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WO1993003033A1 - CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS - Google Patents

CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS Download PDF

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Publication number
WO1993003033A1
WO1993003033A1 PCT/US1992/005856 US9205856W WO9303033A1 WO 1993003033 A1 WO1993003033 A1 WO 1993003033A1 US 9205856 W US9205856 W US 9205856W WO 9303033 A1 WO9303033 A1 WO 9303033A1
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Prior art keywords
pyridazine
biphenyl
imidazo
tetrazol
methyl
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PCT/US1992/005856
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French (fr)
Inventor
Philippe R. Bovy
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G. D. Searle & Co.
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Publication of WO1993003033A1 publication Critical patent/WO1993003033A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • angiotensin II antagonist compounds provided by imidazo[4,5- d]pyridazine biphenylmethyl derivatives having at least one carbonate-type group attached to the 4 and/or 7 positions of the imidazo-pyridazine heterocycle.
  • 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
  • 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.
  • 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 reninangiotensin system through interaction with various tissue receptors.
  • angiotensin II There are several known angiotensin II
  • peptidic 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.
  • peptidic angiotensin II antagonists e.g., Saralasin
  • Saralasin peptidic angiotensin II antagonists
  • Non-peptidic compounds with angiotensin II antagonist properties are known.
  • the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5- acetic acid has specific competitive angiotensin II
  • Blankey et al describes a family of 4,5,6,7-tetrabydro-1H- imidazo(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 imidazoles, as antagonists to the angiotensin II receptor.
  • EP #323,841 published
  • biphenylmethylpyrazoles biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]- 4H-1,2,4-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.
  • imidazole nucleoside produced the compound 1-( ⁇ -D- ribofuranosyl)-imidazo[4,5-d]pyridazine-4,7-dione
  • a family of 4-substituted imidazo[4,5-d]pyridazines including several 4-amino- and 4-alkylamino-1-benzyl-7-chloroimidazo[4,5-d]pyridazines, has been prepared for antitumor evaluation [J.A. Carbon, J. Am. Chem. Soc., 80 , 6083-6088 (1958)].
  • U.S. Patent No. 4,656,171 describes certain 2-phenyl-imidazo-pyridazines for use as cardiotonics, including a benzyloxy-substituted 2-phenyl-imidazole[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-1H-imidazo[4,5- c]pyridine derivatives as antihypertensive agents.
  • 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:
  • m is a number selected from one to four, inclusive; wherein each of R a and R b is independently selected from radicals of the formula and of the formula —XR 2 , with the proviso that at least one of R a and R b must be a radical of the formula wherein each of W and X is independently selected from oxygen atom and sulfur atom;
  • each of R 1 and R 2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R 3 through R 11 and R 39 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, formyl, alkylcarbonyloxy, cycloalkylalkoxy, alkoxyalkoxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,
  • alkylthiocarbonyloxy alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio.
  • arylthio arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,
  • 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
  • R 12 and R 13 taken together, R 14 and R 15 taken together and R 16 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 13 taken together and R 14 and R 15 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
  • 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
  • R 18 is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
  • 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,
  • 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
  • X is selected from oxygen atom and sulfur atom
  • R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 24 and
  • D is selected from oxygen atom, nitrogen atom and sulfur atom and R 24 is selected from hydrido, alkyl,
  • R 20 , R 21 , R 22 , R 23 , R 25 and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl,
  • R 20 ' R 21 , R 22 , R 23 , R 25 and R 26 is further independently selected from amino and amido radicals of the formula
  • haloalkylsulfonyl, aralkyl and aryl, and wherein R 20 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
  • heterocyclic group 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 20 and R 21 taken together and R 25 and R 26 taken together may each form can aromatic heterocyclic group having five ring members
  • aromatic heterocyclic group 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.
  • cardiovascular disorders such as hypertension, congestive heart failure and arteriosclerosis
  • compounds of Formula I could be used in conjunction with certain surgical procedures.
  • these compounds could be used to prevent post- angioplasty re-stenosis.
  • compounds of Formula I are all characterized in having at least one carbonate substituent at one of the R a and R b positions of the imidazopyridazine ring.
  • compounds of Formula I may have one carbonate group at the R a or R b position, or may have carbonate groups at both R a and R b positions.
  • carbonate as used herein, means a substituent selected from radicals of the formula
  • alkyl portion contains 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 the X moiety of the formula
  • 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 11 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.
  • 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).
  • n is zero and A is -COOH
  • the -Y n A moiety such carboxyl group would be attached directly to one of the R 3 -R 11 positions.
  • the Formula I compound may have one -Y n A moiety attached at one of the R 3 -R 11 positions, or may have a plurality of such -Y n A moieties attached at more than one of the R 3 -R 11 positions, up to a maximum of nine such -Y n A moieties.
  • acidic groups other than carboxyl group
  • 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 -Y n A 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.
  • pK a values of the Formula I compound as conferred fcy the -Y n A moiety be in a range from about two to about seven.
  • the -Y n A moiety may be attached to one of the R 3 -R 11 positions through any portion of the -Y n A 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.
  • 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 b is independently selected from radicals of the formula and of the formula —XR 2 , with the proviso that at least one of R a and R b must be a radical of the formula wherein each of W and X is independently selected from oxygen atom and sulfur atom;
  • each of R 1 and R 2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R 3 through R 11 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, formyl, alky
  • mercaptocarbonyl mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,
  • alkylthiocarbonyloxy alkylthiocarbonylthio
  • alkylthiothiocarboryl alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,
  • 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
  • each R 3 through R 11 substituent may be further independently selected from acidic moieties of the formula
  • 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
  • R 18 is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,
  • 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 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 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R 20 , R 21 , R 22 and R 23 is
  • a more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R a and R b is independently selected from radicals of the formula .and of the formula —XR 2 , with the proviso that at least one of R a and R b must be a radical of the formula wherein each X is
  • R 1 and R 2 are independently selected from oxygen atom and sulfur atom; wherein each of R 1 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,
  • each of R 3 through R 11 is independently selected from hydrido, linear or branched alkyl (C 1 -C 10 ), linear or branched alkenyl (C 2 -C 10 ), linear or branched alkynyl
  • alkylsulfinyl alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R 3 -R 11 substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula
  • R 33 is selected from hydrido, linear or branched alkyl (C 1 -C 10 ,), linear or branched alkenyl (C 2 -C 10 ), linear or branched alkynyl (C 2 -C 10 ), cycloalkyl (C3-C10),
  • cycloalkenyl (C 3 -C 10 ), cycloalkylalkyl (C 4 -C 10 ) and
  • R 3 -R 11 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
  • W is selected from O, 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 3 -R 11 or may be attached at any two positions selected from R 3 -R 11 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
  • 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 (C 1 -C 10 ,), linear or branched alkenyl (C 2 -C 10 ), linear or branched alkynyl
  • cycloalkylalkyl (C 4 -C 10 ) and cycloalkenylalkyl (C 4 -C 10 );
  • alkyl 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.
