EP0531382A1 - Composes de 1,2,4-triazolones a substitution n utilises dans le traitement de troubles cardiovasculaires - Google Patents

Composes de 1,2,4-triazolones a substitution n utilises dans le traitement de troubles cardiovasculaires

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Publication number
EP0531382A1
EP0531382A1 EP91910101A EP91910101A EP0531382A1 EP 0531382 A1 EP0531382 A1 EP 0531382A1 EP 91910101 A EP91910101 A EP 91910101A EP 91910101 A EP91910101 A EP 91910101A EP 0531382 A1 EP0531382 A1 EP 0531382A1
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EP
European Patent Office
Prior art keywords
phenyl
aralkyl
alkyl
butyl
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91910101A
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German (de)
English (en)
Inventor
Robert E. Manning
David B. Reitz
Horng-Chih Huang
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GD Searle LLC
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GD Searle LLC
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Publication of EP0531382A1 publication Critical patent/EP0531382A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms

Definitions

  • Non-peptidic N-substituted-1,2,4-triazolone compounds are described for use in treatment of
  • cardiovascular disorders such as hypertension and
  • angiotensin II antagonist compounds provided by 1,2,4- triazolones having a biphenylmethyl moiety attached to the nitrogen atom at the four-position of the 1,2,4-triazolone.
  • the renin-angiotensin system is one of the hormonal mechanisms involved in regulation of
  • angiotensin II the primary active species of this system.
  • This octapeptide, 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 renin-angiotensin system through interaction with various tissue receptors.
  • angiotensin II antagonists most 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.
  • commercially-available peptidic angiotensin II antagonists e.g., Saralasin
  • 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 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., 242 (1), 1-7 (1988)].
  • the sodium salt of 2-butyl-4-chloro-1-(2- nitrobenzyl) imidazole-5-acetic acid has specific
  • U.S. Patent No. 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.
  • cardiovascular-related activities which include
  • EP #283,310 published 18 March 1987 describes a family of N 1 - diarylmethyl-N 2 -aminoalkyl-diaza-heterocyclic derivatives for treating cerebral vascular and ischmic diseases and for protecting against anoxia.
  • a class of biphenylalkyl N-substituted-1,2,4- triazolone compounds useful in treating circulatory and cardiovascular disorders is defined by Formula I:
  • m is a number selected from one to four
  • R 1 is selected from polycycloalkyl
  • polycycloalkylalkyl 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl- methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl,
  • arylalkenyl acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl,
  • alkylthiocarbonyl aralkylsulfinyl, aralkylsulfonyl and radicals of the formula
  • each of R 12 and R 13 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,
  • cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl and wherein R 12 and R 13 taken together may 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 each of R 12 and R 13 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, with the proviso that when X is oxygen atom, then R 12 and R 13 cannot be selected from hydrido and alkyl; wherein each of R 2 through R 11 is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycl
  • polycycloalkylalkyl polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl,
  • alkoxycarbonylalkoxyalkyl carboxyalkoxyalkyl
  • alkylcarbonyloxy mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl,
  • alkylcarbonylthio alkylthiocarbonyloxy
  • alkylthiocarbonylthio alkylthiothiocarbonyl, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy,
  • 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 14 and R 1 5 taken together, R 16 and R 17 taken together and R 18 and R 19 taken together may 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 each of R 14 and R 15 taken together and each of R 16 and R 17 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 R 3 through R 11 may be 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, and the amide, ester and salt derivatives of said acidic moieties;
  • 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 any of the foregoing R 1 through R 19 , y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,
  • alkoxycarbonyloxy alkylcarbonyl, alkoxycarbonyl,
  • aralkoxycarbonyl carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, 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 oxygen atom or sulfur atom; wherein R 20 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, .aralkyl, aryl, DR 25 and
  • D is selected from oxygen atom and sulfur atom and R 25 is selected from hydrido, alkyl, cycloalkyl,
  • R 21 , R 22 , R 23 , R 24 , R 26 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl,
  • alkoxycarbonyl carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl,
  • R 21 , R 22 , R 23 , R 24 , R 26 and R 27 is further independently selected from amino and amido radicals of the formula
  • X is oxygen atom or sulfur atom
  • each of R 21 and R 22 taken together and each of R 23 and R 24 taken together may 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
  • each of R 21 and R 22 taken together and each of R 26 and R 27 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; or a tautomer thereof or a
  • 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
  • these compounds would also be useful as adjunctive therapies.
  • compounds of Formula I may be used in combination with other drugs, such as a diuretic, to treat hypertension.
  • 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
  • cardiovascular disorders or would be precursors to, or prodrugs of, therapeutically-effective compounds.
