WO1992010180A1 - Utilisation d'antagoniste de l'angiotensine ii dans le traitement des infarctus - Google Patents

Utilisation d'antagoniste de l'angiotensine ii dans le traitement des infarctus Download PDF

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Publication number
WO1992010180A1
WO1992010180A1 PCT/GB1991/002218 GB9102218W WO9210180A1 WO 1992010180 A1 WO1992010180 A1 WO 1992010180A1 GB 9102218 W GB9102218 W GB 9102218W WO 9210180 A1 WO9210180 A1 WO 9210180A1
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methyl
alkyl
butyl
pharmaceutically acceptable
angiotensin
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PCT/GB1991/002218
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English (en)
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James Hill
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Smithkline Beecham Plc
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Priority to JP4501017A priority Critical patent/JPH06503322A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • renin-angiotensin system with converting enzyme inhibitors, such as captopril, has proved clinically useful in the treatment of certain disease states, such as hypertension and congestive heart failure [Abrams, et al., Federation Proc., 43:1314 (1984)]. Furthermore, evidence suggests that inhibition of this system may be beneficial in primary and
  • AII is the biologically active component of the renin-angiotensin system responsible for the system's peripheral effects, the most direct approach towards inhibition of RAS and in particular primary and secondary prevention of infarction would be blockade of angiotensin II at its receptor.
  • angiotensin II receptor antagonist angiotensin II receptor antagonist
  • the present invention also provides for the use of an angiotensin II receptor antagonist in the manufacture of a medicament for primary and secondary prevention of infarction. DESCRIPTION OF THE INVENTION
  • the present invention is a therapeutic method for primary and secondary prevention of infarction in mammals.
  • the method utilizes a class of antagonists which have been previously prepared and evaluated as effective All receptor antagonists.
  • suitable angiotensin II receptor antagonists include, but are not limited to, the following: Substituted imidazoles of the formula (I), which are described in U.S. Application Serial No. 07/746,262, filed August 14, 1991:
  • R 1 is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, nitro, A-CO 2 R 7 , tetrazol-5-yl, C 1 -C 6 alkoxy, hydroxy, SC 1 -C 6 alkyl, SO 2 NHR 7 , NHSO 2 R 7 , SO 3 H, CONR 7 R 7 ,
  • NR COC 1 -C 6 alkyl NR 7 CON(R 7 ) 2 , NR 7 COW, W, SO 2 W;
  • n 0-4;
  • R 2 is C 2 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 6 Cycloalkyl, or (CH 2 ) 0-8 phenyl unsubstituted or substituted by one to three substituents selected from C 1 -C 6 alkyl, nitro, Cl, Br, F, I, hydroxy, C 1 -C 6 alkoxy, NR 7 R 7 , CO 2 R 7 , CN, CONR 7 R 7 , W, tetrazol-5-yl,
  • NR 7 COC 1 -C 6 alkyl NR 7 COW, SC 1 -C 6 alkyl, SO 2 W, or
  • X is a single bond, S, NR 7 , or O;
  • R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl,
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazolyl-Y-, thiazolyl-Y-, pyridyl-Y-, or tetrazolyl-Y-, except that R 4 and R 5 are not both selected from hydrogen and
  • C 1 -C 8 alkyl and each heterocyclic ring is unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, I,
  • Y is a single bond, O, S, or C 1 -C 6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is
  • R 6 is -Z-COOR 8 or -Z-CONR 7 R 7 ;
  • Z is a single bond, vinyl, -CH 2 -O-CH 2 -, methylene optionally substituted by C 1 -C 6 alkyl, one or two benzyl groups, thienylmethyl, or furylmethyl, or -C(O)NHCHR 9 -, wherein R 9 is H, C 1 -C 6 alkyl, phenyl, benzyl,
  • W is C n F 2n+1 , C n F 2n+1 , wherein n is 1-3;
  • R 8 is hydrogen, C 1 -C 6 alkyl, or 2-di(C 1 -C 6 alkyl)-amino-2-oxoethyl; or a pharmaceutically acceptable salt thereof.