  • heterocyclic groups which can be used as bioisosteres of carboxylic acid include:
  • each of R 42 , R 43 and R 44 is independently selected from H, Cl, CN, NO 2 , CF 3 , C 2 F 5 , C 3 F 7 , CHF 2 , CH 2 F, CO 2 CH 3 , CO 2 C 2 H 5 , SO 2 CH 3 , SO 2 CF 3 and SC 2 C 6 F 5 ; wherein Z is selected from O, S, NR 4 5 and CH 2 , wherein R 4 5 is selected from hydrido, CH 3 and CH 2 C 6 H 5 .
  • 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;
  • each of R a and R b is independently selected from radicals of the formula and of the formula —OR 2 , with the proviso that at least one of R a and R b must be a radical of the formula wherein R 1 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;
  • said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R 3 -R 11 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
  • a class of compounds of particular interest consists of those compounds of Formula I wherein m is one; wherein each of R a and R b is independently selected from radicals of the formula and of the formula —OR 2 , with the proviso that at least one of R a and R b must be a radical of the formula ; wherein R 1 is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
  • cyclobutyl cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
  • imidazolemethyl imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimicaylethyl, indanqylmethyl,
  • R 2 is hydrido; wherein R 39 is selected from hydrido, linear or branched alkyl (C 1 -C 10 ), linear or branched alkenyl (C 2 -C 10 ), linear or branched alkynyl (C 2 -C 10 ), cycloalkyl (C 3 -C 10 ), cycloalkeryl (C 3 -C 10 ), cycloalkylalkyl (C 4 -C 10 ) and cycloalkenylalkyl (C 4 -C 10 ); wherein at least one of R 5 , R 6 , R 8 and R 9 is an acidic group selected from CO 2 H, SH, PO 3 H 2 , SO 3 H
  • each of R 42 and R 43 is independently selected from Cl, CN, NO 2 , CF 3 , CO 2 CH 3 and SO 2 CF 3 ; 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 b is independently selected from radicals of the formula and of the formula
  • R 1 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, cyclopropylmetbyl, cyclopropyletbyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
  • imidazolemethyl imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmetlyl, pyrimidylethyl, indanoylmethyl,
  • R 5 and R 9 is an acidic group selected from CO 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.
  • hydro 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 CH- group; or, as another example, two hydrido groups may be attached to a carbon atom to form a -CH 2 - group.
  • alkyl is used, either alone or within other terms such as “haloalkyl” and "hydroxyalkyl”
  • alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms.
  • 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.
  • 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.
  • 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
  • a monohaloalkyl group 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-chloromethyl group.
  • Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroetbyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3- tetrafluoropropyl groups.
  • difluoroalkyl embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms.
  • 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.
  • 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.
  • 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.
  • cycloalkenyl embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons.
  • 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.
  • alkoxyalkyl also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form
  • 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.
  • 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.
  • aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
  • aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl.
  • benzyl and "phenylmethyl” are interchangeable.
  • 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.
  • sulfinyl and “sulfonyl”, whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO 2 .
  • aralkoxy alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy.
  • 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.
  • 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.
  • 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
  • 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, pyrimidyl 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 imidazolemethyl moiety.
  • heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment.
  • preferred radicals are those containing from one to about ten carbon atoms.
  • 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.
  • angiotensin II is a potent vasoconstrictor and participates in the formation of aldosterone which regulates sodium and water balance in mammals.
  • 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.
  • hypertensive patient means, in this context, a mammalian subject
  • 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,
  • 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, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosul
  • 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
  • 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:
  • 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
  • Trt trityl
  • AIBN 2,2'-azobisisobutyronitrile
  • KtBuO potassium t-butoxide
  • N-brom uccinimide in the presence of AIBN in a suitable solvent such as carbon tetrachloride.
  • a suitable solvent such as carbon tetrachloride.
  • the resulting benzyl bromide 2 is used to alkylate a 4,5-dicarboxyimidazole 3.
  • 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.
  • bases that can be used are trialkylamines, potassium
  • the reaction is normally brought about at temperatures ranging from 0°C to 120°C.
  • the pyridazines 5 are obtained by a cyclocondensation reaction between the imidazole 4 and hydrazine. Depending on the reactivity of the imidazole 5, 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 6 is obtained from the corresponding ester 5 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.
  • R CH 3 or C(CH 3 ) 3; and R 39 is as defined above.
  • a biphenylcarboxylic acid ester 7 is converted to the cyanoderivative 8 by a method described by J. A. Krynitsky et al [org. Synth. Coll., 3 , 698 (1955)] and J. Cason [org. Synth. Coll., 3, 169 (1955)].
  • the acid obtained by saponification of ester 7 is transformed into the acid chloride which in turn is converted into the primary carboxcamide eventually dehydrated to cyano derivative 8.
  • the cyano derivative 8 is reacted by a 1,3-dipolar cycloaddition with trialkyltin azide to produce the corresponding tetrazole 9 as described by K. Sisido et al [J. Organometal.
  • 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.
  • a non-nucleophilic base such as pyridine or a trialkylamine.
  • the bromination of 10 into the benzyl bromide 11 is performed with N-bromosuccinimide in the presence of AIBN in can inert solvent such as carbon
  • the bromomethylbiphenyl tetrazole 11 is used to alkylate a 4,5-dicarboxyimidazole 13.
  • 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.
  • bases that can be used are trialkylamines, potassium
  • 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 15 are obtained by a cyclocondensation reaction between the
  • 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 dimethylformaimide, ethanol or toluene.
  • the desired free tetrazole derivative 16 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.
  • R 1 , R 2 and R 39 are as defined above.
  • Scheme 4 is a diagram illustrating methods that lead to modification of the substituents R 1 and R 2 .
  • R 1 and R 2 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 18 is obtained when compound 17 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 19 is formed which can be subsequently converted into a dialkoxy compound 20 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.
  • a base which can be organic, e.g., a carbonate or bicarbonate of an alkali or alkaline earth metal.
  • 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.
  • the diester is treated with a reducing agent, preferentially a metallic hydride like diisobutylaluirdnum hydride to give, hy partial reduction the adehyde-ester derivative 23.
  • a reducing agent preferentially a metallic hydride like diisobutylaluirdnum hydride to give, hy partial reduction the adehyde-ester derivative 23.
  • the adehyde-ester 23 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, dimethylformamide, acetonitrile and water. This alkylation reaction is best performed in the presence of at least one equivalent of a base.
  • bases that can be used are trialkylamines, potassium t-butoxcide, sodium
  • the isomers can be separated by crystallization or by a chromatographic method.
