eluting with ethyl acetate / hexane, to give 82 mg (21%) of the desired trityl protected product. Following the Procedure Seral 2 the alkylated product was deprotected, the crude product was chromatographed on gel

of the silica (eluting with isopropanalhexane-acetic acid, δ 5.32 (3H, s), to give 30 mg (55%) of the desired product compound as a white solid. J = 7.2Hz, 2H), 1.15 (br, J = 6.73Hz, 3H), 2.86 (quintet, 27 (1, J = 7.2, 2H, 2H), 2.95 (dd, J = 10.3, 6.9Hz, 1H), 3.14 (dd, J = 16.3, 2H, , Δ (q, J = 8 Hz, 2H), 4.79 (s, 2H), J = 7.3Hz, 1H), 6.4 (d, J = 8.2 Hz, 2H). d, J = 8.0Hz, 2H), 7.15-7.40 (br, 3H), 7.40-7.8 (m, 4H), 7.88 (d, J = 8, 2H, 2H); Calc'd for H-His 580.26 / 2, Found 580.2714.

2-yl) -1,2,3,4-tetrahydro-1H-1,2,3,4-tetrahydro- 4-methyl-3- (1H-1,2,4-triazahexyl)

Following the general procedure for reacting a thiazolone with an alkylating agent (described above)? The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure described in example 1, 3-yl] methyl] -3 H -pyrrolo [3,2-a] quinol in 2 ml of N, N-dimethylformamide was reacted with Î'2. of potassium ierc-butadiene in tetrahydrofuran is 41 μΐ. C (24), of 2-bromo-isobutyrophenone. the reaction mixture was added 15 mg &gt; 0538 mmol) of sodium hydride (66% in oil), the resulting mixture was stirred for 2 hours. The mixture was concentrated in vacuo and chromatographed on silica gel Calc'd with ethyl acetate-hexane to give 3â € ²max (24%) of the protected trityl product.1 H NMR (CDCl3) Î'0.84 (t, O . = 7.31 (t, 3H), 1.18-1.32 (m, 2H); (S, 1H), 2.29 (t, J = 7.7 Hz, 2H), 4.35 (s, 2H), Î'599 Cd 3 J = 8.2Hz, 2H), 6.89 (d, J = 8.2Hz, 2H), Î', 89Cdβ = 7.7Hz, 6H>, 6.97 (d, Î'= 8.08Hz, 2H &gt; 7.15-7.48 (ro, 12H &gt;, 7,48-

(D, J = 7.2 Hz, 2H), 7.90-7.98 (m, 1H) The alkylated product was deprotected following General Procedure step 2 and the product brine was recrystallized to give 0.18 mg (%) of the desired product compound as a white solid 1 H NMR (CDCte) δ δ, 85 < t, J = 7.25Hz, 3H &gt; , 1.32 (t, J = 7.5 Hz, 2H), 1.32 (s, 3H), 1.32 (t, J = 2H), 4.50 (s, 2H), 6.55 (d, J = 8.6Hz, 2H), 6, B7d, J = 8.06Hz, 2H), 7.15-7.3 ? <M, 2H), 7.33-7.42 (m, 2H), 7.45-7.7 (m, 4H), 7.85-7.95 (m, 1H);

Mass spectrum (FAB) m / e (relative intensity) 544 (20), 522 (20), 416 (5), 235 (5), 207 (10), 192 (45), 178 HRMS Calc'd. for M + H + 522.2617 = Found 522.2658.

The title compound was prepared from the title compound as a white solid, mp 218-221Â ° C. 1 H NMR (CDCl3): Î'13.21 (s, 3H) pen. so cool

A mixture of 8æm (ΘΧ &amp; 3 mmol) of ester from example 24 in 3 ml of tetrahydrofuran and 3 ml of 2N lithium hydroxide was stirred at room temperature for 2 hours. Volatiles were removed in vacuo, and the aqueous solution was washed with three portions of ether. The resulting aqueous solution was acidified with 3N hydrochloric acid, extracted with dichloromethane and concentrated in vacuo. The residue was recrystallized from ethyl acetate / hexane to give 74 mg &lt; 94%) of the desired product compound as a white solid &lt; 1 H-NMR (DMSO-d 6) δ 0.8H2 7H2 3 H>, 1.10-1.53 (111.6H), t563 (quintet, J = 8.6 Hz, 2H) (T, J = 7.66Hz, 2H), 3.55 (d, J = 6, S5Hz, 2H), 4.79 (3H, s) , 7.90 (d, J = 8.46Hz, 2H), 7.12 (d, J = 8.06Hz, 2H), 7.45-7.72 (115.4H), 11.7-12 , 3 (br s, 1H &lt; 3 &gt; = A &lt; / RTI &gt;

EmtíkO J2B

5-butyryloxymethyl) -2,4-dihydro-4H-pyrrolo [2,1-f] [1,4] benzodiazepin- 5-one

Following the general procedure for reacting a thiourea with an alkylating agent (described above), 2- (4-chloro-3-methylphenyl) -2,4-dihydro-4 ', 2' - (1-triphenylmethyl- 1-yl) -1,1,1-biphenyl-3-ylmethyl] -1 - [(1,2,4-triazol-3-one in 4 ml of Î ±, β-dimethylformamide was reacted at -0 ° C with θ, 39 mmol of potassium tert-butoxide in tetrahydrofuran and 47 ÂμL (0.48 mmol) of bromomethyl cyclopropane for 1.5 hours and The alkylated product was deprotected following the procedure of Step B, step 2 to give 131 mg (94%) of the desired product compound as a white solid.1 H NMR (DMSO-d6) δ 0.28 J = 5.6Hz, 2H), 0.79 (t, J = 7.25Hz, 3H), 1.04 (s, 1H) , 1.24 &quot; septet Q 3 = 75651 (25 2H>, 1.42 (quintet, J = 7.25 Hz, 2H), 2.39 (t, J = 7.25 Hz, 2H &gt; 2H), 7.49 (s, 2H), 7.06 (d, J = 8.05Hz, 2H), 7.12 (d, J = 8.06Hz, 2H) ), 7.45-7.75 (m, 4H &gt; for M-His 430.2355. Found: 430.2395.

N-N'-Ph

(3-methoxy-2E-propenyl) -1H-tetrazol-1-yl] -3-methyl-1H-imidazol-2-yl] 13-3H-1,2,4-triazol-1-one

Following the procedure for reacting a tris -Hydione with an alkylating agent (described above), 0.5 mg (0.243 mmol) of 5-butyl-2-4-dihydro-4-C2- 4-ylmethyl] -3H-1,2,4-triaza-3-one in 3 ml of N, N-dimethylformamide was made was reacted with 3 mmol of potassium tert-butoxide in tetrahydrofuran and 72 μl (â¼3.6 mmol) of cinnamyl bromide. The alkylated product was deprotected following General Procedure step 2, the crude product was chromatographed on silica gel, sluicing with isopropanol / hexane / acetic acid to give &gt; &lt; 5β% &gt; of the desired product compound as a white solid; 1 H NMR (DMSO-d6) Î'0.78 (1, β, Î'= 7.25 Î', 3H), 1.24 (septet, J = 7, 6 Hz, 2H), 1.42 (quints, = 7.05 Hz, 2H) J = 7.65Hz, 2H), 4.46 (d, J = 5.24Hz, 2H), 4.82 (s, 2H); , 6.31 <dts 0-16.1 ,. 5.6 Hz, 1H &gt; , &, 49Cd, 3-16.1Hz, 1H), 7.07 &lt; d, J = 8.06Hz, 2H), 7.15 (d, J = 8.06Hz, 2H), 7.22-7.55 (m, 9H),

Mass spectrum (FAB) m / s (relative intensity) 492 (38), 464 <3) 476 (3), 243 (1.2), 207 (87), 178 (20), 117 (100). Calc'd for H-s-Hs 492.2512 Found: 492.2542

1-amino-1,4,5-dihydro-1-oxo-Î ± -propyl-4β, 15β- (1H-tatrazal-5-yl

EXAMPLES OF THE INVENTION The present invention relates to a process for the preparation of a compound of formula (I): Zn, Zn, Zn, Zn, Zn, Zn, Zn, Zn,

A mixture of 226 m @ 3 (3 mole) of the bromo product from step 1, 38 mg (0.776 mmol) of sodium cyanide, and 3 ml of water in 4.5 ml of N, N-dimethylformamide was stirred The resulting mixture was concentrated in vacuo and was chromatographed on silica gel (eluting with ethyl acetate / hexane) to give 178 mq (<85%) of triacolone cyanobutyl as a white solid NMR (CDCl3) νB, 75 < t? 3? 7.2? (M, 4H), 1.55 (br m, 4H), 3.34 (dd, J = 7,26Hz, 3H) 8.86, 63.55, Ib> 3,523 <t, 3 = 7.26Hz, 2H), 4.73 <t, J = 15.7Hz, 1H), 4.99 &lt; d, J = 7Hz, 1H), 6.85 (s, 9s, 6H), 7, θ2 α, J = 8.4Hz, 2H), 7.11 (d, J = 8.06Hz, 7.44 (m, 1 H), 7.4-7.55 (m, 2H), 7.85-7.53 (m, 1H).

Following the Bsral procedure of Step 2, 8β mg, 4 4 romol &gt; of chlorobutyl triazolone was deprotected on chromatography (eluting with isopropanol / hexanes / acetic acid) to give 48 mg &lt; 92%) of the desired product compound as a white solid; H-! NMR (DMSO-d 6) δ 0.74 (t, J = 7.3 Hz, 3H), 1.89 (t, J = 7.4 Hz, 3H), 1.29 (quintet, J = 7.3 Hz, 4H) , 1.73 (m, 4H), 3.73 (t, J = 6.96 Hz, 2H) = 4.44 (dd, J = 7.9, 5.7 Hz, 1H), 4.91 (m, AB quartet, 3 = 16.4Hz, 2H), 7.1 (d, J = 8 Hz, 2H), 7.18 (d, J = 7 Hz, 2H), 7.45-7.78 4H). PF (FAB) m / e (real intensity) 457 (18), 429 (5), 235 (10), 192 (8), 149 (25), 147 (10α) HRnSu calcd for M + Hs 457.2404 = Found; 457.2521 = 15-

biological awuAgm

Ensaic As_____ Connecting Activity to ftn.qiptgnsina__.il

The compounds of the invention were tested for the ability to bind to the angiotensin II receptor of smooth muscles using a rat uterine membrane preparation. Angiotensin II (AII) was purchased from Peninsula Labs, II (specific activity of 22.0 Ci / mmol) was purchased from Du Pont-Mew England Nuclear. Other chemicals were obtained from Sigma

Chemical Ca. This assay is carried out according to the method of Douglas et al., J. Med. Chem. 120-124 (1980). Uterine membranes of rats were prepared from fresh tissue. All procedures were carried out at 4 ° C. The uteri were stripped of fat and homogenized in phosphate buffered saline at pH 7 * 4 containing 5 mM EDTA. The homogenate was centrifuged at 1500 κ g for 2 Θ min when the sample was recentrifuged at 100,000 κ g for 6 Φ min. The pellets were resuspended in buffer made up of EGTA 2 mH 50 mM Tris-HCl δ 7-5) final protein concentration of 4 mg / ml. The test tubes were charged with 0.25 ml of a solution containing 5 mM EDTA, 2 mM EDTA, 5% bovine serum albumin ? 5-m HCl-pH 7.5 I-AII &lt; / RTI &gt; Approximately 5 ~ cpm) in the absence or presence of unlabeled ligand. The reaction was started by the addition of protein The incubation was quenched with 5% Tris-HCl (7.5%) and the mixture was filtered to remove the labeled peptide bound to the free ligand membrane. The incubation tube and the filter were washed with ice-cold buffer. The filters were assayed for radioactivity on a qamma counter

The non-specific binding was defined as being the binding in the presence of 10 μl of unlabeled AH. Specific binding was calculated as total binding minus nonspecific binding. Receptor-binding affinity of a tis antagon antagonist compound was indicated by the concentration &gt; of the tested AII antagonist which resulted in 5% shift of the specific binding of the high affinity AU receptor specifically bound. Binding data were analyzed by adjusting the null linear curve of the square ntíniroos. The results are shown in Table I, Table 1. Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta Resposta.

The compounds of the invention were tested for antagonistic activity in rabbit aortic rings. New Zealand white male rabbits (2--2.5 kg) were sacrificed using an excessive dose of pentobarbital and bled through the carotid arteries. The thoracic aorta was removed, cleaned of the adherent fat of the connective tissue, and then cut into segments The endothelium was removed from the rings by a smooth sliding stock if a piece of filter paper wrapped within the lumen of the vessel. The rings were then placed in a tissue bath wrapped with water, maintained at 37 ° C. between movable and fixed ends of a movable-end stainless steel wire attached to a Brass FT®3 transducer coupled to a Brass Model 8 polygraph to record the isometric force responses. The bath was filled with 20 ml of oxygenated Krebs solution (95% OK / 5% carbon dioxide) with the following composition &quot; mM &gt;: 130 MaCl, 1.5 NaHCO 3, KCl, 1 = , 2 ΝηΗ * 2Ρ0 ^? 1.2 æg 30, æ 2.5 CaCl 2, and 11.4 glucose. The preparations were equilibrated for approximately one hour before a gram of passive voltage was placed in the rings. The angiotensin II concentration curves were then recorded (3 x 1β &quot; aix X® w &quot; Each AII concentration was allowed to cause its maximum contraction, and then the AU was washed away repeatedly for 3 minutes before challenge with a higher concentration of AII. The F-rings of the aorta were exposed to antagonist for 5 minutes prior to the AU challenge. Adjoining segments of the same aortic ring were used for all concentration-response curves in the presence or absence of the test antagonist. The efficacy of the test compound was expressed in terms of pAiÎ ± values and were calculated according to HO

Schild et al., J. Pharmacog., Chem. Chem., 2, 189-206 &lt; 1947) 3, PH value, * is the concentration of antagonist which increases the The test antagonist was evaluated on the aorta rings from two rabbits. The results are shown in Table I.

Assay Cs Response to Intraduorianal Pressor Assay In vivo actively reacts to the antagonists.

