WO1992010186A1 - Use of angiotensn ii receptor antagonists for the preparation of a medicament for improving cognitive function - Google Patents
Use of angiotensn ii receptor antagonists for the preparation of a medicament for improving cognitive function Download PDFInfo
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- WO1992010186A1 WO1992010186A1 PCT/GB1991/002224 GB9102224W WO9210186A1 WO 1992010186 A1 WO1992010186 A1 WO 1992010186A1 GB 9102224 W GB9102224 W GB 9102224W WO 9210186 A1 WO9210186 A1 WO 9210186A1
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- 0 C[n]1c(*)nc(*)c1* Chemical compound C[n]1c(*)nc(*)c1* 0.000 description 1
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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
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- 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
Definitions
- angiotensin II receptor antagonists for the preparation of a medicament for improving cognitive function
- 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 improving cognitive function. Since AII is the biologically active renin-angiotensin system (RAS) 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 improving cognitive function. Since AII is the biologically active
- the present invention also provides for the use of an angiotensin II receptor antagonist in the manufacture of a medicament for improving cognitive function.
- the present invention is a therapeutic method for improving cognitive function in mammals.
- the method utilizes a class of antagonists which have been
- angiotensin II receptor antagonists include, but are not limited to, the following:
- 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 7 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, COOR 7 , CONR 7 R 7 , NO 2 , W, CN, NR 7 R 7 , or phenyl;
- 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 6 alkyl and each heterocyclic ring is unsubstituted or substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy / Cl, Br, F, I,
- NR 7 R 7 CO 2 R 7 , SO 2 NHR 7 , SO 3 H, or CONR 7 R 7 , OH, NO 2 , W, SO 2 W, SC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, NR 7 COH, NR 7 COW, or
- 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.
- 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 ⁇ methyl carbonyl]-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 , CN, SO 2 C 1 -C 6 alkyl, or C n F 2n+1 ;
- 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 3 -C 6 Cycloalkyl,
- each phenyl group independently is 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 alkyl,
- R 6 is hydrogen or C 1-6 alkyl
- each R 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
- CONR 8 R 8 CN, SO 2 C 1-4 alkyl, or C n F 2n+1 , wherein n is 1-3;
- 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, hydroxymethy1, CO 2 R 8 , NO 2 , or C n F 2n+1 , wherein n is 1-3;
- 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 (CH 3 ) 0-4 phenyl;
- 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, SC 1 -C 6 alkyl, SO 2 C 1 -C 6 alkyl, tetrazol-5-yl, SO 2 NHR 5 , NHSO 2 R 5 , SO 3 H, PO(OR 5 ) 2 , CONR 5 R 5 , CN, NR 5 R 5 , NR 5 COH, NR 5 COC 1 -C 6 alkyl, NR 5 CON(R 5 ) 2 , NR 5 COW, SO 2 W, or
- 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, C 1 -C 6 alkyl, NR 5 R 5 , CO 2 R 5 , CONR 5 R 5 , NO 2 , CN, phenyl, or
- 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; or a pharmaceutically acceptable salt thereof.
- 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)- (CH2) 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 C 1-6 alkyl, C 1-6 alkoxy, Cl, Br, F, I, OH, NO 2 , C m F 2m+1 , CO 2 R 4 , or NR 4 R 4 ;
- 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- 6alkoxy, 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 4 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-ß- Ala-OH which is also referred to as Saralasin.
- Kisfaludy et al. U.S. Patent No. 4,179,433, issued December 18, 1979.
- Examples of 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. Hallinan et al., U.S. Patent No. 4,204,991, issued May 27, 1980. See also West German Offenlegungschrift No. 2846200 (Chemical Abstracts, Vol. 91, Abstract No. 74989d).
- 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-phenylimidcLzole-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-y1)bipheny1-4-y1)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- methylphenyl)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-hydroxymethylbenzimidazole and 2-n-butyl-1-[(2'-carboxybi ⁇ henyl-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.
- Phegly-OH is a L-C-phenylglycine residue.
- AII receptor antagonist included in this reference is Sar-Arg- Val-Tyr-Val-His-Pro-OH
- 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)bi ⁇ henyl-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-carboxybenzamido)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-l,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
- 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-angiotensin II for binding to vascular
- angiotensin II receptors and by their ability to
- 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.