  • the pyridazines 26 and 27 are obtained by a cyclocondensation reaction between the
  • 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.
  • BT 2 biphenyl trityl tetrazole
  • Scheme 6 describes an alternative preparation of hydroxy-pyridazine, particularly suitable for the 7-hydroxy isomers 27.
  • a first step is shown the preparation of 2-butyl-4, 5-dimethoxycarbonyl-imidazole.
  • the starting material tartaric acid
  • the intermediate diacid is directly converted to the dimethylester 22 by the use of hydrochloric acid (gas) in methanol.
  • hydrochloric acid gas
  • several equivalents of a metallic hydride are used to reduce one of the ester function of 22 to the corresponding primary alcohol 28.
  • 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 29 which can be easily separated by a chromatographic procedure or by crystallization.
  • the pyridazine 27 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 27 is obtained directly from the reaction mixture.
  • NB Bt 2 biphenyl trityl tetrazole.
  • Scheme 7 describes a general procedure for preparation of ester derivatives.
  • R alkyl, aryl, aralkyl
  • reaction mixture was then poured in water made acidic with HCI 4N and extracted with ethyl acetate.
  • the organic phase was dried on MgSO4 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.
  • RPHPLC reverse-phase, high-pressure liquid chromatography
  • R alkyl, aryl, aralkyl
  • the ethyl acetate was dried over MgSO 4 and concentrated in vacuo to yield an oil. This was dissolved in a minimum 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.
  • 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.
  • 125 I-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.
  • 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 (mM) : 130 NaCl, 15
  • test compound concentration-response curves in the presence or absence of the test antagonist.
  • 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 [Br. J. Pharmacol. Chemother.,
  • the pA 2 value is the concentration of the antagonist which increases the EC 50 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.
  • 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.)
  • 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 mmHg for two
  • test compound dissolved in sodium bicarbonate
  • 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
  • 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.
  • 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.
  • 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.
  • angiotensin II-infused pressure divided by 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
  • 2Assay B In vitro Vascular Smooth Muscle Response
  • 3Assays C and D In Vivo Pressor Response (all test compounds administered intragastrically, except for compounds where dose is indicated by asterisk (*), which compounds were given intraduodenally).
  • 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.
  • carrier non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants
  • the compounds of the present invention may be administered by 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.
  • compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
  • 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
  • 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
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • 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
  • 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.

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Abstract

A class of carbonate-substituted imidazo[4,5-d] pyridazine compounds is described for use in treatment of circulatory disorders. Compounds of particular interest are angiotensin II antagonists of formula (I), wherein each of R?a and Rb¿ is independently selected from radicals of formula (a) and of formula (b), with the proviso that at least one of R?a and Rb¿ must be a radical of formula (a); wherein R1 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, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, indanoylmethyl, indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 is selected from hydrido, linear or branched alkyl (C¿1?-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); wherein at least one of R?5, R6, R8 and R9¿ is an acidic group selected from CO¿2?H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6H5, CONHOH, CONHOCH3, CONHSO2CH3 and tetrazole; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. These compounds are particularly useful in treatment or control of circulatory and cardiovascular disorders such as hypertension and congestive heart failure.

Description

CARBONATE-SUBSTITUTED IMIDAZO[4-5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
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 biphenylmethyl 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 reninangiotensin 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-chloro-1-(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-1-(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 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist
properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther.,
250(3), 867-874 (1989)]. U.S. Patent No. 4,816,463 to
Blankey et al describes a family of 4,5,6,7-tetrabydro-1H- imidazo(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 imidazoles, as antagonists to the angiotensin II receptor. EP #323,841, published
12 July 1989, describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles,
biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]- 4H-1,2,4-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 1,2,5-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]pyridazine derivatives [I. Sekikawa, J. Heterocyclic Chem., 6, 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, 3(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., 59(11), 1584-1586 (1970)]. A family of 4-substituted imidazo[4,5-d]pyridazines, including several 4-amino- and 4-alkylamino-1-benzyl-7-chloroimidazo[4,5-d]pyridazines, has been prepared for antitumor evaluation [J.A. Carbon, J. Am. Chem. Soc., 80 , 6083-6088 (1958)]. In view of the antitumor activity of 5-amino-7-hydroxy-y-triazolo[d]pyrimidine, several 4,7-disubstituted imidazo[4,5-d]pyridazines were synthesized including the compound 4,7-bisethylmercapto-1- ethylimidazo [4,5-d]pyridazine [R. N. Castle et al, J. Org. Chem., 23, 1534-1538 (1958)]. Based on the antimalarial activity of certain quinoline derivatives, a family of ω-dialkylaminoalkylaminoimidazo[4,5-d]pyridazines was synthesized including, typically, the compound 4-(3- dmethylairdnopropylamino)-7-chloro-1-(tetrahydro-2'- pyranyl)imidazoi4,5-d]pyridazine [N. R. Patel et al,
J. Heterocyclic Chem., 5, 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]pyridazin-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-imidazole[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-1H-imidazo[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'(1H-tetrazol-5-yl)biphenyl-4-yl)methl ]-3H- imidazo [4,5-d]pyridazine. EP #400,974, published 5 December 1990, describes several families of imidazo-fused six-membered heterocyclics as angiotensin II antagonists including, in particular, 7-metbyl-2-propyl-3-(2'-(tetrazol-5-yl)biphen-4- yl)methyl-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:
Figure imgf000007_0001
wherein m is a number selected from one to four, inclusive; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000007_0002
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000007_0003
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 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, formyl, 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,
aralkylthiocarbonylthio, alkylthiocarbonyl,
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
Figure imgf000008_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R12 and R13 taken together, R14 and R15 taken together and R16 and R17 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 R12 and R13 taken together and R14 and R15 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 R3 through R11 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 YnA 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
Figure imgf000009_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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
Figure imgf000010_0001
wherein X is selected from oxygen atom and sulfur atom;
wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR24 and
Figure imgf000010_0002
wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R24 is selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R20, R21, R22, R23, R25 and R26 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 R20' R21, R22, R23, R25 and R26 is further independently selected from amino and amido radicals of the formula
Figure imgf000010_0003
wherein each of R27, R28, R29, R30, R31 and R32 is
independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylainino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl,
haloalkylsulfonyl, aralkyl and aryl, and wherein R20 and R21 taken together and R22 and R23 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 R20 and R21 taken together and R25 and R26 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 Ra and Rb 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 Ra and Rb positions of the imidazopyridazine ring. Thus, compounds of Formula I may have one carbonate group at the Ra or Rb position, or may have carbonate groups at both Ra and Rb positions. The term "carbonate", as used herein, means a substituent selected from radicals of the formula
Figure imgf000012_0001
wherein X, W and R1 are as defined above. When R1 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 the X moiety of the formula
Figure imgf000012_0002
Compounds having alkyl groups, especially lower alkyl groups at the R39 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 -YnA moiety, is intended to embrace chemical groups which, when attached to any of the R3 through R11 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 pKa in a range from about one to about twelve. More typically, the Formula I compound would have a pKa 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 -YnA moiety, such carboxyl group would be attached directly to one of the R3-R11 positions. The Formula I compound may have one -YnA moiety attached at one of the R3-R11 positions, or may have a plurality of such -YnA moieties attached at more than one of the R3-R11 positions, up to a maximum of nine such -YnA 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 -YnA moiety attached at one of positions R5, R6, R8 and R9 would be expected to have preferred properties, while attachment at R5 or R9 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 pKa values of the Formula I compound as conferred fcy the -YnA moiety be in a range from about two to about seven. The -YnA moiety may be attached to one of the R3-R11 positions through any portion of the -YnA moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the -YnA 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 Ra and Rb is independently selected from radicals of the formula
