Field of the Invention

Non-peptidic carbonate-substituted imidazo[4,5-d] - pyridazine compounds are described for use in treatment of circulatory and cardiovascular disorders such as hypertension and congestive heart failure. Of particular interest are angiotensin II antagonist compounds provided by imidazo[4,5- d]pyridazine biphenyl ethyl derivatives having at least one carbonate-type group attached to the 4 and/or 7 positions of the imidazo-pyridazine heterocycle.

Background of the Invention

The renin-angiotensin system is one of the hormonal mechanisms involved in regulation of pressure/volume homeostasis and in expression of hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, an octapeptide which is the primary active species of this system. Angiotensin II is a potent vasoconstrictor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.

Previous studies have shown that antagonizing angiotensin II at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin- angiotensin system through interaction with various tissue receptors. There are several known angiotensin II antagonists, many of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of

oral bioavailability or their short duration of action. Also, commercially-available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limit their therapeutic application.

Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-c_-loro-l-(2-chlorobenzyl)imidazole-5- acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al. J. Pharmacol. EXP. Ther.. 247(1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-l-(2- nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol.. 157. 13-21 (1988) ] . A family of l-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther.. 2_i__(3). 867-874 (1989)]. U.S. Patent No. 4,816,463 to Blankey et al describes a family of 4,5, 6,7-tetrabydro-lH- i_nidazo(4,5-c)tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP #253,310, published 20 January 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted i idazoles, as antagonists to the angiotensin II receptor. EP #323,841, published 12 July 1989, describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmetlx^lpyrazoles, biphenylmethyl-l,2,3-triazoles and biphenylmethyl 4-substituted-4H-l,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl) ethyl]- 4H-l,2,4-triazole. U.S. Patent #4,880,804 to Carini et al

describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.

Several families of imidazo-pyridazine derivatives have been synthesized. For example, alkaline hydrolysis of l,2,5-thiadiazole-3,4-dicarboxylic acid bishydrazide followed by a cyclization step in the presence of formic acid produced 4,7-dihydroxy- and 4,7-dichloro[4,5-d] yridazine derivatives [I. Sekikawa, J. Heterocyclic Chem.. £, 129-130 (1969)].

Also, synthesis of imidazo-pyridazine nucleoside analogues has been described. For example, ring closure of an imidazole nucleoside produced the compound 1- (β-D- ribofuranosyl)-imidazo[4,5-d]pyridazine-4,7-dione [C. Tapiero et al, J. of Carbohydrates Nucleosides

Nucleotides. 2(3), 191-195 (1976)]. In a study of chemical modification of antibiotic nucleosides, the compound 1- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-imidazo- [4,5- d]pyridazine-4,7 (5H,7H)dione was synthesized [P.D. Cook et al, J. Heterocyclic Chem.. 15, 1 (1978)]. A series of substituted imidazo(4,5-d)pyridazines has been studied for pharmacological properties [G. G. Ferguson et al, J. Pharm. Sci.. 52(11), 1584-1586 (1970)]. A family of 4-substituted imidazo[4,5-d]pyridazines, including several 4-amino- and 4-alkylamino-l-benzyl-7-chloroimidazo[4,5-d]p_/ridazines, has been prepared for antitumor evaluation [J.A. Carbon, J. Am. Chem. Soc. j_Q, 6083-6088 (1958)]. In view of the antitumor activity of 5-amino-7-hydroxy-v-triazolo[d]pyrimidine, several 4,7-disubstituted imidazo[4,5-d] yridazines were synthesized including the compound 4,7-bisethylmercapto-l- ethylimidazo[4,5-d]pyridazine [R. N. Castle et al, J. Orσ. Chem.. 22, 1534-1538 (1958)]. Based on the antimalarial activity of certain quinoline derivatives, a family of ω-dialkylaιrάnoalkyla_xάnoimidazo[4,5-d]pyridazines was synthesized including, typically, the compound 4- (3- dmethylairdnopropylan_i.no)-7-chloro-l-(tetrahydro-2'- pyranyl)imidazo[4,5-d]pyridazine [N. R. Patel et al, J. Heterocyclic Chem.. 2, 13-24 (1968)].

Certain imidazo-pyridazine compounds have been described for treatment of cardiovascular disorders. For example, EP #184,738, published 18 June 1986, describes a family of 2-naphthyl-substituted imidazo[4,5-d] yridazin-4-one compounds having antithrombotic, cardiotonic and hypotensive properties. Japanese Patent #065,202, published 18 March 1987, describes a family of imidazo heterocyclic carbostyril derivatives useful as cardiotonic, hypotensive and antiinflammatory agents. U.S. Patent No. 4,656,171 describes certain 2-phenyl-imidazo-pyridazines for use as cardiotonics, including a benzyloxy-substituted 2-phenyl-__midazole[4,5- c]pyridazine. U.S. Patent No. 4,722,929 describes 2-aryl- imidazo-pyridazine compounds for use as cardiotonics, including a benzyloxy-substituted 2-phenyl-4-chloro-imidazo[4,5- d]pyridazine. EP #245,637, published 19 November 1987, describes a series of 4,5,6,7-tetrahydro-lH-i_midazo[4,5- c]pyridine derivatives as antihypertensive agents. EP #399,731, published 28 November 1990, describes several different families of imidazopyridines and imidazodiazines as angiotensin II antagonists including, in particular, the compounds methyl 4'-[ (2-butyl-4-hydroxy-3H-imidazo[4,5- d]pyridazin-3-yl)methyl]biphenyl-2-carboxylate and 2-butyl-4- bydroxy-3 [(2' (lH-tetrazol-5-yl)biphenyl-4-yl)metlτ^l]-3H- imidazo[4,5-d] yridazine. EP #400,974, published 5 December 1990, describes several families of i idazo-fused six-meπibered heterocyclics as angiotensin II antagonists including, in particular, 7-metbyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4- yl)met_^l-3H-imidazo[4,5-d]pyridine. EP #420,237 published 3 April 1991 describes biphenylmethane imidazopyridine compounds for use as angiotensin II antagonists.

DESCRIPTION OF THE INVENTION

A class of carbonate-substituted imidazo[4,5-d] pyridazine compounds useful in treating circulatory and cardiovascular disorders is defined by Formula I:

wherein m is a number selected from one to four, inclusive;

wherein each of R ^a and R is independently selected from

W II radicals of the formula R ¹ XCX— and of the formula —XR ² , with the proviso that at least one of R ^a and R ^D must be a

W

II radical of the formula R ¹ XCX—; wherein each of W and X is independently selected from oxygen atom and sulfur atom; wherein each of R-*- and R^ is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl;

wherein each of R-^ through R ¹¹ and R-^9 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, forrryl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, forrπyl, alkylcarbonyloxy, cycloalkylalkoxy, alkoxyalkoxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio,

alkylthiothiocarbonyl, alkylthiothiocarbonylthio. arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkyltliiocarbonylthio, alkylthiocarbonyl, aralk lthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula

wherein each of R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ is independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R!2 and R^- ³ taken together, R-*- ⁴ and R^-5 taken together and R!6 and R ¹⁷ taken together may each form a heterocyclic group having five to seven ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R ¹² and R^ ³ taken together and R ¹⁴ and RIS taken together may form an aromatic heterocyclic group having five ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms;

and wherein each of R ³ through R^ may be further independently selected from acidic moieties of the formula

-YnA

wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, wherein said Y _n A group is further characterized in being a radical containing a free carboxylic acid group or being a radical which is a bioisostere of said free carboxylic acid group, 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 heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein Y is further selected from

and -CH=CH-, wherein R ¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R ¹ through R ¹⁸ , R ³⁹ , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, halo, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl,

heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula

wherein X is selected from oxygen atom and sulfur atom; wherein R^-9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR ²⁴ and

wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R ²⁴ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R ² ^, R ² ^, R ²² , R ²³ , R ² ^ and R ² ^ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R ² ^' R21, R22 R23 _/ R25 QX^ R26 ± _S further independently selected from amino and amido radicals of the formula

wherein each of R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ and R ³² is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino _r monoalkylainino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein R ² ^ and R ²¹

taken together and R ²² and R ²³ taken together may each form a heterocyclic group having five to seven ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R ^ and R ² ^ taken together and R ² ^ and R ² ^ taken together may each form can aromatic heterocyclic group having five ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

Compounds of Formula I would be useful in treating a variety of circulatory disorders including cardiovascular disorders, such as hypertension, congestive heart failure and arteriosclerosis, and to treat other disorders such as glaucoma. These compounds would also be useful as adjunctive therapies. For example, compounds of Formula I could be used in conjunction with certain surgical procedures. For example, these compounds could be used to prevent post- angioplasty re-stenosis. Compounds of Formula I are therapeutically effective in treatment of cardiovascular disorders by acting as antagonists to, or blockers of, the angiotensin II (All) receptor. Compounds of Formula I would be therapeutically effective in treatment of the above- mentioned circulatory and cardiovascular disorders or would be precursors to, or prodrugs of, therapeutically-effective compounds.