  • Particularly preferred compounds are (E)-3-[2-n- butyl-1- ⁇ (4-carboxyphenyl)methyl ⁇ -1H-imidazol-5-yl]-2- (2-thienyl)methyl-2-propenoic acid and (E)-3-[2-n-butyl- 1- ⁇ 4-carboxynaphth-1-yl)methyl ⁇ -1H-imidazol-5-yl]-2-(2- thienyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof.
  • the most preferred compound of this invention is (E)-3-[2-n-butyl-1- ⁇ (4-carboxyphenyl)methyl]-1H- imidazolyl-5-yl]-2-(2-thienyl)methyl-2-propenoic acid methanesulfonate.
  • Substituted imidazoles which are described in U.S. Serial No. 07/621,491, filed, November 30, 1990, are prepared following the methods described in European Publication Number EP 0 437 103, published July 17, 1991.
  • Preferred compounds included within the scope of the class of All receptor antagonist are N-[ ⁇ 2-n-butyl- 1-(2-chlorophenyl)methyl-1H-imidazol-5-yl ⁇ methylcarbonyl]-L-phenylalanine and N-[ ⁇ 2-n-butyl-1-(2- chlorophenyl)methyl-1H-imidazol-5-yl ⁇ methylcarbonyl]-L- (2-thienyl)alanine; or a pharmaceutically acceptable salt thereof.
  • R 1 is adamantyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, nitro, CO 2 R 7 , tetrazol-5-yl, C 1 -C 6 alkoxy, hydroxy, SC 1 -C 6 alkyl, SO 2 NR 7 R 7 , NHSO 2 R 7 , SO 3 H, CONR 7 R 7 ,
  • R 2 is C 2 -C 10 alkyl unsubstituted or substituted by CO 2 H, OH, or NR 7 R 7 , C 3 -C 10 alkenyl, C 3 -C 10 alkynyl,
  • X is a single bond, S, or O
  • R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl
  • each n is 1-3;
  • n 0-4;
  • R 4 is CO 2 R 7 , CONR 7 R 7 , or tetrazol-5-yl
  • Y is a single bond or a carbonyl group
  • R 5 is hydrogen, C 1 -C 8 alkyl, C 1 -C 6 Cycloalkyl,
  • R 6 is hydrogen or C 1-6 alkyl
  • each R 7 independently is hydrogen, C 1 -C 4 alkyl, or
  • Preferred compounds included within the scope of formula (VI) are 3-[(2-chlorophenyl)methyl]-2-propylthio-N-butrylhistidine and 3-[(2-chlorophenyl)-methyl]-2-n-butyl-N-butyrylhistidine; or a
  • R 1 is adamanthylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from
  • R 2 is C 2-10 alkyl, C 3-10 alkenyl, C 3- 10 alkynyl,
  • X is a single bond, S, or O
  • R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl
  • q 0 to 4.
  • n 0 to 2;
  • R 4 is H or C 1-6 alkyl
  • z is 0 to 1;
  • R 5 is C 3-6 alkyl, C 3-6 alkenyl, phenyl-Y-, 2- or 3- thienyl-Y-, 2- or 3-furyl-Y-, 2-, 3-, or 4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-, imidazolyl-Y-, pyrazolyl-Y- , thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-, with each aryl ring being unsubstituted or substituted by
  • Y is a single bond or C 1-6 alkyl which is branched or unbranched;
  • R 6 is CO 2 R 8 , CONR 8 R 8 , or tetrazol-5-yl
  • R 7 is H, CO 2 R 8 , or C 1-6 alkyl
  • each R 8 independently is hydrogen, C 1-6 alkyl, or
  • a preferred compound included within the scope of formula (VII) is 3-[2-n-butyl-1- ⁇ (2-chlorophenyl)-methyl ⁇ -1H-imidazol-5-yl]-2-benzylpropanoic acid or a pharmaceutically acceptable salt thereof.