Figure imgf000013_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000013_0002
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy,
alkylaminocarbonyloxy, arylaminocarbonyloxy,
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
Figure imgf000014_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, aryl, ironoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each R3 through R11 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 YnA 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
Figure imgf000015_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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
Figure imgf000016_0001
wherein X is selected from oxygen atom and sulfur atom; wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R20, R21, R22 and R23 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 Ra and Rb is independently selected from radicals of the formula
Figure imgf000016_0002
.and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000016_0003
wherein each X is
independently selected from oxygen atom and sulfur atom; wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein R39 is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and
alkylcycloalkylalkyl, and wherein any one of the foregoing R39 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 R3 through R11 is independently 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), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio,
alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R3-R11 substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula
Figure imgf000017_0001
wherein R33 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 R3-R11 acidic radical is a bioisostere of a free carboxylic acid having a pKa 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
•
Figure imgf000017_0002
wherein W is selected from O, S and N-R40; wherein each of R34, R35' R36 and R40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R37-N-R38, wherein R37 and R38 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 pka 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 R3-R11 or may be attached at any two positions selected from R3-R11 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-R46
wherein R46 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R41 wherein R41 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);
wherein any of the foregoing R33 through R38, R40, R41 and R46 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:
Figure imgf000019_0001
wherein each of R42, R43 and R44 is independently selected from H, Cl, CN, NO2, CF3 , C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SC2C6F5; wherein Z is selected from O, S, NR45 and CH2, wherein R4 5 is selected from hydrido, CH3 and CH2C6H5. 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:
Figure imgf000020_0001
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 Ra and Rb is independently selected from radicals of the formula
Figure imgf000020_0002
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000020_0003
wherein R1 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 R2 is hydrido; wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R3 through R11 is an acidic moiety independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3,
NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OFO3H2, OSO3H, NHCN4H and
Figure imgf000021_0001
and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R3-R11 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
Figure imgf000021_0002
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 Ra and Rb is independently selected from radicals of the formula
Figure imgf000022_0001
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000022_0002
; wherein R1 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, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimicaylethyl, indanqylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 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), cycloalkeryl (C3-C10), cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10); wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6,H5, CONHOH,
CONHOCH3, CONHSO2CH3,
Figure imgf000022_0003
wherein each of R42 and R43 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 Ra and Rb is independently selected from radicals of the formula
Figure imgf000023_0001
and of the formula
—OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000023_0002
wherein R1 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, cyclopropylmetbyl, cyclopropyletbyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmetlyl, pyrimidylethyl, indanoylmethyl,
indanoylethyl, pyrrolyMethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido;
wherein one of R5 and R9 is an acidic group selected from CO2H and tetrazole and the other of R5 and R9 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
Figure imgf000024_0001
CH- 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-chloromethyl 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, pyrimidyl 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 imidazolemethyl 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 mammalian 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:
Figure imgf000028_0001
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 imddazo-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, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (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-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(3-methylpropyloxycarbonyloxy)-7-bydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d] pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4- (ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d] pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(t-butyuoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d] pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metbyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]metlyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazinee 2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-bydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-(cyclohescyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-(t-butyloxycarbonylojy)-7-hydroxy-1H- imiidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d.]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2- ( cyclopropylmethyl ) -11- [2 ' - ( 1H-tetrazol-5-yl ) [1 , 1 ' - biphenyl]-4-yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7- hydroxy-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis[(3- methyl)propyloxycarbonyloxy]-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-
1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7- hydroxy-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine; 2-(cyclopropylmetlyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- bipheryl]-4-yl]methyl]-4-(methoxyethoxycarbonyloxy)-7- bydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(t-butyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl-4-yl]methyl]- 4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; 2-butenyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydrαxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl] -4-hydroxy-7- (methoxyethoxycarbonyloxy) -1H- imidazo[4, 5-d]pyridazine;
2-pentyl-1- [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl] -4-hydroxy-7- (methoxycarbonyloxy) -1H-imidazo [4, 5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- irmidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- bipheryl]-4-yl]methyl]-4-hydroxy-7-(3- methylpropyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-
4-yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl] -4-yl]methyl] -4-bydroxy-7-
(cyclohexyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; and
2-(cyclopropylmethyl)-1-[2'-(1H-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-brom
Figure imgf000041_0001
uccinimide 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 3. 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-butoxcide, sodium methoxcide, 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 5 are obtained by a cyclocondensation reaction between the imidazole 4 and hydrazine. Depending on the reactivity of the imidazole 5, 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 6 is obtained from the corresponding ester 5 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.
Figure imgf000043_0001
wherein R = CH3 or C(CH3)3; and R39 is as defined above.
In Scheme 2, a biphenylcarboxylic acid ester 7 is converted to the cyanoderivative 8 by a method described by J. A. Krynitsky et al [org. Synth. Coll., 3 , 698 (1955)] and J. Cason [org. Synth. Coll., 3, 169 (1955)]. The acid obtained by saponification of ester 7 is transformed into the acid chloride which in turn is converted into the primary carboxcamide eventually dehydrated to cyano derivative 8. The cyano derivative 8 is reacted by a 1,3-dipolar cycloaddition with trialkyltin azide to produce the corresponding tetrazole 9 as described by K. Sisido et al [J. Organometal. 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 10 into the benzyl bromide 11 is performed with N-bromosuccinimide in the presence of AIBN in can inert solvent such as carbon
tetrachloride, the reaction medium being heated at a
temperature from 40°C to reflux of the solvent used.
Figure imgf000045_0001
In Scheme 3, the bromomethylbiphenyl tetrazole 11 is used to alkylate a 4,5-dicarboxyimidazole 13. 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-butoxcide, 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 15 are obtained by a cyclocondensation reaction between the
imidazole and hydrazine. Depending on the reactivity of the imidazole 15, 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 dimethylformaimide, ethanol or toluene. The desired free tetrazole derivative 16 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.