It is understood that, if R ^a and R ^b of Formula I have different values from each other, two regioisomers can be obtained which fall within the scope of the present

invention either as individual compounds or as their mixture in all ratios.

Compounds of Formula I are all characterized in having at least one carbonate substituent at one of the R ^a and R° positions of the imidazopyridazine ring. Thus, compounds of Formula I may have one carbonate group at the R ^a or R-k position, or may have carbonate groups at both R ^a and positions. The term "carbonate", as used herein, means a

W II substituent selected from radicals of the formula R ¹ XCX— wherein X, W and R ¹ are as defined above. When R ¹ is selected to be a hydroxyalkyl or a haloalkyl radical, it is preferred that the alkyl portion contain at least two carbon atoms and the hydroxy or halo substituent not be attached to the alkyl carbon which provides the bond to be attached to

W

II the X moiety of the formula R ¹ XCX—. Compounds having alkyl groups, especially lower alkyl groups at the R ³⁹ position, are particularly useful as angiotensin II antagonists.

The phrase "acidic group selected to contain at least one acidic hydrogen atom", as used to define the -Y _n A moiety, is intended to embrace chemical groups which, when attached to any of the R ³ through R^ positions of Formula I, confers acidic character to the compound of Formula I. "Acidic character" means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pK _a in a range from about one to about twelve. More typically, the Formula I compound would have a pK _a in a range from about two to about seven. An example of an acidic ^" group containing at least one acidic hydrogen atom is carboxyl group (-COOH) . Where n is zero and A is -COOH, in the - πA moiety, such carboxyl group would be attached directly to one of the R -RU positions. The Formula I

compound may have one -Y _n A moiety attached at one of the R3_R11 positions, or may have a plurality of such -Y _n A moieties attached at more than one of the R -RU positions, up to a m-ximum of nine such -Y _n A moieties. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as "bioisosteres of carboxylic acid" or referred to as "acidic bioisosteres" . Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I having the -Yn moiety attached at one of positions R ⁵ , R ⁶ , R ⁸ and R ⁹ would be expected to have preferred properties, while attachment at R ⁵ or R ⁹ would be more preferred. Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pK _a values of the Formula I compound as conferred fcy the -Yn moiety be in a range from about two to about seven. The -YnA moiety may be attached to one of the R ³ -R ^1:L positions through any portion of the -YA moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pK _a criteria. For example, where the -Yn acid moiety is tetrazole, the tetrazole is attached at the ring carbon atom.

A preferred class of compounds consists of those compounds of Formula I wherein m is one;

wherein each of R ^a and R ^D is independently selected from

W radicals of the formula R ¹ XCX— and of the formula —XR ² , with the proviso that at least one of R ^a and R° must be a

W , II radical of the formula R^CX—; wherein each of W and X is independently selected from oxygen atom and sulfur atom; wherein each of R^ and R ² is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl,

pheπylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl;

wherein each of R ³ through R^ and R ³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, for yl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, alkylaminocarbonyloxy, a__ylaminocarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarboryl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms and amino and amido radicals of the formula

-N / ^Rl2 - -C IIN / ^{R nd} -NC-R ¹⁶

, 13 ^* R 15

R 17

wherein each of R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ is independently selected from hydrido, alkyl, cycloalkyl, aryl, ironoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

and wherein each R ³ through RU substituent may be further independently selected from acidic moieties of the formula

"YnA wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, wherein said Y _n A group is further characterized in being a radical containing a free carboxylic acid group or being a radical which is a bioisostere of said free carboxylic acid group, 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 heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; or wherein Y is one or more groups selected from

and -CH=CH-, wherein R ¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R^ through R^ ⁸ , R ³⁹ , Y and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, halo, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula

wherein X is selected from oxygen atom and sulfur atom; wherein R^- ⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl;

wherein each of R ²⁰ , R ²¹ , R ²² and R ²³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylakyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds consists of those compounds of Formula I wherein m is one;

wherein each of R ^a and R° is independently selected from

O radicals of the formula R ¹ XCX— .and of the formula —XR ² , with the proviso that at least one of R ^a and R ^D must be a

O . II radical of the formula R ¹ XCX—; wherein each X is independently selected from oxygen atom and sulfur atom; wherein each of ?- and R ² is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl;

wherein R ³⁹ is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and alkylcycloalkylalkyl, and wherein any one of the foregoing R ³⁹ substituents having a substitutable position may be

substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino, alkylamino, alkylarylamino, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and arylsulfonyl;

and wherein each of R ³ through R ¹¹ is independently selected from hydrido, linear or branched alkyl (Ci-Cio) , linear or branched alkenyl (C2-C10), linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), cycloalkenyl (C3-C10), cycloalkylalkyl (C4-C10), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R ³ -R ^1:L substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula

0

-CO-R ³³ wherein R ³³ is selected from hydrido, linear or branched alkyl (C1-C10, ) linear or branched alkenyl (C2-C10) , linear or branched alkynyl (C2-C10) , cycloalkyl (C3-C10), cycloalkenyl (C3-C10) , cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10) ; or wherein said R ³ -R ^1:L acidic radical is a bioisostere of a free carboxylic acid having a pK _a in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamide, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus-containing and thiophosphorus-containing acids selected from

-P-WH ^• R ³⁴

wherein W is selected from 0, S and N-R ⁴⁰ ; wherein each of R ³⁴ , R ³⁵ ' R ³⁶ and R ⁴⁰ is independently selected from hydrido,

alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R ³⁷ -N-R ³⁸ , wherein R ³⁷ and R ³⁸ can be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl and alkanoyl; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic groups containing 5 to 7 atoms of which one or more heterocyclic ring atoms are selected from oxygen and nitrogen, which heterocyclic group has an ionizable proton with a pk _a in a range from about two to about ten; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which heterocyclic ring contains at least one hetero atom selected from oxygen, sulfur and nitrogen atoms, 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 -R^ or may be attached at any two positions selected from R ³ -RU so as to form a fused-ring system hy incorporating one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein said bioisostere of carboxylic acid may be further selected from substituted amino groups of the formula

NH-R ⁴⁶ wherein R ⁴⁶ is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R ⁴¹ wherein R ⁴¹ is selected from hydrido, linear or branched alkyl (Ci-Cio,), linear or branched alkenyl (C2-C10), linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), cycloalkenyl (C3-Cιo), cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10); wherein any of the foregoing R ³³ through R ³⁸ , R ⁴⁰ , R ⁴¹ and R ⁴⁶ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl , alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and

arylsulphonyl; or a tautomer thereof or a pharmaceutically- acceptable salt thereof.

Examples of heterocyclic groups which can be used as bioisosteres of carboxylic acid include:

wherein each of R ⁴² , R ⁴³ and R ⁴⁴ is independently selected from H, Cl, CN, NO2, CF^ _t C2F5, C3F7, CHF2 _/ CH2F, CO2CH3, CO2C2H5, Sθ2CH3 _/ SO2CF3 and wherein Z is selected from O, S, R ⁴ 5 ^3 CH2, wherein R ⁴ 5 is selected from hydrido, CH3 and CH2C5H5. Attachment of any of the above- depicted groups to the nucleus of Formula I is through a partial bond shown projecting from a ring-carbon atom of the group. Thus, such projecting partial bond should not be interpreted as a short-hand designation of a methyl group.