Male Sprague-Dawley rats weighing 225-3 Âμg were anesthetized with Inactin (1 Âμg / kg, Âμg) and implants were trapped in the trachea, femoral artery, feeder vein 1 and duodenum. Blood pressure was recorded at The femoral vein catheter was used for injections of angiotensin II, mecamylamine and atropine. The tracheal catheter allowed clearance of the airway, and the duodenal catheter was used for intratiodial administration Ci.d.) of the test compounds. After surgery, the rats were allowed to equilibrate for 3 minutes.  € ƒâ € ƒâ € ƒMamamylamine (3 mg / fcg, 0.3 ml / kg)

and atropine (4æg pg / kg, 3 ml / kg) were then administered to produce blockers of the ganglia. These compounds were administered in 9 minutes in the course of the entire test procedure. Angiotensin II was administered as a dose of Dolus v = 30 ng / kg in saline with 5% bovine serum albumin, and mg / kg) in 19 minutes or up to three times in the blood pressure produced was within 3 mm Hg for two consecutive injections of AIL · The mean of the last two injections of AII was calculated and was taken as a control response to the control AII 'Ten minutes after the final control AII injection' the test compound (dissolved in sodium bicarbonate) was administered at a dose of 30 mg / kg in a volume of 2 ml. Angiotensin II injections were then administered 5S: , 45.6Â °, 75.90 &amp; 12 &amp; minutes after administration of the test compound and blood pressure response was monitored. The response to AII was calculated as a percentage of the control response? and then the percent inhibition was calculated as 19% minus the percentage of the control response. The duration of the test compound section was defined as the time from the peak percent inhibition up to 59% peak. Each test compound was tested in two rats and the mean of the rats was calculated for each rat. The results are presented in Table I:

AII antagonists

Spragus-Da male rats weighing 225-30g were anesthetized with methoxyhexyl &lt; 3 mg / kg? i, p "&gt; The catstaras formed a tunnel subcutaneously until they emerged dorsally, posterior to the femoral artery and vein.

head and between the shoulder blades. The catheters were filled with heparin and heparin units / ml saline). The rats were placed in their cage and fed with standard rats and water ad libitum. complete recovery from surgery (3-4 days). The rats were placed in Lucite cables and the arterial line was attached to a pressure transducer. Blood pressure was recorded on a Gouid polygraph (mmHq), A sngiotensiin II was given as bolus 3æg / kg dose via the given venous catheter in a volume of 5 æl with ≤ 2 ml of saline flow. The pressure response in mm Hg was measured by the difference in the pre-injection blood pressure up to the maximum pressure The injection of HA was repeated every 10 minutes until three consecutive injections produced responses within 4 mmHg of each. The mean of these three responses was taken and the control response to AU was repeated. The test compound was suspension was added in 0.05% methylcellulose in water and was administered by probe. The volume administered was 2 ml / kg body weight. The standard dose was 3 mg / kg. Angiotensin II bolus injections were given 45-45 ° C. The response to the HA was measured at a given time. The rats were then put back into their cages for future testing. A minimum of three days was allowed between each test. The percent inhibition was calculated for each time after the probe by the following formula? E (Control Response-Response at a given ins- tant) / Response control! The results are reported in Table I.

ftd.ivid.ada._dDS ..... sgmegstas-de ..... formula I of ..... ftnffÍQtens3jia_Jl_Jji ___ alive

Test Compound Exsmylo # 'Assay A inM &gt; (%) (eiin.) Inhibition Time (%)

1" ? 7: 93-6: 1. 4 η V i im> 29® or 5®> 18® 3 25 8.1 MT MT 4 18 8 ,® 4® 18® 5 7 ;; 9 8.5 2® 18® 6 3.6 3.3 15> 18® 7 16 7.1 2® 3® 8 8.7 8.9 NT NT 9 9 7.8 MT MT 1® 91 7, 8 NT NT 1 5® 7.7 NT NT 12 18 7.9 NT NT 13 5.6 9, ® NT MT 14 18® 8.3 NT NT 15 3Θ 8.6 4®> 18® 1.6 35 7 , 9 NT NT 17 48 NT NT MT 18 5,8® NT NT NT 19 8 8.2 NT NT 2® 2 8 8 NT NT 21 28 7.7 NT MT

vv 22 8.1 MT MT 23 280 6.5 MI NT 24 4.4 9.4 NI WT 2b 'ONLY 7.8 NT NT 26 43 7.7 MT MT 27 12 8.0 NT NT 28 15 8.0 MT NT 2? 290 6.6 NT MT 3 48 48 7.7 MT MT NT = Mio Tested Assay Activity of Angiotensin II Binding Activity &quot; Assay Bs Vascular smooth muscle response in vitro Assay Ca Inhaled pressure response in vivoa Composites of Examples # 1 "and # 2",

Assay of the Intragastric Response in vivo for Compounds Example # 2--30 =

Also encompassed by the invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I in association with one or more carriers and / or agents and / or adjuvants (collectively referred to herein as pharmaceutically acceptable carrier materials) if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to that route, and at a dose effective for the intended treatment. Therapeutically effective doses of the compounds of this invention invention required to prevent or stop the progress of the medical condition are readily calculated by any person skilled in the art. The compounds of the compositions may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may advantageously contain an amount of active ingredient ranging from about 1 to 25 μg, preferably from about 25 to 15 μg. A suitable daily dose for a human can vary widely depending on the situation of the patient and other subjects. However, a dose ranging from about 3 ΘΘΘ mg / kg body weight, particularly from about 1 mg / kg body weight, may be appropriate. The active ingredient may also be administered by injection as a composition in which, for example, saline, dextrose or water solutions may be used as a carrier

A suitable daily dose ranges from about 1 μg / kg body weight per day in multiple doses depending on the disease to be treated. A preferred daily dose would range from about 1 to 50 μg / kg The preferred indicated compounds for the effective therapy are preferably administered in a daily dose generally ranging from about 1 to about 1 mg per kg body weight per day. A more preferred dosage will range from about 1 mg / mg to about 1.0 mg per kilogram body weight. Most preferred is a dosage ranging from about 1 to about 5 mg per kilogram of body weight per day. An appropriate dose may be administered to multiple sub-doses per day. These sub-doses may be administered in dosage unit forms. Typically, a dose or sub-dosage may contain from about 1 mg to about 10 mg of active compound per dosage unit form. dosage plus pr will be about 2 mg to about 50 mg of the active compound per unit dosage form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per dosage unit. The dosage regimen for treating a disease condition with the compounds and / or compositions of this invention is selected according to a number of factors including the type, age, weight, sex, medical condition of the patient, severity of disease, the route of administration, and the particular compound used, thus exhibiting a very broad variation '

For therapeutic purposes the compounds of this invention are usually combined with one or more adjuvants suitable for the indicated route of administration. If administered alone, the compounds may be admixed with lactose, sucrose, starch, cellulose esters of alkanoic acids , alkyl esters of cellulose, talc, stearic acid, magnesium stearate,

magnesium oxide, sodium and calcium salts of phosphoric acid sulfuric acid, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, s, or polyvinyl alcohol, and are then compressed into tablets or encapsulated for convenient administration. tablets may contain a sustained release formulation as may be provided in a dispersion of the active compound in aqueous solutions. The formulations for paranic administration may be in the form of sterile aqueous isotonic solutions or suspensions These aqueous suspension solutions may be prepared from sterile blades or granules having one or more carriers of the diluents mentioned for use in formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycerol, ethanol, corn oil, cottonseed oil, almond oil sesame oil, benzyl alcohol, sodium chloride solutions, and / or various buffer solutions. Other adjuvants and modes of administration are well known and widely known in the pharmaceutical art.

While this invention has been described with regard to specific presentations, the details of these presentations should not be construed as limitations'

Claims (6)

