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WO1994020460A1 - Composes chimiques - 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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alkyl
het
compounds
independently
formula
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Joseph Weinstock
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority claimed from US08/029,542 external-priority patent/US5378933A/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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des antagonistes des récepteurs de l'angiotensine II de la formule (I) qui sont utiles dans le traitement de l'hypertension, de l'insuffisance cardiaque congestive, de l'insuffisance rénale et du glaucome, des compositions pharmaceutiques contenant ces antagonistes, ainsi que des procédés permettant d'utiliser ces composés pour produire un antagonisme vis-à-vis des récepteurs de l'angiotensine II chez les mammifères.
PCT/US1994/002524 1993-03-11 1994-03-08 Composes chimiques Ceased WO1994020460A1 (fr)

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US2964293A 1993-03-11 1993-03-11
US08/029,542 US5378933A (en) 1992-03-31 1993-03-11 Circuit arrangement having a switching amplifier
US08/029,642 1993-03-11

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WO1995028405A1 (fr) * 1994-04-19 1995-10-26 Takeda Chemical Industries, Ltd. Derives du thiopene bicyclique et utilisation commme antagonistes de la gonadoliberine
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
WO1997019931A1 (fr) * 1995-11-28 1997-06-05 American Home Products Corporation Derives de 2-(substitution sulfanyle)-3,5-dihydroimidazol-4-one
US5663363A (en) * 1996-11-21 1997-09-02 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
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US5783707A (en) * 1995-11-28 1998-07-21 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
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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
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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
JP2021516225A (ja) * 2018-03-05 2021-07-01 ゴールドフィンチ バイオ，インク． イミダゾジアゼピンジオン及びその使用方法

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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
WO1995028405A1 (fr) * 1994-04-19 1995-10-26 Takeda Chemical Industries, Ltd. Derives du thiopene bicyclique et utilisation commme antagonistes de la gonadoliberine
US5807869A (en) * 1995-10-19 1998-09-15 Takeda Chemical Industries, Ltd. Quinoline derivatives, their production and use
US5744479A (en) * 1995-10-19 1998-04-28 Takeda Chemical Industries, Ltd. Thienopyridine compounds which have useful pharmaceutical activity
US6087503A (en) * 1995-10-19 2000-07-11 Takeda Chemical Industries Ltd. Quinoline derivatives, their production and use
US5783707A (en) * 1995-11-28 1998-07-21 American Home Products Corporation 2-thioxo-imidazolidin-4-one derivatives
WO1997019931A1 (fr) * 1995-11-28 1997-06-05 American Home Products Corporation Derives de 2-(substitution sulfanyle)-3,5-dihydroimidazol-4-one
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
US6413980B1 (en) 1998-12-23 2002-07-02 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles 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
US7531535B2 (en) 2001-09-21 2009-05-12 Bristol-Meyers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7691846B2 (en) 2001-09-21 2010-04-06 Bristol-Myers 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
US7005435B2 (en) 2001-09-21 2006-02-28 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof 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
US7371761B2 (en) 2001-09-21 2008-05-13 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US9975891B2 (en) 2001-09-21 2018-05-22 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof 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
EP2105436A1 (fr) 2001-09-21 2009-09-30 Bristol-Myers Squibb Company Composés comprenant un lactame et leurs dérivés en tant qu'inhibiteurs du facteur Xa
US6995172B2 (en) 2001-09-21 2006-02-07 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US7960411B2 (en) 2001-09-21 2011-06-14 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US8188120B2 (en) 2001-09-21 2012-05-29 Bristol-Myers Squibb Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US8470854B2 (en) 2001-09-21 2013-06-25 Bristol-Meyers 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
JP2021516225A (ja) * 2018-03-05 2021-07-01 ゴールドフィンチ バイオ，インク． イミダゾジアゼピンジオン及びその使用方法
US20230365575A1 (en) * 2018-03-05 2023-11-16 Goldfinch Bio, Inc. Imidazodiazepinediones and methods of use thereof
US12466834B2 (en) * 2018-03-05 2025-11-11 Gfb (Abc), Llc Imidazodiazepinediones and methods of use thereof

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