Examples of fused ring systems which incorporate the phenyl rings of Formula I are as follows:

Attachment of any of the above-depicted groups to the nucleus of Formula I is through a partial bond shown projecting from a ring-carbon atom of the group. Thus, such projecting partial bond should not be interpreted as a short-hand designation of a methyl group.

An even more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R ^a and R ^D is independently selected from

O radicals of the formula ROCO— and of the formula —OR ² , with the proviso that at least one of R ^a and R must be a

O radical of the formula R^CO—; wherein R is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, naphthyl, pyridyl, pyrimidyl, naphthylalkyl, pyridylalkyl, pyrimidylalkyl, indanoylalkyl, pyrrolylalkyl, thienylalkyl, furanylalkyl and pyrazolealkyl; wherein R ² is hydrido;

wherein each of R ³ through R^ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl _y

alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto;

and wherein at least one of R ³ through R^ is an acidic moiety independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, P03H2, NHSO2CF3, NHS02CgF _5/ SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CO HOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OFO3H2. OSO3H, NHCN4H and

and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R ³ -R^ so as to form a fused ring system to include one of the phenyl rings of the biphenyl moiety of Formula I, said fused ring system selected from

and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. Attachment of any of the above-depicted groups to the nucleus of Formula I is through a partial bond shown projecting from a ring-carbon atom of the group. Thus, such projecting partial bond should not be interpreted as a short- hand designation of a methyl group.

A class of compounds of particular interest consists of those compounds of Formula I wherein m is one; wherein each of R and R is independently selected from

O radicals of the formula R ¹ OCO— and of the formula —OR ² , with the proviso that at least one of R ^a and R ^D must be a

O radical of the formula R ¹ OCO— wherein R^ is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl, imidazolemethyl, i idazoleethyl, pyridylmethyl, pyridylethyl, pyrimic_ylmethyl, pyrimiaylethyl, indanqylmethyl, indanoylethyl, pyrrolylmethyl, pyrrolyleth l, thienyl ethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R ² is hydrido;

wherein R ³⁹ is selected from hydrido, linear or branched alkyl (C_ _. -Cιo), linear or branched alkenyl (C2-C10) , linear or branched alkynyl (C2-C10) , cycloalkyl (C3-C10) , cycloalkeryl (C3-C10) , cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10);

wherein at least one of R ⁵ , R ⁶ , R ⁸ and R ⁹ is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSθ2C6,H5, CONHOH, CONHOCH3, CONHSO2CH3,

wherein each of R ⁴² and R ⁴³ is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. Attachment of

any of the above-depicted groups to the nucleus of Formula I is through a partial bond shown projecting from a ring-carbon atom of the group. Thus, such projecting partial bond should not be interpreted as a short-hand designation of a methyl group.

A class of compounds of even more particular interest consists of those compounds of Formula I wherein m is one; wherein each of R ^a and R ^D is independently selected

O , H from radicals of the formula RΌCO— and of the formula

—OR ² , with the proviso that at least one of R ^a and R ^D must

O be a radical of the formula ι " wherein R ¹ ι RΌCO-; is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmetby1, cyclopropyletbyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl, imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmetlyl, pyrimidylethyl, indanoylmethyl, indanoylethyl, pyrroly ethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R ² is hydrido; wherein R ³⁹ is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is hydrido; wherein one of R ⁵ and R ⁹ is an acidic group selected from C0 ₂ H and tetrazole and the other of R ⁵ and R ⁹ is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

The term "hydrido" denotes a single hydrogen atom (H) . This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a

group; or, as another example, two hydrido groups may be attached to a carbon atom to form a -CH2- group. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The term "cycloalkyl" embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromet yl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroetbyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3- tetrafluoropropyl groups. The term "difluoroalkyl" embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The terms "alkylol" and "hydroxyalkyl" embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term "alkenyl" embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either

cis or trans geometry within the alkenyl moiety. The term "alkynyl" embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term "cycloalkenyl" embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The "alkoxy" or "alkoxyalkyl" radicals may be further substi-tuted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term "alkylthio" embraces radicals containing a linear or branched alkyl group of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. Preferred aryl groups are those consisting of one, two, or three benzene rings. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl and biphenyl. The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl. The terms "benzyl" and "phenylmethyl" are interchangeable. The terms "aryloxy" and "arylthio" denote aryl radicals having, respectively, an oxygen or sulfur atom through which the radical is attached to another atom or radical, examples of which are phenoxy and phenylthio. The terms "sulfinyl" and "sulfonyl", whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO2. The term "aralkoxy", alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term "acyl" whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. "Lower alkanoyl" is an example of a more prefered sub-class

of acyl. The term "amido" denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. The amido radical can be attached to the nucleus of a compound of the invention through the carbonyl moiety or through the nitrogen atom of the amido radical. The term "alkenylalkyl" denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term "heteroaryl" (unless otherwise defined) embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimic_yl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of imidazolernethy1 moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment. For any of the foregoing defined radicals, preferred radicals are those containing from one to about ten carbon atoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.

Compounds of Formula I have been found to inhibit the action of angiotensin II in mammals. Angiotensin II is a potent vasoconstrictor and participates in the formation of aldosterone which regulates sodium and water balance in mammals. Thus, compounds of Formula I are therapeutically useful in methods for treating hypertension by administering to a hypertensive patient a therapeutically-effective .amount of a compound of Formula I. The phrase "hypertensive ^' patient" means, in this context, a m_ammalian subject suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.

Included within the family of compounds of Formula I are the tautomeric forms of the described compounds.

Examples of tautomeric forms which are included in the family of compounds of Formula I are as follows:

Also included in the invention are compounds which are optical isomeric forms, including diastereoisomers, of the compounds of Formula I. Further included within the invention are the regioisomers of compounds of Formula I where the biphenylalkyl group is attached to the nitrogen atom at the three-position of the im dazo-pyridine ring system of Formula I. Further included within the invention are the pharmaceutically-acceptable salts of compounds of Formula I. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically- acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,

citric, ascorbic, glucuronic, aleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, e bonic (pamoic) , methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-metlrylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.

A family of specific compounds of particular interest within Formula I is provided hy compounds, and their pharmaceutically-acceptable salts, of the group consisting of:

2-butyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-

4-(methoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5-d]pyridaz ine;

2-butyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl] - 4,7-bis(methoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine;

2-butyl-l-[2' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-

4- (benzyloxycarbonyloxy) -7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-butyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(3-methylpropyloxycarbonyloxy)-7-bydroxy-lH-imidazo[4,5- d]pyridazine;

2-butyl-l-[2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-

4,7-bis[ (3-methyl)propyloxycarbonyloxy]-IH-imidazo[4,5- d]pyridazine; 2-butyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-

4,7-bis- (isopropyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butyl-l- [2 * - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4- (isopropyloxycarbonyloxy) -7-hydroxy-lH- imidazo [4, 5- d] pyridazine;

2-butyl-l-2 ' - (lH-tetrazol-5-yl) [1, 1 'biphenyl] -4-yl]methyl] -4- (ethoxycarbonyloxy) -7-hydroxy-lH- imidazo [4, 5-d] pyridazine; 2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4, 7-bis (ethoxycarbonyloxy) IH- imidazo [4, 5-d] pyridazine; 2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4- (cyclohexyloxycarbonyloxy) -7 -hydroxy- IH- imidazo [4, 5- d] pyridazine;

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4- (phenoxycarbonyloxy) -7-hydroxy-lH-im_idazo [4, 5-d] pyridazine; 2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4- (t-butyloxycarbonyloxy) -7-hydroxy-lH- imidazo [4, 5- d] pyridazine;

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ^■ -biphenyl] -4-yl]methyl] - 4- (propoxycarbonyloxy) -7-hydroxy-lH- imidazo [4, 5-d] pyridazine; 2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] - 4- (methoxyethoxycarbonyloxy) -7 -hydroxy- IH- imidazo [4, 5- d] pyridazine ;

