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WO1994020460A1 - Chemical compounds - Google Patents

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Publication number
WO1994020460A1
WO1994020460A1 PCT/US1994/002524 US9402524W WO9420460A1 WO 1994020460 A1 WO1994020460 A1 WO 1994020460A1 US 9402524 W US9402524 W US 9402524W WO 9420460 A1 WO9420460 A1 WO 9420460A1
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Prior art keywords
alkyl
het
compounds
independently
formula
Prior art date
Application number
PCT/US1994/002524
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French (fr)
Inventor
Joseph Weinstock
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Smithkline Beecham Corporation
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Publication date
Priority claimed from US08/029,542 external-priority patent/US5378933A/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO1994020460A1 publication Critical patent/WO1994020460A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to new chemical compounds which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma.
  • This invention also relates to pharmaceutical
  • compositions containing these compounds and methods for using these compounds as antagonists of angiotensin II, as antihypertensive agents and as agents for treating congestive heart failure, renal failure, and glaucoma.
  • angiotensin The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (All), being one of the most potent endogenous vasoconstrictors known, exerts
  • renin-angiotensin system by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
  • the compounds of this invention inhibit, block and antagonize the action of the hormone All, and are therefore useful in regulating and moderating
  • angiotensin induced hypertension congestive heart failure, renal failure and other disorders attributed to the actions of All.
  • compounds of this invention are administered to mammals, the elevated blood pressure due to All is reduced and other manifestations based on All intercession are minimized and controlled.
  • Compounds of this invention are also expected to exhibit diuretic activity.
  • U.S. Patent 4,340,598 discloses imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic acids. Specifically, the discloser includes 1-benzyl-2- n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2- phenyl-5-chloroimidazole-4-propanoic acid.
  • U.S. Patent 4,355,040 discloses substituted imidazole-5-acetic acid derivatives.
  • a compound specifically disclosed is 1-(2-chlorobenzyl)-2- n-butyl-4-chloroimidazole-5-acetic acid.
  • Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids.
  • Two intermediates described in this patent are ethyl 3-[1-(4-nitrobenzyl)-2-butyl-4- chloroimidazol-5-yl]propenoate and ethyl 3-[2-butyl-4- chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoate.
  • Wareing in PCT/EP 86/00297, discloses as intermediates certain imidazolylpropenoate compounds.
  • Formula (CX) is ethyl 3-[1(-4-fluorophenyl)- 4-isopropyl-2-phenyl-1H-imidazol-5-yl]-2-propenoate.
  • X is absent or present as any accessible
  • each R 1 independently is hydrogen, C 1-6 alkyl, or (CH 2 ) n phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF 3 , or
  • each n independently is 0-4; each m independently is 1-2;
  • Q is O, S, NH, NC 1-6 alkyl
  • U is absent or present as O, S, NH, or NC 1-6 alkyl
  • each R 2 independently is C 1-8 alkyl, -OC 2-8 alkyl, -SC 2-8 alkyl, -(CH 2 ) 0-2 C 3-6 cycloalkyl, -O(CH 2 ) 0-2 Phenyl, or -S(CH 2 ) 0-2 Phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF 3 , or C 1-6 alkyl; R 3 is Cl, Br, F, I, CF 3 , SC 1-6 alkyl, NR 4 R 4 , or each R 4 independently is H or C 1-6 alkyl;
  • each R 6 independently is H, C 1-6 alkyl
  • each R 7 independently is C 1-4 alkyl or C 1-4 alkoxy;
  • R 8 and R 9 independently is C 1-4 alkyl or R 8 and R 9 taken together are -(CH 2 ) 4-6 -;
  • R 10 is H, C 1-4 alkyl, or -(CH 2 ) 1-2 OCH 3;
  • R 11 is H, C 1-4 alkyl, -(CH 2 ) 1-4 -OH, or CO 2
  • R 1 and R 18 is R 4 or R 11 and R 18 taken together are -(CH 2 ) 3 - or -(CH 2 ) 4 -;
  • each R 12 independently is H, C 1-4 alkyl, Cl, Br, F, or I;
  • each R 13 independently is CO 2 R 1 , Cl, Br, F, or I;
  • each R 15 independently is H, C 1 - 4 alkyl, or CO 2 R 1 ;
  • R 16 is H, C 1 - 4 alkyl, Cl, Br, F, I, SC 1-4 alkyl, or NR 4 R 4 ;
  • R 17 is H, C 1-4 alkoxy, or NR 4 R 4 ;
  • R 19 is H, NR 4 R 4 , or NR 4 C(O)NR 4 R 4 ;
  • R 20 is -(CH 2 ) 1-3 -O-CH 3 , -(CH 2 ) 0-3 -CO 2 R 4 or R 2 ;
  • R 21 is C 1-6 alkyl, -(CH 2 ) 1-4 OH, -(CH 2 ) 1-3 -O-CH 3 , -(CH 2 ) 1-2 -phenyl or -SCH 2 -phenyl, wherein the phenyl is unsubstituted or substituted by CO 2 R 1 , Cl, Br, F, or I;
  • R 22 is -(CH 2 ) 3 - or -(CH 2 ) 4 -;
  • R 23 is H, -O (CH 2 ) 1 - 2 F, -OCH 2 CF 3 , or
  • R 24 is C 1-4 alkyl, - (CH 2 ) 1-4 -OH, or CO 2
  • R' and R 25 is R 4 or R 24 and R 25 taken together are -(CH 2 ) 3 _ or
  • each Y independently is NR 4 , O, or CH 2 ;
  • each r independently is 0-2;
  • alkyl and alkoxy mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor
  • combination means any combination of substituents that is available by chemical synthesis and is stable.
  • Formula (la) includes presently preferred Formula (I) compounds:
  • X is A-CO 2 R 1 , CONR 1 R 1 -, or tetrazolyl.
  • the most preferred Formula (I) or (la) compounds are those wherein X is CO 2 H.
  • the most preferred Het groups of Formula (I) and (la) include:
  • the invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).
  • angiotension II receptor antagonists they may also be of value in the treatment of left ventricular
  • these compounds may be expected to be useful in the primary and secondary prevention of infarction, in the prevention of atheroma progression and in the regression of antheroma, in the prevention of restinosis after angioplasty or bypass surgery and in the improvement of cognitive funtion.
