JPH06503338A - Use of angiotensin 2 receptor antagonists in the preparation of drugs for improving cognitive function - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Invention of the use of angiotenone receptor antagonist in the preparation of a drug for improving cognitive function background Renine-anneotenone (R) using convertase inhibitors such as captopril Interference with AS) may be useful in treating certain conditions such as hypertension and congestive heart failure. have been shown to be clinically useful in [Abrams] et al., Federation Proc. ), 43:1314 (1984)]. Furthermore, some evidence suggests that the inhibition of this system This suggests that the system may be effective in improving cognitive function. Ru. An is a biological component of chain threads involved in the peripheral action of the renin-angiotensin system. Being an active ingredient, it is the most direct for inhibiting RAS, especially for improving cognitive function. A possible solution is to block angiotensin ■ at its receptor.

Summary of the invention The present invention provides effective, non-toxic doses of angiotensin receptor antagonists for improving cognitive function. A method of improving said function in a mammal, comprising administering said benefit to a subject in need thereof. It provides law.

The present invention also provides angiotensin receptor in the production of a medicament for improving cognitive function. It provides for the use of antagonists.

Description of the invention The present invention is a method of therapeutically treating improvement of cognitive function in a mammal.

The method has already been produced and evaluated as an effective An receptor antagonist. A series of antagonists are used. Appropriate angio, including but not limited to Examples of tenone receptor antagonists are as follows.

U.S. Patent Application No. 07/746.262 filed August 14, 1991 Formula (1) described in No. [In the formula, R1 is adamantyl, phenyl, biphenyl or naphthyl; The group is unsubstituted or CI, Br5F, L Cr Ca alkyl, nitro B, A-CO2R', tetrazol-5-yl, Cr Cm alkoxy, hydro xy, SC, -C, alkyl, SO, NHR7, NHS○, R7, SO, H, C 0NR'R', CN, So□C, -C, alkyl, NH3○2R7, PO(OR ’) x, NR’R’, NR’COH, NRfCOC+-Ca alkyl, NR’C 0N(R’)2, NR’COW.

Substituted with 1 to 3 substituents selected from w, so, w; m is 0 ~4; R2 is CtC1o7)Lzkyl, C3-CIO alkenyl, CsC1oful quinyl, C3-cm cycloalkyl, or unsubstituted or C,-C,a alkyl, nitro, C1, Br, F, I, hydroxy, c, -c, alkoxy, N RfR7, C02R', CN5CONR'R7, W1tetrazol-5-yl, NR’COC+-C6 al+ru, NR’COW, SCr-cs a/H-ru, 5C hWmar': is 1 to 3 substituents selected from 5O2c+-Csflu+ Therefore, it is substituted (CHz) o-s phenyl.

X is a single bond, S, NR' or ○: R31 is hydrogen, C1, Br, F, L CHO, hydroxymethyl, C0OR', C0NR'R', No2, W, CN, NR'R or phenyl; R4 and R5 are independently hydrogen, C, - C, alkyl, chenyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazoly Ru-Y-, pyrrolyl-Y-, triazolyl-Y-, oxacylyl-Y-, iso- xacylyl-Y-, thiazolyl-Y-, pyridyl-Y- or tetrazolyl-Y - (provided that both R4 and R5 are selected from hydrogen and C, -C, alkyl) <), each heterocyclic ring is unsubstituted or C, -C, Kill, C, -C, Alcoquine, C1, Br, F, ■, NRfRf, C02Rγ , 5O2NHR", 5O3H* or C0NR'R, OH, No2, WS S○, wSSC+ Ca alkyl, S O2C+ Cs alkyl, NR’COH .

NR'COW or NR'COC, substituted by -C6 alkyl.

Y is a single bond, ○, S or C, -C, alkyl, and is straight or branched. optionally substituted with phenyl or benzyl, where and each aryl group is unsubstituted or halo, No2, CF3, C, -C, Al substituted with Kyl, C, -C, alkoxy, CN or CO2H2; R6 is -Z-C○○R8 or -Z-CONR'R'.