Figure imgf000047_0001
wherein R1 , R2 and R39 are as defined above.
Scheme 4 is a diagram illustrating methods that lead to modification of the substituents R1 and R2. For example, when each of R1 and R2 is a chloro substituent, compound 17 can be substituted by nucleophiles such as amines, aminoalkyls, thiol, hydroxy and alkoxy groups. A compound of formula 18 is obtained when compound 17 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 19 is formed which can be subsequently converted into a dialkoxy compound 20 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.
Figure imgf000049_0001
wherein R1, R2 and R39 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. Org. 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 diisobutylaluirdnum hydride to give, hy partial reduction the adehyde-ester derivative 23. The adehyde-ester 23 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, dimethylformamide, 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-butoxcide, sodium
methoxcide, 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. This reaction gave a mixture of the tetrasubstituted imidazoles 24 and 25, isomeric by 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 26 and 27 are obtained by a cyclocondensation reaction between the
imidazole and hydrazine. Depending on the reactivity of the imidazole, 24 or 25, 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.
Figure imgf000052_0001
NB: BT2 = biphenyl trityl tetrazole Scheme 6 describes an alternative preparation of hydroxy-pyridazine, particularly suitable for the 7-hydroxy isomers 27. 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 28 is isolated in good yield. This alcohol ester 28 can be alkylated by the bromomethyl biphenyl tetrazole 11 (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 29 and 30. 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 29 which can be easily separated by a chromatographic procedure or by crystallization. The pyridazine 27 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 27 is obtained directly from the reaction mixture.
Figure imgf000055_0001
NB Bt2 = biphenyl trityl tetrazole. Scheme 7 describes a general procedure for preparation of ester derivatives.
A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-1H-imidazo[4,5- d]pyridazine 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).
7
Figure imgf000057_0001
R = alkyl, aryl, aralkyl
A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-1H-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 by 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 MgSO4 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
Figure imgf000059_0001
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 expressed are in degrees centigrade.
EXAMPLE 1
Figure imgf000060_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4- yl]methyl]-4-methoxycarbonyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazine
A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-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 mL of 0.5 mL of 0.5N HCI then exctracted with ethyl acetate. The ethyl acetate was dried over MgSO4 and concentrated in vacuo to yield an oil. This was dissolved in a minimum 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: 1H NMR (DMSO-d6) δ 7.45- 7.13 (m, 4H), 6.91-6.72 (m, 4H), 5.45(s, 2H), 3.78(s, 3H), 3.68(s, 3H), 2.55-2.4 (m, 2H), 1.52-1.35(m, 2H), 1.15-0.97 (m, 2H), 0.70-0.50 (m, 3H).
EXAMPLE 2
Figure imgf000061_0001
2-butyl-1-[2'-(1H-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 (m, 2H), 0.55-0.42 (m, 3H). EXAMPLE 3
Figure imgf000062_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzyloxycarbonyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazine
A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl][-4-yl]metbyl]4,7-bis-bydroxy-1H- 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 MgSO4 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) : 1H HMR (DMSO-d6): δ 7.61(m, 2H), 7.55(d, 1H, J = 8Hz), 7.38 (d, 1H, 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
Figure imgf000063_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7- hydroxy-1H-imidazo[4,5-d]pyridazine
A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-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 MgSO4 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: 1H 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, 1H), 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
Figure imgf000064_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]- 1H-imidazo[4,5-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): 1H NMR (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 (m, 12H), 0.69-0.61 (m, 3H). EXAMPLE 6
Figure imgf000065_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-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 MgSO4 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): 1H 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(m, 4H) 0.89-0.78(m, 3H). EXAMPLE 7
Figure imgf000066_0001
2-butyl-1-[2'-(1H-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: 1H 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, 1H), 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
Figure imgf000067_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine
A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-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: 1H NMR (DMSO-d6) δ l2.66(s, 1H) , 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
Figure imgf000068_0001
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine
A solution of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-bipheiyl]-4-yl]-4,7-bis-hydroxy-1H-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 mL 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: 1H NMR (DMSO-d6) δ 7.72- 7.50(m, 4H), 7.16(m, 2H), 7.09 (m, 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. 125I-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 125I-AII (approximately 105 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 mM 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 Micromedic 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 125I-AII 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 (mM) : 130 NaCl, 15
NaHCO3, 15 KCI, 1.2 NaH2PO4, 1.2 MgSO4, 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 [Br. 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 mmHg 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 (mmHg). 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 by 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
Figure imgf000073_0001
1Assay A: Angiotensin II Binding Activity
2Assay B: In vitro Vascular Smooth Muscle Response 3Assays C and D: In Vivo Pressor Response (all test compounds administered intragastrically, 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 by 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, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably 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 mg, 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.

Claims

What Is Claimed Is:
1. A compound of Formula I:
Figure imgf000077_0001
wherein m is a number selected from one to four, inclusive; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000077_0002
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000077_0003
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, 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,
aralkylthioccirbonylthio, alkylthiocarbonyl,
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
Figure imgf000078_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R12 and R13 taken together, R14 and R1 5 taken together and R16 and R17 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical 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 R12 and R13 taken together and R14 and R15 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R3 through R11 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, 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
Figure imgf000079_0001
and -CH=CH- , wherein R18 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 R1 through R18, R39, 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
Figure imgf000080_0001
wherein X is selected from oxygen atom and sulfur atom;
wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR24 and
Figure imgf000080_0002
wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R24 is selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R20, R21, R22, R23, R25 and R26 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 R20, R21 , R22, R23, R25 and R26 is further independently selected from amino and amido radicals of the formula
Figure imgf000080_0003
wherein each of R27, R28, R29, R30, R31 and R32 is
independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl,
haloalkylsulfonyl, aralkyl and aryl, and wherein R20 and R21 taken together and R22 and R23 taken together may each form a heterocyclic group having five to seven ring members
including the nitrogen atom of said amino or amido radical, 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 R20 and R21 taken together and R25 and R26 taken together may each form an aromatic heterocyclic group having five ring members
including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may 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.
2. Compound of Claim 1 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000081_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000081_0002
wherein each of W and X is independently selected from oxygen atom and sulfur atom; wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 throughR11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy,
mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,
alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio,
aralkyIthiocarbonyloxy, 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
Figure imgf000082_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, aryl- monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each R3 through R11 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, 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
Figure imgf000083_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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
Figure imgf000083_0002
wherein X is selected from oxygen atom and sulfur atom;
wherein R1 9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R20, R21, R22 and R23 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.