2-propyl-l- [2 ' - ( lH-tetrazol-5-yl ) [1, 1 ' -biphenyl] -4- yl]metbyl] -4- (methoxycarbonyloxy) -7-hydroxy-lH-imidazo [4, 5- d] pyridazine; 2-propyl-l- [2 ^r - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl] -4, 7-bis (methoxycarbonyloxy) -IH- imidazo [4, 5- d] pyridazine;

2-propyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]metlyl] -4- (benzyloxycarboπyloxy) -7-hydroxy-lH- imidazo [4, 5- d] yridazine; 2-propyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl] methyl] -4- (3-methylpropyloxycarbonyloxy) -7 -hydroxy- 1H- imidazo [4, 5-d] pyridazine;

2-propyl-l- [2 ^r - ( lH-tetrazol-5-yl ) [1, 1 ' -biphenyl ] -4- yl]methyl] - , 7-bis [ (3 -methyl ) propyloxycarbonyloxy] -1H- imidazo [4 , 5-d] pyridazine;

2-propyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl] methyl] -4, 7-bis- (isopropyloxycarbonyloxy) -IH- imidazo [4, 5- d] yridazine;

2-propyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (isopropyloxycarbonyloxy) -7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-propyl-l-2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4- (ethoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5-d]pyridazine;

2-propyl-l-[2 '-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)IH-imidazo[4,5- d]pyridazine;

2-propyl-l-[2 '- (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4- (cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-propyl-l- [2'- (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-lH-imidazo[4,5- d]pyridazine; 2-propyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl] -4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-propyl-l-[2'- (lH-tetrazol-5-yl) [1,1--biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-propyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butenyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d] yridazine;

2-butenyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine; 2-butenyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (benzyloxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-butenyl-ll- [2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butenyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl] -4,7-bis[ (3-methyl)propylo_ycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;

2-butenyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yljmethyl]-4,7-bis-(isopropyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butenyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yljmethyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butenyl-ll-2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-bydroxy-lH-iιr_idazo[4,5 -

<3]pyridazine; 2-butenyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)IH-imidazo[4,5- d]pyridazine;

2-butenyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metbyl]-4-(cyclohescyloxycarbonyloxy)-7-hydroxy-lH- imidazo[4,5-d]pyridazine;

2-butenyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-lH-_Lmidazo[4,5- d]pyridazine;

2-butenyl-ll- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yljmethyl] -4- (t-butyloxycarbonylojy) -7 -hydroxy- 1H- i iidazo [4 , 5-d] pyridazine;

2-butenyl-ll- [2 • - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yljmethyl] -4- (propoxycarbonyloxy) -7-hydroxy-lH- imidazo [4, 5- d] pyridazine; 2-butenyl-ll- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl]-4- (methoxyethoxycarbonyloxy) -7 -hydroxy- 1H- imidazo [4, 5-d] pyridazine;

2-pentyl-ll- [2 ' - (lH-tetrazol-5-yl) [1,1 ' -biphenyl] -4- yl]metlyl] -4- (methoxycarbonyloxy) -7 -hydroxy- lH-imidazo [4, 5- d] pyridazine ;

2-pentyl-ll- [2 ^« - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl] methyl] -4, 7-bis (methoxycarbonyloxy) -IH- imidazo [4, 5- d] pyridazine;

2-pentyl-ll- [2 ' - (lH-tetrazol-5-yl ) [1 , 1 ' -biphenyl] -4- yljmethyl] -4- (benzyloxycarbonyloxy) -7 -hydroxy- IH- imidazo [4, 5- d] pyridazine;

2-pentyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-pentyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4,7-bis[ (3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;

2-pentyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy) -IH-imidazo[4,5- d]pyridazine; 2-pentyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl] -4- (isopropyloxycarbonyloxy) -7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-pentyl-ll-2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (ethoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-pentyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yljmethyl]-4,7-bis (ethoxycarbonyloxy)IH-imidazo[4,5- d]pyridazine;

2-pentyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexy1oxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-pentyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4- (phenoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine; 2-pentyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4- (t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-pentyl-ll- [2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-lH-imidazo[4,5- d]pyridazine;

2-pentyl-ll-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4- (methoxyethoxycarbonyloxy) -7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-ll- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-IH-imidazo[4,5- d.]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-IH-imidazo[ ,5- d]pyridazine;

2-isobutyl-ll-[2 ^» -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine; 2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis[ (3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-ll-[2 ^« -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-ll-2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)IH-imidazo[4,5- d]pyridazine; 2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-lH-imidazo[4,5- d]pyridazine;

2-isobutyl-ll-[2 ^« -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-lH- imidazo[4,5-d]pyridazine;

2-isobutyl-ll-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-IH-imidazo[4,5- d]pyridazine;

2-isobutyl-ll- [2 ' - (lH-tetrazol-5-yl) [1,1' -biphenyl] -4- yl]methyl]-4- (methoxyethoxycarbonyloxy) -7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 ' -(lH-tetrazol-5-yl) [1,1'- biphenyl] -4-yl]methyl]-4- (methoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2'- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl] -4,7-bis(methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; 2- (cyclopropylmethyl)-11- [2 '- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4- (benzyloxycarbonyloxy) -7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 '- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4- (3-me hylpropyloxycarbonyloxy)-7- hydroxy-lH-imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 '- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4,7-bis[ (3- methyl)propyloxycarbonyloxy]-IH-imidazo[4,5-d]pyridazine;

2-(cyclopropylmethyl)-11- [2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4,7-bis- (isopropyloxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 '- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4- (isopropyloxycarbonyloxy)-7-hydroxy-

1H-imidazo[4,5-d]pyridazine; 2- (cyclopropylmethyl)-11-2 '- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 '-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4,7-bis (ethoxycarbonyloxy) 1H- imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl] -4- (cyclohexyloxycarbonyloxy) -7- hydroxy-lH-imidazo[4,5-d]pyridazine;

2- (cyclopropylmethyl)-11- [2 '-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4- (phenoxycarbonyloxy) -7-hydroxy-lH- imidazo[4,5-d]pyridazine;

2-(cyclopropylmetlyl)-11-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy- 1H-imidazo[4,5-d]pyridazine;

2-(cyclopropylmetlyl)-11-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-lH- imidazo[4,5-d]pyridazine;

2-(cyclopropylmethyl)-11-[2'-(lH-tetrazol-5-yl) [1,1'- bipheryl]-4-yl]methyl]-4-(methoxyethoxycarbonyloxy)-7- bydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(methoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine ; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(benzyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine; 2-butyl-l-[2'-(IH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(isopropyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butyl-l-2 ^• -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(ethoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2 ^• -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(cyclohexyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(phenoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine ; 2-butyl-l-[2 ^• -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7- (t-butyloxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butyl-l-[2 ^• -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(propoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine ; 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(methoxyethoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-propyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl-4-yl]methyl]- 4-hydroxy-7-(methoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine ;

2-propyl-l-[2 ' -(lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-hydroxy-7- (benzyloxycarbonyloxy)-IH-imidazo[4,5- d] yridazine;

2-propyl-l-[2 '-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (3-methylpropyloxycarbonyloxy)-1H- imidazo[4, 5-d]pyridazine;

2-propyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl] -4-hydroxy-7- (isopropyloxycarbonyloxy) -1H- imidazo[4,5-d] yridazine; 2-propyl-l-2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4-yl]methyl] -

4-hydroxy-7- (ethoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine;

2-propyl-l-[2'-(lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl] ethyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine; 2-propyl-l-[2'- (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-hydroxy-7- (phenoxycarbonyloxy) -lH-imidazo[4, 5- d] yridazine;

2-propyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metbyl] -4-hydroxy-7-(t-butyloxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine;

2-propyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (propoxycarbonyloxy)-IH-imidazo[4, 5- d]pyridazine;

2-propyl-l- [2 '-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (methoxyethoxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine;

2-butenyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (methoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine; 2-butenyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-IH-imidazo[4,5 - d]pyridazine;

2-butenyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4-hydroxy-7- (3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-butenyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4-hydroxy-7- (isopropyloxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine;