A process for the preparation of a compound of formula CD where m is a number selected from one to four, inclusive alkylalkyl, 3-phenylpropyl, 2- &quot; OKO &quot; 2 &quot; phenyl &quot; 2-hydroxy-2-phenylethyl, 1,1-dimethylethylcarbamoylmethyls, ethyloctylmethyl, ethyl, naphthalenylmethyl, 2-cyclohexyl, pentyl, ethoxycarbonylmethoxyethyl substituted with substituted carbymethyl, (2-phenylmethoxy) -1- (phenylmethyl) ethylsilyl] -1-hensoyl-2-phenylethyl, i-Q-malethyl, 2- [ 2,5-dichloro-benzoyl) -2- (2-naphthalenyl) methyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, 2-naphthalenylmethyl, substituted by benzoyl, 1-benzoyl-1-methylethyl, 1-pentanoic acid, cyclopropy. Cycloalkenyl, aralkylcarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyloxycarbonyl, aralkylcarbonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulphonyl, arylsulphonyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, of formula 12 12 / XRS! / -CN Wherein each of R and R 13 is independently R3 is selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, and wherein R &quot; and R.sup.2 can form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may additionally contain one or more hateroatoms as ring members selected from oxygen atoms, nitrogen is sulfur and which heterocyclic group is unsaturated or partially unsaturated. wherein each of Rx 'and R' taken together may form an aromatic heterocyclic group having five members of the ring including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may additionally contain one or more more heteroatoms as well as ring atoms selected from the oxygen, nitrogen and sulfur atoms, with the proviso that, when X is oxygen atom, then R and R can not be selected from hydrogen and alkyl, wherein each R 'is hydrogen; to R "&quot; is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxy-.alpha.- c. &quot; aralkoxyalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, arkoxycarbonyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkynyl, alkynyl, cis-5-nitro, carboxhoyl, aroylcarbonyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, nilo5 slcoxicarboniloxi, alkylthio, alqu.il tiocarhonllo, alkyl carboniltio, alquiltiocarboniloxi5 alquiltiocarboniitio, alkyl tiotiocarbonilo, alquiliiotiocarboniltio, ariltia, ariltiocarbo-nila5 arilcarhoniltio, ariltiocarboniloxi, ariltiocarboniltio, ariltiotiacarbanilo, ariltíotiocarbonilfcio, aralqui1 alkylthio, aralkyl-quiltiocarbonilo, aralquilcarboniltio, araIquíliiocarhoniloxi, aralquiltiocarboniltio aralkylsulfonyl, arylsulphonyl, arylsulphonyl, arylsulphonyl, heteroaryl having one or more oxygen atoms selected from oxygen, sulfur and nitrogen atoms, and radicals selected from the group consisting of hydrogen, alkylthiocarbonyl, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, smino and amido of the formula: wherein X is an oxygen atom or a sulfur atom; wherein R 1, R 1, R 1, R 2, R 3 and R 4 are each independently selected from the group consisting of: is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, acyloxyalkyl, aralkyl, aryl, ε in examples taken together, R &quot;; and R &quot; Taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino or amido radical to which the heterocyclic group may additionally contain one or more heteroatoms as ring members saturated from oxygen, nitrogen and sulfur atoms and whose heterocyclic group may be saturated or otherwise unsaturated wherein each of R1-V and R1 'taken together and each of R1 and R2 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may additionally contain one or more heterocyclic as well as ring atoms selected from oxygen, nitrogen and sulfur atoms? 1 wherein each of N 1 through H 3 may additionally be independently selected from the group consisting of acidic moieties of the formula wherein n is a number from (a) to (b), and in which A is an acidic group sexected to contain at least one acidic hydrogen atom and the amide ester derivatives and salts of said acidic moieties in which Y is a spacer group independently selected from one or more alkyl cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, and heteroaryl having one or more ring atoms selected from the group consisting of oxygen atoms, sulfur and nitrogen, and wherein any of the foregoing R &quot; up to R3 groups Y and A having a substitutable position may be substituted by one or more groups selected from haloxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, oxanoamino, nitro, alkoxycarbonyl, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, mercapfca mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, heieraryl, having one or more ring atoms selected from oxygen atoms, sulfur, and amino amido compound of the formula IX ???????? n -CR 20 R '&quot; X in which X is an oxygen atom or a sulfur atom, is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and wherein D is selected from the group consisting of oxygen and sulfur and is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl in which each of R * '&quot;', RJ &quot; A &quot;; R1 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, carboxyl, alkylsulfonyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, halo alkylsulphonyl, haloalkylsulphonyl, aralkyl and aryl. &amp; wherein each R &gt; R &lt; 2 &gt; and R &lt; 1 is independently hydrogenated from amino and amido radicals of the formula wherein R &lt; 2 &gt; &quot; &quot; Wherein X is an oxygen atom or sulfur atom in which R 9, R 9, R 9, R 9, R 9, R 3 *, R 31, "v" K & R &quot; is synthesized from hydrogen, alkyl, cycloalkyl, cyano, hydroxyxy, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl, εrryl, ε wherein each is 2-2, of R * &quot; * and R'1 &quot; -1 &quot; taken together and each of Ri '' &quot; and R &quot; taken together may form a heterocyclic group having from five to five ring member sets including nitrogen atom of said amino or amido radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms, nitrogen and sulfur, and which heterocyclic group may be saturated or partially unsaturated in which each R 'to R 1' '. taken together and each taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical, which aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from the oxygen atoms; nitrogen and sulfur or a tautomer thereof or a pharmaceutically acceptable salt thereof characterized in that; - reacting a compound of formula n-ν 'r ^ nX ° I Η with a base ·'; followed by reaction with a compound of formula CH 2 Br - reacting a compound with trifluoroacetic acid when Râ, â, ... Nâ,,Oâ, ... CHâ,,Clâ,,). the -j with HDAc when R ': &quot; CN CPh4 qs- or with hs2 SnN2 when R 5 = CN, CO 2 C (CH 3) 3 s1pui. : sq: om R &quot; Xs wherein all the radicals have the above-mentioned sequences. A compound according to claim 1, wherein said compound is wherein m is one; wherein R3 is selected from polycycloalkyl; 3-phenylpropyl, 2-chloro-2-phenylethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted by phenyl, carboxyphenylsilyl-substituted phenyl, 3β, 3β-trimethylhexyl (γ-isomethyl) -1- (phenylmethyl) , &gt; 2-phenoxy-2-phenyloxy) ethyl] -2-hydroxy-2- (2-hydroxyphenyl) 2? 5-disethoxyphenyl) -2-hydroxy-2-naphthalenylmethyl, methoxycyarbonylbutyl, substituted benzoyl-1-methylstylyl-substituted stoxycarbonylethyl, 1-penyanic acid, cyclopropylmethyl, arylalkenyl, acrylonitrile, cycloalkenyl, cycloalkynyls arylthiocarbonyl, aralkylcarbonyl, aralkylsulfonyl, and radicals of the formula I-XR &quot; "/ -CW. Wherein A is an atom of the oxygen or hydrogen atom; wherein each of R3 and R4 is hydrogenated independently from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is an oxygen atom, then R4 '' '' can not be selected from hydrogen, wherein R * &quot; is selected from hydrogen, alkyl, hydroxyalkyl, halo, bicycloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, arylKalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylskoxyalkyl, alkoxy, aralkyl, aryl, aryl, aryl, aralkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyanalkyl, cyan, carboxyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, alkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alquilcarboniltio, alquiltiocsrboniloxi, alquiltiocarboniltio, alquiltiotiocarbonilo, alquiltiotiocarhoniltio, arylthio, arylthio-carbonyl, arylcarbonylthio, ariltiocarboniloxi, ariltiocarbonil-thio, tiotiocarbonil aryl, aryl txatioearhoniliia, aralqu.il thio, aralquiltiocarbonilo, aralquilcarboniltio, aralquiltiocarbonil-oxy, aralquiltiocarboniltio , aralkylthiocarbonyl, aralkylsulfonyloxy, arylsulfonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and acetyl atoms, each of which is optionally substituted with one or more heteroatoms selected from the group consisting of hydrogen, R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyl, alkylthiocarbocyloyl, alkylthiocarbonyl, arylthio, arylthiocarbonyl, arylthio, alkylthiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiocarbonyl, arylthiocarbonyl, arylthiocarbonyl, arylthiocarbonyl, carbanylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, amino and amido radicals of the formula R 1, X 1, X 1, ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒNC-R wR wW wherein X is an oxygen or independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, arylalkyl. 11 and wherein each R2 to R3 may be independently added independently from acidic moieties of the formula wherein n is a number selected from the group to which also A is an acidic group selected from of acids containing one or more atoms selected from oxygen, sulfur, phosphorus to nitrogen, wherein said acidic group is selected to contain at least one acidic hydrogen atom, and amide, ester and salt derivatives of said acidic moieties ? wherein Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkyl, alkynyl, alkynyl, aryl, aralkyl and heteroaryl moieties having one or more ring atoms selected from oxygen, sulfur and R 3 and R 4 are as defined in claim 1 wherein R 1 and R 2 are independently selected from the group consisting of hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, qkd " alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, carboxycarbonyl, carboxy, oxy, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino-amido radicals of formula X -CR 2 NXH -NC-R &quot; '&quot; wherein X is an oxygen or sulfur atom in which R "is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR ''; wherein D is selected from an oxygen atom at the atom of sulfur and R 'is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl and aryl; and each of R 1, R 2, R 2 and R 3 is independently selected from hydrogen, alkyl, cycloalkyl, hexane, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alconylcarbonyl, carboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl and aryl; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. A process according to claim 2 characterized in that a compound wherein m is wherein R '1 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2- phenylethyl, 2-hydroxy, 2-phenylethyl, 1,1-dimethylhexycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, i-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethylphenyl, phenyl substituted carbymethylcarbamoylmethyl, 3,5,5-triethylthioxy, (2-phenylmethyl) -1- (phenylmethyl) ethanesulfonate, 2-phenyl-2-phenyl-2-phenyl-2-phenyl-2-phenyl- 2-naphthylmethyl, 2-naphthylsilylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl substituted by benzoyl, 1-benzoyl-1-methylethyl, 1-pentanoic acid, cyclopropyl, 2-naphthylmethyl, Imet.yl? aracharyl, acronitrile, cycloalkanyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula -1'? 1Λ where each of k - and R * &quot; is independently selected from cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl arylophenyl, wherein R * is selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryl, karykyl, 2-hydroxy-2-arylalkyl, alkoxycarbonylalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxy, cyanoalkyl, alkoxy, aralkyl, aryl, aryloxy, alkynyloxy, alkoxyalkylalkylcarbonyl, aralkylcarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkenyl, aralkyl, aralkyl, aralkyl, aralkyl, cycloalkynyl, cycloalkynyl, carbamoyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthioconsulfonylthio, alkylsulfonyl, aralkylsulfonyl, and arylsulfonyl; wherein each of R 1 to R 1 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxy, alkoxyalkyl, alkylcarbonyl, alkenyl, cycloalkenyl, allyl, cyano, nitro, carhoxyl, alkylcarbonyl, hydroxy, alkoxycarbonyloxy, aiquxl &quot; uncle? arylthio, aralkylthio, msrcapto, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl radicals; amido compound of the formula R14 is hydrogen or halogen; -M, -CN and -NC-R * 55 'R 15 V 7, wherein each of R 2, R 3, R 4 'is independently selected from hydrogen, alkyl, cycloalkyl, Clano, amino, C 1 -C 10 -alkyl, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl; wherein each R1 to R1 may be an acidic moiety further independently selected from acidic moieties of formula That n is a number selected from zero to three inclusive? wherein A is selected from carboxylic acid and carboxylic acid histamus esters selected from the group consisting of H, -CH2 -OH, -SH, -NR &quot;, -C-WH, -S -WH, -S-WH, -P-WHg -P-NH and -P-WH and wherein each W is independently selected from oxzgenzo atom, sulfur atom and NR &quot;; r.u r-; A. &Numsp; &numsp; &numsp; wherein R 5 '', R 5 '' and R 5 '' is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfanyl, haloalkylcarbonyl, cycloalkyl cycloalkylalkyl, aryl, and aryl groups; in which case one of R ', R' ', R and R' '; may be further independently selected from the amino radical of the formula &quot; &quot; wherein each R'J 'and RH' &quot; is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and wherein K 1 'and K 1' taken together may form a group of heterocyclic group having from five to seven ring members including the nitrogen atom of said amino radical whose heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms; nitrogen and sulfur atoms of which the heterocyclic group may be saturated or otherwise. Try A π is your rad θ ~ ~ 4.0 4.0 4.0 4.0 4.0 eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo eo. taken together may form an aromatic hetero-cyclic group having five ring members including nitrogen atom of said radical whose aromatic heterocyclic group may further contain one or more heteroatoms selected from the nitrogen, nitrogen and sulfur atoms p ~ rr? wherein each of and may additionally be selected from hydrazinoalkoxyalkylalkyl, aralkylaryl, aralkylthio and aralkoxides of the ester amide derivatives of said acyl groups, wherein said carboxylic acid biosorbate may be selected from heterocyclic acidic groups consisting of heterocyclic rings of from four to about nine members of amino which heterocyclic ring contains at least one heteroatom selected from axexg 5 sulfur and acoto 3 atoms whose heterocyclic ring may be saturated, such unsaturated or partially unsaturated, and which heterocyclic ring may be attached in a single position selected from Fr 'to χ or may be attached to any two adjacent positions selected from R' To form a ring system condensed with one of the phenyl rings of formula 1% and the amide, ester and salt derivatives of said heterocyclic acyl groups in which Y is a leaving group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl groups, 1 ·? Wherein any of the foregoing R &quot; to H &quot; ' and R '' to H '', groups Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, aralkyl, aralkyl, hydroxyalkyl, halo, οκο, haloalkyl, alkoxy, aryloxy, aralkoxy alkoxycarbonyl, alkoxycarbonyl, carboxy, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio, s-alkylthiocarbonyl, and amino and amido radicals of the formula X wherein R 1, R 2, Wherein X is selected from an oxygen atom or a sulfur atom; - wherein R 'is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR4 &quot; wherein D is selected from an oxygen atom and sulfur atom; wherein R5 is unsubstituted from the alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and silyl hydrogens wherein each of R4 'is hydrogen; Η * &quot; 1 *, R * &quot; -, R 's R &quot; to R &quot; &quot; cycloalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl and aryl, or a pharmaceutically acceptable tautomer or pharmaceutically acceptable salt thereof The process of Claim 3 is characterized in that a compound in which m is a; where R &quot; is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyls, 2-hydroxy-2-phenylethyl] -1,1-dimethylethyloxycarbonylmethyl, 1-carboxymethyl-1-naphthalen-1-ylmethyl, 2-cyclohexylthio-1- phenyl) -carbamoyl] -ethoxycarbonylmethoxyethyl, phenyl-substituted