  • R 1 is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C 1 -C 6 alkyl, nitro, CO 2 R 5 , C 1 -C 6 alkoxy, hydroxy, S C 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, tetrazol-5-yl,
  • R 2 is C 2 -C 10 alkyl, C 3 -C 10 alkenyl, (CH 2 ) 0-8 - C 3-6 Cycloalkyl, or (CH 2 ) 0-8 phenyl unsubstituted or substituted by one to three substituents selected from
  • C 1 -C 6 alkyl nitro, Cl, Br, F, I, hydroxy, C 1 -C 6 alkoxy, tetrazol-5-yl, NR 5 R 5 , CO 2 R 5 , CN, CONR 5 R 5 , W, NR 5 COH, NR 5 COC 1 -C 6 -alkyl, NR 5 COW, SO 2 W, SO 2 C 1 -C 6 alkyl, or
  • X is a single bond, S, NR 5 , or O;
  • n 0-4;
  • R 3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl
  • R 4 is CO 2 R 5 , CONR 5 R 5 , or tetrazol-5-yl
  • Z is hydrogen, Cl, Br, F, I, C 1 -C 6 alkyl
  • Y is a single bond or C 1 -C 6 alkyl, which is straight or branched;
  • W is C m F 2m+1 , wherein m is 1-4,;
  • each R 5 independently is H or C 1 -C 6 alkyl
  • a preferred compound included within the scope of formula (IV) is 3-[2-n-butyl-1- ⁇ (2-chlorophenyl)- methyl ⁇ -1H-imidazol-5-yl]benzoic acid or a
  • R 1 is -C(O)NH-CH(Y)-(CH 2 ) n -aryl, -C(O)NH-CH(Y)- (CH 2 ) n -heteroaryl, or phenyl unsubstituted or
  • R 2 is hydrogen, C 2-10 alkyl, C 3-10 alkenyl, C 3-6 -cycloalkyl, C m F 2m+1 , or (CH 2 ) 0-8 phenyl unsubstituted or substituted by one to three substituents selected from
  • Y is CO 2 R 4 or tetrazol-5-yl
  • X is Cl, Br, F, I, C m F 2m+1 , C 1-6 alkyl, C 1-6 alkoxy, OH, O-phenyl, CO 2 R 4 , tetrazol-5-yl, CN, or (CH 2 ) 0 - 4 phenyl unsubstituted or substituted by Cl, Br, F, I, C 1-6 alkyl, C 1-6 alkoxy, OH, C m F 2m+1 , CN, CO 2 R 4 , NO 2 , or NR 4 R 4 ;
  • aryl is phenyl, biphenyl, or naphthyl wherein each aryl group is unsubstituted or substituted by C 1-6 alkyl, C 1-6 alkoxy, Cl, Br, F, I, OH, NO 2 , CF 3 , CO 2 R 4 , or NR 4 R 4 ; heteroaryl is 2- or 3-thienyl, 2-, or 3-furanyl, 2-, 3-, or 4- pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, or tetrazolyl wherein each heteroaryl group is unsubstituted or substituted by C 1-6 alkyl,
  • each n independently is 0-2;
  • each R independently is H or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
  • a preferred compound included within the scope of formula (V) is 2-n-butyl-1-(4-carboxyphenyl)methyl-5-chloro-1H-benzimidazole-7-carboxylic acid or a
  • angiotensin II receptor antagonists are also included within the scope of the instant invention. Since it is contemplated that any All receptor antagonist will possess the novel utility herein described, the list below does not limit the scope of the present invention.
  • AII receptor antagonists are disclosed in the following:
  • a particularly preferred compound in this class of AII receptor antagonists is Sar-Arg-Val- Tyr-Val-His-Pro- ⁇ - Ala-OH which is also referred to as Saralasin.
  • Kisfaludy et al. U.S. Patent No. 4,179,433, issued December 18, 1979.
  • this class of compounds include aminooxyacetyl-Arg-Val-Tyr-Ile-His-Pro-Leu-OH and D- ⁇ -aminooxypropionyl-Arg-Val-Tyr-Ile-His-Pro-Leu-OH.