2-butenyl-l-2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yljmetbyl]-4-hydroxy-7-(ethoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butenyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yljmethyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-butenyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydrαxy-7-(phenoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine; 2-butenyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-butenyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(propoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-butenyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl] -4-hydroxy-7- (methoxyethoxycarbonyloxy) -1H- imidazo [4 , 5-d] pyridazine;

2-pentyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl] -4-hydroxy-7- (methoxycarbonyloxy) -IH-imidazo [4, 5- d]pyridazine;

2-pentyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-IH-imidazo[4,5 - d]pyridazine; 2-pentyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-pentyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-pentyl-l-2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-

4-hydroxy-7-(ethoxycarbonyloxy)-IH-imidazo[4,5-d]pyridazi ne;

2-pentyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-pentyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (phenoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-pentyl-l- [2' - (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-hydroxy-7- (t-butyloxycarbonyloxy)-1H- ir idazo[4,5-d]pyridazine;

2-pentyl-l-[2 '- (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-hydroxy-7- (propoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine;

2-pentyl-l- [2 '- (lH-tetrazol-5-yl) [1,1' -biphenyl]-4- yl]methyl]-4-hydroxy-7- (methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; 2-isobutyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (methoxycarbonyloxy) -lH-imidazo[4,5- d]pyridazine;

2-isobutyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4- yl]methyl]-4-hydroxy-7- (benzylox carbonylox )-IH-imidazo[4,5- d]pyridazine;

2-isobutyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl] ethyl]-4-hydroxy-7- (3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (isopropyloxycarbonyloxy)-1H- iπ_Ldazo[4,5-d]pyridazine;

2-isobutyl-l-2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-IH-imidazo[4,5- d]pyridazine; 2-isobutyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-isobutyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (phenoxycarbonyloxy)-lH-imidazo[4,5- d]pyridazine;

2-isobutyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (t-butyloxycarbonyloxy) -1H- imidazo[4,5-d]pyridazine;

2-isobutyl-l- [2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7- (propoxycarbonyloxy) -IH-imidazo[4,5- d]pyridazine;

2-isobutyl-l-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[ ,5-d]pyridazine;

2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7- (methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;

2-(cyclopropylmetlyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7- (benzyloxycarbonyloxy)-IH- imidazo[4,5-d]pyridazine; 2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- bipheryl]-4-yl]methyl]-4-hydroxy-7-(3- methylpropyloxycarbonylox )-IH-imidazo[4,5-d]pyridazine;

2-(cyclopropylmethyl)-1-[2'- (lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7- (isopropyloxycarbonyloxy)- IH-imidazo[4,5-d]pyridazine;

2-(cyclopropylmetlTTyl)-1-2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-

4-yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-IH-imidazo[4 ,5- d]pyridazine;

2-(cyclopropylmethyl)-1-[2*-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-bydroxy-7-

(cyclohexyloxycarbonyloxy)-IH-imidazo[4,5-d]pyridazine;

2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; 2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-

IH-imidazo[4,5-d]pyridazine;

2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; and

2-(cyclopropylmethyl)-1-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(methoxyethoxy)-1H- imidazo[4,5-d]pyridazine.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized in accordance to the following procedures which are modeled upon a subset of biphenylmethyl carboxylic acid or biphenylmethyl tetrazole compounds of the family of compounds of Formula I. The reactions are performed in a solvent appropriate to the reagent and material employed and suitable to the transformation being performed. Some of the steps will involve reagents and substrates with functionality that will require protection. For the synthetic description and examples which follow, abbreviations which have been used have the following meanings:

CHCI3 chloroform

IMF dimethylformamide

EMSO dimethylsulfoxide g gram

MeOH methanol min minute h hour mol- mole mmol millimole mw molecular weight

TLC thin layer chromatography

Trt trityl

AIBN 2,2'-azobisisobutyronitrile

KtBuO potassium t-butoxide

Other abbreviations may be explained in the text.

In Scheme 1, as a first step, there is shown bromination of a biphenylcarboxylic ester 1 with

N-broιr;succinimide in the presence of AIBN in a suitable solvent such as carbon tetrachloride. The resulting benzyl bromide 2_ is used to alkylate a 4,5-dicarboxyimidazole 2- A

variety of solvents can be used to perform this alkylation reaction, including alcohols, dimethylformamide, acetonitrile and water. This alkylation reaction is performed in the presence of at least one quivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided hy the acidity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from 0°C to 120°C. The pyridazines 2 are obtained by a cyclocondensation reaction between the imidazole _4 and hydrazine. Depending on the reactivity of the imidazole a stoichiometric or an excess quantity of the hydrazine is used and the reaction occurs at a temperature which may vary from below room temperature to the reflux temperature of the reaction medium. The reaction solvent can either be an inert solvent or one of the reagents. The free acid 2 is obtained from the corresponding ester 2 by treatment with TFA in dichloromethane when R is a t-butyl group or by treatment with potassium hydroxide when R is a methyl group. An excess quantity of either TFA or KOH is used and the temperature may vary from below room temperature to the reflux terrperature of the reaction medium.

SCHEME 1

R 'CO

_R 39

N

R'CO 3.

wherein R = CH ₃ or C(CH ₃ ) _3; and R 39 is as defined above.

In Scheme 2, a biphenylcarboxylic acid ester 7. is converted to the cyanoderivative 2 hy a method described by J. A. Krynitsky et al rorσ. Svnth. Coll.. 3 , 698 (1955)] and J. Cason rorσ. Svnth. Coll. , 2, 169 (1955)]. The acid obtained by saponification of ester 7. is transformed into the acid chloride which in turn is converted into the primary carboxamide eventually dehydrated to cyano derivative 2- The cyano derivative 8 is reacted by a 1,3-dipolar cycloaddition with trialkyltin azide to produce the corresponding tetrazole 2 as described by K. Sisido et al fJ. Orσanometal. Chem.. 33, 337-46 (1971) ] . The reaction is advantageously performed with an excess of the trialkyltin azide in refluxing toluene or dimethylformamide as inert solvent. The N-(trimethyl- stannyl)tetrazole 9_ can be converted to the free tetrazole by bubbling dry gaseous hydrochloric acid in an ethereal or alcoholic solution. Intermediate free tetrazole is reacted with an aralkylhalide, such as trityl chloride, which will provide a removable protecting group for the tetrazole. This reaction is best performed with trityl chloride in an inert solvent such as dichloromethane in the presence of at least one equivalent of a non-nucleophilic base such as pyridine or a trialkylamine. The bromination of 12 into the benzyl bromide .11 is performed with N-bromosuccinimide in the presence of AIBN in an inert solvent such as carbon tetrachloride, the reaction medium being heated at a temperature from 40°C to reflux of the solvent used.

SCHEME 2

&

11

In Scheme 3, the bromomethylbiphenyl tetrazole 11 is used to alkylate a 4,5-dicarboxyimidazole 12- A variety of solvents can be used to perform this alkylation reaction including alcohols, dimethylforiiamide, acetonitrile and water. This alkylation reaction is best performed in the presence of at least one equivalent of a base. Among the bases that can.be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the activity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from about 0°C to about 120°C. The pyridazines 12 are obtained by a cyclocondensation reaction between the imidazole and hydrazine. Depending on the reactivity of the imidazole 12 _. a stoichiometric or an excess quantity of the hydrazine is used and the reaction occurs at a temperature which may vary from below room terrperature to the reflux temperature of the reaction solvent. The reaction may be performed neat or in the presence of an inert solvent such as dimethylfoii.mair__.de, ethanol or toluene. The desired free tetrazole derivative 12 is obtained by removal of the protecting group. The deprotection reaction can be performed thermally at temperatures from about 50°C to about 150°C or preferably at a lower temperature in the presence of aqueous acetic acid.

SCHEME 3

Nh NH,

1 2 39 wherein R , R and R are as defined above.