  • 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 acidic group containing at least one acidic hydrogen atom is carboxyl group (-COOH). Where n is zero and A is -COOH, in the -Y n A moiety, such carboxyl group would be attached directly to one of the R 3 through R 11 positions.
  • the Formula I compound may have one -Y n A moiety attached at one of the R 3 through R 11 positions, or may have a plurality of such -Y n A moieties attached at more than one of the R 3 through R 11 positions, up to a maximum of nine such -Y n A moieties.
  • 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
  • Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pK a values of the Formula I compound as conferred by the -YnA 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 through 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. For example, where the -Y n A 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 R 1 is selected from polycycloalkyl, polycycloalkylalkyl, 3- phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl-methyl, hexyl,
  • ethoxycarbonylmethyl carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl,
  • arylalkenyl acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl,
  • X is oxygen atom or sulfur atom
  • each of R 12 and R 13 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,
  • R 12 and R 13 cannot be selected from hydrido and alkyl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl,
  • polycycloalkyl polycycloalkylalkyl, aryloxyalkyl,
  • alkylthiocarbonyloxy alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,
  • cycloalkynyl cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,
  • alkylthiocarbonyloxy alkylthiocarbonylthio
  • X is oxygen atom or sulfur atom
  • R 3 through R 11 may be further selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R 11 may be further
  • 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; and wherein any of the foregoing R 1 through R 19 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula
  • X is oxygen atom or sulfur atom; wherein R 19 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR 23 and wherein D is selected from oxygen atom and sulfur atom, and R 25 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 21 , R 22 , R 23 , R 24 , R 26 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a
  • a more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from polycycloalkyl, polycycloalkylalkyl, 3- phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl-methyl, hexyl,
  • ethoxycarbonyImethyl carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl
  • each of R 12 and R 13 is independently selected from cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl,
  • R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl,
  • polycycloalkyl polycycloalkylalkyl, aryloxyalkyl,
  • each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,
  • haloalkyl cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl,
  • alkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula y
  • each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from w w
  • each W is independently selected from oxygen atom, sulfur atom and NR 38 ; wherein each of R 34 , R 35 , R 36 , R 37 and R 38 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,
  • each of R 34 , R 35 , R 36 and R 37 may be further independently selected from amino radical of the formula wherein each of R 39 and R 40 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 39 and R 40 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino 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
  • R 39 and R 40 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R 35 and R 36 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; 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 through R 11 or may be attached at any two adjacent positions selected
  • R wherein X is selected from oxygen atom and sulfur atom; wherein R 20 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR 25 and
  • D is selected from oxygen atom and sulfur atom
  • R 25 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl
  • each of R 21 , R 22 , R 23 , R 24 , R 26 and R 27 is
  • alkoxyalkyl alkanoyl, alkoxycarbonyl, carboxyl,
  • haloalkylsulfinyl haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
  • R 1 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2- phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonyImethyl, carboxymethyl, 1 -naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-o
  • arylalkenyl acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula
  • each of R 12 and R 13 is independently selected from cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of R 2 is selected from hydrido, alkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl,
  • each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,
  • each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties of the formula
  • n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from
  • each W is independently selected from oxygen atom, sulfur atom and NR 38 ; wherein each of R 34 , R 37 and R 38 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl,
  • each of R 34 and R 37 may be further independently selected from amino radical of the formula wherein each of R 39 and R 40 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 39 and R 40 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino 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 R 39 and R 40 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms;
  • carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which 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 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;
  • Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R 1 through R 19 , R 34 and R 37 through R 40 , Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and
  • Formula I consists of those compounds wherein m is one; wherein R 1 is selected from polycycloalkyl. polycycloalkylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl- methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl,
  • each of R 12 and R 13 is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloalkyl,
  • polycycloalkylalkyl polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl,
  • alkoxycarbonylalkoxyalkyl carboxyalkoxyalkyl
  • each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl,
  • each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties of the formula
  • n is a number selected from zero through two, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from 4
  • each W is independently selected from oxygen atom, sulfur atom and NR 38 ; wherein each of R 34 , R 37 and R 38 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 34 and R 37 may be further independently selected from amino radical of the formula wherein each of R 39 and R 40 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; 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 ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which
  • heterocyclic ring unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;
  • Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; wherein each of R 1 through R 19 , R 34 and R 37 through R 40 , Y and A and independently may be substituted at any
  • alkylsulfonyl haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
  • An even more highly preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from adamantyl, adamantylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2- phenylethyl, 1,1-dimethylethyloxycarbonyImethyl, hexyl, ethoxycarbonyImethyl, carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2
  • R 2 is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl,
  • each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,
  • each of R 3 through R 11 may be an acidic moiety further independently selected from acidic moieties
  • NHSO 2 CF 3 NHSO 2 C 6 F 5 , SO 3 H, CONHNH 2 , CONHNHSO 2 CF 3 , CONHOCH 3 , CONHOC 2 H 5 , CONHCF 3 , OH, CH 2 OH, C 2 H 4 OH, OPO 3 H 2 , OSO 3 H ,
  • each of R 41 , R 42 and R 43 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 SO 2 C 6 F 5 ;
  • Z is selected from O, S, NR 44 and CH 2 ;
  • R 44 is selected from hydrido, CH 3 and CH 2 C 6 H 5 ; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R 3 through R 11 so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from
  • esters, amides and salts of said acidic moieties or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3- ⁇ henyIpropyl, 2-oxo-2- phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, hexyl,
  • ethoxycarbonyImethyl carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,
  • ethoxycarbonylmethoxyethyl substituted with phenyl carboxymethoxyethyl substituted with phenyl, 3,5,5- trimethylhexyl, (2-phenylmethoxy)-1-(phenyImethyl)-E- ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5- dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-
  • 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, CONHNH 2 ,
  • 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.