  • Kisfaludy et al. U.S. Patent No. 4,209,442, issued June 24, 1980.
  • Examples include hydroxyacetyl-Arg-Val-Tyr-Ile-His-Pro-Leu-OH, hydroxyacetyl-Arg-Val-Tyr-Ile-His-Pro-Ala-OH, and ⁇ -hydroxypropionyl-Arg-Val-Tyr-Ile-His-Pro-Ile-OH.
  • exemplary compounds of this class are Sar-Arg-Val-Tyr-Ile-His-Pro-Lac, Sar-Arg-Val-Tyr-Ile-His-Pro-Lac(OC 2 H 5 ), and Sar-Arg-Val-Tyr-Ile-His-Pro-2-hydroxy-3-methylvaleric acid.
  • Furukawa et al. U.S. Patent No. 4,340,598 issued June 20, 1982.
  • Examples include 1-benzyl-4-chloro-2-phenylimidazole-5-acetamide, 1-benzyl-2-n-butyl-4-chloroimidazole-5-acetamide, and 1-benzyl-2-n-butyl-5-chloroimadazole-4-acetic acid.
  • Furukawa et al. U.S. Patent No. 4,355,040, issued October 19, 1982.
  • Examples include 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole-5-acetic acid and 1-benzyl-4-chloro-2-(4-chloro-3,5-dinitrophenyl)imidazole-5-acetic acid.
  • a preferred compound included within the scope of this class of AII receptor antagonists is 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid or a pharmaceutically acceptable salt thereof.
  • Preferred compounds included within this class of AII receptor antagonists are 2-n-butyl-4-chloro-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]-5- (hydroxymethyl)imidazole and 2-n-butyl-4-chloro-1-[(2'- (carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)- imidazole; or a pharmaceutically acceptable salt
  • Preferred compounds included within the scope of this class of AII receptor antagonists are 1-(2-phenylethyl)- 5-phenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine-6-carboxylic acid and 1-(4-amino-3- methyIphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahydro- 1H-imidazo[4,5-c]pyridine-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds included in this class of AII receptor antagonists are 5-n-propyl-1-[(2'- carboxybiphenyl-4-yl)methyl]pyrrole-2-carboxylic acid, 3-methoxymethyl-5-n-propyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,4-triazole, and 3-methoxymethyl-5-n-butyl-1-[2'-carboxybiphenyl-4-yl)methyl]pyrazole; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds included within this class of AII receptor antagonists are 2-n-butyl-1- [(2'-carboxybiphenyl-4-yl)methyl]-5-hydroxymethylbenz-imidazole and 2-n-butyl-1-[(2'-carboxybiphenl1-4-yl)methyl]-6-hydroxymethylbenzimidazole; or a
  • a preferred compound included within this class of AII receptor antagonists is 5-[4-(3-(N-iso-propylamino)hydroxypropoxy)indole-2-carboxamidomethyl]-2-n-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloroimidazole or a pharmaceutically acceptable salt thereof.
  • Examples include Boc-Phe-Leu amide of (4S)-3-oxo-4-amino-2,2-difluoro-1-isopropyl-mercapto-5-cyclohexylpentane and Boc-Phe-Leu amide of (3R,4S,EZ)-3-hydroxy-4-amino-2-fluoro-1-isopropyl-sulfonyl-5-cyclohexyl-1-pentene; or a pharmaceutically acceptable salt thereof.