  • the compounds of this invention are prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and functionality on the naphthalene and other fragments of the molecule must be consistent. with the proposed chemical
  • the compounds of Formula (I) are generally prepared by reacting a compound of the formula (II) with a compound of the formula (III) :
  • L 1 is a displaceable group
  • L 2 is an alkali metal salt
  • the term "displaceable group” means a halide, mesylate, tosylate, or acetate group and the term “alkali metal salt” means a sodium, lithium, or potassium salt.
  • reactive functional groups protected is meant that certain groups on the naphthyl or Het rings are protected, for example a CO 2 H group is protected as its C 1-4 alkyl ester derivative and a hydroxy group is protected as its C 1-4 alkoxy or
  • a suitable base such as an alkali metal hydride, or potassium or sodium carbonate, preferably potassium carbonate, at a reaction temperature of about 25°C to about 100°C, preferably at about 70°C.
  • methyl 4-methylnaphthalene-1- carboxylate is methyl halogenated using, for example, N- bromosuccinimide in the presence of an initiator, such as benzoylperoxide, and UV light, in a suitable solvent, such as carbon tetrachloride.
  • the various Het compounds used in the synthesis Fomula (I) compounds are prepared employing conventional techniques. Each of Het compounds is treated with a base, such as an alkali metal hydride, for example sodium, lithium or potassium hydride, or sodium or potassium carbonate, to prepare the formula (III) compounds.
  • a base such as an alkali metal hydride, for example sodium, lithium or potassium hydride, or sodium or potassium carbonate.
  • Het is a pyrazole of formula (1) and (18) are detailed in U.S. Patent No. 5,081,127, EP Publication Nos. 323 841, 411 507, 446 062, and 449 699 and PCT Publication No. WO 91/15479.
  • Methods for preparing Het compounds wherein Het is a imidazothiophene of formula (2) are detailed in EP Publication No 407 102.
  • Compounds of Formula (I) in which the naphthyl group is substituted by carboxy are formed from Formula (I) compounds in which the naphthyl group is substituted by CO 2 C 1-4 alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.
  • acetonitrile/dimethylformamide yields the nitrile compounds, which are the immediate precursors to the Formula (I) tetrazole compounds.
  • Tetrazole formation is accomplished by reacting the nitriles with azide, preferably aluminum azide prepared in situ by the reaction of sodium azide with aluminum chloride, in a suitable solvent, for example tetrahydrofuran.
  • acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic,
  • compositions of Formula (I) are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide;
  • Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vitro and in vivo
  • In vitro antagonist activity is determined by the ability of the compounds to compete with 125 I- angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the
  • the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 42:278, 1980).
  • a particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125 I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C.
  • the incubation is terminated by rapid filtration and receptor bound 125 I- angiotensin II trapped on the filter is quantitated with a gamma counter.
  • IC 50 is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.
  • angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (K B ) are calculated by the dose ratio method using the mean effective concentrations.
  • Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg
  • angiotensin II is compared at various time points prior to and following the administration of the compounds intravenously or orally at doses of 0.1 to 300 mg/kg.
  • the dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC 50 ) is used to estimate the potency of the compounds.
  • the antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent
  • Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery ligation, the time at which plasma renin levels are highest, the conscious rats are placed in restrainers and mean arterial pressure is continuously recorded prior to and following the
  • the intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1 (2):161-168 (1985).
  • the compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts.
  • Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds;
  • buffering ingredients such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
  • suitable ophthalmic vehicles may be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems.
  • the pharmaceutical preparation may also be in the form of a solid insert.
  • a solid water soluble polymer as the carrier for the medicament.
  • Solid water insoluble inserts such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral, parenteral, or topical products.
  • pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably 1 - 100 mg/kg.
  • the selected dose is administered to a human patient in need of angiotensin II receptor antagonism from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
  • Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Preferably, lower dosages are used for parenteral administration.
  • Topical formulations contain the active compound in an amount selected from 0.0001 to 0.1 (w/v%), preferably from 0.0001 to 0.01.
  • an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.
  • the compounds of this invention may be co- administered with other pharmaceutically active compounds for example in combination, concurrently or sequentially. Conpressively the compounds of this
  • diuretics such as thiazides and related compounds, for example bendrofluazide, chlorthiazide, chlorthalidone, and hydrochlorothiazide, and other diuretics, for example frusemide and triamterene, calcium channel blockers, for example verapamil and nifedipine, ⁇ - adrenoceptor blockers, for example propanolol, renin inhibitors, for example enalkinen and angiotensin converting enzyme inhibitors, for example captopril and enapril.
  • diuretics such as thiazides and related compounds, for example bendrofluazide, chlorthiazide, chlorthalidone, and hydrochlorothiazide, and other diuretics, for example frusemide and triamterene, calcium channel blockers, for example verapamil and nifedipine, ⁇ - adrenoceptor blockers, for example propanolol, renin inhibitor
  • the method of this invention of antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
  • the methods of this invention of treating comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I).
  • hypertension, congestive heart failure, glaucoma, and renal failure comprise administering a compound of
  • Formula (I) to a subject in need thereof an effective amount to produce said activity.
  • Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.
  • Examples 2-20 in Table I are prepared following the procedure of Example 1 using the appropriate Het group in place of 2-n-butyl-6-[N-(cyclohexylaminocarbonyl)- amino]benzimidazole.
  • An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.
  • sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • a topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below.

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Abstract

Angiotensin II receptor antagonists having formula (I) which are useful in the treatment of hypertension, congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.

Description

CHEMICAL COMPOUNDS
The present invention relates to new chemical compounds which are angiotensin II receptor antagonists and are useful in regulating hypertension induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure, and glaucoma. This invention also relates to pharmaceutical
compositions containing these compounds and methods for using these compounds as antagonists of angiotensin II, as antihypertensive agents and as agents for treating congestive heart failure, renal failure, and glaucoma.
BACKGROUND OF THE INVENTION The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (All), being one of the most potent endogenous vasoconstrictors known, exerts
stimulation on the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular hemeostasis.