  • a class of compounds of more particular interest consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from 2-oxo-2- (tricyclo[3.3.1.1. 3.7 ]dec-2-yl) ethyl, 3-phenyIpropyl,
  • ethoxycarbonylmethyl carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,
  • 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, CONHNH 2 , CONHNHSO 2 CF 3 , OH,
  • 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.
  • a class of compounds of even more particular interest consists of those compounds of Formula I wherein m is one; wherein R 1 is selected from 2-oxo-2- (tricyclo [3.3.1.1. 3.7 ]dec-2-yl) ethyl, 3-phenyIpropyl, 2- oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, hexyl,
  • ethoxycarbonylmethyl carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,
  • a family of specific compounds of particular interest within Formula I consists of compounds, and their pharmaceutically-acceptable salts, of the group of
  • hydroxo denotes a single hydrogen atom (H).
  • This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a group; or, as another example, two hydrido groups may be attached to a carbon atom to form a -CH 2 - group.
  • 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.
  • 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.
  • polycycloalkyl denotes a radical having two or more cycloalkyl rings; for example, two cycloalkyl rings may share a single atom to form a spiroring system, such as a dicyclohexyl-spiro ring system; or an alkylene group of one or more methylene radicals may bridge a cycloalkyl ring to form, for example, an adamantyl group.
  • Preferred polycycloalkyl groups contained 10 to about 20 carbon atoms.
  • 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.
  • 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.
  • polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of
  • a dihaloalkyl group 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-difluoroethyl, 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 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.
  • 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 methythion group.
  • aryl groups are those consisting of one, two, or three benzene rings.
  • aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl.
  • te.rm “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenyl- ethyl, phenyIbutyl and diphenylethyl .
  • benzyl and phenylmethyl are interchangeable.
  • aryloxy and arylthio denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, 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
  • benzyloxy 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 unsaturation.
  • heteroaryl 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 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
  • 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.
  • 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.
  • compounds of Formula I are therapeutically useful in methods for treating hypertension by administering to a hypertensive patient a
  • hypertensive patient means, in this context, a mammalian subject suffering from or afflicted by the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.
  • optical isomeric forms including
  • regioisomers of the compounds of Formula I e.g., compounds having the biphenylalkyl moiety exchanged with the R 1 substituent on the triazole ring nitrogen atoms shown in Formula I.
  • pharmaceutically-acceptable salts of the Formula I are also included in this invention.
  • Suitable 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.
  • 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, glut-amic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, malonic, galact
  • 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,
  • Synthetic Scheme I shows the preparation of 1,2,4-triazolone 1 from isothiocyanate 2 via N- ethoxycarbonyl thioamide 2. according to the general procedure outlined by Papadopoulos, E. P. and George, B., J. Org. Chern., 41, 3233 (1976).
  • N- ethoxycarbonyl thioamide 3 can be prepared from
  • N-ethoxycarbonyl thioamide 3 can be converted to triazolone 1 by the action of the
  • Synthetic Scheme II shows the preparation of the alkylating agent 6 from the corresponding precursor 7.
  • R 5 equals CO 2 CH 3
  • 7 was purchased from Chemo Dynamics Inc.
  • step 3 the acid
  • step 4 the amide is converted to the corresponding nitrile 9 by the action of thionyl chloride at reflux.
  • Synthetic Scheme IV shows the coupling reaction of the 1,2,4-triazolone 1 with the appropriate alkylating reagent 6 and subsequent conversion to the compounds of the invention.