Z is a single bond, vinyl, -CH2-0-CH, -1 optionally C, -C, alkyl , substituted with one or two benzyl groups, thenylmethyl or furylmethyl methylene, or -C(○)NHCHR'- (where R9 is HSc ,-c.

alkyl, phenyl, benzyl, thenylmethyl or furylmethyl) can be: W is C, F2n+1, C,, F2. , , (where n is 1 to 3) and: A is -(CH2), -1-CH=CH-1-0(CHz)e or -5(CH 2). − and: R7 is each independently hydrogen, C, -C, alkyl or (CHJ-phenyl( where m is 0 to 4); and R8 is hydrogen, C, -C, alkyl or or 2-di(CrCa alkyl)amino-2-oxoethyl] or a pharmaceutically acceptable salt thereof.

Preferred compounds falling within the scope of formula (1) are: (E)-3-[2-n-butyl -1-(4-carboxynaphthhol)methyl)-IH-imidazol-5-yl ]-2-(2-chenyl)methyl-2-propenoic acid, (E)-3-[2-n- Butyl-1-(4-carboxyafth-1-yl)methyl)-IH-imidazo [ru-5-yl]-2-(2-chenyl)methyl-2-propenoic acid, (E)-3-[2-n-butyl-1-(2-chloro-4-carboxyphenyl) methyl)-IH-imidazol-5-ylco-2-(2-chenyl)methyl-2 -propenoic acid, and (E)-3-[2-n-butyl-1-(4-carboxy-2,3-dichlorophene) methyl)-IH-imidazol-5-ylco2-(2-thenyl, methyl) -2-propenoic acid; or a pharmaceutically acceptable salt thereof.

A particularly preferred compound is (E)-3-[2-n-butyl-1-((4-carboxylated) Cyphenyl)methyl 1-IH-imidazol-5-yl]-2-(2-chenyl ) Methyl-2-propenoic acid and (E)-3-[2-n-butyl-1-(4-carboxylic acid) ruboxynaphth-1-yl)methyl)-IH-imidazol-5-ylco2- (2-9-Edenyl)methyl-2-propenoic acid: or a pharmaceutically acceptable salt thereof One of the most preferred compounds of the present invention is (E) 3-[2-n-butyl-1-+( 4-carboxyphenyl)methyl 1-IH-imidazolyl-5-yl]-2-( 2-chenyl)methyl-2-propenoic acid methanesulfonate (formula (1)) The compound of the European patent publication published on December 19, 1990 (patent publication number EP Manufactured according to the method described in O403159.

U.S. Patent Application No. 07/746.024 filed August 14, 1991 The substituted imidazole described in the No. Manufactured according to the method described in patent publication number EP O403158.

Preferred compounds within this class of AII receptor antagonists are: (E)-3 -[2-n-butyl-1-t(2-chlorophenyl)methyl)-IH-imidazo 2-(3,4-methylenedioxyphenyl)methyl-2-yl]-2-(3,4-methylenedioxyphenyl) Lopenic acid, (E) -3-[2-n-butyl-1-f(4-carbo"F-7phenyl)methy )-IH-imidazol-5-yl]-2-n-butyl-2-propenoic acid, and (E)-3-[2-n-butyl-1-((4-carboxyphenyl)methyl) )-IH-imidazol-5-yl]-2-n-benzyl-2-propenoic acid: or a pharmaceutically acceptable salt thereof.

U.S. Patent Application No. 071590,207 filed September 28, 1990 The substituted imidazoles described in the European patent publication dated May 2, 1991 Manufactured according to the method described in Publication No. EP O425211.

Preferred compounds within the scope of this class of An receptor antagonists are: (E)-1- [2-n-butyl-1-f(4-carboxyphenyl)methyl)-IH-imida sol-5-yl]-2-(IH-tetrazol-5-yl)-3-(2-che nyl)-1-propene, and (E)-1-[2-n-butyl-1-[(4-(IH-tetrazol-5-yl) )phenyl)methyl)-IH-imidazol-5-yl]-2-(LH-tetra sol-5-yl)-3-(2-chenyl)-1-propene: or its pharmaceutical It is an acceptable salt.

U.S. Patent Application No. 071590.206 filed September 28, 1990 The substituted imidazole described in No. Manufactured according to the method described in publication number EP O427463.

Preferred compounds falling within the scope of formula (■) are: N-[(1-(4-carboxy) phenyl)methyl(2-n-butyl-IH-imidazol-5-yl)methyl ]-β-(2-chenyl)alanine, and N-[H-(2-chlorophenyl) methyl]-2-n-butyl-IH-imidazol-5-yl)methyl]-β- (2-chenyl)alanine; or a pharmaceutically acceptable salt thereof.