3. Compound of Claim 2 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000084_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a
0
radical of the formula
Figure imgf000084_0002
wherein each X is
independently selected from oxygen atom and sulfur atom; wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, pherylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein R39 is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and
alkylcycloalkylalkyl, and wherein any one of the foregoing R39 substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino, alkylamino, alkylarylamti.no, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfinyl and arylsulfonyl; and wherein each of R3 through R11 is independently 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), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R3-R11 substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula
Figure imgf000084_0003
wherein R33 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 R3 - R11 acidic radical is a bioisostere of a free carboxylic acid having a pKa in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxcamide, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus-containing and thiophosphorus-containing acids selected from
Figure imgf000085_0001
wherein W is selected from O, S and N-R40; wherein each of R34, R35' R36 and R40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R37-N-R38, wherein R37 and R38 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 pka 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 R3 - R11 or may be attached at any two
positions selected from R3 - R11 so as to form a fused-ring system by 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-R46
wherein R46 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R41 wherein R41 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);
wherein any of the foregoing R33 through R38, R40, R41 and R46 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.
4. Compound of Claim 3 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from
Figure imgf000087_0001
Il N N
wherein each of R42, R43 and R44 is independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C5F5; wherein Z is selected from O, S, NR45 and CH2, wherein R45 is selected from hydrido, CH3 and CH2C5H5.
5. Compound of Claim 3 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from
Figure imgf000088_0001
6. Compound of Claim 3 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000088_0002
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula wherein R1 is selected from
Figure imgf000088_0003
hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, naphthyl, pyridyl, pyrimiciyl, naphthylalkyl, pyridylalkyl, pyrjjmidylalkyl, indanoylalkyl, pyrrolylalkyl, thienylalkyl, furanylalkyl and pyrazolealkyl; wherein R2 is hydrido; wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R3 through R11 is an acidic moiety independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H, NHCN4H and
Figure imgf000089_0001
and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R3-R11 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
Figure imgf000089_0002
and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
7. Compound of Claim 6 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000089_0003
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000089_0004
wherein R1 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, cyelopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, indanoylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thierylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 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); wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3 , OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6,H5, CONHOH,
CONHOCH3, CONHSO2CH3,
Figure imgf000090_0001
wherein each of R42 and R43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
8. Compound of Claim 7 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000090_0002
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000090_0003
wherein R1 is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, metbylbutyl. dimethylbutyl, neopentyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmethyl, cyclopropylethyl,
cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl , cyclohexylethyl, cyclohexylpropyl , naphthyl , imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, indanoylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido; wherein one R5 and R9 is an acidic group selected from CO2H and tetrazole and the other of R5 and R9 is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
9. Compound of Claim 8 selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d] pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d] pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-4-
( ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(t-butyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- iinidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-butenyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-pentyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d] pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlτyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5- d]pyridazine; 2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-11-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(methoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis(methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(benzyloxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(3-methylpropyloxycarbonyloxy)-7- bydroxy-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis[(3- methyl)propyloxycarbonyloxy]-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(isopropyloxycarbonyloxy)-7-hydroxy-
1H-imidazo[4,5-d]pyridazine; 2-(cyclopropylmethyl)-11-2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(ethoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4,7-bis(ethoxycarbonyloxy)1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(cyclohexyloxycarbonyloxy)-7- hydroxy-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(phenoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(t-butyloxycarbonyloxy)-7-hydroxy- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2*-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(propoxycarbonyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-11-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-(methoxyethoxycarbonyloxy)-7- hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-bydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(t-butyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl-4-yl]methyl]- 4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-propyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmethyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(cyclohexyloxycarboiyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yljmetlyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butenyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-lydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metbyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-pentyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-lydroxy-7-(3-methylpropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; 2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-7-(cyclohexyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1- [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4- yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]metlyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-isobutyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-bydroxy-7-(methoxyethoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(methoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(benzyloxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- bipheryl]-4-yl]methyl]-4-hydroxy-7-(3- methyIpropyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(isopropyloxycarbonyloxy)- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmetlyl)-1-2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]- 4-yl]methyl]-4-hydroxy-7-(ethoxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine; 2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-
(cyclohexyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(phenoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(t-butyloxycarbonyloxy)- 1H-imidazo[4,5-d]pyridazine;
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(propoxycarbonyloxy)-1H- imidazo[4,5-d]pyridazine; and
2-(cyclopropylmethyl)-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-hydroxy-7-(methoxyethoxy)-1H- imidazo[4,5-d]pyridazine.
10. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4- methoxycarbonyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.
11. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)-[1,1'biphenyl]-4-yl]methyl]4,7- bis (methoxycarbonyloxy)-1H-imidazo(4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.
12. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4- benzyloxycarbonyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.
13. Coirpound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-methyl- propyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.
14. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis[3- methyl)propyloxycarbonyloxy]-1H-imidazo[4,5-d]pyridazine.
15. Compound of Claim 9 which is 2-butyl-1-[2'-
(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4- (isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine.
16. Compound of Claim 9 which is 2-butyl-1-[2'-
(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7- bis(isopropyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine.
17. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7- bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine.
18. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4- (ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine.
19. A pharmaceutical composition comprising a therapeutically-effective amount of an angiotensin II
antagonist compound and a pharmaceutically-acceptable carrier or diluent, said antagonist compound selected from a family of compounds of Formula I:
Figure imgf000105_0001
wherein m is a number selected from one to four, inclusive; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000105_0002
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000105_0003
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, 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,
aralkylthiocarbonylthio, alkylthiocarbonyl, 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
Figure imgf000106_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R12 and R13 taken together, R14 and R15 taken together and R16 and R17 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical 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 R12 and R13 taken together and R14 and R15 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R3 through R11 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, 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
Figure imgf000107_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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
Figure imgf000107_0002
wherein X is selected from oxygen atom and sulfur atom;
wherein R1 9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR24 and
Figure imgf000108_0001
wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R24 is selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R20, R21, R22, R23, R25 and R26 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 R20, R21, R22, R23, R25 and R26 is further independently selected from amino and amido radicals of the formula
Figure imgf000108_0002
wherein each of R27, R28, R29, R30, R31 and R32 is
independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl,
haloalkylsulfonyl, aralkyl and aryl, and wherein R20 and R21 taken together and R22 and R23 taken together may each form a heterocyclic group having five to seven ring members
including the nitrogen atom of said amino or amido radical, 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 R20 and R21 taken together and R25 and R26 taken together may each form an aromatic heterocyclic group having five ring members
including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may 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.
20. The composition of Claim 19 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000109_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000109_0002
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy,
alkylaminocarbonyloxy, arylcjminocarbonyloxy,
mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio,
alkylthiothiocarbonyl, 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
Figure imgf000110_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylc-minoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each R3 through R11 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, 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
Figure imgf000110_0002
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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 <
Figure imgf000111_0001
wherein X is selected from oxygen atom and sulfur atom;
wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R20, R21, R22 and R23 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.
