WO1993003033A1 - COMPOSES D'IMIDAZO[4,5-d] PYRIDAZINE SUBSTITUES PAR CARBONATE S'UTILISANT DANS LE TRAITEMENT DE MALADIES CARDIOVASCULAIRES - Google Patents

COMPOSES D'IMIDAZO[4,5-d] PYRIDAZINE SUBSTITUES PAR CARBONATE S'UTILISANT DANS LE TRAITEMENT DE MALADIES CARDIOVASCULAIRES Download PDF

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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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pyridazine
biphenyl
imidazo
tetrazol
methyl
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PCT/US1992/005856
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English (en)
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Philippe R. Bovy
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G. D. Searle & Co.
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Publication of WO1993003033A1 publication Critical patent/WO1993003033A1/fr

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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.

Abstract

L'invention décrit une catégorie de composés d'imidazo[4,5-d] pyridazine substitués par carbonate s'utilisant dans le traitement de maladies circulatoires. Lesdits composés sont des antagonistes de l'angiotensine II représentés par la formule (I), dans laquelle Ra et Rb sont chacun indépendemment sélectionnés à partir de radicaux représentés par la formule (a) et par la formule (b) à condition qu'au moins l'un de Ra et de Rb soit un radical représenté par la formule (a); dans laquelle R1 est sélectionné à partir de hydrido, méthyle, éthyle, n-propyle, isopropyle, n-butyle, sec-butyle, isobutyle, tert-butyle, n-pentyle, isopentyle, méthylbutyle, diméthylbutyle, néopenthyle, cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, cycloheptyle, cyclooctyle, cyclononyle, cyclodécyle, cyclopropylméthyle, cyclopropyléthyle, cyclopentylméthyle, cyclopentyléthyle, cyclohexylméthyle, cyclohexyléthyle, cyclohexylpropyle, naphtyle, imidazole, pyridyle, pyrimidyle, naphtylméthyle, naphtyléthyle, imidazoleméthyle, imidazoléthyle, pyridylméthyle, pyridyléthyle, pyrimidylméthyle, pyrimidyléthyle, indanoylméthyle, indanoyléthyle, pyrrolylméthyle, pyrrolyléthyle, thiénylméthyle, thiényléthyle, furanylméthyle, furanyléthyle, pyrazoleméthyle et pyrazoléthyle; dans laquelle R2 représente hydrido; dans laquelle R39 est sélectionné à partir d'hydrido, d'alkyle (C¿1?-C10) linéaire ou ramifié, alcényle (C2-C10) linéaire ou ramifié, alkynyle (C2-C10) linéaire ou ramifié, cycloalkyle (C3-C10), cycloalcényle (C3-C10), cycloalkylalkyle (C4-C10) et cycloalcénylalkyle (C4-C10); dans laquelle au moins l'un de R?5, R6, R8 et R9¿ représente un groupe acide sélectionné à partir de CO¿2?H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6H5, CONHOH, CONHOCH3, CONHSO2CH3 et tétrazole; ou un de leurs tautomères ou un de leurs sels acceptables pharmaceutiquement. Ces composés sont particulièrement efficaces dans le traitement ou la régulation de troubles circulatoires et cardiovasculaires, tels que l'hypertension ou l'insuffisance cardiaque congestive.
PCT/US1992/005856 1991-07-26 1992-07-21 COMPOSES D'IMIDAZO[4,5-d] PYRIDAZINE SUBSTITUES PAR CARBONATE S'UTILISANT DANS LE TRAITEMENT DE MALADIES CARDIOVASCULAIRES WO1993003033A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0722746A1 (fr) 1995-01-21 1996-07-24 Dieter Prof. Dr. med. KÖHLER Appareil générateur d'aérosol à partir d'une substance pulvérulente
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 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
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 (fr) * 1989-05-23 1990-11-28 Zeneca Limited Azaindènes
EP0400974A2 (fr) * 1989-05-30 1990-12-05 Merck & Co. Inc. Antagonistes d'angiotensine II du type imidazo condensé à un hétérocycle à 6 chaînons substitués
EP0415886A2 (fr) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Composés aza
EP0461040A1 (fr) * 1990-06-08 1991-12-11 Roussel Uclaf Dérivés de l'imidazole, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant
WO1991019715A1 (fr) * 1990-06-15 1991-12-26 G.D. Searle & Co. COMPOSES DE [4,5-d]PYRIDAZINE IMIDAZO A SUBSTITUTION 1H UTILISES DANS LE TRAITEMENT DE TROUBLES CARDIOVASCULAIRES
EP0470543A1 (fr) * 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Imidazoles hétérocycliques, médicaments contenant ces composés et procédés pour leur préparation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399731A1 (fr) * 1989-05-23 1990-11-28 Zeneca Limited Azaindènes
EP0400974A2 (fr) * 1989-05-30 1990-12-05 Merck & Co. Inc. Antagonistes d'angiotensine II du type imidazo condensé à un hétérocycle à 6 chaînons substitués
EP0415886A2 (fr) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Composés aza
EP0461040A1 (fr) * 1990-06-08 1991-12-11 Roussel Uclaf Dérivés de l'imidazole, leur procédé de préparation, les intermédiaires obtenus, leur application à titre de médicaments et les compositions pharmaceutiques les renfermant
WO1991019715A1 (fr) * 1990-06-15 1991-12-26 G.D. Searle & Co. COMPOSES DE [4,5-d]PYRIDAZINE IMIDAZO A SUBSTITUTION 1H UTILISES DANS LE TRAITEMENT DE TROUBLES CARDIOVASCULAIRES
EP0470543A1 (fr) * 1990-08-10 1992-02-12 Dr. Karl Thomae GmbH Imidazoles hétérocycliques, médicaments contenant ces composés et procédés pour leur préparation

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0722746A1 (fr) 1995-01-21 1996-07-24 Dieter Prof. Dr. med. KÖHLER Appareil générateur d'aérosol à partir d'une substance pulvérulente
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 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles

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