- 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 125 I-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,
- 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(s) 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 pharmaceutical carrier(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 improving cognitive function 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
- the ester was hydrolyzed with aqueous sodium hydroxide solution to give 1-(2-chlorophenyl)methyl-2-thiopropyl-1H-imidazole-5-carboxylic acid; m.p. 158159.5°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-diethoxyorthoamide 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,
- 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).
- Example 4 The procedures of Example 4 is illustrative of the synthesis of compounds encompassed by generic formula (V).
- Crystallization was achieved by dissolving the solid ih acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225229°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.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
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Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4501731A JPH06503338A (en) | 1990-12-12 | 1991-12-12 | Use of angiotensin 2 receptor antagonists in the preparation of drugs for improving cognitive function |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909027197A GB9027197D0 (en) | 1990-12-14 | 1990-12-14 | Medicaments |
GB9027197.4 | 1990-12-14 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08074811 A-371-Of-International | 1993-06-10 | ||
US32574994A Continuation | 1990-12-14 | 1994-10-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992010186A1 true WO1992010186A1 (en) | 1992-06-25 |
Family
ID=10687033
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1991/002224 WO1992010186A1 (en) | 1990-12-12 | 1991-12-12 | Use of angiotensn ii receptor antagonists for the preparation of a medicament for improving cognitive function |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0561896A1 (en) |
JP (1) | JPH06503338A (en) |
AU (1) | AU9069291A (en) |
GB (1) | GB9027197D0 (en) |
WO (1) | WO1992010186A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0577025A2 (en) * | 1992-07-01 | 1994-01-05 | Hoechst Aktiengesellschaft | Angiotensin-II-receptorantagonist for the treatment and prophylaxis of coronary heart diseases |
EP0641203A4 (en) * | 1991-08-14 | 1994-06-09 | Smithkline Beecham Corp | Imidazolyl-alkenoic acids. |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
EP0403158A2 (en) * | 1989-06-14 | 1990-12-19 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
EP0403159A2 (en) * | 1989-06-14 | 1990-12-19 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
WO1991014367A1 (en) * | 1990-03-20 | 1991-10-03 | E.I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
-
1990
- 1990-12-14 GB GB909027197A patent/GB9027197D0/en active Pending
-
1991
- 1991-12-12 AU AU90692/91A patent/AU9069291A/en not_active Abandoned
- 1991-12-12 JP JP4501731A patent/JPH06503338A/en active Pending
- 1991-12-12 EP EP92900687A patent/EP0561896A1/en not_active Withdrawn
- 1991-12-12 WO PCT/GB1991/002224 patent/WO1992010186A1/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0323841A2 (en) * | 1988-01-07 | 1989-07-12 | E.I. Du Pont De Nemours And Company | Substituted pyrrole, pyrazole and triazole angiotensin II antagonists |
EP0403158A2 (en) * | 1989-06-14 | 1990-12-19 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
EP0403159A2 (en) * | 1989-06-14 | 1990-12-19 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
WO1991014367A1 (en) * | 1990-03-20 | 1991-10-03 | E.I. Du Pont De Nemours And Company | Treatment of central nervous system disorders with imidazole angiotensin-ii receptor antagonists |
Non-Patent Citations (2)
Title |
---|
J. Pharmacol. Exp. Ther., vol. 252, no. 2, February 1990, (US), P.C. WONG: "Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent", pages 726-732, see the abstract; page 731 * |
Neuroreport, vol. 1, nos. 3-4, November-December 1990, (GB), N.M. BARNES et al.: "Cognitive enhancing actions of DuP 753 detected in a mouse habituation paradigm", pages 239-242, see the introduction; discussion * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0641203A4 (en) * | 1991-08-14 | 1994-06-09 | Smithkline Beecham Corp | Imidazolyl-alkenoic acids. |
EP0641203A1 (en) * | 1991-08-14 | 1995-03-08 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
EP0577025A3 (en) * | 1992-07-01 | 1998-02-04 | Hoechst Aktiengesellschaft | Angiotensin-ii-receptorantagonist for the treatment and prophylaxis of coronary heart diseases |
EP0577025A2 (en) * | 1992-07-01 | 1994-01-05 | Hoechst Aktiengesellschaft | Angiotensin-II-receptorantagonist for the treatment and prophylaxis of coronary heart diseases |
EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
Also Published As
Publication number | Publication date |
---|---|
JPH06503338A (en) | 1994-04-14 |
EP0561896A1 (en) | 1993-09-29 |
GB9027197D0 (en) | 1991-02-06 |
AU9069291A (en) | 1992-07-08 |
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