  • 1 is treated with a base, such as potassium t-butoxide, to generate the corresponding anion 10.
  • Anion 10 is reacted with an alkylating agent 6 to give coupled product 11.
  • the trisubstituted 1,2,4- triazolone 11 can be subsequently converted to the
  • Synthetic Scheme V shows the preparation of semicarbazide 14 from bromide 6.
  • Semicarbazide 14 can be prepared from aminomethylbiphenyl 15 and the corresponding hydrazide 16 which can be obtained by treating its ester precursor with hydrazine.
  • Amine 15 can be prepared by hydrogenation of the corresponding azide 17 which can be obtained from its bromide precursor 6 by treatment with sodium azide.
  • Synthetic Scheme VI shows the cyclization of 14. to 18 and the subsequent alkylation to 11.
  • triazolone 18 can be prepared by dehydration of semicarbazide 14 in alcohol with a base catalyst, such as sodium methoxide. Then triazolone 18 is treated with a base, such as potassium t-butoxide, to generate the corresponding anion 19. Anion 19 is reacted with an alkylating agent 20 to give alkylated product 11 which may be converted to the corresponding acid 12 or tetrazole 13 by treatment with one of the appropriate reagents as shown in Scheme IV.
  • Step 1 Preparation of 2-(p-tolyl)benzoic acid
  • a mixture of 52 g (0.23 mol) of methyl 2-(p- tolyl) benzoate (Chemo Dynamics Inc.) and 100 mL (0.25 mol) of 2.5 N aqueous sodium hydroxide solution in 100 mL of methanol was stirred at room temperature for about 6 h, then at reflux for about 6 h.
  • the resulting solution was concentrated in vacuo to half of its original volume.
  • the aqueous solution was acidified with 3 N hydrochloric acid to about pH 3 and extracted with methylene chloride. The extracts were dried
  • Step 6 Preparation of tert-butyl 4'-[[[[2- (1- oxopentyl)hydrazino]carbonyl]amino]methyl] [1,1'- biphenyl]-2-carboxylate
  • IM 6.4 mmol
  • Step 7 Preparation of tert-butyl 4'-[(3-butyl-4,5- dihydro-5-nxo-1,2,4-triazol-4-yl)methyl] [1,1'-biphenyl]- 2-carboxylate
  • a moisture trap molecular sieve, 3A
  • Step 8 Preparation of tert-hutyl 4'-[ (1 ,3-dibutyl-4,5- dihydro-5-oxo-1H-1,2,4-triazol-4-yl)methyl][1,1'- biphenyl]-2-carboxylate
  • Step 9 Preparation of 4'-[(1,3-dibutyl-4,5-dihydro-5- oxo-1H-1,2,4-triazol-4-yl)methyl] [1,1'-biphenyl]-2-carboxylic acid
  • Step 2 Preparation of 5-bntyl-2,4-dihydro-1,2, 4- triazol-3-one
  • N-ethoxycarbonyl thiovaleramide in 6 mL of absolute ethanol at room temperature was added 190 mL (6 mmol) of 98% hydrazine in 1.5 mL of ethanol.
  • the resulting solution was stirred at about 84°C for 30 min, and concentrated in vacuo.
  • the resulting solid was rinsed with ether- hexane, and collected by filtration to give 320 mg (76%) of 5-butyl-triazol-3-one as a white solid: 1 H NMR
  • Step 3 Preparation of N-triphenylmethyl-5-[2-(4'- bromomethylbiphen-2-yl]tetrazole.
  • Step 4 Preparation of 5-butyl-2,4-dihydro-4-[[2-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4'- yl]methyl]-3H-1,2,4-triazol-3-one To 247 mg (1.75 mmol) of the 5-butyl-triazol-
  • Step 5 Preparation of 2 , 5-dibntyl-2 , 4-dihydro-4- [ [2 -
  • Step 1 Alkylation of 5-butyl-2,4-dihydro-4-[2'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one
  • Step 2 Deprotection of trityl tetrazolyl biphenyl triazolone
  • step 1 The alkylated product obtained from step 1 was dissolved in 12 mL of glacial acetic acid and 1.2 mL of water. The resulting solution was stirred at room temperature
  • Step 1 Bromination of 2,5-dibutyl-2,4-dihydro-4-[2'- (1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one
  • Assay A Angiotensin ll Binding Activity Compounds of Formula I 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 l- 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
  • the bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (mM) : 130 NaCl, 15 NaHCO 3 , 15 KCl, 1.2 NaH 2 PO 4 , 1.2 MgSO 4 , 2.5 CaCl 2 , and 11.4 glucose.