Interruption of the renin-angiotensin system with converting enzyme inhibitors, such as captopril, has proved to be clinically useful in the treatment of hypertension and congestive heart failure (Abrams, W.B., et al., (1984), Federation Proc., 43, 1314). The most direct approach towards inhibition of the renin- angiotensin system would block the action of All at the receptor. Compelling evidence suggests that All also contributes to renal vasoconstriction and sodium retention that is characteristic of a number of
disorders such as heart failure, cirrhosis and
complications of pregnancy (Hollenberg, N.K., (1984), J . Cardiovas. Pharmacol., 6, S176). In addition, recent animal studies suggest that inhibition of the renin- angiotensin system may be beneficial in halting or slowing the progression of chronic renal failure
(Anderson, S., et al., (1985), J. Clin. Invest., 76,
612). Also, a recent patent application (South African Patent Application No. 87/01,653) claims that All antagonists are useful as agents for reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.
The compounds of this invention inhibit, block and antagonize the action of the hormone All, and are therefore useful in regulating and moderating
angiotensin induced hypertension, congestive heart failure, renal failure and other disorders attributed to the actions of All. When compounds of this invention are administered to mammals, the elevated blood pressure due to All is reduced and other manifestations based on All intercession are minimized and controlled.
Compounds of this invention are also expected to exhibit diuretic activity.
Recognition of the importance of blocking and inhibiting the actions of All has stimulated other efforts to synthesize antagonists of All. The following references have disclosed imidazole derivatives which are described as having All blocking activity and useful as hypotensive agents.
Furukawa et al., U.S. Patent 4,340,598 discloses imidazol-5-yl-acetic acids and imidazol-5-yl-propanoic acids. Specifically, the discloser includes 1-benzyl-2- n-butyl-5-chloroimidazole-4-acetic acid and 1-benzyl-2- phenyl-5-chloroimidazole-4-propanoic acid.
Furukawa, et al., U.S. Patent 4,355,040 discloses substituted imidazole-5-acetic acid derivatives. A compound specifically disclosed is 1-(2-chlorobenzyl)-2- n-butyl-4-chloroimidazole-5-acetic acid.
Carini et al. in EP 253,310 disclose certain imidazolylpropenoic acids. Two intermediates described in this patent are ethyl 3-[1-(4-nitrobenzyl)-2-butyl-4- chloroimidazol-5-yl]propenoate and ethyl 3-[2-butyl-4- chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoate.
Also, Wareing, in PCT/EP 86/00297, discloses as intermediates certain imidazolylpropenoate compounds. On page 62, Formula (CX) is ethyl 3-[1(-4-fluorophenyl)- 4-isopropyl-2-phenyl-1H-imidazol-5-yl]-2-propenoate.
DESCRIPTION OF THE INVENTION
The compounds of the present invention that are blockers of angiotensin II receptors are represented by the following Formula (I):
in which:
Figure imgf000005_0001
X is absent or present as any accessible
combination of up to three substituents selected from Cl, Br, F, I, CF3, C1-6alkyl, NO2, A-CO2R1, tetrazolyl, C1-6alkoxy, OH, SC^alkyl, SO2HR1, NHSO2R7, S03H, CONR1R1, CN, SO2C1-6alkyl, NR1R1, NR1COH, or
NR1COC1-6alkyl;
each R1 independently is hydrogen, C1-6alkyl, or (CH2)nphenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or
C1-6alkyl;
A is -(CH2)n-, -CH=CH-, -Q-CH(R6)-, or
-Q-(CH2)m-U-(CH2)m-;
each n independently is 0-4; each m independently is 1-2;
Q is O, S, NH, NC1-6alkyl;
U is absent or present as O, S, NH, or NC1-6alkyl,
Het is
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
each R2 independently is C1-8alkyl, -OC2-8alkyl, -SC2-8alkyl, -(CH2)0-2C3-6cycloalkyl, -O(CH2)0-2Phenyl, or -S(CH2)0-2Phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or C1-6alkyl; R3 is Cl, Br, F, I, CF3, SC1-6alkyl, NR4R4, or
Figure imgf000009_0002
each R4 independently is H or C1-6alkyl;
R5 is
Figure imgf000010_0001
each R6 independently is H, C1-6alkyl,
- (CH2) 1-2CF3, - (CH2 ) 1-2C3- 6cycloalkyl , or
-(CH2)0-2phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or
C1-6alkyl;
each R7 independently is C1-4alkyl or C1-4alkoxy; R8 and R9 independently is C1-4alkyl or R8 and R9 taken together are -(CH2)4-6-;
R10 is H, C1-4alkyl, or -(CH2)1-2OCH3;
R11 is H, C1-4alkyl, -(CH2)1-4-OH, or CO2R1 and R18 is R4 or R11 and R18 taken together are -(CH2)3- or -(CH2)4-;
each R12 independently is H, C1-4alkyl, Cl, Br, F, or I;
each R13 independently is CO2R1, Cl, Br, F, or I; R14 is C1-4alkyl or =0;
each R15 independently is H, C1 - 4alkyl, or CO2R1 ; R16 is H, C1 - 4alkyl, Cl, Br, F, I, SC1-4alkyl, or NR4R4;
R17 is H, C1-4alkoxy, or NR4R4;
R19 is H, NR4R4, or NR4C(O)NR4R4;
R20 is -(CH2)1-3-O-CH3, -(CH2)0-3-CO2R4 or R2;
R21 is C1-6alkyl, -(CH2)1-4OH, -(CH2)1-3-O-CH3, -(CH2)1-2-phenyl or -SCH2-phenyl, wherein the phenyl is unsubstituted or substituted by CO2R1, Cl, Br, F, or I;
R22 is -(CH2)3- or -(CH2)4-; R23 is H, -O (CH2 ) 1 - 2F, -OCH2CF3 , or
-O (CH2 ) 1 -2NR4R4 ;
R24 is C1-4alkyl, - (CH2) 1-4-OH, or CO2R' and R25 is R4 or R24 and R25 taken together are -(CH2)3 _ or
-(CH2)4-;
each Y independently is NR4, O, or CH2; and
each r independently is 0-2;
or a pharmaceutically acceptable salt thereof. As used herein, the terms alkyl and alkoxy mean carbon chains which are branched or unbranched with the length of the chain determined by the descriptor
preceding the term. The phrase "any accessible
combination" means any combination of substituents that is available by chemical synthesis and is stable.
Formula (la) includes presently preferred Formula (I) compounds:
Figure imgf000011_0001
( )
in which X is A-CO2R1, CONR1R1-, or tetrazolyl.
The most preferred Formula (I) or (la) compounds are those wherein X is CO2H.