carbamoyl] -methoxymethyl ester, 3,5-dimethylhexyl-2- (phenylmethoxy) -1- (phenylmethyl) 1-ethyl-2-oxobutyl = 2 - [(1-dimethoxyphenyl)] - -2-cyclohexyl] -2-phenyl-2-phenylmethoxy) ethyl] -2- (2,5-dimethoxyphenyl) -2-hydroxyethyl] 2-naphthalenemethyl-3-methoxycarbonylbutyl, ethoxycarbonyl-substituted benoxy-1-bensoyl-1-methylethyl, 1-pentanoic acid, cyclopropylmethyls, acetonitrile, cycloalkyl, mercaptocarbonyl, aralkylsulfonyl and formula I *? _ ι *%: where each of R &quot; and KJ '&quot;' is independently selected from cycloalkyl, amino, monoalkylamino, dialkylamino, hydroxyalkylalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; Wherein each of R 9 is selected from hydrogen, alkyl, polycycloalkyl, polycycloalkylalkyl, arylCyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carbyalkyalkyl, alkoxycarbonylalkyl, carboalkoxyalkyl, aralkylalkyl, arylalkyl, aralkyl, aralkyl alkenyl, cycloalkyl, alkynyl, carbowyl, alkylcarbonyl, arylalkyl, arylalkyl, arylalkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, arylalkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkylthio, alkylsulfonyl, aralkylsulfonyl, and arylsulfonyls wherein each of R 5 through R 8 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, aralkyl, aralkyl, aryl, aroyl, aryl, hydroxy, aralkyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carbo Milo, alkylthio, aralkylthio and mercaptop and wherein each R &quot; to R &quot; &quot; may be an additional acid additionally independently selected from the acidic moieties of the formula: which is a number selected from wax to three in which A is selected from carboxymic acid and carboxylic acid esters selected from HW W i !! Sf -OH, -SH, -NRW ·, -C-WH, -S-WH, -S-WH, wherein each W is independently selected from the group consisting of oxygen, sulfur atom where each R '&quot;', &quot; &quot; '&quot; and is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl5-, wherein each of R '' ', and R' 'may be independently independently selected from an amido radical of the formula ## STR4 ## in which each R &quot; and K 'is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and wherein R4 is H; taken together may form a heterocyclic group having from five to five ring member sets including the nitrogen atom of said amino radical, which heterocyclic group may additionally require to contain one or more heteroatoms as ring members selected from oxygen atoms, nitrogen atoms are sulfur whose heterocyclic group may be saturated or partially unsaturated &quot; &quot; 4-v 'where R &quot; 'and R' taken together may form an aromatic heterocyclic group having five ring members including the atom of said radical of which the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms isolated from of oxygen, nitrogen and sulfur atoms are the amide derivatives? a salt ester of said acidifying groups wherein said carbonyl acid bioisostere may additionally be selected from the heterocyclic acid groups consisting of heterocyclic rings of from four to about nine ring members, the ring of which contains at least one heteroatom selected from oxygen atoms, sulfur and acarate, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 1 to R ', or may be attached to any two adjacent positions selected from R &quot; to R "&quot; so as to form an amino system fused to one of the phenyl rings of formula I ' the amide, ester and salt derivatives of said acidic heterocyclic groups wherein Y is an independent spacer group is selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkylopentries wherein each of R1 to R5 R & and R ** can be independently substituted at any substitutable position by one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, , alkylsulfonyl, or haloalkylsulfonyl, aryl, alkoxy aryl, aryloxy, aralkonyl, or a tautomer thereof or a pharmaceutically acceptable salt thereof. The failure of Claim 4 is characterized in that a compound in which m is a compound wherein R 1 is selected from polycycloalkyl, 1 to 1 to 1 to 1 to 3, 1-hydroxy-2-phenylethyl-1-naphthyl-2-naphthylcarbamoyloxycarbonylmethyl, , carboxylcarboxylmethyl 5-carboethylmethyl-1-naphthalenylmethyl, 2-cyclohexylsilyl, (2-phenylmethyl) -1- (phenylmethylol-E-ethenyl) -1-benzoyl-10-2-furo [2,1-f] [1,4] benzodiazepine-4-carboxylate. (2,5-di-methoxyphenyl) -2-oxoethyl] -2- (1-phenylphenoxy) ethyl] ? 2-methylthiophenyl) -2-hydroxyethyl] -2-naphthalenylmethyl] -3-methoxycarbonylbutyl-3-sioncarbonyl-ethyl ester substituted by henzoylc, benzoyl-1-methylstil, cyclopropylmethyl, araphenyl, acronitrile, aralkylsulfonyl, and Formula 0 -, 12 H -CN F 13 __ | . T sm qus each tís H "&quot; â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR1 '' is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, cycloalkyl, phenalkyl, phenyl, wherein R3 is selected from hydrogen, alkyl, hydroxy, haloalkyl, cycloalkyl, polycycloalkyls cycloalkylalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, alkoxy, aralkyl, aryl, aryloxy, arkoxy, alkoxyalkyl, alkylsulfonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkyl and arylsulfanyl groups; wherein each H '&quot; alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxy-toonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, and mercapto; In which each R 2 through R 3 may be an additional acid moiety selected from the acidic moieties of the formula wherein n is a number from zero to two; wherein A is selected from carboxylic acid and carboxylic acid biosorbers selected from the group consisting of the groups selected from the group consisting of H, Wherein each W is independently selected from the oxygen atom, sulfur atom and NR 2 '; 3 &lt; α ... where each of R &quot; '? K '&quot; and R "'is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benoyl; In which each of Kâ, , and R '' 'may be further independently selected from the radical of the formula ## STR4 ## in which each CF' and R '' is independently selected from hydrogen, alkyl, cycloalkyl, halo, halogen, haloalkyl, benzyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups wherein said carboxylic acid isostearate can additionally be selected from heteroejic acid groups consisting of heteroocyclic rings of from four to about nine ring members, the ring contains at least one heteroatom selected from oxygen, sulfur and alkoxy groups, the heterocyclic ring of which may be saturated, fully unsaturated or partially unsaturated, wherein the heterocyclic ring may be attached at a single position selected from R &quot; 1 to RA or may be attached to any two adjacent positions selected from K to R "" as well as to form a ring system condensed with one of the phenyl rings of formula I ' and the amide derivatives, ester and salt of said heterocyclic acidic groups? in which Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenylsulfonyl and aralkylamino, wherein each of R '' to R "'' R 3 and R 4 may be substituted at any substitutable position by one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo , dko, haloalkylamino, alkoxycarbonylamino, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, heteroaryl, arylalkyl, or a tautomer or pharmaceutically acceptable salt thereof. A compound of the formula I wherein R is selected from adamantyl, adamantylalkyl, 3-phenylpropyl, 2-chloro-phenylethyl, 2-hydroxy-2-phenylethyl, carboxylmethyl, carboxymethyl, β-naphthalenylmethyl, β-cyclohexylcarbamoylmethoxycarbonylmethylcarbamoylmethylcarbamoylmethylcarbamoylmethylcarbamoylmethylcarbamoylmethyl ester β-trimethylhexylcarbodiimide, β-methoxycarbonylmethyl, β- C-phenylmethyl &gt; 2-phenyl-2-phenylsethyl, 1-oxobutyls 2- (2-dimethoxyphenyl) -2-oxosyl, γ-phenyl 11-2- (phenylmethoxy) ethoxy, 2- (2 S -dimethylsilyloxy) 2-naphthylmethyl, methoxycarbonylbutyl, ethoxycarbonyl, benzoyl, 1-benzoyl, 1-benzoyl-1-methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkyl and acetonitrile. cycloalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, 1-oxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkyl; ialqui lo carboxyalkyl, aralkyloxyalkenyl, aralkylalkyl, aralkylalkyl, aralkenyl, cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenoxy, alkoxy, alkylcarbonyl, alkoxycarbonyl, arylCyalkyl, aroylDK, alkenylalkyl, alkylthioalkyls, alkylthioalkyls, alkylthioalkyls, alkylthioalkyls, alkylthioalkyls, alkylthioalkyls; alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, halo, isoxyalkyl, acyl, acyl, alkynyl, alkenyl, alkenyl, cyano, nitro, carbocyclic, ? alkylthio-roercapto | and in which each H 'to H " may be an additional acidic part which is independently selected from the following acidic moieties: SH, CH3 SH, C7 H.4 SH, ΡO-, Η2? CONHNHSO3 CF3 CONHOCH3, OPO2 H4, OSO3 H, NHSO3 CF3, CONHOCH2, CH3 CH3, (1) The compound of the formula (I) -CONH, CONHNH-5, CONHNH, OH, CH3 OH, CH2 OH, each one of K'v &quot; , R'y ~ and rC &quot; The compounds of formula (I) are prepared from H, Cl, CN, NO 2, CF 3 SC 2 F 3, CH 2 F 2, CH 2 F 2, CH 2 F 2 CO 2 CH 2, ζ and SO₂C ^;; , Wherein s is selected from 0 to 5 NR; Wherein R 1 'is selected from the group consisting of hydrogen, CH 2, and R 3, R 4, ???????? - ???????? wherein said acidic moiety may be an acidic group? heterocyclic ring attached to any two adjacent passages of the R 'to R "so as to form a ring system fused to one of the phenyl rings of the phenylene moiety of Formula I, said phenyl ring system being silylated from and the esters, are salts of said acidic moieties; or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. 7. A process according to claim 6 which is characterized in that a compound wherein m is a compound selected from the group consisting of adamantyl, adamantylmethyl, dimethylethyl) carbonylmethyl, adamantylpropyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenyl-2-hydroxy-2 " cyclohexyl, ethoxycarbonylmethyl, carbamoylamino, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, phenyl substituted benzoylmethoxyethyl, carbamoyl substituted by phenyl, 3,555-tri-methylbetic, C2- me t ο κ i &gt; 1-benzo [2,1-f] [1,4] diazepin-1-yl] 2- (2,5-dimethoxyphenyl) -2-phenyl-2- (2-phenylmethoxy) ethyl, 2- (2,5-dimethoxyphenyl) -2- 1-benzoyl-1-methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl, and 2-naphthalenylmethyl, 2-naphthalenylmethyl, methoxycarbonylmethyl, is unsubstituted or substituted by hydroxy, methyl, ethyl, n-propyl, isopropyl, sec-butyl, isohufine, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantylmethyl, 3-phenylpropyl, 3-phenylpropyl, 2-amino-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethylcarbonylmethyl, hexylethyl, ethylestrichylmethyl, carboxymethyl, .alpha.- naphthienylmethyl, 2- cyclohexylmethyl, pentyl, cyclopropylmethyl, phenyl substituted carbocyclic, (2-phenylmethoxy) -1- (phenylmethyl) -E-ethenyl, N-benzoyl-2-phenylethyls, N, N-diisobutyl, 2- (2,5-dimethoxyphenyl) (2-oxoethyl) -2-oxoethyl, 2-phenyl 11-2- (phenylmethyl) ethyl) -2- (2,5-dimethoxyphenyl) -2-hydroxy; 3-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted by benzoyl, 1-benzoylmethylamine, i-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propan-2-ol, acetonitrile, phenyl, benzyl, phenyl, benzyl, phenyl, benzyl, cyclohexylmethyl, propylthio, butylthio, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-pentopyloxy, 1,1-dimethoxypropyl, , 1,1-dimethylM-1-pentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoro -pentyl; wherein at least one of E '% E is selected from CO' H ' CuNHNHSu, CFT, OH, 5 R, &lt;? R 'is an acidic group SH, pcu-u, so, h5 ····. CONHNH-, JX. H I H 1 H | 1 N-N 'N z &lt; = - 3va. wherein each of R4 and R4 is independently selected from Cl, CN, NO2, CCUC3 and SCUCF-, or a or a pharmaceutically acceptable salt thereof. 8. A process according to Claim 7, characterized in that a compound wherein m is one wherein R 1 is selected from 2-O- 2-yl-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl-1-phenyl- , 1-naphthenylmethyl, 2-cyclohexyl-ethyl) pentyl, 2-ethoxycarbonylmethylsilyl, phenyl substituted carbostines, methylsulfonylmethylsulfonyl, N, N-dimethylaminophenylmethylsulfonylmethyl, (phenylmethyl) ethenyl 5-benzoyl-2-phenylethyl, 1-Gobutyl, 2- (2-dimethylaminophenyl) -2-oxoethyl G5 2-phenyl-2- (phenylmethyl) ethyl] 255-di-Gly; ifenyl) "hydroxymethyl" 2-naphthalenylmethyl, methoxycarbonylbutylcarbonyloxy substituted benzoyl, 1-naphthylsulfonyl, 4-pentaoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and t-cyanobutyl; wherein R3 is selected from the group consisting of n-propyl, isopropyl-10-n-butyl-9-sec-butyl-isobutyl- 4-methylbutyl-5- tert -butyl; n-pentyl and naphthyl, 1-cyanobutyl * propylphthio, and triphthylthio; Wherein at least one of R5 and R5 is an acidic group selected from the group consisting of hydrogen, C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, CONHNHSO3 CF3 OH,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein each R and R '' ? . A process according to claim 5, characterized in that the compound of formula (I) wherein R 1 is selected from 2-chloro-2- 3 ', 3', 3 ', 3', 3 ', 3', 3 '-ethylenyl, 2-oxo-2', 5 ' 2-hydroxy-t-phenylethyl, i-dimethylethyloxycarbonyloxy, hexyls ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenyl-2-cyclohexylethyl, pentyl, ethoxycarbonylsilystituted by phenylsulfonyl substituted by phenyl; 3-trifluoromethyl-3-trifluoromethyl-3-trifluoromethyl- 1-benzoyl-2-phenyl-1-oxobutyl) -2- (2,5-dimethylphenyl) o- 2-phenyl-ethyl) -2-phenyl-1 - [(phenylmethoxy)] methyl] -2- [5- 2-naphthalenylmethyl-5-methoxycarbonylbutyl] -cyclohexyl-2-naphthalenylmethyl] -2-naphthalenylmethyl] benzoyl-1-methylethyls Î ± -pentanoic acid? R 3 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl-3-isobutyl, 4-methylbutyl-3-cyclopentyl- n-pentyl, 1-cyanobatiloyl, propylthio, butylthio, each of which is optionally substituted with one or more substituents selected from the group consisting of: R? V and R? 5? 1 is hydrogen? Wherein one of R ε R 'is hydrogen and the other of R &quot; and R '& a scidic group selected from CO, or a tautomer thereof or a pharaceutically acceptable salt thereof. 10. A process according to claim 9 for preparing a compound or a pharmaceutically acceptable salt selected from compounds, a group consisting of 4'-E &lt; Dihydro-5-amino-1 H -1,2,4-triazol-4-yl) -methyl] -1,1,1-biphenyl-2-carboxylic acid. Dihydro-2- (2-oxo-2-trifluoromethyl) -1,2,3,4-tetrahydro-2-4- (2 H -1-tetrahydro-1H- 1-yl) -1,2,3,4-tetrahydro-2-methyl-3-phenylpropyl] 4-E2 '- (1H-tetrazol-5-yl) Ethyl-biphenyl-4-sulfonic acid-2 H -3,15-triasol-3-one; 5-tetramethyl-4-dihydro-2- (2-oxo-2-phenylethyl) -4- 1 H-tetrazol-1-yl) -1- 1'-biphenyl-3-4-ylmethyl] -3H-isoxazol-3-one; 5-butyl-2? 4-dihydro-2? 4-ylmethyl) -3H-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (2-methoxyphenyl) 4-triazol-3-one 13-dimethylformyl 3-fluoro-4,5-dihydro-5-oxo-4-oxo- 5-yl) -1-biphenyl-4-ylmethyl] -1H-1,2,4-triazol-5-yl} ; 5H-tetrazol-5-yl) -1,5-biphenyl-1-ylmethyl] -1H- 2-yl) -3,4-dihydro-5-oxo-3,4-dihydro-5-methyl-1 H -tetrazol-5- 3-butyl-4,5-dihydro-5-oxo-4-C2 '- (1H-tetrazol-5-yl) -1,3-dihydro- 1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazol-1-acetic acid; 5-bufcyl-4-yl) -2- [1-naphthalenyl) -4-C2 '- &lt; (1H-t) -1,1'-biphenyl-4-ylmethyl] -3 H -1,2,4-triazol-3-one; 5-butyl-2- &lt; 2-cyclohexyl. methyl) -2P-4-dihydro-4-C2 '- &lt; (4-Triazol-3-yl) -biphenyl-4-ylmethyl] -3H-imidazo [4,5-b] dihydro-2-penyl-4-C2 '- &lt; 1H-tetrazol-5-yl) -1,1'-biphenyl-4-ylmethyl] -3 H -1,2,4-triazol-3-one Acetate C2 -C3 -butyl-4 "S-dihydro-5-oxo-4-C2 '- &lt; 1H-tetrazol-5-yl) thio] -1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazolidin-1-yl] L2-Z3-Butyl-4,5-dihydro-5-oxo-4-12 * - &lt; 1 H -tetrahydrofuran-5-yl) -1,1-biphenyl-4-ylmethyl] -1H-1,2,4-triazolidin-1-phenylethyl] acetic acid; S-butoxy-2,4-dihydro-4-12,12-tetrazol-5-yl) -1,1-biphenyl-4-ylmethyl] -2- (3,5,5- trimethylsilyl) -3H-1,2,4-triazol-3-ones 5-butyl] -2,4-dihydro-2-phenyl-2- (phenylmethyl) -1- (phenylmethyl) -5- 4-ylmethyl] -3H-1,2,4-triazol-3-ones, 2-yl-3-benzoyl-2-phenyl) -5-butyl-2,4-dihydro- 4-C2 '- < tetrahydro-5-yl) -1,3-biphenyl-3-4-ylmethyl-3 H -132,4-triazole-3-one; 5-butyl-2,4-dihydro-2- (4-oxobutyl) -4 - [(1H-tetrazol-5-yl) 1-yl) -2-oxoethyl 3-4-E2 '- (1-H-tetrahydro-1H-imidazol-1-yl) -5-yl) -1H-1,2,4-triazol-3-one; 5-yl] -2,4-dihydro-2-E-2-phenyl-2- (phenylmethoxy) , 4'-biphenyl-4-methyl-4-ylmethyl-3-3H-1S2S4-triazol-3-one 5-butyl-2,4-dihydro-2-E2- , 4-triazal-4-ylmethyl) -3H-1,2,4-triazal-5-yl) -3-hydroxyphenyl] 5apos; -bis-2,4-dihydro-2-C2-naphthalenylmethyl) -4-C2 '- &lt; 1H-tetrazol-5-yl) 1-biphenyl-3-ylmethyl-3H-1,2,4-triazole-3-ones; 1-pentanoate of 3-hutil-455-dihydro-5-DKD-4-E2 '- < 5-yl) Cl, 1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazoles 1-propanoate of (S) -benzoyl] -3-butyl-4,5-dihydro-5-o-4 "[2 '- (1H-tetrazol-5-yl) 3-ylmethyl] -4-ylmethyl] -1H-is2,4-triazepin-2-yl] benzyl] -1-methyl- S-yl) 11? 