  • the preparations were equilibrated for one hour before approximately 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 exposed 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 pA 2 values and were calculated according to H.O. Schild [Br. J. Pharmacol.
  • the pA 2 value is the concentration of the antagonist which increases the EC 50 value for All by a factor of two.
  • Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table I.
  • Assay C In Vivo Tntraduodenal 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 allows for airway patency, and the duodenal catheter was used for intraduodenal (i . d. ) administration of test
  • 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 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 ln Vivo Tntragastric Pressor Assay Response for All Antagonists
  • rat were placed in Lucite holders and the arterial line was connected to a pressure transducer. Arterial pressure was recorded on a Gould polygraph (mmHg). Angiotensin II was administered as a 30 ng/kg bolus via the venous catheter delivered in a 50 ⁇ l volume with a 0.2 ml saline flush. The pressor response in mm Hg was measured by the difference from preinjection arterial pressure to the maximum pressure achieved. The All injection was repeated every 10 minutes until three consecutive injections yielded responses within 4 mmHg of each other. These three responses were then averaged and represented the control response to All. The test compound was suspended in 0.5% methylcellulose in water and was administered by gavage. The volume
  • 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
  • compositions 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,
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pha.rmaceutical 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 by 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.
  • 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.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of
  • 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
  • capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection
  • 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
  • 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

L'invention concerne une classe de composés de 1,2,4-triazolones à substitution N utilisés dans le traitement de troubles cardiovasculaires. Les composés présentant un intérêt particulier sont des antagonistes d'angiotensine II de la formule (I), dans laquelle R1 est choisi parmi 2-oxo-2-(tricyclo[3.3.1.1.3.7]dec-2-yl)ethyl, 3-phénylpropyle, 2-oxo-2-phényléthyle, 2-hydroxy-2-phényléthyle, 1,1-diméthyléthyloxycarbonylméthyle, hexyle, éthoxycarbonylméthyle, carboxyméthyle, 1-naphtalènylméthyle, 2-cyclohexyléthyle, pentyl, éthoxycarbonyleméthoxyéthyle remplacés par phényle, carboxyméthoxyéthyle remplacés par phényle, 3,5,5-triméthylhexyle, (2-phénylméthoxy)-1-(phénylméthyle)-E-éthènyle, 1-benzoyl-2-phényléthyle, 1-oxobutyl, 2-(2,5-diméthyoxyphényle)-2-oxoéthyle, 2-phényle-2-(phénylméthoxy)éthyle, 2-(2,5-diméthyoxy-phényle)-2-hydroxyéthyle, 2-naphtalènylméthyle, méthoxycarbonyle-butyl, éthoxycarbonyléthyle remplacés par benzoyle, 1-benzyoyle-1-méthyléthyle, acide-1-pentanoïque, cyclopropylméthyle, 3-phényle-2E-propényle et 3-acétonitryle; dans laquelle R2 est choisi entre éthyle, n-propyle, isopropyle, n-butyle, sec-butyle, isobutyle, 4-méthylbutyle, tert-butyle, n-pentyle, néopentyle, 1-cyanobutyle, propylthio et butylthio; dans laquelle R3 à R11 représentent chacun hydrido à condition qu'au moins un des éléments R5 et R9 soient choisis parmi COOH, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, (a), (b) et (c), dans lesquels R42 et R43 sont choisis indépendamment entre chloro, cyano, nitro, trifluorométhyle, méthoxycarbonyle et trifluorométhylsulfonyle. Ces composés sont particulièrement utiles dans le traitement ou la régulation de l'hypertension et de l'insuffisance cardiaque.
EP91910101A 1990-05-25 1991-05-23 Composes de 1,2,4-triazolones a substitution n utilises dans le traitement de troubles cardiovasculaires Withdrawn EP0531382A1 (fr)

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CN1074412C (zh) * 1996-09-18 2001-11-07 立德化学株式会社 新的2,4－二氧代吡咯烷和2,4－二氧代四氢呋喃衍生物以及含有它们作为活性成分的药物

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EP0412594B1 (fr) 1989-07-28 1996-01-03 Merck & Co. Inc. Triazolinones, triazolinethiones et triazolinimines substituées comme antagonistes d'angiotensine II
US5411980A (en) * 1989-07-28 1995-05-02 Merck & Co., Inc. Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists
US5164403A (en) * 1991-04-05 1992-11-17 G. D. Searle & Co. N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders
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CA2083735A1 (fr) 1991-11-26
AU7903091A (en) 1991-12-31
WO1991018888A1 (fr) 1991-12-12
JPH05506443A (ja) 1993-09-22

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