The most preferred Het groups of Formula (I) and (la) include:
Figure imgf000011_0002
Figure imgf000012_0001
Figure imgf000013_0001
The invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of a compound of Formula (I).
Also included in the present invention are methods for antagonizing angiotensin II receptors which
comprises administering to a subject in need thereof an effective amount of a compound of Formula (I). Methods of treating hypertension, congestive heart failure, glaucoma, and renal failure by administering these compounds are also included in this invention.
Because the compounds of Formula (I) are
angiotension II receptor antagonists, they may also be of value in the treatment of left ventricular
hypertrophy regression, diabetic nephropathy, diabetic retinopathy, macular degeneration, haemorrhagic stroke, angina, and anxiety. Additionally, these compounds may be expected to be useful in the primary and secondary prevention of infarction, in the prevention of atheroma progression and in the regression of antheroma, in the prevention of restinosis after angioplasty or bypass surgery and in the improvement of cognitive funtion.
The compounds of this invention are prepared by procedures described herein and illustrated by the examples. Reagents, protecting groups and functionality on the naphthalene and other fragments of the molecule must be consistent. with the proposed chemical
transformations. Steps in the synthesis must be
compatible with the functional groups and the protecting groups on the naphthalene and other parts of the
molecule.
The compounds of Formula (I) are generally prepared by reacting a compound of the formula (II) with a compound of the formula (III) :
Figure imgf000014_0001
wherein X, n and Het are as defined in Formula (I), with any reactive functional groups protected;
L1 is a displaceable group; and
L2 is an alkali metal salt;
and thereafter removing any protecting groups, and optionally forming a pharmaceutically acceptable salt.
As used hereinabove, the term "displaceable group" means a halide, mesylate, tosylate, or acetate group and the term "alkali metal salt" means a sodium, lithium, or potassium salt. By the term "reactive functional groups protected" is meant that certain groups on the naphthyl or Het rings are protected, for example a CO2H group is protected as its C1-4alkyl ester derivative and a hydroxy group is protected as its C1-4alkoxy or
benzyloxy derivative.
The substituted naphthyl-(CH2)n -group is
incorporated onto the Het ring by known procedures, for example, by reaction with a substituted naphthyl- (CH2)n halide, mesylate, tosylate, or acetate, such as methyl 4-bromomethylnaphthalene-1-carboxylate, in a suitable solvent, such as dimethylformamide (DMF), in the
presence of a suitable base, such as an alkali metal hydride, or potassium or sodium carbonate, preferably potassium carbonate, at a reaction temperature of about 25°C to about 100°C, preferably at about 70°C.
The substituted naphthyl-(CH2)n halides, mesylates of acetates of Formula (II) are known to the art or are synthesized by known procedures .Can. J. Chem., 59:2629 (1981)]. For example, methyl 4-methylnaphthalene-1- carboxylate is methyl halogenated using, for example, N- bromosuccinimide in the presence of an initiator, such as benzoylperoxide, and UV light, in a suitable solvent, such as carbon tetrachloride.
The various Het compounds used in the synthesis Fomula (I) compounds are prepared employing conventional techniques. Each of Het compounds is treated with a base, such as an alkali metal hydride, for example sodium, lithium or potassium hydride, or sodium or potassium carbonate, to prepare the formula (III) compounds. The publications hereinbelow detail the preparation of the various Het compounds and reference should be made to such publications for their
disclosure, which are incorporated herein by reference.
Methods for preparing Het compounds herein Het is a pyrazole of formula (1) and (18) are detailed in U.S. Patent No. 5,081,127, EP Publication Nos. 323 841, 411 507, 446 062, and 449 699 and PCT Publication No. WO 91/15479. Methods for preparing Het compounds wherein Het is a imidazothiophene of formula (2) are detailed in EP Publication No 407 102.
Methods for preparing Het compounds wherein Het is a imidazopyridine of formula (3) are detailed in EP
Publication Nos. 399 731, 400 974, 420 237, and 456 510 and U.S. Patent Nos. 5,053,329 and 5,102,880.
Methods for preparing Het compounds wherein Het is a triazole of formula (4) and (19) are detailed in EP Publication Nos. 323 841, 409 332, and 412 594 and U.S. Patent No. 5,093,346.
Methods for preparing Het compounds wherein Het is a imidazole fused to a 7 membered carbocyclic ring of formula (5) are detailed in EP Publication No. 432 737.
Methods for preparing Het compounds wherein Het is a imidazopyrimidine of formula (6) are detailed in EP Publication No. 399 731.
Methods for preparing Het compounds wherein Het is a benzodiazepine of formula (7) are detailed in U.S. Patent No. 5,064,825.
Methods for preparing Het compounds wherein Het is a benzothiadiazine of formula (8) are detailed in
Weller, et al., Binorganic & Medicinal Chemistry
Letters, 2(9):1115 (1992).
Methods for preparing Het compounds wherein Het is a pyridopyridine of formula (9) are detailed in EP
Publication No. 487 252 and PCT Publication No. WO
91/07404.
Methods for preparing Het compounds wherein Het is a aminopyrimidine of formula (10) are detailed in EP Publication No. 475 206.
Methods for preparing Het compounds wherein Het is a benzimidazole of formula (11) and (17) are detailed in EP Publication Nos. 392 317, 468 470, 400 835, 425,921 and 459,136, U.S. Patent No. 4,880,804 and German Patent Nos. 4,031,287 and 3,928,177.
Methods for preparing Het compounds wherein Het is a benzopyrimidine of formula (12) and (30) are detailed in EP Publication Nos. 411 766, 481 614, 407 342, and 445 811.
Methods for preparing Het compounds wherein Het is a tetrazole of formula (13) are detailed in EP
Publication No. 323 841.
Methods for preparing Het compounds wherein Het is an imidazole of formula (14) are detailed in EP
Publication Nos. 253 310, 324 377, 380 959, 409 332 and 479 479.
Methods for preparing Het compounds wherein Het is a quinoline of formula (15) and (16) are detailed in EP Publication Nos. 412 848 and 456 442 and Great Britain Patent No. 2,234,748.
Methods for preparing Het compounds wherein Het is a imidazopyrimidinone of formula (20) are detailed in EP Publication No. 467 207.
Methods for preparing Het compounds wherein Het is a imidazopyrimidine-dione of formula (21) are detailed in EP Publication No. 430 300.
Methods for preparing Het compounds wherein Het is a aminopyridine of formula (22) and (23) are detailed in EP Publication No. 475 206.