3-butyl-4,5-dihydro-5-oxo-4-2- (4-methoxyphenyl) -3-methyl- 4-ylmethyl) -1H-1,2,3,4-triazole-4-carboxylic acid: 5-butyl-2-cyclopropylmethyl) -2,4-dihydro- 4-ylmethyl] -3H-1,2,4-triazin-3-one; 5-butyl-2,4-dihydro-2- (3-phenyl- 2E-propenyl} -4-2 '- (1H-tetrazol-5-yl) Cytidine-4-ylmethyl-3 H -1,2,4-triazol-3-one and 1-butyl-4- , 5-dihydro-5-oxo-α-propyl-4- [2 '- [1 H -tetrazol-5-yl] -biphenyl-4-yl] -ethyl, Claim 1, characterized in that 5-butyryl-234-dihydro-β-pentyl-4-2- (1H-tetrazol-5-yl) 4-triazal-3-one The process according to claim 1 for preparing 3β-butyl-2,4-dihydro-2-hexy-4 - [[2 '- (1H-tetrazol-5-yl ) C151 '-biphenyl-3-4-ylmethyl] -3,4-dihydro-4-thiazol-3-one. The title compound was prepared according to claim 1, which is characterized in that 5-butyl-2 '- (2-cyclohexylethyl) -254-dihydro-4- (2'H-tetrazol-5-yl) 4-ylmethyl-3 H -1,2,4-triazolo3,3-a] Process according to claim 1 &amp; The title compound was prepared by preparing 5-butyl-2- (2-cyclopropylmethyl) -2,4-dihydro-4- (2'H-istrazol-1-yl) biphenyl] -4-methyl-3 H -1,2,3,4-triaza-thiazol-3-one, A process according to claim 10 for preparing 3-butyl-4,5-dihydro-5-oxo-4-2- (1 H - tetrahydroisoindol-5-yl) -1,1apos; -phenophenyl 3-4- (methylsulfonyl) -1H-1,2,4- A process according to claim 10 characterized in that 3-butyl-4,5-dihydro-5-oxo-4-E2 - (1H-tetrazol-5-yl) ethyl 1-acetate 1) 11? A process according to claim 10 characterized in that the 3-butynyl-4 ', 3'-dihydro-3-methyl-1-pentanesulfonic acid 1-methyl- -5-CKO-4- [2 '- (1H-tetrazol-5-yl) -1'-biphenyl] -4-ylmethyl] -1 H -1,2,4-triazole, The process of claim 10 characterized by preparing 3-fluoro-4,5-dihydro-5-oxo-4-2- (1H-tetrazol-5-yl) A process according to claim 10 characterized in that 5-butyl-1,2,4-dihydro-2-methyl-1,2,4-triazol-1-pentanoic acid 1-yl) -1'-biphenyl-4-ylmethyl] -3 H -1,2,4-triazol-3-one hydrochloride A process according to claim 10, characterized in that 5-butyl-4,4-dihydro-2- (2-α-furyl) -2- © ti! ) 4-C2- (1H-tetrazol-5-yl) -1H-imidazol-3-yl] methyl] -3 H -1,2,4-triazole -3-one A compound according to claim 10 characterized in that 5-butyl-2,4-dihydro-2- (2-hydroxy-2-phenylethyl) 4-ylmethyl-3 H -1 -1,2,3,4-tetrahydroisoquinoline-4-yl] -1-hydroxy-5- for the preparation of a pharmaceutical composition comprising mixing a pharmaceutically acceptable amount of an angiotensin II antagonist compound and a pharmaceutically acceptable carrier or diluent (s), said antagonist compound being selected from the compounds of formula (I) wherein m is a number selected from one to four inclusive; wherein R A is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-benzo-2-phenylethyl; 2-hydroxy-2-phenylethyl and 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyloxy-5-carboxymethyl naphthalenylmethyl, 2-cyclohexylmethylphenyl, pentymethylcarbamoylmethyl, phenyl substituted carbymethylmethyl, 3,5,5-trimethyl- % 2- en, i j. methoxyphenyl) -1-benzoyl-2-naphthyl. i -q x ohu ti 1 or 5 2- < 2 5 5 d imeto x i f sn l1o &gt; (2-oxoethyl) -2-oxoethyl] -2-phenylethyl] -2-naphthalenyl] -2- (2-methoxyphenyl) -2- methylthiocarbonylethyl) ethoxycarbonylsilyl substituted by benzylmethyl benzoylmethylethylic acid; aralkylthiocarbonyl, aralkothiocarbonyl, aralkylthiocarbonyl, aralkylsulfonyl, aralkylsulfonyl, and radicals of the formula X may be prepared from the group consisting of hydrogen, alkyl, arylalkylaminocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, X is an oxygen or sulfur atom; Wherein each of R1 and R2 is independently selected from hydrogen, cycloalkyl, cyanohydroxyalkyl, cycloalkylalkylC1-6 alkoxyalkyl, aralkyl, and aryl, and wherein H and R taken together may form a heterocyclic group having three to five ring member salts including the nitrogen atom of said asino or amido radical, the heteroaryl group of which may additionally contain one or more heteroatoms as ring members selected from nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; 1 "Γ where each of R &quot; and K '&quot; taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical whose aromatic beterocyclic group may additionally contain one or more heteroatom salts as well as ring atoms selected from of oxygen atoms? sulfur, with the proviso that * | Wherein X is oxygen atom, then R 'and R' '' '' can not be selected from hydrogen and alkylop, each of up to R 2 'being independently selected at R 14 X R10 X / -NR6, R6, R6, R6, R6, From hydrogen ,; alkyl, hydroxyalkyl, halo, haloalkyl, heteroalkyl, cycloalkylalkyl, polycycloalkyl, ραϊ icycloalkyl, aralkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carfooxyalkyl, alkoxycarbonylalkoxyalkyl, carbooxyalkoxyalkyl, aralkoxyalkyl, aroylalkyl, aralkoxyalkyl, aralkoxy, aralkoxy, aralkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxy, aroyloxyalkyl, aryloxy, aryloxycarbonyl, Alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arxylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, thiocarbonyl, arylthiothiocarbonyl, aralkylthio, araalkylcarbonyl, aralkylcarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulphinyl, alkylsulfonyl, aralkylsulphenyl, aralkylsulphonyl, arylsulphinyl, arylsulphonyl, heteroaryl having one or more ring atoms hydrolyzed from oxygen, sulfur to nitrogen, and amino and amido radicals of the formula wherein X is an oxygen atom or sulfur atom; 14, 15, 16, 16, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, 17, cycloalkylalkyl, C 1 -C 10 cycloalkylalkyl, C 1 -C 10 cycloalkylalkyl, aralkyl and aryl, and R 5 is taken together. taken acn set b R * '&quot; to R.sup.2 taken together may comprise a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which beterocyclic group may contain one or more heteroatoms individually as ring moieties selected from oxygen atoms * nitrogen & sulfur and which heterocyclic group may be saturated or otherwise unsaturated in which each of R5 and R4 taken together; each of R &quot; and R1 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino acid radical and which aromatic heterocyclic group may additionally contain one or more heteroatoms as well as ring atoms selected from of oxygen * nitrogen and sulfur? s in which each of R &quot; up to R3 may also be independently selected from hydroxy and acidic moieties of the ferulae wherein n is a number selected from zero to three, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl * cycloalkyl * cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl, and hsteroaryl groups having one or more ring atoms selected from oxygen, sulfur and steroid atoms and wherein any of the foregoing R to R ', groups V and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl. haloalkyl, halo, oxo-alkoxy, aryloxy, s-arkoxy, aralkylthio, alkoxyalkyl, cycloalkyl- cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkyloxycarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxy, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl, hatroaryl, having one or more ring atoms selected from oxygen atoms, alkylsulfinyl, arylsulfinyl, arylsulfinyl, arylsulfinyl, sulfur, and amido radicals of the formula V 1, wherein X is an oxygen atom or sulfur atom -> g) wherein R &quot; is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, in which I) is selected from an oxygen atom and a sulfur atom and is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl- V? R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carhoxyl, alkylsulfonyl, alkylsulfonyl, arylsulfinyl, arxlsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl groups. , 21, 22, 23, 24, 26-227. . ,. and wherein the alkyl moiety is independently selected from amino to the amido radicals of the formula: and wherein R 1, R 2, R 3, in which X is an oxygen atom or a sulfur atom, wherein each R '', R '' '', R '&quot;' ' And R3 is independently selected from hydrogen, alkyl, cycloalkyl. cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl, and aryl, and wherein each taken together and each of R4 taken together may form a five-membered heterocyclic group to the seven ring members including the SKa atom of said amino or amido radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from the oxygen, the halide and sulfur atoms and whose group heterocyclic may be saturated or partially unsaturated in which each R '' '' '' R '' - '' is taken together at each R '' * '' and R &quot; '' taken together may form an aromatic heterocyclic group having five ring members including the atom of the said amino or amido radical whose aromatic heterocyclic group may additionally contain one or more heteroatoms as an anal atom selected from oxygen, nitrogen and soko-f rep or a tautomer thereof or a pharmaceutically acceptable salt thereof, the amount of the active ingredient being from about 1 to 25 mg for oral administration of 1 to 10 mg for administration by injection. according to claim 22 characterized in that m is 5 or 6, R 6 is selected from polycycloalkyl, polycycloalkylalkyl, or 3-phenylpropyl; 2-oKG-2-phenylsilyl-2-hydroxy-2-phenylstyloxy-1-diflethylethylcarbonyloxymethyl, ethyloxycarbonylmethylcarbamoyl, naphthalenylmethyl, 2-cyclohexylmethyl, phenylmethylcarbamoyl-2-phenylethylcarbamoyl-2-phenylethylcarbamoyl-2-phenylmethylcarbamoyl- 5-Ethenyl, 2-phenyl-2- (phenylmethoxy) ethyl-2- (3,5-dimethylphenyl) -2-methyl- , 2- (2-dimethoxyphenyl) -2-hydroxyethyl] -2-naphthalenemethyl-5-methoxycarbodiimide. 1-benzoyl-1-methylethyl acrylate, 1-penta-acetic acid, cyclopropylmethyl acrylonitrile, cyclobutyl acrylonitrile, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarpayl, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylsulfonyl radicals of formula X Wherein X is an oxygen atom or a sulfur atom; Wherein each of R &quot; alkyl, arylalkyl and aryl, with the proviso that when X is an oxygen atom, then R 2 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryloxyalkyl, aralkyl and aryl, â € ƒâ € ƒâ € ƒR '' can not be selected from hydrogen and alkyls. by being selected from hxdrogenxo, alkyl, hydroxy, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, acyloxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, 1-carbonyl, 1-chlorobutyl, arylsulfonyl, cyclohexyl, cyclohexyl, alkenyl, cycloalkenyl, alkynylthiocarbonylthio, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylthiocarbonylthio, arylthiocarbonyloxy, arylthiocarbonyl, thioethiocarbonyl, thiocarbonyloxy, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonyl, mercapto, alkylsulfonyloxy, arylsulfonyloxy, arylsulfonyl and heteroaryl groups having one or more ring atoms selected from the of oxygen, sulfur s aeotos &quot; for each of -R- 'to H &quot; R3 is selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, naloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyl, aralkyl, aryl, aryl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkynyl, cycloalkenyl, alkynyl, cycloalkynyl , cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyldiyl, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarhanyloxy, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylcarbonylthio aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkyl-iiocaroonylthio, mercapto, alkylsulfonium, aralkylsulfonyl and arylsulfforyl, and amino and amido radicals of the formula R14. X is an oxygen atom or a sulfur atom wherein each of R R 'and R' 'is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl and the like. 1 Ί and wherein each R '&quot; up to R &quot; * may be further independently selected from acidic moieties of the formula wherein n is a number selected from: up to and including three; wherein A is an acidic group selected from [1S- The amide, ester and salt derivatives of said acidic moieties are selected from the group consisting of hydrogen, sulfur, phosphorus and carbon atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and amide, ester and salt derivatives of said acidic moieties in which is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkynyl, silyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and acyl atoms, and wherein any of the above groups R through R ', Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, , aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl alkylthio, alkylthio-carhonyl, and amino and amido radicals of the formula X in which X is an oxygen atom or sulfur atom, C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, Wherein R 'is selected from hydrogen, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR'-N / R wherein D is selected from the oxygen atom and the sulfur atom and is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; Wherein each of R '', R &quot; &quot; ', H' 5 R ** ', R "and R *' ' &amp; independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyanoalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl, arylop, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof. The process according to claim 3 characterized in that R is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-chloro-2-phenylethyl, 4-hydroxy- 2-phenylethyl) -1H-dimethylsilyloxycarbonyl] 2-phenylmethoxy) -1-phenylmethylol, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 2-cyclohexylethyl, 5-ethoxycarbonylsulfonyl, -E-stenyl. 2-phenyl-2-phenylethyl] -1-oxobutyl] -2- (2-dimethyl) methyl] -2- i) ethyl 5-25- (5-dimethoxyphenyl) -2-hydrazinoethylphenyl. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10, 10, 10, 10, 10, 10, ϊ 1 and ϊ is substituted by b 1 -cycloalkyl-1-methyl-ethyl, i-pentanoic acid, cyclopropylmethyl, aralkersyl, acetonitrile, cycloalkenyl, or mercaptocarbonyl; cycloalkyl, aralkylsulfonyl and amido radicals of the formula i / -CM wherein each of R3 and R4 is selected from the group consisting of cycloalkyl, hydroxy, alkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; R 2 is selected from hydrogen, alkyl, hydroxy-alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polyethylenealkylsilyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxy-alkylsiloxy, carboxyalkoxyalkyl, alkoxycarbonyl, aralkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, aryloxyalkyl, aryloxyalkyl, aryloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkoxy, aralkoxy, aralkoxy, aralkoxy, aralkoxy, aralkoxy, arylalkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, and arylsulfonyls for each of Hâ,,O; R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano , nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, mercapto, alkylthio, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of formula which is one of, R ^ J, Γι '&quot; R 1 and R 2 'is independently selected from hydrogen, alkyl, cycloalkyl, cis-amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, and R 11 and R 11 may be an acidic acid additionally selected independently from acidic moieties of the formula wherein n is a number selected from up to three inclusive, wherein A is selected from carboxylic acid and carboxylic acid bioisosters selected from - and -PH-NH- w w n! *. Wherein each W is independently selected from oxygen atom, sulfur atom and R ° °°, wherein each R 'is selected from the group consisting of hydrogen, R 'is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, has 1 to 1 carbon atoms. cycloalkyl, cycloalkylalkyl, aryl, and aralkyl groups in which each of R434 is selected from the group consisting of hydrogen, halogen, may be additionally from the amino radical of the R 4 'wherein R 4 is each independently selected from hydrogen, alkyl, cycloalkyl, hydrosyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and in &lt; 4θ R &quot; taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may have one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated, wherein R 'and R 1 taken together may form an aromatic heterocyclic group having five ring members including nitrogen atom of said amino radical and which aromatic heterocyclic group may additionally contain one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms. 7 ': where each of R' &quot; &quot; and R pode may be independently selected from hydroxy, alkoxy, alkylthio, aryloxy, aryl, aralkylthio and aralkoxy, and the amide, ester and salt derivatives of said acyloxy groups, wherein said bioisosterase is carboxylic acid may additionally be selected from acidic heterocyclic groups consisting of esterifying rings of from four to about one ring members, which heterocyclic ring contains at least one heteroatom selected from Oxygene and sulfur atoms, which the heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached in a single position / is selected from K &quot; to R '' or may be attached to any two adjacent positions selected from R '&quot;' to R "so as to form a ring system fused to one of the phenyl rings of formula Is and the amide, ester derivatives to said bipycyclic sodium groups? wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and aryl; | IO XaIi "&gt; and wherein any of the foregoing R to R 'and R "' to R", Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo alkoxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxy, cyano, nitro, alkylsulfonyl, baloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkyl thioalkylthiocarbonyl, amino and amido radicals of formula XX -N- wherein X is selected from the group consisting of an oxygen atom or a sulfur atom wherein H is selected from hydrogen, alkyl, cyloalkyl, cycloalkylalkyl, aralkyl, aryl, and wherein D is selected from an oxygen atom and a sulfur atom, wherein it is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; v 1 7 &quot; *? wherein each of R23, R24, R24, R2, 2 &quot;? and R is independently selected from hydrogen, alkyl, cycloalkyl, cyanohydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfonyl, haloalkylsulfonyl, aralkyl, aryl, or a thiouromethane or a pharmaceutically acceptable salt thereof acceptable. 