Scheme 4 is a diagram illustrating methods that lead to modification of the substituents R ¹ and R ² . For example, when each of R ¹ and R ² is a chloro substituent, compound 17 can be substituted by nucleophiles such as amines, aminoalkyls, thiol, hydroxy and alkoxy groups. A compound of formula 12 is obtained when compound 12 is heated in presence of a thiolate salt in a polar solvent such as water or dimethylformamide. If hydroxide ion is used as the nucleophilic species, the diol 1£ is formed which can be subsequently converted into a dialkoxy compound 22 by treatment with a halide, alkyltosylate or alkylmesylate. The reaction is preferably performed in the presence of at least one equivalent of a base which can be organic, e.g., a carbonate or bicarbonate of an alkali or alkaline earth metal. Depending on the reactivity of the alkylating agent, a stoichiometric or an excess quantity is used, and the reaction occurs at a temperature which may vary from about 0°C to reflux temperature of the reaction medium.

SCHEME 4

1 2 Q wherein R , R and R are as defined before.

Scheme 5 describes the preparation of 4- or 7-hydroxy pyridazine derivatives. As a first step is shown the preparation of the 2-butyl-4,5-dimethoxycarbonyl- imidazole. According to the Maquenne procedure [Snyder et al. Orσ. Synth.. 1947, 22,65] the starting material, tartaric acid, is treated sequentially by fuming nitric acid, ammonia and valeraldehyde. The intermediate diacid is directly converted to the dimethylester 22 by the use of hydrochloric acid (gas) or sulfuric acid in methanol. In the second step, the diester is treated with a reducing agent, preferentially a metallic hydride like diisobutylaluir num hydride to give, hy partial reduction the adehyde-ester derivative 22- The adehyde-ester 2 can be alkylated hy the bromomethyl biphenyl tetrazole H (prepared in Scheme 2) . A variety of solvents can be used to perform this alkylation reaction including alcohols, d-Lmethylformamide, acetonitrile and water. This alkylation reaction is best performed in the presence of at least one equivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided hy the activity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from about 0°C to about 120°C. This reaction gave a mixture of the tetrasubstituted imidazoles 24 and 22, isomeric hy the position of the aldehyde and carbomethoxy groups on the imidazole nucleus. The isomers can be separated by crystallization or by a chromatographic method. The pyridazines 22 and 22 are obtained by a cyclocondensation reaction between the imidazole and hydrazine. Depending on the reactivity of the imidazole, _έ or / a stoichiometic or an excess quantity of the hydrazine is used and the reaction occurs at a temperature which may vary from below room temperature to the reflux temperature of the reaction solvent. The reaction may be performed neat or in the presence of an inert solvent such as dimethylformamide, chloroform, isopropanol, ethanol or toluene. The cyclization reaction may be catalyzed by the use of a base such as trialkylamines or alcoholates. The

desired free tetrazole derivative is obtained by removal of the protecting group. The deprotection reaction can be performed thermally at temperatures from about 50°C to about 150°C in a variety of solvents including methanol, ethanol, isopropanol, dimethylformamide or chloroform, or preferably at a lower temperature in the presence of aqueous acetic acid.

SCHEME S

₂

21 22

NB: BT2 = biphenyl jtrityl .tetrazole

Scheme 6 describes an alternative preparation of hydroxy-pyridazine, particularly suitable for the 7-hydroxy isomers 22. As a first step, is shown the preparation of 2-butyl-4,5-dimethoxycarbonyl-imidazole. According to the Maquenne procedure the starting material, tartaric acid, is treated sequentially by fuming nitric acid, ammonia and valeraldehyde. The intermediate diacid is directly converted to the dimethylester 22 by the use of hydrochloric acid (gas) in methanol. In the second step, several equivalents of a metallic hydride are used to reduce one of the ester function of 22 to the corresponding primary alcohol 28. Preferentially 3 equivalents of lithium triethylborohydride ( "superhydride") in an inert solvent such as an ether or a cyclic ether such as tetrahydro furane are used. After acidic aqueous workup, the alcohol-ester 22 is isolated in good yield. This alcohol ester 22 can be alkylated by the bromomethyl biphenyl tetrazole H (prepared in Scheme 2) . A variety of solvents can be used to perform this alkylation reaction, including alcohols, dimethylformamide, acetonitrile and water. This alkylation reaction is performed in the presence of at least one equivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the acidity of the imidazole proton to be abstracted. The alkylation reaction results in the formation of a mixture of alkylated imidazoles 22 and 22- The treatment of this mixture with an oxidizing system such as pyridinium chlorochromate in dichloromethane, lead tetraacetate in pyridine or, preferentially manganese dioxide in dichloromethane or acetonitrile. The temperature may vary from below room temperature to the reflux terrperature of the reaction mixture. The reaction is normally brought about at temperatures ranging from 0°C to 120°C. This oxidative process produces preferentially the adehyde 22. which can be easily separated by a chromatographic procedure or by crystallization. The pyridazine 22 is obtained by a

cyclocondensation reaction between the imidazole 24. and hydrazine. A stoichiometric quantity or preferentially an excess of the hydrazine can be used and the reaction occurs at a terrperature which may vary from below room terrperature to the reflux terrperature of the reaction medium. The reaction solvent can either be an inert solvent or one of the reagents. The desired derivative 22 is obtained directly from the reaction mixture.

SCHEME 6

21

28 1 1

_n _

_n . _Bu

NB Bt2 = biphenyl trityl tetrazole.

Scheme 7 describes a general procedure for preparation of ester derivatives.

A solution of 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'- biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-lH-imidazo[4,5- d] yridazine and a non nucleophilic base, preferentially a trialkylamine, and more preferentially triethylamine in a polar solvent such as acetonitrile or DMF is stirred at 25°C and 1 equivalent of the desired acid chloride. The reaction is monitored by TLC and/or HPLC. Several more equivalents (up to 5 equivalents total) may be added, depending whether the mono or the disubstituted product is desired. After aqueous work up the products of the reaction can be separated and purified by preparative reverse-phase, high-pressure liquid chromatography (RPHPLC) .

SCHEME

R = alkyl, aryl, aralkyl

A solution of 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-IH-imidazo[4,5- d]pyridazine (0.5 g, 1.1 mmol) and nonnucleophilic base, preferentially a trialkylamine, and more preferentially triethylamine in a polar solvent such as acetonitrile DMF was stirred at 25°C and 1 equivalent of the desired acid chloride or chlorofornate was added. The reaction was monitored hy TLC and/or HPLC. Several more equivalents (up to 5 equivalents total) may be added, depending whether the mono or the disubstituted product was desired. The reaction mixture was then poured in water made acidic with HCI 4N and extracted with ethyl acetate. The organic phase was dried on MgS04 and concentrated in vacuo. The products of the reaction could be separated and purified by preparative reverse-phase, high-pressure liquid chromatography ( (RPHPLC) using water/acetonitrile as the eluant. The products were identified by proton NMR and mass spectroscopy.

SCHEME 8

R = alkyl, aryl, aralkyl

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures excpressed are in degrees centigrade.

EXAMPLE 1

O

II

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1, 1'biphenyl] -4- yl] ethyl] -4-met_ιoxycarbonyloxy-7-hydroxy-1H- imidazo[4 ,5-d]pyridazine

A solution of 2-butyl-l-[2'-(lH-tetrazol-5- yl} [1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-lH-imidao[4,5- d]pyridazine (0.5 gg, 1.1 irmol) and triethylamine (0.77 mL, 5 equivalents) in 2 mL DMF was stirred at 25°C and methyl chlorofarmate (0.77 mL, 6.2 equivalents) was added. The reaction was monitered by TLC. The reaction mixture was poured into 50 miL of 0.5 mL of 0.5N HCI then exctracted with ethyl acetate. The ethyl acetate was dried over MgSθ4 and concentrated in vacuo to yield an oil. This was dissolved in a irάniiπum amount of acetone and precipitated using hexcane to yield 450 mg of a white solid. This crude material was dissolved in 25 mL acetone, then diluted with 25 mL water and purified by RPHPLC using water/acetonitrile as the eluant. The product was exctracted from the acetonitrile/water mixture using ethyl acetate. It was concentrated in vacuo to give 80 mg (14.5% yield) of a white solid: K NMR (DMSO-d6) δ 7.45- 7.13 ( , 4H) , 6.91-6.72 (m, 4H) , 5.45(s, 2H) , 3.78(s, 3H) ,

3.68(s, 3H), 2.55-2.4 ( , 2H) , 1.52-1.35(m, 2H) , 1.15-0.97 (m, 2H), 0.70-0.50 (m, 3H) .