Methods for preparing Het compounds wherein Het is a piperidine of formula (24) are detailed in Murray, et al., Bioorganic & Medicinal Chemistry Letters, 2(12): 1775 (1992).
Methods for preparing Het compounds wherein Het is a quinolone of formula (25) are detailed in EP
Publication No.498 721.
Methods for preparing Het compounds wherein Het is a pyridothiophene of formula (26) are detailed in EP Publication No. 443 568.
Methods for preparing Het compounds wherein Het is a alkoxypyridine of formula (27) are detailed in EP Publication Nos. 453 210 and PCT Publication No. WO 91/19697. Methods for preparing Het compounds wherein Het is a dihydropyrimidine of formula (28) and (29) are detailed in EP Publication No. 481 448.
Methods for preparing Het compounds wherein Het is a pyridothiadiazine of formula (31) are detailed in Weller, et al., Bioorganic & Medicinal Chemistry
Letters, 2(9):1115 (1992).
Methods for preparing Het compounds wherein Het is a imidazopyridazine of formula (32) are detailed in PCT Publication No. WO 91/19715.
Methods for preparing Het compounds wherein Het is a imidazolone of formula (33) are detailed in PCT
Publication No. WO 91/14679.
Methods for preparing Het compounds wherein Het is an acylated alpha amino acid derivative of formula (34) are detailed in EP Publication No. 443 983.
Compounds of Formula (I) in which the naphthyl group is substituted by hydroxy are formed from Formula (I) compounds in which the naphthyl already present is substituted by C1-C4alkoxy using an ether-cleaving reagent, such as boron tribromide or hydrobromic acid.
Compounds of Formula (I) in which the naphthyl group is substituted by carboxy are formed from Formula (I) compounds in which the naphthyl group is substituted by CO2C1-4alkyl using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acidic hydrolysis, such as aqueous hydrochloric acid.
Compounds of Formula (I) in which the naphthyl group is substituted by a tetrazol-5-yl group are prepared from the correponding carboxy compounds. For example. Formula (I) acid compounds are reacted with a halogenating agent, such as thionyl chloride, in a suitable solvent, for example benzene, to give the corresponding acid halide compounds. The acid halides are then converted to primary amide compounds in a reaction with concentrated ammonia to give Formula (I) compounds wherein the naphthyl group is substituted by CONH2. Subsequent dehydration of the amides with oxalyl chloride/dimethylformamide in
acetonitrile/dimethylformamide yields the nitrile compounds, which are the immediate precursors to the Formula (I) tetrazole compounds. Tetrazole formation is accomplished by reacting the nitriles with azide, preferably aluminum azide prepared in situ by the reaction of sodium azide with aluminum chloride, in a suitable solvent, for example tetrahydrofuran.
Pharmaceutically acceptable acid addition salts of compounds of Formula (I) are formed with appropriate organic or inorganic acids by methods known in the art. For example, the base is reacted with a suitable
inorganic or organic acid in an aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or
chloroform, with the desired salt separating directly or isolated by removing the solvent. Representative examples of suitable acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic,
stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
Pharmaceutically acceptable base addition salts of compounds of Formula (I) are prepared by known methods from organic and inorganic bases, including nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide;
ammonium hydroxide, and nontoxic organic bases, such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine, and trommthamine. Angiotensin II antagonist activity of the compounds of Formula (I) is assessed by in vitro and in vivo
methods. In vitro antagonist activity is determined by the ability of the compounds to compete with 125I- angiotensin II for binding to vascular angiotensin II receptors and by their ability to antagonize the
contractile response to angiotensin II in the isolated rabbit aorta. In vivo activity is evaluated by the efficacy of the compounds to inhibit the pressor
response to exogenous angiotensin II in conscious rats and to lower blood pressure in a rat model of renin dependent hypertension.
Binding
The radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 42:278, 1980). A particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125I-angiotensin II with or without angiotensin II antagonists for 1 hour at 25°C. The incubation is terminated by rapid filtration and receptor bound 125I- angiotensin II trapped on the filter is quantitated with a gamma counter. The potency of angiotensin II
antagonists is expressed as the IC50 which is the concentration of antagonist needed to displace 50% of the total specifically bound angiotensin II.
Aorta
The ability of the compounds to antagonize
angiotensin II induced vasoconstriction is examined in the rabbit aorta. Ring segments are cut from the rabbit thoracic aorta and suspended in organ baths containing physiological salt solution. The ring segments are mounted over metal supports and attached to force displacement transducers which are connected to a recorder. Cumulative concentration response curves to angiotensin II are performed in the absence of antagonist or following a 30-minute incubation with antagonist. Antagonist disassociation constants (KB) are calculated by the dose ratio method using the mean effective concentrations.
Inhibition of pressor response to
angiotensin II in conscious rats
Rats are prepared with indwelling femoral arterial and venous catheters and a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two to three days following surgery the rats are placed in a restrainer and blood pressure is continuously monitored from the arterial catheter with a pressure transducer and recorded on a polygraph. The change in mean arterial pressure in response to intravenous injections of 250 mg/kg
angiotensin II is compared at various time points prior to and following the administration of the compounds intravenously or orally at doses of 0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibition of the control response to angiotensin II (IC50) is used to estimate the potency of the compounds.
Antihypertensive activity
The antihypertensive activity of the compounds is measured by their ability to reduce mean arterial pressure in conscious rats made renin-dependent
hypertensive by ligation of the left renal artery
(Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal artery ligated rats are prepared with indwelling catheters as described above. Seven to eight days following renal artery ligation, the time at which plasma renin levels are highest, the conscious rats are placed in restrainers and mean arterial pressure is continuously recorded prior to and following the
administration of the compounds intravenously or orally. The dose of compound needed to reduce mean arterial pressure by 30 mm Hg (IC30) is used as an estimate of potency .
The intraocular pressure lowering effects employed in this invention may be measured by the procedure described by Watkins, et al., J. Ocular Pharmacol., 1 (2):161-168 (1985).
The compounds of Formula (I) are incorporated into convenient dosage forms, such as injectable
preparations, or for orally active compounds, capsules or tablets. Solid or liquid pharmaceutical carriers are employed. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid, such as an ampoule, or an aqueous or nonaqueous liquid suspension.