  • receptor antagonists is ⁇ -hexyl-4-[(2-carboxy-3-hydroxybenzoyl)amino]-1H-imidazole-1-acetic acid ethyl ester or a pharmaceutically acceptable salt or solvate thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 2-n-butyl-3-(2'-tetrazol-5- yl)biphenyl-4-yl)methyl06,7-dihydroimidazo[4,5- e][1,4]diazepine-8(3H)-one or a pharmaceutically
  • a preferred embodiment of this class of AII receptor antagonists includes 4,6-dimethyl-2-ethyl-1-[2- (tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 3-n-butyl-4-[4-(2-carboxy-benzamido)benyl]-5-(2-methylbenzylthio)-4-1,2,4-triazole or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 2-n-butyl-1,5-dihydro-4,5-dimethyl-1-[(2'- ⁇ 1H-tetrazol-5-yl ⁇ 1,1-biphenyl ⁇ -4-yl)methyl]-pyrrolo[3,4-d]imidazole or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 2-n-propyl-4-pentafluoroethyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid or a
  • embodiment of this class of AII receptor antagonists includes 2-n-butyl-7-methyl-3-[(2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 2-methyl-4-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 2-ethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy-1,5-naphthyridine or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of this class of AII receptor antagonists includes 4-[(2-n-butyl-1H-benzimidazol-1-yl)methyl-N-phenylsulphonlybenzamide or a pharmaceutically
  • a preferred embodiment of this class of AII receptor antagonists includes 7-methyl-2-n-propyl-3-[(2'(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-b] or a
  • a preferred embodiment of this class of AII receptor antagonists includes 4'-[(6-n-butanoylamino-2-n-butyl-benzimidazol- 1-yl)methyl]biphenyl-2-carboxylic acid or a
  • An angiotensin II receptor antagonist of the formula (VI) is an angiotensin II receptor antagonist of the formula (VI) :
  • examples 1-4 teach how to make compounds encompassed by the generic Formulae of (II)-(V).
  • AII antagonists are known in the art and may be prepared by known methods or by variations thereof. Certain AII antagonists employed in the invention may exist in isomeric form. This invention includes all such isomers both in pure form and admixture, including racemic mixtures and their pharmaceutically acceptable salts.
  • Angiotensin II antagonist activity is assessed by in vitro methods.
  • In vitro antagonist activity is determined by the ability of the compounds to compete with 125 I-angiotensm 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.
  • the preferred AII antagonists are compounds which are capable of inhibiting the action of AII by at least 50% at a concentration of 1mM or less, and especially preferred AII antagonists are compounds which are capable of inhibiting the action of AII by at least 50% at a concentration of 25nM or less when tested by the following standard methods. Binding
  • the radioligand binding assay is a modification of a method previously described in detail (Gunther et al., Circ. Res. 47:278, 1980). A particular fraction from rat mesenteric arteries is incubated in Tris buffer with 80 pM of 125I-angiotensin II with or without angiotensin
  • 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 dissociation constants are calculated by the dose ratio method using the mean effective concentrations.
  • AII receptor antagonizing compounds of this invention are incorporated into standard pharmaceutical compositions. They can be administered orally, parenterally, rectally, topically or transdermally.
  • the compounds of the instant invention and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or
  • a suitable liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier for example, ethanol, glycerine, non-aqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier (s) routinely used for preparing solid formulations.
  • Such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable
  • s for example aqueious gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • infusion can be formulated as solutions or suspensions.
  • a composition for parenteral administration will generally consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be
  • a typical suppository composition conprises a compound of the instant invention or a pharmaceutically acceptable salt thereof which is active when
  • lubricating agent such as polymeric glycols, gelatins or coca butter or other low melting vegetable or synthetic waxes or fats.
  • a typical transdermal formulation comprises a conventional aqueous or non-aqueous vehicle, for
  • a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane.
  • 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.
  • pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting, and bodying agents, as for example,
  • polyethylene glycols polyethylene glycols
  • antibacterial components such as quaternary ammonium compounds
  • buffering ingredients such as alkali metal chloride; antioxidants such as sodium metabisulfite; and other conventional ingredients such as sorbitan monolaurate.
  • composition is in unit dose form.
  • Doses of the compounds of the instant invention in a pharmaceutical dosage unit 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 primary and secondary prevention of infarction induced by angiotensin II from 1-6 times daily, orally, rectally, topically, by injection, or continuously by infusion.