U.S. Patent Application No. 07/621.49 filed November 30, 1990 The substituted imidazole described in No. 1 was Produced according to the method described in patent publication number EP O437103.

Preferred compounds within this class of AI [receptor antagonists include N-[+2 -n-butyl-1-(2-chlorophenyl)methyl-IH-imidazole-5- yl)methylcarbonyl]-L-phenylalanine and N-[+2-n-butyl -1-(2-chlorophenyl)methyl-IH-imidazol-5-yl)methy L-lponyl-L-<2-thenyl)alanine, or a pharmaceutically acceptable thereof It's salt. The substituted imidazole of formula (n) is [In the formula, R1 is adamantyl, or phenyl, biphenyl or naphthyl, Each aryl group is unsubstituted or C1, Br, F, L CI-Cs alkyl do, CO2R', tetrazol-5-yl, CI 0g alkoxy, hydroxy shi, SC+ Ca full kill, SOzNR'R 7, NHSO. R), So, H, Select from CONR'R', CNSSO2CI C6 alkyl or CaF2**1 is substituted with 1 to 3 selected substituents.

R2 is unsubstituted or substituted by CO2H, OH or NR'R' L C2 - C +. Alkyl, Cs CIo alkenyl, Cs CI.

alkynyl, CsCs-cycloalkyl, or unsubstituted or CIC m alkyl BrSF, I, hydroxy, CI Cs alkoxy, NR'R", C (by 1 to 3 substituents selected from hR', CN or CONR'R') Substituted (CHt). −3 phenyl; X is a single bond, S or O: R3 is hydrogen, CISBr, FS L CHO, t: doxy Jfh, COOR ? , CONR'R', NO3 or C. F2, , , where n is 1 to 3, respectively. can be.

m is 0 to 4; R4 is CO2R", CONR7R, or tetrazol-5-yl; Y is Single bond or carbonyl group.

R5 is hydrogen, CI C8 alkyl, Cs Cm chloroalkyl, (CHz) o- <Phenyl or (CH2). -3CH-diphenyl, each phenyl group ( =, independently unsubstituted or c, -C. Alkyl, nitro, C1, Br, F, T, hydroxy, c, -C. Alkyl, NR7R? , C○, R7 or CO NR) R is substituted with 1 to 3 substituents selected from 1: R6 is is hydrogen or C1-6 alkyl; and R7 is each independently hydrogen, c, -C4 alkyl or (CH2). -4 phenyl] or a pharmaceutically acceptable salt thereof.

Preferred compounds falling within the scope of formula (Vl) are 3-[(2-chlorophenyl ) methyl]-2-propylthio N-butyrylhistidine and 3-[(2-k lorophenyl)methyl]-2-n-butyl-N-butyrylhistidine; It is a pharmaceutically acceptable salt thereof.

A compound of formula (II) is prepared as described in Example 1.

The substituted imidazole of formula (III) is: [In the formula, R1 is adamantylmethyl, phenyl, biphenyl or (naphthyl) Therefore, each aryl group is unpurchased or +tC1, Br, FS L CI- s-almol, nitro, C○2Rs, tetrazol-5-yl, C1-6 alkoxy ノ, hydroxy, SC+-4 alkyl, So2NHR', NHSO2R'SSo 3HSCONR'R', CN, SO2Cl-4 alkyl or C-F2-+ ( where n is 1 to 3) substituted with 1 to 3 substituents selected from It is.

R2 is C2-10 alkyl, C3-1. Alkenyl, C3-1. alkynyl, C , -6socroalkyl, or unsubstituted or C1-6alkyl, nitro , C1, Br, F.

11 hydroxy, C1-6 alkoxy, NR@R”, C○, Ra, CN or C ON-R @ R G) substituted with 1 to 3 substituents selected from 8 (CH2)O-, phenyl; X is a single bond, S or ○: R3 is hydrogen, C1, BrSF, I, CHO, hydroxymethyl, COIR", N O! or C. F2. , , (where n is 1 to 3).

q is O~4.

m is 0 to 2.

R4 is H or C1-, alkyl.