25. The process of claim 24 wherein R ser is selected from the group consisting of polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy 2-phenylethyl, t-1-dimethylethyloxycarbonylethyl, hexyl, eioxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, substituted phenyl, substituted phenylsulfonyloxyethyl, 355.5 &quot; trymethylsilyl, 2-phenylmethylphenylmethyl &lt; / RTI &gt; E-ethynyl, 1-benzoyl-2-phenylethyl] -butyl] -2- (2,2-dimethylsilyloxy) -2-methylamino] -2- (2-methoxyphenyl) (2S-dimethyl) phenyl) -2-hydroxyethylC2 -naphthalenesylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl, mercaptocarbonyl or aralkylsulfonyl radicals to radicals of the formula wherein each of Râ, "is independently selected from cycloalkyl, cycloalkyl, monoalkylaminoplyl, dialkyl -aminoalkylaminoalkyl, cycloalkylalkyl, alkynyalkyl, aralkyl, arylalkyl, arylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, aralkylalkyl, carboxyalkoxyalkyl, aralkoxyalkyl, are alkyl, aralkox haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aralkoxy, aryl, aralkoxy, alkyloxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, carbonyloxy, alkylcarbonyloxy and alkylthio, aryl. (aryl) thio, alkylsulfonyl, aralkylsulfonyl, and arylsulfonyls, each of H 'to R' '' is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, arylalkyl, aryl, aroyl, arxloxy, aralkoxy, alkyloxycarbonyl, alkylcarbonyl, alkynyloxycarbonylopentenylO, cycloalkenyl, cyano, nitro, carboxy, alkylthio, aralkylthio, mercaptopyloxy, for each R3 to R4 may be an acidic moiety independently selected from the following acidic moieties of formula wherein n is a number from zero to t inclusive ? in which A is selected from carboxylic acid and carboxylic acid biosynthesis is prepared from H-OH, -SH, -L · 54, W-C-WH, S-WH, -S-WH W Í! and -F-WH W WR '&quot; in which each W is independently selected? from the atom - μg of μg, sulfur atom and NR &quot; s &quot; &quot; &quot; &quot; ) where each H &quot; R "is independently selected from hydrogen, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyls; and R qu is each independently selected from the group consisting of hydrogen, of IT '* and R w' may be independently selected from an amino acid radical of formula 39 of the alkyl, cycloalkyl, hydroxyalkyl? haloalkyl-C 1-6 cycloalkylalkyl, alkynyalkyl, aralkyl, aryl, and wherein R 39 taken together may form a heterocyclic group having from five to seven ring members including the nitrogen atom of said ring having the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms? atoms of sulfur and which heterocyclic group may be saturated or partially unsaturated in which R 'and R' taken together may form an aromatic heterocyclic group having five ring members including nitrogen atom of the wherein said aromatic heterocyclic group may further contain one or more heteroatoms as ring atoms selected from the nitrogen and sulfur atoms and the amide, ester and salt derivatives of said aromatic heterocyclic groups, CGS S wherein said carboxylic acid bioisostere can additionally be selected from heterocyclic acidic groups consisting of heterocyclic rings of from four to about nine ring members5 whose ring contains at least one heterotomo; selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from H '&quot; to Ri4 or may be attached to any two adjacent -t1 positions selected from R &quot; to R &quot; &quot; to form a ring system condensed with one of the phenyl rings of formula Is and the amide, ester and salt derivatives of said acidic heterocyclic groups wherein Y is a spacer group independently selected from or alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyls;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein each of Râ, groups selected from hydroxy, halo, haloalkyl, acyloxycarbonyl, cyano, nitro, alkylsulfonyl, D-haloalkylsulfonyl, aryl, aralkyl, alkoxy aryloxy, aralkoxy of a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. The process according to claim 25, be selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylstilcxycarbonylethyl, Hsysilo, stoxycarbonyimethyl, carboxymethyl, (2-phenylmethoxy) -1- (phenylmethyl) -E-ethenyl, 1-benzoyl-2-cyclohexyl, 2-cyclohexyl, 2-cyclohexyl, 2-cyclohexyl, phenyl-ethyl, i-oxobutyl, 2 '' - (2,5-dimethoxyphenyl) -2-oxoethyl, 2-phenyl-2-methoxyethoxy) ethyl, -dimethylphenyl)] - 2-hydroxyethyl α 2-naphthenylcarbonylethyl, cyclohexylmethyl, aralkyl, acetanitrile, aralkylsulphonyl, and amido radicals of the formula ## STR4 ## wherein R 1, Wherein each of cycloalkyl, cyano, phenalkyl and phenyl is independently selected from amino, hydroxyalkyl, alkoxyalkyl, and R is selected from hydrogen, alkyl, Hydroxycarboxylalkyl, alkoxycarbonylalkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkylalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkylalkyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyskyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl for each of R "to R"; alkylsulfonyl, alkoxyalkyl, alkoxy, alkoxyalkyl, alkoxy, alkoxyalkyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, alkoxyalkyl, s mercapto; and each R ° to R11 may be an acidic portion further selected independently from acidic moieties in which n is a number selected from zero to 1 inclusive in which A is selected. from thistle acid; carboxylic acid bioisosterols selected from H-1 H, -SH, -NRW '; W W n 51 -C-WH, -S-WH, -S ..... WH :;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒW3 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein each $ is independently selected from 7R atom of methyl, wherein each R3 is hydrogen or C1-4 alkyl; and R is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl with benzyl, wherein each of R³ and may be additionally selected independently from the amino radical of formula / \ &quot; TISIS 4.3 where each R &quot; ' and R 2 is optionally selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, henyl, phenyl and the amide, ester and salt derivatives of said acidic groups rather that said carboxylic acid bioisostere may additionally be selected from heterocyclic acidic groups consisting of heterocyclic rings of from about four to about nine ring members whose ring contains at least one heteroatom selected from oxygen, sulfur and acetal, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached in a single position selected from R '&quot; to R-1 &quot; or may be attached to any two adjacent motions selected from R'J to ΡΪΑ " as well as to form a ring system condensed with one of the phenyl rings of the formula Is and the ester and amide derivatives of said acetic acid groups, in which Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkylopiol. &quot; , Where each of R to R &quot; May be substituted at any substitutable position by one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, haloalkyl, haloalkyl, , cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, araalkyl, alkoxy, aryloxy and aralkoxy groups or a pharmaceutically acceptable tautomer or a pharmaceutically acceptable salt thereof. The process according to claim 2, R 2 is selected from adamantyl, adamantylalkyl, 3-phenylpropyl * 2-oxo-phenylethyl, 2-hydroxy-2-phenethyl, 3 - [(dimethyl) ethyl] carbonyl] 1-naphthalenylmethyl, 2-cyclohexyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, carboxymethylmethyl, 1-naphthalenylmethyl, 2-cyclohexylmethyl, ethoxycarbanylmethoxystilide substituted by phenylcarbonyl substituted by methyl, 3,5,5-trimethylhexy, in 1 ms ms) ~ E ~~ s? 1-benzoyl-2-phenylethyl, 1-benzoyl-2-naphthyl, 2-aminoethyl, 2-phenyl- 2- &lt; (2,5-dimethylaminophenyl) -2-hydroxyethyl 2-naphthalenemethyl, benzoylcarbonylbutyl, ethoxycarbonylethyl substituted by benzyl, 1-benzoyl, 1-benzoyl- 1-methylpentanoic acid, cyclopentylmethyl, arylsynyl and acetonitrile, and which R &quot; is selected from alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, adamantyl, adamylaminoalkyl, aralkylalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkylalkyl, aralkylalkynyl, aralkylalkyl, aralkoxyalkyl, aralkoxy, aralkenyl, cyanoalkyl , haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalcoK1, alkoxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, aryloxyalkyl, aroyl oxyalkyl, alkenyl, cycloalkenyl, alkenyl, alkylthio, phtheno and phenalkylthio; for each of up to κ is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and in-part for each R ° to R'11 may be an acidic part further indecently depected from acidic moieties consisting of CO 2 H, CH 2 CH 2, CH 2 CH, SH 2, CH 2 CH 2, CH 2 CH , NHSO2 CF6, NHSO2 C6 F5, SO3 H, C-ONHNH2, CONHNHSO3 CF3, COOHH2 O, COOHH2 O, CONHCF2, OH, CH3 OH, COHAOH, OPO3, OSO-, H, JL. Eur-lex.europa.eu eur-lex.europa.eu 2-cyclohexylethyl, pentyl-3-ethoxycarbonylmethoxyethyl substituted with phenyl substituted phenyl-oxymethoxythiophene, 3,555,5-trimethylhexyloxy- (S -phenylmethoxy) -1- (phenylmethyl) -β-ethoxycarbonylmethyl- 1-benzoyl-2-naphthyl) -4-methylbut-2- (2-methoxyphenyl) -2-oxoethyl] 2-phenyl-2-phenylphenyloxy) -2-hydroxy-2-naphthalenemethyl-methoxycarbonyl-4-ethoxy-ethylsulfonyl-ethyl ester, and 1-benzoyl-1-ethylhexylamine, 1-pentanoic acid, 3-phenyl-2E-propenyl and acetonitrilon by R-4 &quot; is prepared from hydroxymethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isopropyl, n-pentyl, isopentyl, naphthyl, adamanthem, adamantriftyl, camphor, adamant. 3-phenylpropyl, 2-acetyl-2-phenylethyl, 2-hydroxy-2-phenylethyl, 5-difluylethylcarbamylmethyl, hexyl, ethoxycarbonylphenyl, carboxymethyl, 1-naphthalenylmethyl), 2-cyclohexylimethyl, pentyl- ethoxycarbonyl-2-phenylmethoxy) -ethoxyethyl) -ethoxyethoxyethyl substituted with phenyl] -3,5,5-trimethoxyethyl, 2-phenylmethoxy) -1- (phenyl-ethyl) 2-phenylsethyl] -5-oxobutyl, 2- (2-dimethylphenethyl) -2-oxoethyl, 2-phenyl-2-phenylmethoxy) ethyl, 2- (2,5-dimethoxyphenyl) -2-hydroxyethyl 2-naphthalen-1-one 5-benzoyl substituted ethoxycarbonylethyl; benzoyl-1-phthylethyl] -1-pentanoic acid and cyclopropylmethyl- 3-phenylene-2-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, i-oxoethyl-1-oxopropyl, · -Οκορβηϋ1ο, í? dimethoxypropyl, 1,4-dimethoxybutyl, 1,3-difethoxyethynyl, hydroxyalkyl, difluoromethyl, 151-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 15β-difluoropentyl. And wherein at least one of R '' '', R '' ', R' 'and R' '' is an acyclic group selected from C4-C7-C6 alkyl; SQ-H, 20NHNH · -, CNNHNHSO CF CF ,, OH, OH, H H H 4 ··?  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein each R3 and R4 is independently selected from Cl, and SO 2 CF 3, or a tautomer or a pharmaceutically acceptable salt thereof. 29. A process according to claim 28 characterized in that it is a compound of formula 2-hydroxy-1-phenylethyl; i 1-dimethylethyloxycarbonylheteryl, hexyl, ethoxycarbonylmethyl, carboxymethyl, naphthalenylmethyl, 2-cyclohexylethyl, phenyl substituted pentyl, ethoxycarbonylmethoxyethylG, phenyl substituted carbymethyl] ethyl, 3,5,5-trimethylhexyl, phenylmethoxy) -Î ± - &lt; (2-methoxyphenyl) -2-oxoethyl 2-phenyl-2-phenyl-2-methoxy) ethyl] -2-phenylethyl] -2-phenylethyl] - (25-dimethoxyphenyl) -2-hydroxy-2-naphthalen-1-yl] I'm fine, I'm fine and denzoyl substituted benzyl 1-ethyl. benzoyl-1-naphthylethyl- i-butanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and 1-cyano-butyl wherein R * &quot; is selected from ethyl, n-propyl isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 1-cyanobutylpropylthio and butylthio; acr that at least one of the Rfs. R f and R 'and R' is an acidic group selected from C, HH SH, CH₂ and CH₂, CH₂, CH₂, CH₂, CH₂, CH₂, CH₂, CH₂, CH₂, CH₂; The compound of formula (I) 4 &quot; in which each H &quot; and R &quot; are more preferably selected from Cl, CN, NO 2, CF 3, CO 2 CH 2, SO 2, CF 3, or a tautomer thereof with a pharmaceutically acceptable salt thereof. m ssr um5 for R 'to be selected? from d-2-Oko --- 2 ~ < tricyclo [3.3.1] heptadec-2-yl) ethyl, 3-phenylpropyl; 2-oko-2-phenylethyl, 2-hydroxy-2 "-phenylethyl] b-naphthalenylmethyl, 2-cyclohexylsethyl, methyl, substituted phenyl, substituted phenyl, 3,5,5-trimethoxy, benzimidazolylmethyl, carboxymethyl, benzimidazolylmethyl, 2-phenylmethoxy. ) - (phenylsulfonyl) -E-ethenyl, i-benzyl-2-phenylethyl, 1-benzoyl, (2 s S-dimotoxins in 1 or 2) - 2-oxoethyl or 2-phenyl-2 (S) -methyl-3 2- &lt; Ξ 5-methyl-2-naphthalenylmethyl, ethoxycarbonylbutyl, ethoxycarbonyl-ethyl-substituted-2-naphthalenylmethyl, 1-benzoyl-1-methylethyl, 1-pentanoic acid and cyclopropylmethyl- wherein R1 is selected from cyano, n-propyl, isopropyl, n-butyl, sec-butyl, n-propyl, n-propyl, n-propyl, , isobutyl, 4-methylbutyls, n-perryl, 1-cyanobutyl, propylthio-butylthio. wherein each of R ", R ', k' &quot; ? R ', R &quot;, K and R &quot; is hydrogen; = C? The am one of R '&quot; b H &quot; b is hydrogen and the other of R 2 is R 3 is an acidic group selected from CCUH and N, N- or yours. tautomer or one of them. A process according to claim 3, wherein said antagonist compound is selected from compounds, and pharmaceutically acceptable salts thereof, from the group consisting of 4- ácido. -1,4,5-dihydro-5-α-1H-1,2,4-triazol-4-yl) -methyl] -benzophenyl] -2-carboxylic acid 5-butyl- 2-yl-2-trifluoromethyl-2-trifluoromethyl-2-trifluoromethylphenyl) -6- (2-methoxy- biphenyl 3-4'-ylmethyl-3 H -1,2,4-tetrazol-S-one; 5-butyl-5- (4-dihydro-2 '- (3-phenylpropyl) -4- (2' - (1H-tetrazol-5-yl) 4-ylmethyl] -3 H -1,2,4-triazol-3-yl] 2-Phenylethyl) -4- [2 '- (1H-tetrazol-5-yl) -1H-imidazol-4-ylmethyl] -3H- 4-dihydro-2-ethyl-2-methyl-4- (2-hydroxyethyl) -4- 3-ylmethyl] -3H-1S-2S-pyridazin-1-one 1apos; -diphenylmethyl ester 3-methyl-4-methyl-3- , 5-dihydro-5-a-4-C2 '- (1H-tetrazol-5-yl) -1,1-biphenyl-4-ylmethyl) -1H-1,2,4-triazole; 2-heyl-4-C2 '- (1H-tetrazol-5-yl) -1H-imidazol-2-ylmethyl ester. 3-Butyl-4 ', 5-dihydro-5-oxo-4-C2' - [1 H -tetrahydro-3- Zol-5-yl &gt; 111, 1'-biphenyl-4-ylmethyl] -1H-imidazol-3-yl] -4,5-dihydro-5-GKa-4- 1 H -tetrazol-5-yl) -1,3-biphenyl-3-4-ylmethyl] -1 H -isoxazol-1-acetic acid; 5-butyl-254, &quot; dibor-2-yl-naphthalenylmethyl) -4-C2 ' -1H-tetrazol-5-yl) -1,1,1-biphenyl-4-ylmethyl] -3H-1,2,4-triazol-3-one 5-butyl 2 ··· (2- dihydro-4 - [(2-methoxyphenyl) -1H-indol-1-yl] -biphenyl-3- 4-triazcosl-3-one 5-butyl] -2,4-dihydro-2-penty-4-C2-yl] -1H-tetrazol-5-yl] -1,2-biphenyl] -4- 1? 2 ? (4-methoxy-4-methoxy-4-methoxy-4-methoxy-3- (1H-tetrazol-5-yl) 1'-biphenyl-4-ylmethyl-1H-1 = 2? 