EXAMPLE 2

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) - [1, 1 'biphenyl] -4- yl] methyl] 4 /7-bis (methoxycarbonyloxy) -1H- imidazo (4, 5-d] pyridazine

This product was obtained from the reaction mixture in Example 1 using the same procedures. 115 mg (18.7% yield) of the product was recovered as a white powder: NMR (DMSO-d6) δ 7.35-7.08 (m, 4H) , 6.83-6.70(m, 4H) , 5.34(s, 2H), 3.57(s, 3H), 2.45-2.30 (m, 2H) , 1.39-1.22 (m, 2H) , 1.09- 0.98 ( , 2H) , 0.55-0.42 (m, 3H) .

EXAMPLE 3

II

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1.1 ' -biphenyl] -4- yl] ethyl] -4-benzyloxycarbonyloxy-7-hydroxy-lH- imidazo [4,5-d]pyridazine

A solution of 2-butyl-l-[2'-(lH-tetrazol-5- yl) [1,1"-biphenyl] [-4-yl]metbyl]4,7-bis-bydroxy-lH- imidazol[4,5-d}pyridazine (0.5 g, 1.13 mmol) and triethylc-mine (0.31 mL, 2 equivalents) in 10 mL DMF was . stirred at 25°C and 1 equivalent of benzylchloroformate was added. The reaction was monitered hy TLC and/or HPLC for complete disappearance of benzylchloroformate. Four more equivalents (5 equivalents total) were added. The reaction mixture was then poured in water made acidic with HCI 4N and exctracted with ethyl acetate. The organic phase was dried on MgSθ and concentrated in vacuo to an orange oil (1.1 g) . The products of the reaction could be separated by preparative RPHPLC using water/acetonitrile as the eluant. The last product to elute was collected and obtained after lyophilization as a white powder (167 mg) : NMR (DMSO-d6) : δ 7.61(m, 2H), 7.55(d, IH, J = 8Hz) , 7.38 (d, IH, J = 8Hz) , 7.4(m, 5H), 7.1(m, 4H) , 5.7(s, 2H) , 5.3 (s, 2H) , 2.7(t, 2H,

J = 7Hz ) , 1 . 55 (m, 2H) , 1.3 (m, 2H) , 0 . 9 t , 3H, J = 7Hz ) ; HRMS . Calc ' d for M+H (C31H28N8O4 ) : 577 .2312 . FOUND 577 .2312 .

EXAMPLE 4

2-butyl-l- [2' - (lH-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl] -4- (3-methylpropyloxycarbonyloxy) -7- hydroxy-lH-imidazo [4, 5-d]pyridazine

A solution of 2-butyl-l- [2 '-(lH-tetrazol-5- yl) [1,1' -biphenyl]-4-yl]-4,7-bis-hydroxy-lH-imidazo[4,5- d]pyridazine (0.3 g, 0.7 mmol) and triethylamine (0.55 mL,

5.7 equivalents) in 4 mL DMF was stirred at 25°C and isobutyl chloroformate (0.31 mL, 3.2 equivalents) was added. The reaction was monitered by TLC. The reaction mixture was poured into 50 mL of 0.5 N HCI, then extracted with ethyl acetate. The ethyl acetate was dried over MgSθ4 and concentrated in vacuo to an oil. This crude material was dissolved in 10 mL acetone, then diluted with 10 mL water and purified hy RPHPLC using water/acetonitrile as the eluant. The product was lyophilized to give 65 mg (17.1% yield) of a white solid: ^λ E NMR (DMSO-d6) δ 7.72-7.49(m, 4H) , 7.20-

7.08(m, 4H), 5.76(s, 2H) , 4.08(d, J = 4, 2H) , 2.75-2.7 (m,

2H), 2.08-1.93 (m, IH) , 1.61-1.50 (m, 2H) , 1.36-1.21(m, 2H) , 0.95-0.90 (m, 6H) , 0.87-0.78 (m, 3H) .

EXAMPLE 5

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1.1 ' -biphenyl] -4- yl]methyl] -4, 7-bis [ (3 -methyl) propyloxycarbonyl oxy] - lH-imidazo [ , 5-d] pyridazine

This product was obtained from the reaction mixture in Example 4 using the same procedures. 120 mg (13.1%) of the product was recovered as a white powder (mp 101-105°C) : R N R (DMSO-d6) δ 87.73-7.49 (m, 4H) , 7.20- 7.02(m, 4H), 5.76(s, 2H) , 4.23-4.08(m, 4H) , 2.82-2.68(m, 2H) , 2.14-1.93(m, 2H) , 1.62-1.49 (m, 2H) , 1.38-1.23 (m, 2H) , 1.04-0.79 ( , 12H) , 0.69-0.61 (m, 3H) .

EXAMPLE 6

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1.1 ' -biphenyl] -4- yl]methyl] -4,7-bis (isopropyloxycarbonyloxy) -1H- imidazo [4, 5-d]pyridazine

A solution of 2-butyl-l-[2 '-(lH-tetrazol-5- yl) [1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-IH-imidazo[4,5- d]pyridazine (0.5 g, 1.1 mmol) and triethylamine (0.40 mL, 2.6 equivalents in 5 mL DMF was stirred at 25°C and isopropyl chloroformate (1 M solution in toluene, 2.2 mL, 2.2 equivalents) was added. The reaction was monitered by TLC. The reaction mixture was poured into 50 mL of 0.5N HCI, then extracted with ethyl acetate. The ethyl acetate was dried over MgS04 and concentrated in vacuo to an oil. This crude material was dissolved in 10 mL acetone, then diluted with 10 mL water and purified by RPHPLC using water/acetonitrile as the eluant. The product was lyophilized to give 75 mg (12.2% yield) of a white solid (mp 108-110°C) : ^λ E NMR (DMSO- dδ) δ 7.76-7.51(m, 4H) , 7.19-7.01(m, 4H) , 5.74(s, 2H) , 4.99- 4.84(m, 2H) , 2.76-2.68(m, 2H) , 1.58-1.48 (m, 2H) , 1.40-1.23 (m, 10H), 1.08-1.01(11., 4H) 0.89-0.78(m, 3H) .

EXAMPLE 7

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1 ' -biphenyl] -4- yl]methyl] -4- (isopropyloxycarbonyloxy) -7 -hydroxy- 1H- imidazo [4, 5-d] pyridazine

This product was obtained from the reaction mixture in Example 6 using the same procedures. 50 mg (8.6% yield) of the product was recovered as a white powder: ^H. NMR (DMSO-d6) δ 7.71-7.52 (m, 4H) , 7.21-7.08 (m, 4H) , 5.74(s, 2H) , 4.95-4.88 (m, IH) , 2.82-2.73 (m, 2H) , 1.64-1.53 (m, 2H) , 1.37- 1.26 (m, 8H), 0.88-0.75 (m, 3H) .

EXAMPLE 8

2-butyl-l- [2 ' - (lH-tetrazol-5-yl) [1,1 ' -biphenyl] -4- yl]methyl] -4- (ethoxycarbonyloxy) -7-hydroxy-1H- imidazo [4, 5-d]pyridazine

A solution of 2-butyl-l- [2 '- (lH-tetrazol-5- yl) [1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-IH-imidazo[4,5- d]pyridazine (0.5 g, 1.1 mmol) and triethylamine (1.0 mL, 6.5 equivalents) in 10 mL DMF was stirred at 25°C and ethyl chlόroformate (0.17 mL, 1.5 equivalents) was added. The reaction was monitered by HPLC. Next, 2 mL acetic acid were added to the reaction mixture. This mixture was diluted to 25 mL total volume with water, then purified by RPHPLC using water/acetonitrile as the eluant. The product was lyophilized to give 145 mg (25.7% yield) of a white solid: ^λ E NMR (DMSO-d6) δ l2.66(s, IH) , 7.71-7.48(m, 4H) , 7.17 (d, J = 6, 2H) , 7.08(d, J = 5, 2H) , 5.75(s, 2H) , 4.32(q, J = 12, 2H) , 2.74(t, J = 6, 2H), 1.60-1.48 (m, 2H) , 1.37-1.20 (m, 5H) , 0.82 (t, J = 9, 3H) .