  • Oral dosage units for human administration preferably contain from 10 to 500 mg of active compound. Lower dosages are used generally for parenteral
  • Oral administration is used when safe, effective, and convenient for the patient.
  • compositions are representative of the AII receptor antagonists included within the scope of the instant invention, but therapeutically effective amounts of other AII antagonists as discussed hereinabove may be substituted.
  • Example 1 The procedure of Example 1 is illustrative of the synthesis of compounds encompassed by generic formula
  • This formylated product (17.0 g, 0.071 mol) was dissolved in methyl formate (13.3 mL, 0.216 mol) and added dropwise to a sodium methoxide mixture prepared by adding sodium metal (1.79 g, 0.0778 g-atom) to tetrahydrofuran (325 mL) followed by slow addition of methanol (3.15 mL, 0.0778 mol). The combined mixture was stirred at' room temperature for 18 hours, then evaporated to dryness. This crude product was dissolved in 50% aqueous methanol (200 mL), treated with charcoal, filtered and the solution was cooled in ice.
  • the ester was hydrolyzed with aqueous sodium hydroxide solution to give 1-(2-chlorophenyl)methyl-2-thiopropyl-1H-imidazole-5-carboxylic acid; m.p. 158-159.5°C (from ethanol).
  • tetrahydrofuran 100 mL was cooled to -78°C under argon and a solution of n-butyl lithium (30 mL of 2.5 M in hexane) was added. The mixture was stirred at -78°C for 30 minutes and at 0°C for 10 minutes. After being recooled to -78°C, a solution of N-(diphenylmethylene)-glycine ethyl ester (Tetra.
  • Imidazole was converted to the 1-diethoxyortho-amide derivative by the method of Curtis and Brown, J. Org . Chem., (1980), 45, 20.
  • Imidazole (12.8 g, 0.19 mol) and 118.4 g (0.8 mol) of triethylorthoformate were reacted in the presence of 1 g of p-toluenesulfonic acid to give 20.6 (61%), bp 65-70°C (0.1 mm) of 1-diethoxyorthoamide imidazole.
  • This product (24.0 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250 mL), cooled to -40°C and n-butyl lithium (0.14 mol, 56.4 mL of 2.5 M in hexane) was added at -40°C to -35°C. After 15 minutes n-butyl iodide (31.1 g, 0.169 mol) was added at -40°C, and the reaction was stirred overnight at ambient temperature. The reaction was partitioned between ether and 0.3 N hydrochloric acid, and the organic layer was repeatedly extracted with dilute hydrochloric acid.
  • This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at -15°C and then was allowed to warm to ambient temperature with stirring, and then stirred an additional 19 hours.
  • the acetic anhydride was evaporated at reduced pressure, the residue taken up in methylene chloride, and the organic phase was washed with 5% sodium bicarbonate solution and water.
  • the extract was dried over sodium sulfate and concentrated to give 323 g (83%) of 1-acetyl-4-acetoxymethyl-2-n-butylimidazole.
  • This diacetate was N-alkylated by the following procedure. To a solution of triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL) at -78°C under argon was added a solution of diisopropyl ethylamine (128 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.72 mol) in methylene chloride (350 mL) over a period of 20 minutes.
  • Example 3 The procedure of Example 3 is illustrative of the synthesis of compound encompassed by generic formula (IV).
  • Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229°C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).
  • 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.

Abstract

L'invention se rapporte à l'utilisation d'un agent, antagoniste du récepteur de l'angiotensine II dans la fabrication d'un médicament destiné à la prévention primaire et secondaire des infarctus.