4-triazol-1-yl] -1- (naphthyl) C 2 -C 3 -acetyl-butyl-4-5-dihydro-4-methyl-4-methyl-3- (4-methoxy- 5-Butyl-2,4-dihydro-4-E2 -1H-tetrasuccin-5-yl) N, N'-biphenyl-4-yl] 11H-1,2,4-triazal-3-one 5-butoxy-1,2,4-dihydro-2- (3,5-dimethyl- (2-Methoxy-1-methylphenyl) -E-ethenyl] -3-4- [2 '- (1H-tetrazal-5-yl) -biphenyl-4-ylmethyl] -3 H -1,2,3,4-tetrahydronaphthalene-2-carboxylate , 4-dihydro-4-C2 '-ylH-tetrazol-5-yl) -1,1'-biphenyl-3-ylmethyl] -3 H -1,2,4-triazal-3-one 4-ylmethyl) -1H-tetrazol-5-yl) -1,1'-biphenyl-2-4-ylmethyl] -3H- 1,2,4-triazol-3-one 5-butyl] -2,4-dihydro-2-E2- (2,5-dimethoxyphenyl) -2-oxoethyl] -4-E2'-Cl-H-tetrazol-S 3-yl) -3,4H-1,2,4-triazol-3-one S-butyl-2,4-dihydro-2-C2- phenyl- &lt; 3- [2- (2- : ¹H-tetrac-5-yl &gt; Cl, 1'-biphenyl-4-methyl-4-ylmethyl-3 H -1,2,4-triazol-3-one p 5-butoxy-2,4-dihydro-2- ; 2,5-dimethoxyphenyl) -2-hydroxyethyl] -4-C-2 '- (1H-tetrazol-5-yl) -1H-imidazolyl] -3H-1,2,4-triazol-3- 2-naphthalenylmethoxy] -4-E2 '- (1H-tetrazol-5-yl) -1,1'-biphenyl-3-4- 3-ylmethyl-3 H -indole-2,4-dihydroazetidin-3-one 1-pentanoate, methyl 3-butyl-4,5- 1-trazol-5-yl &gt; Cl, N'-biphenyl-4-ylmethyl] -1H-1,2,4-triazole; (1 H-tetrazal-5-yl) -1apos; -biphenyl-3-carboxylic acid ethyl ester -4-ylmethyl] -1H-1,2,4-triazole-1-benzyl-1-methylethyl) -b-butyl-12-dihydro-4-E2H-tetrazol- 5-yl) -1H-imidazo [3,1-b] [1,4] diazabicyclo [3.3.0] heptane-3-carboxylic acid; a-4- [2 '- (1H-tetrazol-5-yl) (R) -biphenyl-4-ylmethyl] | 5-butyl (cyclopropylmethyl) -2,4-dihydro-4-C2 '- (1H-tetrazol-5-yl) 1-biphenyl-13-yl] methyl] -3H-1,2,3,4-triazin-3-one 5-butyl-4,5-dihydro-2- (3-phenoxy- 2 '- (1H-tetrazol-5-yl) -1,5-biphenyl-3-4-11-methyl-3 H -1,2,4-triazal-3-dien-1-butyl-4. Dihydro-5-oxo-α-propyl-1-4- (2 H -1,2-tstrazol-5-yl) A therapeutic method for the treatment of circulatory disorders such as cardiovascular disorders such as congestive heart failure, hypertension, and hypertension. -zone for understanding the administration to a patient with those referred to | disorders of a therapeutically effective amount of about 3 æg / kg body weight in oral administrations & about 1 g to 1 mg / kg body weight for administration by injection into an active compound of the formula I prepared according to claim 1, where m is a number selected from one to four, inclusive; in which R 1 is selected from polycycloalkyl, polycyano-1-alkyl, 1-cyclopropylmethyl, 2-hydroxy-2-propenyl, 2-phenylethyl, 1,1-dimethylethylcarbonylethyl, hexyl, ethoxycarbonylmethylcarbamoylmethyl, carbamimethyl, 1-naphthalenylmethyl, 2-cyclohexyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carbonyldiethyl-substituted phenyl, 3,555 &quot; -trimetylmethyl &lt; 2-phenylmethoxyphenylmethyl &gt; What's up? bensoii-2-phenylethyl; 2-oxo-2- (2,5-dimethoxyphenyl) -2-oxoethyl, 2-phenyl-2- (2-naphthyl) -2-naphtho-1-methyl-methoxycarbonyl-butyloxy ethoxycarbonylethyl substituted with bensoyl, 1-benzoyl 1-methylamino, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, eicloaicenyl, aralkylcarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl, arthithiothioconsulfonyl, aralkylthiocarbonyl, alkylthiocarbonyl, aralkylsulfonyl, aralkylsulfonyl and radicals of the formula X 1 X 1 Τ. wherein each of R 1 'and R 2' are independently selected from hydrogen, alkyl, cycloalkyl, hydroxycyanoalkyl, cycloalkylalkyl, steroalkylalkyl, aralkyl and aryl, and in each case, ; T that h ** &quot; and R &quot; taken together may form a 5- to 7-membered ring hetero-cyclic group including the asotoxic atom of said amino or amido radical and which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated in which each of R3 and R4 is hydrogen, taken together may form an aromatic heterocyclic ring having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may additionally contain one or more heteroatoms as well as ring atoms selected from oxygen atoms, nitrogen and sulfur, with the proviso that when R1 is oxygen atom, R3 and R4 are hydrogen. can not be selected from hydrogen and C1-4 alkyl; to K "is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-.beta.-aralkyl. alkoxycarbonylalkyl * carboxyalkyl * alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl * aralkoxyalkyl * aralkoxyalkyl * aralkoxyalkyl * aralkenyl * cyanoalkyl * formyl * alkoxy * aralkyl * aryl * aryl * aryloxy * aralkoxycarbonyl * alkoxyalkyl * alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, cycloalkenyl, alkynyl, cyano, nitro, carfooxyloxy, aroyloxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, monobutyl, thiocarbonyl, alkoxycarbonyloxy, alkylthiocarbonyl, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alquiltiotiocarbonilo, alquiltiotiocarboniitio, arylthio, arilti - ocarbonilo, arilcarbaniltia9 ariItiocarfooniIoxi, ariltiocarbonil-uncle, sriltiotiocarboniio, sriltiotiocarboniltio, sralquiltio, aralquiltiocarbonilo9 ara1qui1carbonx11iaP aralquiltiocarbonilo ~ xi, aralquiltiocarboniltios alquiltiocarhonilo, aralquiltiocarbo-niltiOj msrcaptoj alkylsulfonic inilOj, aralquilsul-alquilsulfonilo9 alkylsulfinyl, arylsulfinyl aralquilsulfonilOj, arilsulfonila, heteroaryl having one or more ring atoms selected from oxygen atoms, sulfur and acupoints, and amino-to-amido radicals of the formula R14 X R16 / S5 / -N, -CM 'is R'w &gt; is an oxygen atom X U ·;  € ƒâ € ƒâ € ƒE-NC-Râ € ƒâ € ƒâ € ƒ1x9 or sulfur atom. , wherein each of rc, i- < 'S- < , â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ R 2 'taken together and R 2' taken together may form a heterocyclic group having from five to seven ring members including the asioto atom of said amino or amido radical and which heterocyclic group may contain additionally one or more hateroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or unsaturated. wherein R 1 and R 2 taken together are each R 4 and R 5 taken together may form an aromatic heterocyclic group having five ring members including the linking atom to said amino or starch radical s whose heterocyclic group aromatic heterocyclic ring may additionally contain one or more heteroatoms as well as ring atoms selected from oxygen, nitrogen and sulfur atoms wherein each H &quot; up to R3 may also be independently selected from hydroxyl and acidic moieties of the formulas in which n is a number selected from zero to three, inclusive, wherein A is a group acyclic acid selected from the group consisting of at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a leaving group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkoxy, alkenyl, alkynyl, aryl, aralkyl, heteralkyl having one or more ring atoms selected from oxygen atoms, sulfur and nitrogen? and in which any of the foregoing R 2 to R 3 groups Y 2 A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkyloxycarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulphinyl, arylsulphonyl, arylsulfinyl, arylsulphonyl, hateroaryloyl, having one or more ring atoms selected from the group consisting of? oxygen, sulfur and acamides, and amine amides of the formula X- X 7 * ·? Wherein X is a hydrogen atom or a carbon atom, wherein R 1 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and aryl; wherein D is selected from a hydrogen atom and a leaving atom, and R 'is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and arylpiperines which each of R &quot; R 5, R 5, R 5, R 5, R 5, R 5, R 5, is independently selected from hydrogen, alkyl, cycloalkyl, cyano, cycloalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboalkyl, alkylsulfinylsulphonyl, arylsulfinyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, araalkyl and aryl groups, and wherein each R3, R7, , F 1, independently selected from the amino and starch radicals of the formula R '' and R '' ' is further: 3 r28 X R3 X / M 11, ~ &quot; CN / V: s -NC- in which each RA, '% ¥ {* &quot;% Rw% R' &quot; '&quot; and R &quot; is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl, aryl, s, wherein each of R &quot;; &quot; and R '' taken together, and each R '' '' ' and â € ‡ â € ‡ â € ‡ taken together may form a heterocyclic group having from five to seven ring members including nitrogen atom of said amino or amido radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or unsaturated or unsaturated in which each R '&quot; 1 is taken together and each R11 and R &quot; taken together may form a aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more heteroatoms ring atoms selected from oxygen, nitrogen and sulfur atoms or a tautomer thereof or a pharmaceutically acceptable salt thereof. A method according to claim 32 wherein m is a 2- &lt; 2-phenothiophenyl) -2-oxoethyl] -2-phenyl- per R &quot; be selected from polycycloalkyl: polyether alkylalkyl, S-phenylpirapyl, 2-OMO-2-phenylethyl, 2-hydroxy-2-phenylethyl ,; (2-phenylcarbonyloxy) phenyl, 3,5,5-trimethylhexyl, carboxymethyl substituted by phenyl, 3,5,5-trimethylhexyl, 2-cyclohexyl-ethyl, pentyloxy, ethoxycarbonylmethyl, 1- (phenylmethyl) -E-ethenyl] -1-benzoyl-2-phenyl-ethyl, 1-oxobutyl, 2-naphthalenylmethyl, oethoxycarbonylmethyl, ethoxycarbonylethyl substituted by methyl, N-methyl-N-methyl-2-naphthalenylmethyl, 2-naphthylmethyl cyclopropylmethyl, cyclopropylmethyl, arylaleenyl, acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, arylthiothiocarbonyl, aralkylsulfonyl and radicals of the formula wherein X is an oxygen atom or a sulfur atom; Wherein each of Hâ,,Oâ, "is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl groups, with the proviso that when X is an oxygen atom, then F '&quot; and R &quot; -1 can not be selected from hydrogen and C1-4 alkyl; R6 is selected from hydrogen, alkyl, hydroxy, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy Aralkoxyalkyl, aralkoxyalkyl, aralkoxyalkyl, alkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroxloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, carboxyl, alkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alkylthiocarbonylthio, alkylthiocarbonyl, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbamoyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthioconsulfonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiobarbitriyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiooconsulfonyl, aralkylthio, arylsulfonyloxy, arylsulfonyl and bsteroaryl having one or more nitrogen atoms selected from the oxygen atoms, sulfur atom, 1 for each of R 1 to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarachyl, alkoxycarbonyl, alkoxycarbonyloxy, alkylthio, alkylthio, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiocarbonyloxy, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl radicals, and the amide-to-amide radicals of the formula R14 X N, -CN, and -NC-R? R &lt; 1 &gt; and X is an oxygen atom or sulfur atom, each of which is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and the like. iano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, arylop Γζ ι ι - s for each R &quot; up until? R ~ be able to be selectively independent. from the acidic moieties of formula ## STR4 ## wherein n is a number of salts selected from the group consisting of oxygen atoms, sulfur atoms, sulfur atoms, phosphorus and nitrogen, wherein said acidic group is selected to contain at least one acidic hydrogen atom, esters thereof, ester salts of said acidic moieties, wherein Y is a spacer group independently selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl groups having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and in which any of the foregoing &quot; K to R &quot; '? V and A having a substitutable position may be substituted by one or more groups selected from hydrasyl, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, ethoxy, aryloxy, alkoxyalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxy , cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio, alkylthio-carbonyl, and amino and amido radicals of formula X / -Ν \ X X is an oxygen atom or sulfur atom? wherein: D is selected from an oxygen atom and an atom independently from hydrogen, alkyl, cycloalkyl, cyano, hydroxy, haloalkyl, cycloalkylalkyl, alkoxy &quot; alkanoyl, &quot; alkoxycarbonyl &quot;, carboxyl &quot; haloalkylsulfonyl, haloalkylsulfonyl &quot; aralkyl &quot;, or a tautomer or pharmaceutically acceptable salt thereof. The method according to claim 33, wherein m is a? by Ra being selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl * 2-D-oxo-2 "phenyl] ethyl, 2-hydroxy-2-phenylethyl * 1,1-dimethylsethyloxycarbonylmethyl * hexyl * ethoxycarbonylmethyl * carboxymethyl * 1-naphthalenylmethyl, 2-cyclohexylethyl * pentyl, and phenyl substituted benzyloxymethoxyethyl * phenylcarbamoyl) -E-ethenyl, benzoyl-2-phenyl-ethyl, 1-oxobutyl] -piperidin-3-yl) -amide, 2- (2,5-difluoromethyl) -2-hydroxyethyl 2-phenyl-2-methylphenyl) ethyl 2- (2,5-dimethylsulfonyl) -2- in the form of a benzoyl, 1-benzoyl-1-methylethyl, β-pentanoic acid, cyclopropylmethyl, aralkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl, and amido radicals of the formula wherein each of K &quot; and K is independently selected from the group consisting of cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryls per 11 'is selected from hydrogen, alkyl, haloalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, , polycycloalkylalkyl, aryloxyalkyl, aralkoxyalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryl, hydroxy, aralkyl, aralkyl, aralkoxy, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, aralkylsulfonyl, for each of R '' 'to R' '' be independently selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, halo. alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkenyl, cycloalkyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, arylthio, arylthio, arylthio, arylthio, arylthio, arylthio, arylthio, , mercapto, alkylsulfonyl, aralkylsulphonyl and arylsulphonyl, and amino acid amides of the formula ## STR4 ## -N, -CN, and -NC-R? "14, .. 15" 16, .. 17 "18, -, 19,. . alkyl, cycloalkyl, cyano, amino, monoalkylamino, cyanoalkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aryl; s for each Rw to R &quot; &quot; may be an acidic moiety additionally independently selected from acidic moieties of the formula wherein n is a number selected from within up to three times wherein A is selected from carboxylic acid and carboxylic acid bioisosterols selected from from -OH, -SH, H-Ar34, ww-I; -C-WH, -B-WH, -S-UIH, -F-WH, -H-P-NH and -P-WH each W is independently selected from the group consisting of oxygen atom, nitrogen atom and NH2; eur-lex.europa.eu eur-lex.europa.eu ~: where each R '' '', R "w, R '' ' R 1 'and R 2' '' 'is independently selected from hydrogen, alkyl, alkanoyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, wherein each of R3, R4, R4, &quot; and R &quot; may be additionally independently selected from the amino radical of the formula: wherein each R 'and R' &quot; is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, wherein R 'and R' taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom referred to as said amino radical, which heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially halogenated in which R '' and R '' taken together may form an aromatic heterocyclic group having five ring members including nitrogen atom of said amino radical and which aromatic heterocyclic group further prunes containing one or more heteroatoms selected from oxygen, carbon atoms and sulfur atoms, wherein each of R '' and may additionally be selected from nitro, arylthio, aralkylthio and aralkoxy, and the ester and amide derivatives of said acyl groups; wherein said carboxylic acid biosorbate may additionally be selected from heterocyclic acidic groups consisting of heterocyclic rings of from four to about nine ring members * the heterocyclic ring of which contains at least one heteroatom selected from sulfur and nitrogen, the heterocyclic ring of which may be saturated * fully unsaturated or partially unsaturated * to which the heterocyclic ring may be attached at a single n-1 position selected from K to R 'or may be attached to any two adjacent positions sequestered from PT * to form a ring system condensed with one of the phenyl rings of formula I? and the ester and amide derivatives of said heterocyclic acidic groups; wherein Y is a group spaced independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, unsubstituted or substituted aryl and aryl; and in which any of the foregoing R'1 to R''' to groups Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkenyl, alkenyl, aralkyl, hydroxy, oxo, haloalkyl, alkoxy, silyloxy, aralkoxy, alkoxyalkyl, alkylcarbamoyl, alkoxycarbonyl, carbamoyl, cyano, nitro, alkylsulfonyl. 