For topical ophthalmolgic administration, the pharmaceutical compositions adapted include solutions, suspensions, ointments, and solid inserts. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water soluble ophthalmologically acceptable non-toxic
polymers, for example, cellulose derivatives such as methyl cellulose. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example, polyethylene glycols; antibacterial components, such as quarternary ammonium compounds;
buffering ingredients, such as alkali metal chloride; antioxidants, such as sodium metabisulfite; and other conventional ingredients, such as sorbitan monolaurate.
Additionally, suitable ophthalmic vehicles may be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems.
The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. Solid water insoluble inserts, such as those prepared from ethylene vinyl acetate copolymer, may also be utilized.
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral, parenteral, or topical products.
Doses of the compounds of Formula (I) in a
pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from the range of .01 - 200 mg/kg of active compound, preferably 1 - 100 mg/kg. The selected dose is administered to a human patient in need of angiotensin II receptor antagonism from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Preferably, lower dosages are used for parenteral administration. Oral
administration, at higher dosages, however, also can be used when safe and convenient for the patient. Topical formulations contain the active compound in an amount selected from 0.0001 to 0.1 (w/v%), preferably from 0.0001 to 0.01. As a topical dosage unit form, an amount of active compound from between 50 ng to 0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.
The compounds of this invention may be co- administered with other pharmaceutically active compounds for example in combination, concurrently or sequentially. Conviently the compounds of this
invention and the other active compound or compounds are formulated in a pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of Formula (I) are diuretics, such as thiazides and related compounds, for example bendrofluazide, chlorthiazide, chlorthalidone, and hydrochlorothiazide, and other diuretics, for example frusemide and triamterene, calcium channel blockers, for example verapamil and nifedipine, β- adrenoceptor blockers, for example propanolol, renin inhibitors, for example enalkinen and angiotensin converting enzyme inhibitors, for example captopril and enapril.
The method of this invention of antagonizing angiotensin II receptors in mammals, including humans, comprises administering to a subject in need of such antagonism an effective amount of a compound of Formula (I). The methods of this invention of treating
hypertension, congestive heart failure, glaucoma, and renal failure comprise administering a compound of
Formula (I) to a subject in need thereof an effective amount to produce said activity.
Contemplated equivalents of Formula (I) compounds are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (I) compounds provided such compounds have the pharmaceutical utility of Formula (I) compounds.
The following examples illustrate preparation of compounds and pharmaceutical compositions of this invention. The examples are not intended to limit the scope of this invention as defined hereinabove and as claimed below. Exampl e 1
2-n-Butyl - 1 - [ (4-carboxynaphth- 1 -y l ) methy l ] - 6- [ N-
(cyclohexylaminocarbonyl)aminolbenzimidazole (i) 2-n-butyl-6-[N-(cyclohexylaminocarbonyl)- amino]-benzimidazole
The title compound is prepared according to the procedure of EP Publication No. 392 317. (ii) 2-n-butyl-1-[(4-carbomethoxynaphth-1- yl)methyl]-6-[N-(cyclohexylaminocarbonyl)- amino]benzimidazole
A suspension of 0.214 mol of powdered potassium carbonate, 0.214 mol of 2-n-butyl-6-[N-(cyclohexyl- aminocarbonyl)amino]benzimidazole and 0.235 mol of methyl 4-bromomethylnaphthalene-1-carboxylate (E.A.
Dixon, A. Fischer, and F.P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 mL of dimethylformamide is stirred for 5 hours under argon at 70°C. An additional 0.0235 mol of the bromomethyl ester is added and the suspension is stirred an additional 15 hours at 70°C. The reaction mixture is poured into water and the resulting solid is collected by filtration, washed with water, and
triturated several times with boiling methanol.
(iii) 2-n-butyl-1-[(4-carboxynaphth-1- yl)methyl]-6-[N-(cyclohexylaminocarbonyl)amino]- benzimidazole
A slurry containing 26.14 mmol of 2-n-butyl-1- [(4-carbomethoxynaphth-1-yl)methyl]-6-[N-(cyclohexylaminocarbonyl)amino]benzimidazole and 2.09 mmol of potassium hydroxide in a mixture of 165 mL of ethanol and 85 mL of water is stirred at ambient temperature for 18 hours. Concentration under vacuum and dilution with water gives a clear solution. Adjustment of the pH to about 4 with hydrochloric acid gives the title compound. Examples 2-21
Examples 2-20 in Table I are prepared following the procedure of Example 1 using the appropriate Het group in place of 2-n-butyl-6-[N-(cyclohexylaminocarbonyl)- amino]benzimidazole.
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Exampl e 21
Figure imgf000029_0001
N- [ ( 1 -Carhoxynaphth-4-yl ) methyl] -N-va l eryl-L - vallne.
A solution of methyl 4-bromomethylnapthalene-1- carboxylate (2.0g, 7.16 mmol), L-valine methyl ester hydrochloride (1.44g, 8.59 mmol) and 5 mL of
disopropylethylamine in 15 mL of dimethylformamide was heated to 75°C for 1 hour and then allowed to stand -at ambient temperature for 5 days. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with 5% sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to give an oil
(TLC Rf, SiO2, 20% ethyl acetate/hexane). The
unpurified product (2.3g, 7 mmol) was dissolved in 25 mL of methylene chloride and was treated with 2.7 g (21 mmol) of disopropylethylamine and 1.09 g (9.1 mmol) of valeryl chloride. The reaction mixture was stirred at ambient temperature for 8 hours and then an additional 1 g of valeryl chloride was added and the mixture was stirred for one hour. Then 25 mL of 5% sodium
bicarbonate solution was added, the mixture was stirred for 1 hour and then extracted with methylene chloride.
The extract was dried and chromatographed (on silica gel, eluting with 5% ethyl acetate/methylene chloride) to give 2.44 g of an oil (the amide diester). A
solution of 1.5 g (3.63 mmol) of this product and 1.27 g (22.6 mmol) of potassium hydroxide in a mixture of 60 mL of ethanol and 10 mL of water was stirred at ambient temperature for 5 days. The reaction mixture was concentrated under vacuum and 30 mL of water was added. Addition of 12 N hydrochloric acid solution to pH 2 gave 1.07 g of a white solid, mp 106-108°C. (The NMR was consistent for the di-acid, but the elemental analysis indicated the presence of potassium.) After stirring the product with aqueous hydrochloric acid at pH 1 for 1 hour, 1.0 g of white crystals were obtained, mp 112- 114°C. Anal. Calcd for C22H27 N05•½H2O; C,66.99; H, 7.15; N, 3.55. Found: C, 66.90; H, 7.09; N, 3.95.