21. The composition of Claim 20 wherein m is wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000111_0002
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula wherein each X is
Figure imgf000111_0003
independently selected from oxygen atom and sulfur atom; wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein R39 is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and
alkylcycloalkylalkyl, and wherein any one of the foregoing R39 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 R3 through R11 is independently 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), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R3 - R11 substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula
Figure imgf000112_0001
wherein R33 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 R3 - R11 acidic radical is a bioisostere of a free carboxylic acid having a pKa in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamide, sulfonamides, hydroxcamic acid, hydroxamate, aminotetrazole, phosphorus-containing and thiophosphorus-containing acids selected from
Figure imgf000113_0001
wherein W is selected from O, S and N-R40; wherein each of R34, R35' R36 and R40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl,
arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R37-N-R38, wherein R37 and R38 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 pka 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 R3 - R11 or may be attached at any two
positions selected from R3 - R11 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-R46
wherein R46 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R41 wherein R41 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);
wherein any of the foregoing R33 through R38, R40, R41 and R46 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,
alkylsulf inyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl; or a tautomer thereof or a pharmaceutically- acceptable salt thereof.
22. The composition of Claim 21 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from
Figure imgf000114_0001
wherein each of R42, R43 and R44 is independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2 , CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR45 and CH2, wherein R45 is selected from
hydrido, CH3 and CH2C6H5.
23. The composition of Claim 21 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from
Figure imgf000115_0003
24. The composition of Claim 21 wherein m is one; wherein each of Ra and Rb is independently selected from compounds of the formula
Figure imgf000115_0001
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a compound of the formula
Figure imgf000115_0002
wherein R1 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 R2 is hydrido; wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R3 through R11 is an acidic moiety independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3,
NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H, NHCN4H and
Figure imgf000116_0001
and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R3-R11 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
Figure imgf000116_0002
and the esters, amides and salts of said acidic moieties;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
25. The composition of Claim 24 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula R
Figure imgf000116_0003
— and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000117_0002
wherein R1 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, imidazoleethyl, pyridylmethyl, pyridylethyl, pyriirticylmetlyl, pyrimidylethyl, indanoylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 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); wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6,H5, CONHOH,
CONHOCH3, CONHSO2CH3,
Figure imgf000117_0001
wherein each of R42 and R43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
26. The composition of Claim 25 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000118_0001
.and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula R
Figure imgf000118_0002
; wherein R1 is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
methylbutyl, dimetlylbutyl, neopentyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimiidylethyl, indanqylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thierylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido; wherein one R5 and R9 is an acidic group selected from CO2H and tetrazole and the other of R5 and R9 is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
27. The composition of Claim 26 wherein said antagonist compound is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]- 4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4- (benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d] pyridazine;
2-butyl-l-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4-(3-methyl-propyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]- 4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-
(ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine.
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(t-butyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; and
2-butyl-1-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-
4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine.
28. The composition of Claim 27 wherein said antagonist compound is selected from comopunds, and their pharmaceutically-acceptable salts, of the group consisting of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]- 4-(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(3-metbyl-propyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4- (ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine.
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(t-butyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(propoxycarbonyloxy)-7-lydroxy-1H-imidazo[4,5-d]pyridazine; and 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine.
29. A therapeutic method for treating a circulatory disorder, said method comprising administering to a subject having such disorder a therapeutically-effective amount of a compound of Formula I:
Figure imgf000121_0001
wherein m is a number selected from one to four, inclusive; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000121_0002
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000121_0003
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl , cycloalkyloxy, formyl, alkoxy, aralkyl , aryl , aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, alkylcarbonyloxy, cycloalkylalkoxy, alkoxyalkoxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, alkylaminocarbonyloxy, arylamtinocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,
alkylthiocarbonyloxy, alkylthiocarbonylthio,
alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarboryl,
arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkylthiocarbonylthio, alkylthiocarbonyl,
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
Figure imgf000122_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R12 and R13 taken together, R14 and R15 taken together and R16 and R17 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical 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 R12 and R13 taken together and R14 and R15 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R3 through R11 may be further
independently selected from acidic moieties of the formula
-YnA wherein n is a number selected from zero through three,
Figure imgf000123_0002
inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties;
wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein Y is further selected from
Figure imgf000123_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, halo, 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
Figure imgf000124_0001
wherein X is selected from oxygen atom and sulfur atom;
wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR24 and
Figure imgf000124_0002
wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R24 is selected from hydrido, alkyl,
cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R20, R21, R22, R23, R25 and R26 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 R20, R21, R22, R23, R25 and R26 is further independently selected from amino and amido radicals of the formula
Figure imgf000124_0003
wherein each of R27, R28, R29, R30, R31 and R32 is
independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl,
haloalkylsulfonyl, aralkyl and aryl, and wherein R20 and R21 taken together and R22 and R23 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, 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 R20 and R21 taken together and R25 and R26 taken together may each form an aromatic heterocyclic group having five ring members
including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may 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.
30. The method of Claim 29 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000125_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000125_0002
wherein each of W and X is independently selected from oxygen atom and sulfur atom;
wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein each of R3 through R11 and R39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, aralkyloxycarbonyloxy, aralkylcarbonyloxy,
alkylaminocarbonyloxy, arylaminocarbonyloxy,
mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkyIthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,
arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy,
aralkyIthiocarbonylthio, aralkyIthiocarbonyl,
aralkyIthiocarbonylthio, 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
Figure imgf000126_0001
wherein each of R12, R13, R14, R15, R16 and R17 is
independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each R3 through R11 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, 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
Figure imgf000127_0001
and -CH=CH-, wherein R18 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 R1 through R18, R39, 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
Figure imgf000127_0002
wherein X is selected from oxygen atom and sulfur atom;
wherein R19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R20, R21, R22 and R23 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.
31. The method of Claim 30 wherein m is one; wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000128_0001
and of the formula —XR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000128_0002
1 wherein each X is
independently selected from oxygen atom and sulfur atom; wherein each of R1 and R2 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, halocycloalkyl, halocycloalkylalkyl, phenyl, phenylalkyl, halophenyl, halophenylalkyl, heteroaryl and heteroarylalkyl; wherein R39 is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and
alkylcycloalkylalkyl, and wherein any one of the foregoing R39 substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino, allylamino, alkylarylamino, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio,
arylsulfinyl and arylsulfonyl; and wherein each of R3 through R11 is independently 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), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R3 - R11 substituents is an acidic radical; wherein said acidic radical may be a carboxylic acid radical of the formula
Figure imgf000128_0003
wherein R33 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 R3 - R11 acidic radical is a bioisostere of a free carboxylic acid having a pKa in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamti.de, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus-containing and thiophosphorus-containing acids selected from
Figure imgf000129_0001
wherein W is selected from O, S and N-R40; wherein each of R34, R35' R36 and R40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R37-N-R38, wherein R37 and R38 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 pka 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 R3 - R11 or may be attached at any two
positions selected from R3 - R11 so as to form a fused-ring system by 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 ai-dno groups of the formula
NH-R46
wherein R46 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R41 wherein R41 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);
wherein any of the foregoing R33 through R38, R40, R41 and R46 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.