1 to 1 qu. I I su n f i n t i o ry 5 a r i a t i o n, a 1 q u. alkylthio, and alkylthiocarbonyl radicals and amino and amido radicals of the formula Xâ € ƒâ € ƒâ € ƒwherein X is selected from an oxygen atom or an atom of VM sulfur ox which R &quot; is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl. aryl, BR "and wherein D is selected from an oxygen atom and sulfur atom. wherein R * 'is selected from hydrogen, alkyl, cyloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein n is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, , alkoxy-alkyl, alkanoyl, alkanoyl, arylalkyl, aralkyl, aralkyl, aralkyl, or a tautomer thereof or a pharmaceutically acceptable salt thereof. The method of Claim 34 wherein m is one; R 2 is selected from the group consisting of polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethylcarbonyldiethyl and hexyl, ethoxycarbonylmethyl, carboxymethyl, thienylmethyl, S-cyclohexyl-ethyl, pentyl, and ethoxycarbonylmethoxyethyl substituted by phenyl-carboxymethoxy-substituted by 3-hydroxy-5- (5-trimethylhexyl) 1-naphthyl) -E-naphthyl, 1-naphthyl-2-naphthyl, 1-oxobutyl, 2- (2,5-dimethoxyphenyl) -2- 2-naphthylmethoxy) ethyl, 2- (2,5-dimethoxyphenyl) -2-hydroxyethyl, 2-naphthylmethyl, 1-benzoyl, 1-benzoyl-1-methyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, , aralkylsulfonyl and radicals of the formula 1 ? wherein each of H 2 &quot; cycloalkylalkyl, alkoxyalkyl, aralkyl and aralkyl are each independently selected from hydrogen, C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy, alkyl, polyalkylalkyl, polycycloalkylalkyl, aryloxyalkyl and 2-hydroxy-2-aralkylO and alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkyl, alkoxy, aralkyl aryl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkyl-carnonoxyl, cycloalkyl, aralkyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, alkylsulfonyl, aralkylulfonyl, and arylsulfonyl; -? R1 is independently selected from hydrogen, hydroxy, alkyl, hydronyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aralkyl, alkoxy, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkynyl, cycloalkenyl, alkynyl, piano, nitro, carbamoyl, alkylthio, aralkyl, aralkyl and mercaptopiol groups and wherein each R3 to R4 may be an acidic moiety additionally independently selected from acidic moieties of the formula wherein n is a number selected from zero to three inclusive, wherein A is selected from carboxylic acid and carboxylic acid selected from HW-WW, H-is-WH. -S-WH. -S-WH, and -P-WH! W "R &quot; &quot; ' in which each W is independently selected from the oxygen atom, wherein each R 'is selected from the group consisting of oxygen, and R &quot; * is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylarcombinylcycloalkyl, cycloalkylalkyl, aryl and aralkyl group, wherein R is a group of R ' may be additionally selected from the group consisting of a radical of the formula R3, Alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, acyloxyalkyl, aralkyl, aryl, and wherein K &quot; 39 and R 4 taken together may form a heterocyclic group having from five to five ring member sets including the nitrogen atom of said amino radical whose heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atom, nitrogen and sulfur atoms and which heterocyclic group may be saturated or unsaturated in which R ' and K '&quot; taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may additionally contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur derivatives and the amide, aster, and salt derivatives of said acid groups, wherein said carboxylic acid biosester is additionally selected from heterocyclic acidic groups consisting of heterocyclic rings of from four to about of nine members of the ring, which ring contains at least one heteroatom. selected from oxygen, sulfur and fully atota atoms, which heterocyclic ring may be saturated, unsaturated or partially unsaturated, which heterocyclic ring may be attached in a single position selected from R &quot; to R 1 may be attached to any two adjacent positions selected from K 2 to R 3 to form a ring system fused to one of the phenyl rings of the formula: said acidic heterocyclic groups are and wherein Y is an independently spaced group selected from one or more alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and silyl. X7 β, ιΆ where each ds R &quot; up to R3, Y and A may independently be substituted at any position substitutable by one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro , alkylsulfenyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryl, and aralkoxy; or a tautomer thereof or a pharmaceutically acceptable salt thereof. The method of Claim 35 wherein m is a? by R 2 is selected from polycycloalkyl, 1-cycloalkyl, 3-phenylpropyl, 2-amino-2'-phenethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethylcarbonyloxymethyl, hexyl, stoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted by phenyl, 3,5-trimethylhexyl substituted 3,5- 2-phenylmethoxy) -1- (phenylmethyl) -E-ethenyl, i-benzoyl-2-f-lithium, l-oxobutyl, 2-l- 2,5-dideoxyphenyl) -2-oxo-2-oxo-2-phenyl-2-phenylmethoxy) -1H-indol- sn 11 &gt; -2 ·····························, sn i I m t t y or more t D κ i c a r hon i. 1 bu t i o, s t o gt; benzoyl-1-fluoroethylether, β-cyclopentylmethyl, aralkenyl, aceanenitrile, aralkylsulfonyl, or amido radicals of the formula ## STR4 ## --T. wherein each of K '&quot; 1' and FT '&quot; is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, alkyl, aryl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, alkyl, alkoxycarbonylalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, arylalkyl, aralkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aryl, aralkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, aryloxyalkyl, aralkoxyalkyl, alkenyl, alkynyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl, for example wherein R1 to R3 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano nitro, carboxyl, alkylthio, and mercapto; X t 1 - :. and for each R &quot; to R &quot; may be an optionally acid addition moiety independently selected from acidic moieties of the formula wherein n is a number selected from Z is up to two inclusive, wherein A is selected from carboxylic acid and bioisosterols of carboxylic acid selected from HWW 5 w is -P-WH-OH, -SH, -ArO * 4 *, -C-WH, -S-WH5 -S-WH, wherein each W is independently selected from the group consisting of N, N-dimethylformamide, N, N-diisopropylcarboxamide; s -: 3. xo xp. wherein each of R 2, R 3 and R 4 is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarhonyl, cycloalkyl, phenyl and phenyl; R 2 '' may be independently selected independently from the amino radical of the formula wherein each R &quot; and K '& independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl, and the amide derivatives? ester salts of said acidic groups wherein said carboxylic acid heteroester may further be sequestered from heterocyclic acidic groups consisting of heterocyclic rings of from four to about nine ring members 5 whose ring contains at least one heteroaryl , selected from oxygen, sulfur and aspartic acids whose heterocyclic ring may be saturated; fully unsaturated or partially unsaturated, which heterocyclic ring may be attached at a single position selected from R '&quot; to R &quot; &quot; or may be attached to any two adjacent passages selected from R 'to R "as well as to form a ring system condensed with one of the phenyl rings of the formula 15 to the amide, ester and salt derivatives of said acyl groups Wherein Y is a leaving group independently selected from one or more alkyl, cycloalkyl, or heterocyclyl groups; cycloalkylalkyl, alkenyl, phenyl, naphthalyl and aralkyls wherein each of R4 to R4 is hydrogen, R3 and R4 to R4, Y and A independently may be substituted at any substitutable position by one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, halohydroxyalkyl, haloalkyl, alkoxycarbonyl, cyano, nitro, aralkyl, alkoxy, aryloxy and aralkoxy groups or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. A method according to claim 36 characterized in that it is a by being selected from adamantyl, s-mannosyl, 3-fersyl propyl, 2-oxo-phenylsilyl, 2-hydroxy, -2'-phenylethyl, 3'-dimethylcarbonylethylsethylsilyl, etoxycarbonylsilyl, carboxy- naphthalenylaminoethyl, 2-cyclohexylethyl, methyl, siloxycarbonylmethylsubstituted phenyl, carbonyldiethylsilyl, 3,5-dimethylcarbonyloxyethyl, 2-phenyethoxy) -1-phenylmethyl) -E-et (2-methoxyphenyl) -2-phenylethyl, 2-phenyl-2-oxoethyl, 2-oxobutyl, 2-oxobutyl, 2-oxobutyl, 2-naphthalenylmethyl, ethoxycarbonyl, butyl, ethoxycarbonylethyl substituted by bensoyl, 1-bensoyl, A-bensoyl-1-methylethyl, 1-naphthanoic acid, cyclopropylmethyl, arylalkyl and acetonatryl; 5 by R 'is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxyalkyl, carboxykoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, alkynyl, alkyloxy, alkylthio, phenylthio, phenylthio, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkynyl, alkylthio, phenylthiophene, for each of R &quot; R 2 is selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, bensoyl, phenoxy, alkoxyalkyl, acetylet, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, 5 ' -f 1 s for each R 'to R -' 'may be an additional acidic moiety. The present invention also relates to a process for the preparation of a compound of the formula (II): ## STR1 ## in which the compound of the formula (I) is prepared from acyclic moieties consisting of C ^ HH, CO₂CH₂, SH, C H. H.H₂, NH₂, NH₂CH₂CHF, jL, * NHSOâ, ", NHâ,", NHâ, ", NHâ,", CONHNHâ,ƒ, CONHNHSâ,ƒ, CFâ,ƒ, u &gt; H, OH, OPO, H ', OSO, H, H, CONHOCH wjj A &quot; V &quot; wherein one of R &quot; R &quot; and R &quot; The reaction is carried out in the presence of a compound of the formula: ## STR1 ## in which R @ 3 is hydrogen, C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy. -CH2 -CH2 -CH2, -SO2 -CH2, -SO2 -CH2, -S ,. 7 &gt; Wherein R 'is selected from hydrogen, wherein said acidic moiety may be a bonded heterocyclic acidic group of the formula wherein R 1 is selected from hydrogen, to any two adjacent positions of R '&quot;' to R1, so as to form a ring system fused to one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl condensed ring system being selected from and the esters, amides and salts of said acidic moieties or a tautomer thereof or a pharmaceutically acceptable salt thereof. A method according to claim 37 characterized in that R 1 is selected from adamantyl, adamantylmethyl, propyl, propyl, propyl, propyl, propyl, propyl, propyl, propyl, propyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phthalylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthacenylmethyl, 2-cyclohexyl, ethyl, pentyl or 5-ethoxycarbonylmethoxyethyl substituted by phenyl, carboxymethoxyethyl substituted by phenyl, 3,5,5-trimethoxyhexyl, 2-f i i m e to x i) -1. - - (f en i 1 nie t i 1 o) -E-ethenyl- 2-phenylethyl) -2-phenylethyl] -2-oxabutyl] -2- (2,5-dimethylamino) -2-oxoethyl, 2-phenyl-2-phenylphenyl) ethyl, 2-5,5-dimethoxyphenyl 2-naphthalenylmethyl, methoxycarbonylethyl, benzoyl-substituted ethoxycarbonyleyl, 1-benzoyl-1-methylethyl, β-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and acetonitrile wherein Râ, is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantylmethyl , 2-aminoaminopropylpropyl, 3-phenylpropyl, 2 '- [[2- -Phenylethyl, 2-hydroxyethyl 2-phenylethyl, 1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, i-naphthalenylmethyl, 2-cyclohexylmethyl, penyl, ethoxycarbonylmethyl, phenyl substituted, carboxymethoxyethyl substituted by phenyl, 3,5,5 1-oxoethyl, 2- (2,5,5-dimethoxyphenyl) -N-methyl-N-methyl-N-methyl-N-methyl- 2-oxyethyl, 2-naphthalenylmethyl, matoxycarbonyl-heptyl, 2-phenylethyl) -2-hydroxyethyl, 2-naphthalenylmethyl, , i-benzoyl-i-methylthio, i-pantanedioate, cyclopropylmethyl, 3-phenyl-2E-propenyl, acetonitrile, phenyl, benzyl, phenylethyl, cyclohexyl, cyclohexyl. Aminopropyl, i-1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, imidazolyl, isobutyl, imidazolyl, , 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluorophenyl. wherein at least one of R &quot; and R 1 is selected from CO 2 H 9 SH CONHNHSO 2 CF 3, OH, R 8 and RV is an acidic group PO 1 H 4, SO 4 H, CONHNH 2, H H H N-N 43 R42 or a tautomer thereof or a pharmaceutically acceptable salt thereof. The method of claim 38 wherein m is a? ethoxycarbonylmethyl, carbofurylmethyl, 1-naphthalenylmethyl, cyclohexylethyl, methyl, ethoxycarbonylmethyltaxyl substituted with phenyl, carbocyclethyl substituted by phenyl, 3,5-dihydro- (2-phenylmethoxy) -1- (phenethyl) -E-ethenyl, -benzoyl-2-phenethyl, i-oxabutyrate, 2- [2,9-d] imetlox phenyl-2-phenyl-2-phenylmethoxy) ethyl, 2 "(23S-diynoeryloxyphenyl) -2-hydroxyethyl] -2-naphthalenylmethyl] methoxycarbonylbutyl] ethyloxycarbonyl-ε, substituted by benzoyl, 1-benzoyl-1-methylethyl, i-pentanoic acid, cyclopropylmethyl, 3-phenyl-2 H -propenyl and 1-ethano-butyl; for R '* &quot; may be selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, 4-methoxybutyl, tert-butyl, n-methylnaphthyl, cyclobutyl, propylthio and butylthio. wherein R 1, R 2, R 3 and R 4 are independently selected from the group consisting of ΟΟ, -, Η, SH, ΡΟ -, Η, , ΘΟ -, Η, CONHNOSO CF CF,, OH, , wherein each R? J? s K &quot; independently of one another are selected from Cl, CH3, CH3, CH3, CH3, and SO2 CF3. Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A method according to claim 39 characterized in that it is a compound of the formula: be sequestered from 2 ·· -οκο-2 · "&lt; ethyl, 3-phenylpropyl, 2-QKO "2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyl, 2-hydroxyethyl, 1-naphthalenylmethyl, 2-cyclohexylmethyl, pentyl, exycarbarylene, phenyl-substituted phenyl, phenyl-substituted phenyl, 3,5,5-tris (4-methylhexyl) -hexyl, Methyl &lt; / RTI &gt; - J. - &lt; 2-oxoethyl 2-phenyl-2-phenyl-2-phenyl-2-phenyl-2-phenyl-2-phenylethyl, 2- (2,5-dimethoxyphenyl) -2-hydroxyethyl 2-naphthenemethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted by benzoyl, i-benzoyl-i-osylethyl, i-peritoneic acid, cyclopropyl, ethyl, 3-methyl-2E-propenyl and 1-cyanobutyl. from π-propyl, isopropyl, -DUutyl, X-naphthyl, 4-isopropyl, Ibutil. n-propylthio and butylthio-3α-7α, 10--11h, -----, K, R,, R,, R e and H are hydroxymethyl; R 2 is hydrogen and the other is hydrogen. -SO 2 O from CCLH and n-butyl. H I N-N JL N 41â - the claim 40 comprising the compound and the pharmaceutically acceptable salts thereof is selected from the group consisting of acids, 153-dibutyryl-4, b-dihydro-5-methyl-1H-1,2,4-triazole; 1-biphenyl-13-2-carboxylic acid tert-butyl 2-4-dihydro-2-oxo-2-hydroxy-2-cyclohexyl- 3dec-2-yl) ethyl] -4- [2 '- &lt; 1 H -tBrSzDl-5-yl] 1 ', 4'-biphenyl-4'-ylmethyl-3'H-1,2,4-triazol-1'-yl; dihydro-2- (3-isopropyl-4-methyl-1H-indol-3-yl) -1H-pyrazole-4-carboxylic acid 1-Biphenyl-3-yl) -1H-tetrazol-4-yl] [1,4] dihydro-2- (2-methyl- 4-ylmethyl] -3 H-N, N-dimethyl-3- 5-butyl] -2-hydroxy-2- (2-hydroxy-2-phsylsilyl) -4- [2- (1H-tetrazol-5-yl) -1 H -biphenyl- 3-butyl-4-hydroxy-3-oxo-3-oxo-5-oxo-1H- 3-ylmethyl-1H-15,2,4-triazol-5-yl) -2,4-dihydro-2-heptyl 1-biphenyl-3-4-ylmethyl] -3H-1,2,4-triazole-3-carboxylic acid ethyl ester of 3- 4H-tetrazol-3-yl) -1,1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazole 3-Butyl- . 5-dihydro-5-GKO-4-C2 '- (1H-tetrazol-5-yl) -1 H -benzimidazol- 1,2,4-triazol-1-acetic acid-5-butyl-4-dihydro-2-naphthalenylmethyl-4- 3-ylmethyl] -3 H -pyrazol-5-yl) -3,4-dihydro-3-naphthalene-5- 4-dihydro-4-C2-1H-tetrazol-5-yl) benzopyran-4-yl] methyl] -3 H -1,2,4-triazol-3-one; 5-butyl] -2,4-dihydro-2-penicill-4-C2- (1H-tetrazol-5-yl) Cl, 1'-biphenyl-4-ylmethyl] -3 H -1,2,3,4- -Hydroxy-5-hydroxy-5-oxo-3- (2-methoxyphenyl) ethyl] -hexahydro-3- '-biphenyl-4-ylmethyl] -1H-islsulfonyl] -1H-benzimidazol-3-yl] C2 -C3 -hexyl-4,5-dihydro-5-Gxa-4-C2 -C-H-tetrasol-4-yl) -ethyl] -1 H -biphenyl-4-ylmethyl] -1H-1,2,3,4-triazolo [ 3-acetic acid; 5-byyl-2,4-dihydro-4-E2 * - <1H-tetraso1,5-i1) 4-ylmethyl-2- (3,5-trimethylhexyl) -3H-1,2,4-triazal-3-ones 5-butyl-2-4-dihydro-2-L-2-phenyl-2 (Phenylmethyl) -E-ethenyl] -4- [2 '- (1H-tetrazal-5-yl)] N', N'-biphenyl-4-ylmethyl] -3H- 4-yl) -phenyl] -amide; 2- (1-benzoyl-2-methylsulphonyl) -5-butyl] -2,4-dihydro-4 ', 2' - (1H-tetrazol-5-yl-biphenyl- 3H-1,2,4-triazol-3-one 5-butyl] -2,4-dihydro-2-oxobutyl) -4- [2 '- (1H-tetrazol-5-yl) 4-yl] methyl] -3H-1? Tris-3-one; 5-butyl-2- (4-dihydro-2-C2-C2-S-dimethoxyimino) -2-oxoethyl 3-4-2- (C1-H-tetrazol-5-yl) C 1 ¥ i &quot; 3- [4-ylmethyl] -3 H -1,2,4-triszol-3-one; 5-butyl-2-4-dihydro-2-12-phenyl-2-propenethoxy &gt; 3-ylmethyl-3 H -1,2,4-triazol-3-ylmethyl) -1H-benzimidazol-3-yl) dihydro-2- [2- (2-dimethoxyphenyl) -2-hydroxyethyl] -4- [2 '- (1H-tetrazol-5-yl) -1,1-biphenyl] -4- 4-Dihydro-2- (2-naphthalenylmethyl) -4-E2 '- (1H-ietrazol-5-yl) -1H-imidazo [ 1) C 15X -biphenyl-4-ylmethyl] -3 H -1,2,4-triazol-3-one; 3-Butyl-4,5-dihydro-5-oxa-4-E2 '-hexahydro-5-yl) -1,5'-biphenyl-4-ylmethyl] -1 H -1,2,4- triazale; 5-O-Methyl-4 '' - (1H-tetrazol-5-yl) -1 ', 3'-biphenyl-5-carboxylic acid ethyl ester 4-yl] methyl] -1,2,3,4-triazolo [2 '- [1-benzoyloxy-1-methylsulphonyl] -5-butyl-4-4- 5-yl) -1,1-biphenyl-4-ylmethyl-3 H -1,2,4-triazac-3-one; 3-Butyl-4,5-dihydro-5 - [[4-C2 ''] -1H-tetrazol-5-yl biphenyl-4-ylmethyl] -1H- 4-fluoro-4- [Î ± -H-tetrazol-5-yl] -1,2-biphenyl-3- (4-fluorophenyl) 4-yl) -3-hydroxy-2- (3-methoxyphenyl) -β-2 ' - (1H-tystetrahydrofuran-5-yl) -1,1'-biphenyl-4-ylmethyl] -3H-1S2S4-phenyleth-3- s-butyl-4,5-dihydro-5 '' '' - '' '' propyl 4-C2 '-H-tetrazol-5 &quot; &quot; 3-ylmethyl 3- (1H-1,2,3,4-triazol-3-yl) quinoline = J. PEREIRA DA CRUZ Official Agent of Industrial Property RUA ViCTOR COROON, 10-A 3 «1200 USBOA