Example 22
An oral dosage form for administering orally active Formula (I) compounds is produced by screening, mixing and filling into hard gelatin capsules the ingredients in proportions, for example, as shown below.
Ingredients Amounts
2-n-Butyl-1-[(4-carboxy- naphth-1-yl)methyl]-6-[N- (cyclohexylaminocarbonyl)- amino]benzimidazole 100 mg
magnesium stearate 10 mg
lactose 100 mg
Example 23
The sucrose calcium sulfate dihydrate and orally active Formula (I) compounds are mixed and granulated with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet. Ingredients Amounts
2-ethyl-4-[(4- carboxynaphth-1- yl)methoxy]quinoline 75 mg
calcium sulfate dihydrate 100 mg
sucrose 15 mg
starch 8 mg
talc 4 mg
stearic acid 2 mg
Example 24
2-n-Butyl-1-[(4-carboxynaphth-1-yl)methyl]-6-[N- (cyclohexylaminocarbonyl)amino]benzimidazole, 50 mg, is dispersed in 25 mL of normal saline to prepare an injectable preparation.
Example 25
A topical opthamological solution for administering Formula (I) compounds is produced by mixing under sterile conditions the ingredients in proportions, for example, as shown below.
Ingredients Amounts
(mg/mL)
2-ethyl-4-[(4- carboxynaphthyl-1- yl)methoxy]quinoline 1.0
dibasic sodium phosphate 10.4
monobasic sodium phosphate 2.4
chlorobutanol 5.0
hydroxypropanol
methylcellulose 5.0
sterile water q.s.ad 1.0mL
1.0 N sodium hydroxide q.s.ad pH 7.4
It is to be understood that the invention is not limited to the embodiments illustrated hereabove and the right to the illustrated embodiments and all
modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A compound of the formula:
Figure imgf000033_0001
in which:
X is absent or present as any accessible
combination of up to three substituents selected from
Cl, Br, F, I, CF3, C1-6alkyl, NO2, A-CO2R1, tetrazolyl, C1-6alkoxy, OH, SC1-6alkyl, SO2 HR1, NHSO2R7, SO3H,
CONR1R1, CN, SO2C1-6alkyl, NR1R1, NR1COH, or
NR1COC1-6alkyl;
each R independently is hydrogen, C1-6alkyl, or
(CH2)nphenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or
C1-6alkyl;
A is -(CH2)n-, -CH=CH-, -Q-CH(R6)-, or
-Q-(CH2)m-U-(CH2)m-;
each n independently is 0-4;
each m independently is 1-2;
Q is O, S , NH, NC1-6alkyl ;
U is absent or present as O, S, NH, or NC1-6alkyl;
Het is
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
each R2 independently is C1-6alkyl, -OC2-8alkyl, -SC2-8alkyl, - (CH2) 0-2C3-6Cycloalkyl, -O (CH2) 0-2Phenyl, or -S (CH2) 0-2Phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or C1-6alkyl;
R3 is Cl, Br, F, I, CF3, SC1-6alkyl, NR4R4, or
Figure imgf000037_0002
each R4 independently is H or C1-6alkyl;
R5 is
Figure imgf000037_0003
each R6 independently is H, C1-6alkyl,
-(CH2)1-2CF3, -(CH2)1-2C3-6cycloalkyl, or - (CH2) 0-2Phenyl, wherein the phenyl is unsubstituted or substituted by any accessible combination of up to three substituents selected from Cl, Br, F, I, CF3, or
C1-6alkyl;
each R7 independently is C1-4alkyl or C1-4alkoxy;
R8 and R9 independently is C1-4alkyl or R8 and R9 taken together are -(CH2)4-6-;
R10 is H, C1-4alkyl, or - (CH2) 1-2OCH3;
R11 is H, C1-4alkyl, - (CH2) 1 - 4-OH, or CO2R1 and R18 is R4 or R11 and R18 taken together are -(CH2)3- or -(CH2)4-;
each R12 independently is H, C1-4alkyl, Cl, Br, F, or I;
each R13 independently is CO2R1, Cl, Br, F, or I; R14 is C1-4alkyl or =0;
each R15 independently is H, C1-4alkyl, or CO2R1;
R16 is H, C1-4alkyl, Cl, Br, F, I, SC1-4alkyl, or NR4R4;
R17 is H, C1-4alkoxy, or NR4R4;
R19 is H, NR4R4, or NR4C(O)NR4R4;
R20 is -(CH2)1-3-O-CH3, -(CH2)0-3-CO2R4 or R2;
R21 is C1-6alkyl, -(CH2)1-4OH, - (CH2) 1-3-O-CH3, -(CH2)1-2-Phenyl or -SCH2-phenyl, wherein the phenyl is unsubstituted or substituted by CO2R1, Cl, Br, F, or I;
R22 is -(CH2)3- or -(CH2)4-;
R23 is H, -O(CH2)1-2F, -OCH2CF3, or
-O(CH2)1-2NR4R4;
R24 is C1-4alkyl, -(CH2)1-4-OH, or CO2R' and R25 is R4 or R24 and R25 taken together are -(CH2)3- or
-(CH2)4-;
each Y independently is NR4, O, or CH2; and
each r independently is 0-2;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 of the formula:
Figure imgf000039_0001
in which X is A-CO2R1, CONR1R1, or tetrazolyl,
3. The compound according to claim 2 wherein X is CO2H.
4. The compound according to claim 3 wherein Het is
Figure imgf000039_0002
5. The compound according to claim 3 wherein Het is
Figure imgf000039_0003
6. The compound according to claim 3 wherein Het is
Figure imgf000039_0004
7. The compound according to claim 3 wherein Het is
Figure imgf000040_0001
8. The compound according to claim 3 wherein Het is
Figure imgf000040_0002
9. The compound according to claim 3 wherein Het is
Figure imgf000040_0003
10. The compound according to claim 3 wherein Het is
Figure imgf000040_0004
11. The compound according to claim 3 wherein Het is
C
Figure imgf000040_0005
12. The compound according to claim 3 wherein Het i s
Figure imgf000041_0001
13. The compound according to claim 3 wherein Het is
Figure imgf000041_0002
14. The compound according to claim 3 wherein Het is
Figure imgf000041_0003
15. The comound according to claim 3 wherein Het is
Figure imgf000041_0004
16. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1.