PCT/GB1991/002218 1990-12-14 1991-12-12 Utilisation d'antagoniste de l'angiotensine ii dans le traitement des infarctus WO1992010180A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4501017A JPH06503322A (ja) 1990-12-14 1991-12-12 梗塞形成の処置におけるアンジオテンシン２拮抗剤の使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9027208.9 1990-12-14
GB909027208A GB9027208D0 (en) 1990-12-14 1990-12-14 Medicaments

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WO1992010180A1 true WO1992010180A1 (fr) 1992-06-25

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AU (1) AU9052991A (fr)
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WO (1) WO1992010180A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0577025A2 (fr) * 1992-07-01 1994-01-05 Hoechst Aktiengesellschaft Antagonistes du récepteur d'angiotensine-II pour le traitement et la prophylaxie des maladies coronaires du coeur
EP0641203A4 (fr) * 1991-08-14 1994-06-09 Smithkline Beecham Corp Acides amidazolyle-alcenoiques.
WO2000044378A1 (fr) * 1999-01-26 2000-08-03 Novartis Ag Utilisation des antagonistes du recepteur d'angiotensine ii dans le traitement de l'infarctus aigu du myocarde
US6544968B2 (en) 1999-01-26 2003-04-08 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0241201A2 (fr) * 1986-04-07 1987-10-14 Merck & Co. Inc. Inhibiteurs de l'enzyme de conversion de l'angiotensine, utiles pour prolonger la survie des mammifères avec un défaut cardiaque congestif
EP0323841A2 (fr) * 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Antagonistes d'angiotensine II du type pyrrole, pyrazole et triazole substitués
EP0403158A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazolyl-alcénoiques
EP0403159A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazoalcénoiques
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0241201A2 (fr) * 1986-04-07 1987-10-14 Merck & Co. Inc. Inhibiteurs de l'enzyme de conversion de l'angiotensine, utiles pour prolonger la survie des mammifères avec un défaut cardiaque congestif
EP0323841A2 (fr) * 1988-01-07 1989-07-12 E.I. Du Pont De Nemours And Company Antagonistes d'angiotensine II du type pyrrole, pyrazole et triazole substitués
EP0403158A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazolyl-alcénoiques
EP0403159A2 (fr) * 1989-06-14 1990-12-19 Smithkline Beecham Corporation Acides imidazoalcénoiques
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0641203A4 (fr) * 1991-08-14 1994-06-09 Smithkline Beecham Corp Acides amidazolyle-alcenoiques.
EP0641203A1 (fr) * 1991-08-14 1995-03-08 Smithkline Beecham Corporation Acides amidazolyle-alcenoiques
EP0577025A3 (fr) * 1992-07-01 1998-02-04 Hoechst Aktiengesellschaft Antagonistes du récepteur d'angiotensine-II pour le traitement et la prophylaxie des maladies coronaires du coeur
EP0577025A2 (fr) * 1992-07-01 1994-01-05 Hoechst Aktiengesellschaft Antagonistes du récepteur d'angiotensine-II pour le traitement et la prophylaxie des maladies coronaires du coeur
US7560446B2 (en) 1999-01-26 2009-07-14 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
WO2000044378A1 (fr) * 1999-01-26 2000-08-03 Novartis Ag Utilisation des antagonistes du recepteur d'angiotensine ii dans le traitement de l'infarctus aigu du myocarde
US6544968B2 (en) 1999-01-26 2003-04-08 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
AU766453B2 (en) * 1999-01-26 2003-10-16 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
US6767905B2 (en) 1999-01-26 2004-07-27 Novartis, Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
AU766453C (en) * 1999-01-26 2004-11-25 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
EP1714651A1 (fr) * 1999-01-26 2006-10-25 Novartis AG Utilisation des antagonistes du recepteur de l' angiotensine II pour le traitement de l' infractus du myocarde aigu
KR100674053B1 (ko) * 1999-01-26 2007-01-25 노파르티스 아게 급성 심근경색의 치료를 위한 안지오텐신 ⅱ 수용체길항물질의 용도
US6552033B1 (en) 2000-05-16 2003-04-22 The Procter & Gamble Co. Imidazo-containing heterocyclic compounds, their compositions and uses
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation

Also Published As

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JPH06503322A (ja) 1994-04-14
AU9052991A (en) 1992-07-08
EP0561878A1 (fr) 1993-09-29
GB9027208D0 (en) 1991-02-06

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