EXAMPLE 9

O

2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1' -biphenyl] -4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)IH-imidazo[4,5- d]pyridazine

A solution of 2-butyl-l-[2'-(lH-tetrazol-5- yl) [1,1*-bipheiyl]-4-yl]-4,7-bis-hydroxy-lH-imidazo[4,5- d]pyridazine (1.0 g, 2.3 mmol) and triethylamine (2.0 mL, 6.3 equivalents) in 10 mL DMF was stirred at 25°C and ethyl chloroformate (0.90 mL, 4.0 equivalents) was added. The reaction was monitered by HPLC. The reaction mixture was diluted with 10 mL methanol, then 2 mL acetic acid were added. This mixcture was diluted to 50 iriL total volume with water, then purified by RPHPLC using water/acetonitrile as the eluant. The product was lyophilized to give 600 mg (45.3% yield) of a white solid: ^-H NMR (DMSO-d6) δ 7.72- 7.50(m, 4H), 7.16(m, 2H) , 7.09 ( , 2H) , 5.74(s, 2H) _. 4.48- 4.30(m, 4H), 2.74(t, 2H, J = 7Hz,), 1.61-1.49(m, 2H) , 1.38- 1.21(m, 8H), 0.81(t, 3H, J = 7Hz) ; MS. Calc'd for M+H: 587.3. M+Lϊ: 593.3. High Res. Calc'd: 587.2367. Obs: 587.2404 + 3.7.

BIOLOGICAL EVALUATION

Assay A: Angiotensin II Binding Activity

Compounds of the invention were tested for ability to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin II (All) was purchased from Peninsula Labs. 1251-angiotensin II (specific activity of 2200 Ci/mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Sigma Chemical Co. This assay was carried out according to the method of Douglas et al .Endocrinology. 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4°C. 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 x g for 20 min., and the supernatant was recentrifuged at 100,000 x g for 60 min. The pellet was resuspended in buffer consisting of 2 mM EGTA and 50 mM Tris-HCl (pH 7.5) to a final protein concentration of 4 mg/ml. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgCl2,

2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and ¹²⁵ I-AII (approximately 10 ⁵ cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the addition of membrane protein and the mixture was incubated at 25°C for 60 min. The incubation was terminated with ice-cold 50 iriM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micrα edic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μM of unlabelled All. Specific binding was calculated as total binding minus nonspecific binding. The receptor binding affinity of an All antagonist compound was indicated hy the concentration (IC50) of the tested All antagonist which gives 50% displacement of the total specifically bound 125ι_&χχ from the high affinity ("Type 1") All receptor. Binding data were analyzed by a

non-linear least-squares curve fitting program. Results are reported in Table I.

Assay B: In Vitro Vascular Smooth Muscle-Response for All

The compounds of the invention were tested for antagonist activity in rabbit aortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificed using an overdose of pentobarbital and exsanguinated via the carotid arteries. The thoracic aorta was removed, cleaned of adherent fat and connective tissue and then cut into 3-mm ring segments. The endothelium was removed from the rings by gently sliding a rolled-up piece of filter paper into the vessel lumen. The rings were then mounted in a water-jacketed tissue bath, maintained at 37°C, between moveable and fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 8 Grass Polygraph for recording isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (iriM) : 130 NaCl, 15

NaHC03, 15 KCI, 1.2 N-1H2PO4, 1.2 MgSθ4, 2.5 CaCl2, and 11.4 glucose. The preparations were equilibrated for one hour before approxcimately one gram of passive tension was placed on the rings. Angiotensin II concentration-response curves were then recorded (3 X 10 ^~10 to 1 X 10 ^-5 M) . Each concentration of All was allowed to elicit its maximal contraction, and then All was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of All. Aorta rings were excposed to the test antagonist at 10 ^~ 5 M for 5 minutes before challenging with All. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H.O. Schild fBr. J. Pharmacol. Chemother. ,

2,189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for All by a factor

of 2. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table I.

Assay C: In Vivo Intraduodenal Pressor Assay Response for All Antagonists

Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with Inactin (100 mg/kg, i.p.) and catheters were implanted into the trachea, femoral artery, femoral vein and duodenum. Arterial pressure was recorded from the femoral artery catheter on a Gould chart recorder (Gould, Cleveland, OH) . The femoral vein catheter was used for injections of angiotensin II, mecamylamine and atropine. The tracheal catheter allow for airway patency, and the duodenal catheter was used for intraduodenal (i.d.) administration of test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Mecamylamine (3 mg/kg, 0.3 ml/kg) and atropine (400 ug/kg, 0.3 ml/kg) were then given i.v. to produce ganglion blockade. These compounds were administered every 90 minutes throughout the test procedure. Angiotensin II was given in bolus does i.v. (30 ng/kg in saline with 0.5% bovine serum albumin, 0.1 ml/kg) every 10 minutes three times or until the increase in arterial pressure produced was within 3 m Hg for two consecutive All injections. The last two All injections were averaged and were taken as the control All pressor response. Ten minutes after the final control All injection, the test compound (dissolved in sodium bicarbonate) was administered i.d. at a dose of 3, 10, 30 or 100 mg/kg in a volume of 0.2 ml. Angiotensin II injections were then given 5, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after administration of the test compound and response of arterial pressure was monitored. The response to All was calculated as percent of the control response and then the percent inhibition is calculated as 100 minus the percent control response.

Duration of action of a test compound was defined as the time from peak percent inhibition to 50% of peak. One compound at one dose was tested in each rat. Each test compound was

tested in two rats and the values for the two rats were averaged. Results are reported in Table I.

Assay D: In Vivo Intragastric Pressor Assay Response for All Antagonists

Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with methohexcital (30 mg/kg, i.p.) and catheters were implanted into the femoral artery and vein. The catheters were tunneled subcutaneously to excit dorsally, posterior to the head and between the scapulae. The catheters were filled with heparin (1000 units/ml of saline) . The rats were returned to their cage and allowed regular rat chow and water ad libitum. After full recovery from surgery (3-4 days), rats were placed in Lucite holders and the arterial line was connected to a pressure transducer. Arterial pressure was recorded on a Gould polygraph ( mHg) . After 1-2 hours of stable baseline recording, the intravenous infusion of angiotensin II (50 ng/kg/min) was given at a rate of 0.0096 ml/min. After allowing one hour for pressure to stabilize, the test compound (suspended in 0.5% methylcellulose in water) was administered hy gavage. The volume administered was 2 ml/kg body weight. Arterial pressure was monitored for 5 hours post-dosing. The angiotensin II infusion was then discontinued .and pressure was allowed to reach a stable recovery level. Percent inhibition (%I) of the angiotensin II pressor response was calculated from the difference in pressure at a given timepoint post-dosing with the test compound and the angiotensin II-infused pressure, divided hy the difference in pressure with and without the angiotensin II infusion; this value was multiplied by 100. Duration of action of a test compound was defined as the time taken for pressure to return to angiotensin II-infused baseline levels after compound administration. A compound at one dose was tested in two rats. Results are reported in Table I.

TABLE I

In Vivo and In Vitro Angiotensin II Activity of Compounds of the Invention

^Assay A: Angiotensin II Binding Activity 2j^ _ssa y B _: in vitro Vascular Smooth Muscle Response 3Assays C and D: In Vivo Pressor Response (all test compounds administered intragas- trically, except for compounds where dose is indicated by asterisk(*), which compounds were given intraduodenally) .

Also embraced within this invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The compounds of the present invention may be administered hy any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intra¬ muscularly 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 made 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 with advantage contain an amount of active ingredient from about 1 to 250 g, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered hy injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. A suitable daily dose is from about 0.1 to 100 mg/kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 30 mg/kg body weight. Compounds indicated for prophylactic therapy will preferably be administered in a

daily dose generally in a range from about 0.1 mg to about 100 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of 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 unit dose.

The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.

For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxcypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared

from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.