17. A method of antagonizing angiotensin II receptors which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
18. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
19. A method of treating congestive heart failure which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
20. A method of treating renal failure which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
21. A method of treating glaucoma which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.
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US5554607A (en) * 1995-11-28 1996-09-10 American Home Products Corporation Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis
US5599829A (en) * 1995-11-28 1997-02-04 American Home Products Corporation 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives for increasing HDL cholesterol levels
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US5663363A (en) * 1996-11-21 1997-09-02 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5744479A (en) * 1995-10-19 1998-04-28 Takeda Chemical Industries, Ltd. Thienopyridine compounds which have useful pharmaceutical activity
US5783707A (en) * 1995-11-28 1998-07-21 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5807869A (en) * 1995-10-19 1998-09-15 Takeda Chemical Industries, Ltd. Quinoline derivatives, their production and use
US5821372A (en) * 1995-11-28 1998-10-13 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5861517A (en) * 1996-11-21 1999-01-19 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5877324A (en) * 1995-11-28 1999-03-02 American Home Products Corporation 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives
US5977132A (en) * 1995-12-08 1999-11-02 Takeda Chemical Industries, Ltd. Prolactin production inhibitory agent
US6001850A (en) * 1996-04-26 1999-12-14 Takeda Chemical Industries, Ltd. Thienopyridine derivatives, their production and use
US6413980B1 (en) 1998-12-23 2002-07-02 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
US6858616B2 (en) 1998-12-23 2005-02-22 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6998408B2 (en) 2001-03-23 2006-02-14 Bristol-Myers Squibb Pharma Company 6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors
US7338963B2 (en) 2001-09-21 2008-03-04 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7495004B2 (en) 2002-06-17 2009-02-24 Glaxo Group Limited Purine derivatives as liver X receptor agonists
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4812462A (en) * 1986-04-01 1989-03-14 Warner-Lambert Company 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity
US4816463A (en) * 1986-04-01 1989-03-28 Warner-Lambert Company Substituted diimidazo [1,5-a: 4',5'-d]pyridines having antihypertensive activity
US4927822A (en) * 1985-08-31 1990-05-22 Fisons Plc 1,3,4-thiadiazoles
US5073566A (en) * 1989-11-30 1991-12-17 Eli Lilly And Company Angiotensin ii antagonist 1,3-imidazoles and use thereas
US5245035A (en) * 1991-01-17 1993-09-14 Imperial Chemical Industries Plc Heterocyclic boron compounds as intermediates for angiotensin ii antagonists
US5276168A (en) * 1990-06-18 1994-01-04 E. R. Squibb & Sons, Inc. Benzopyran derivatives and heterocyclic analogs thereof as antiischemic agents
US5294631A (en) * 1990-04-13 1994-03-15 Smithkline Beecham Corporation Substituted benzimidazoles useful as angiotension II receptor antagonists
US5310927A (en) * 1991-05-16 1994-05-10 Glaxo Group Limited Benzofuran derivatives

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927822A (en) * 1985-08-31 1990-05-22 Fisons Plc 1,3,4-thiadiazoles
US4812462A (en) * 1986-04-01 1989-03-14 Warner-Lambert Company 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid analogs having antihypertensive activity
US4816463A (en) * 1986-04-01 1989-03-28 Warner-Lambert Company Substituted diimidazo [1,5-a: 4',5'-d]pyridines having antihypertensive activity
US5073566A (en) * 1989-11-30 1991-12-17 Eli Lilly And Company Angiotensin ii antagonist 1,3-imidazoles and use thereas
US5312936A (en) * 1989-11-30 1994-05-17 Eli Lilly And Company Angiotensin II antagonists
US5294631A (en) * 1990-04-13 1994-03-15 Smithkline Beecham Corporation Substituted benzimidazoles useful as angiotension II receptor antagonists
US5276168A (en) * 1990-06-18 1994-01-04 E. R. Squibb & Sons, Inc. Benzopyran derivatives and heterocyclic analogs thereof as antiischemic agents
US5245035A (en) * 1991-01-17 1993-09-14 Imperial Chemical Industries Plc Heterocyclic boron compounds as intermediates for angiotensin ii antagonists
US5310927A (en) * 1991-05-16 1994-05-10 Glaxo Group Limited Benzofuran derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514988B1 (en) 1994-04-19 2003-02-04 Takeda Chemical Industries, Ltd. Condensed-ring thiophene derivatives, their production and use
US6187788B1 (en) 1994-04-19 2001-02-13 Takeda Chemical Industries, Ltd. Condensed-ring thiophene derivatives, their production and use
US5817819A (en) * 1994-04-19 1998-10-06 Takeda Chemical Industries, Ltd. Condensed-ring thiophene derivatives, their production and use
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US6087503A (en) * 1995-10-19 2000-07-11 Takeda Chemical Industries Ltd. Quinoline derivatives, their production and use
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US5821372A (en) * 1995-11-28 1998-10-13 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5599829A (en) * 1995-11-28 1997-02-04 American Home Products Corporation 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives for increasing HDL cholesterol levels
US5877324A (en) * 1995-11-28 1999-03-02 American Home Products Corporation 2-(substituted sulfanyl)-3,5-dihydro-imidazol-4-one derivatives
US5554607A (en) * 1995-11-28 1996-09-10 American Home Products Corporation Use of 2-thioxo-imidazolin-4-one derivatives in the treatment of atherosclerosis
US5977132A (en) * 1995-12-08 1999-11-02 Takeda Chemical Industries, Ltd. Prolactin production inhibitory agent
US6001850A (en) * 1996-04-26 1999-12-14 Takeda Chemical Industries, Ltd. Thienopyridine derivatives, their production and use
US5861517A (en) * 1996-11-21 1999-01-19 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US5663363A (en) * 1996-11-21 1997-09-02 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
US6673810B2 (en) 1998-12-23 2004-01-06 Bristol-Myers Squibb Pharma Company Imidazo-heterobicycles as factor Xa inhibitors
US6858616B2 (en) 1998-12-23 2005-02-22 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
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US7371761B2 (en) 2001-09-21 2008-05-13 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7531535B2 (en) 2001-09-21 2009-05-12 Bristol-Meyers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6989391B2 (en) 2001-09-21 2006-01-24 Bristol-Myers-Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
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