32. The method of Claim 31 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from
Figure imgf000131_0001
wherein each of R42, R43 and R44 is independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR45 and CH2, wherein R45 is selected from hydrido, CH3 and CH2C6H5.
33. The method of Claim 31 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from
Figure imgf000132_0001
34. The method of Claim 31 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula and of the formula —OR2,
Figure imgf000132_0002
with the proviso that at least one of Ra and Rb must be a radical of the formula wherein R1 is selected from
Figure imgf000132_0003
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 R2 is hydrido; wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R3 through R11 is an acidic moiety independently selected from acidic moieties consisting Of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3 , OH, CH2OH, C2H4OH, OPO3H2 , OSO3H, NHCN4H and
Figure imgf000133_0001
3
and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R3-R11 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
Figure imgf000133_0002
and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
35. The method of Claim 34 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000133_0003
and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula
Figure imgf000133_0004
wherein R1 is selected from hydrido, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
methylbutyl, dimetbylbutyl, neopentyl, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropylmetlyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, naphthyl, imidazole, pyridyl, pyrimidyl, naphthylmethyl, naphthylethyl,
imidazolemethyl, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimid ylmetbyl, pyriinicylethyl, indanoylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmetlyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 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); wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2,
CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6,H5, CONHOH, CONHOCH3, CONHSO2CH3,
Figure imgf000134_0001
wherein each of R42 and R43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
36. The method of Claim 35 wherein m is one;
wherein each of Ra and Rb is independently selected from radicals of the formula
Figure imgf000134_0002
t and of the formula —OR2, with the proviso that at least one of Ra and Rb must be a radical of the formula wherein R1 is selected from
Figure imgf000134_0003
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, imidazoleethyl, pyridylmethyl, pyridylethyl, pyrimidylmetlyl, pyrimidylethyl, indanoylmethyl,
indanoylethyl, pyrrolylmethyl, pyrrolylethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, pyrazolemethyl and pyrazoleethyl; wherein R2 is hydrido; wherein R39 i s selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido; wherein one R5 and R9 is an acidic group selected from CO2H and tetrazole and the other of R5 and R9 is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
37. The method of Claim 36 wherein said compound is selected from compounds, and their pharmaceutically- acceptable salts, of the group consisting of 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-
(methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(3-methyl-propyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5- d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4- (ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine.
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(t-butyloxycarbonyloxy)-7-bydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; and
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine.
38. The method of Claim 37 wherein said compound is selected from compounds, and their pharmaceutically- acceptable salts, of the group consisting of 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4- (methoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis(methoxycarbonyloxy)-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(benzyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(3-metlyl-propyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis[(3-methyl)propyloxycarbonyloxy]-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4,7-bis-(isopropyloxycarbonyloxy)-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(isopropyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-
( ethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4,7-bis(ethoxycarbonyloxy)1H-imidazo[4,5-d]pyridazine.
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(cyclohexyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(phenoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 4-(t-butyloxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(propoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; and
2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-
4-(methoxyethoxycarbonyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine.
39. The method of Claim 29 wherein said circulatory disorder is a cardiovascular disorder.
40. The method of Claim 39 wherein said cardiovascular disorder is hypertension.
41. The method of Claim 39 wherein said cardiovascular disorder is congestive heart failure.
PCT/US1992/005856 1991-07-26 1992-07-21 CARBONATE-SUBSTITUTED IMIDAZO[4,5-d] PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS WO1993003033A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0722746A1 (en) 1995-01-21 1996-07-24 Dieter Prof. Dr. med. KÖHLER Device for generating an aerosol using a powdery substance
US6124463A (en) * 1998-07-02 2000-09-26 Dupont Pharmaceuticals Benzimidazoles as corticotropin release factor antagonists
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6365589B1 (en) 1998-07-02 2002-04-02 Bristol-Myers Squibb Pharma Company Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists
EP1925303A2 (en) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399731A1 (en) * 1989-05-23 1990-11-28 Zeneca Limited Azaindenes
EP0400974A2 (en) * 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0415886A2 (en) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0461040A1 (en) * 1990-06-08 1991-12-11 Roussel Uclaf Imidazol derivatives, their process for production, intermediates, their application as medicaments and the pharmaceutical compositions containing them
WO1991019715A1 (en) * 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
EP0470543A1 (en) * 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Heterocyclic imidazoles, remedies containing them and processes for their preparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399731A1 (en) * 1989-05-23 1990-11-28 Zeneca Limited Azaindenes
EP0400974A2 (en) * 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0415886A2 (en) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0461040A1 (en) * 1990-06-08 1991-12-11 Roussel Uclaf Imidazol derivatives, their process for production, intermediates, their application as medicaments and the pharmaceutical compositions containing them
WO1991019715A1 (en) * 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
EP0470543A1 (en) * 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Heterocyclic imidazoles, remedies containing them and processes for their preparation

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0722746A1 (en) 1995-01-21 1996-07-24 Dieter Prof. Dr. med. KÖHLER Device for generating an aerosol using a powdery substance
US6143743A (en) * 1997-07-03 2000-11-07 Dupont Pharmaceuticals Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6362180B1 (en) 1997-07-03 2002-03-26 Bristol-Myers Squibb Pharma Company Imidazopyridines for the treatment of neurological disorders
US6642230B2 (en) 1997-07-03 2003-11-04 Bristol-Myers Squibb Pharma Company Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders
US6124463A (en) * 1998-07-02 2000-09-26 Dupont Pharmaceuticals Benzimidazoles as corticotropin release factor antagonists
US6365589B1 (en) 1998-07-02 2002-04-02 Bristol-Myers Squibb Pharma Company Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists
US6521636B1 (en) 1998-07-02 2003-02-18 Bristol-Myers Squibb Company Imidazo-pyridines as corticotropin releasing factor antagonists
EP1925303A2 (en) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure
EP2277519A2 (en) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Use of Angiotensin II type 1 receptor antagonists for the prevention of stroke, diabetes and/or congestive heart failure
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
EP4424697A2 (en) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Ultra-pure agonists of guanylate cyclase c, method of making and using same
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles
US12037324B2 (en) 2016-06-29 2024-07-16 Bristol-Myers Squibb Company Biarylmethyl heterocycles

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