Z is O~1; R5 is cs-a alkyl, C3-6 alkenyl, phenyl-Y-, 2- or (yo); 3-chenyl-Y-, 2- or 3-furyl-Y-, 2-, 3- or 4-pi1 Nojiru Y-, Tetrazolyl-Y-, Triazolyl-Y-, Imidazolyl-Y- , bira-noryl-Y-, thiazolyl-Y-, pyrrolyl-Y- or oxacylyl -Y-, and each aryl ring is unsubstituted or C,-6 alkyl, C1, Br-F 11 sCl-6 alkoxy, NR’R”, C○2Rs or CO NR"R' is substituted.

)′ is a single bond or CI-6 alkyl, branched or unbranched: R 6 is CO2 R　'', C　ONR　'R'' or tetrazole-5 -It's il.

R7 is H, CO2R1 or C1-6 alkyl; and R8 are each independently and hydrogen, C1-6 alkyl or (CH3). -4 phenyl] or a pharmaceutically acceptable salt thereof.

Preferred compounds falling within the scope of formula (■) are 3-[2-n-butyl-1-( (2-chlorophenyl)methyl)-IH-imidazol-5-yllo-2-ben Norpropanoic acid or a pharmaceutically acceptable salt thereof.

A compound of formula (Iff) is prepared as described in Example 2.

U.S. Patent Application No. 07/621,18 filed November 30, 1990 The substituted imidazole of formula (TV) described in No. 8 is [wherein, R1 is adamantylmethyl, or phenyl, biphenyl or naphthyl Therefore, each aryl group is unsubstituted or C1, Br5F, I, CI Ca a alkyl, nitro, CO2R5, C, -C, alkoxy, hydroxy, SC, -C , alkyl, 5OtC+-Csfulki/Lz, Tet5sol-5-i) Lt, 5o2NHR5, NH-8O1R5, 503H,, PO(○R5)2, C0NR 5R5, CN, NR5R', NR5-COH, NR'COC+-C17#kill, NR5C0W (R')2, NR5C0W.

Substituted with 1 to 3 substituents selected from S○2W or W.

R2 is C, -C,. Alkyl, O3CIO alkenyl, (CH2). -a　O3 -a-chloroalkyl, or unsubstituted or C,-C6alkyl, nitro , C1, Br.

F, I, hydroxy, C, -C, alkoxy, tetrazol-5-yl, NR5 R5, CO, R5, CN, C0NR'R'5WSNR5COH, NR5C0W, -C, furkyl, NR5C0W, S○2W, S○aet c, alkyl or S di-substituted with 1 to 3 substituents selected from C, -C, alkyl ( CH2). −8 phenyl; X is a single bond, S, NR5 or ○.

n is O-4.

R3 is hydrogen, C1, Br5F, l5CHO, hydroxymethyl, C, -C, alkyl Kill, NRSR', C0tR', C0NR5R5, No1, CN, Phenyl or is W; R'l; ICo, RS, C0NR'R'* or tetrazo-/l/-5-i)l At); Z is hydrogen, C1, Br, FS ISC, -C6 alkyl, C, -C, a Lucoxy, hydroxy, CN, Not, CO, R', COR'R', W, 7z2 /1z-y-, Nafuchi/L.

-Y-, chenyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl-Y -, thiazolyl-Y-, tetrazolyl-Y-, pyrrolyl-Y-, triazolyl- Y-, oxasilyl-Y- or isoxasilyl-Y-, in which each aryl or heteroaryl group is unsubstituted or C,-C,alkyl,C,- C.

Alkoxy, C1, Br, F, I, CO, R4, hydroxy, NO2, CN, C 0N-R5R5 or W: Y is a single bond or C, -C, a linear or branched: W is C, F, ... (where m is 1 ~4): and Rs are each independently hydrogen or C, -C, alkyl It is a compound represented by ``K'' which means ``kill'' or a pharmaceutically acceptable salt thereof.

Preferred compounds falling within the scope of formula (■) are 3-[2-n-butyl-1-( (2-chlorophenyl)methyl)-IH-imidazol-5-yl]benzoic acid or a pharmaceutically acceptable salt thereof.

A compound of formula (IV) is prepared as described in Example 3.

The substituted benzimidazole of formula (V) is: [wherein, R1 is -C(0)NH-CH(Y)-(CH2), -aryl, -C(○)NH -CH(Y)-(CH2), -heteroaryl, or unsubstituted or C 1, Br, F, I, C1-6 alkyl, CI-67 Rucoki’), ○H, CN, No,, C02R', Tetraso/L/-5-yl, C0NR4R', S○sH , C-F2-I, SC+-gfurkyl or 5OtC1-6furkyl. phenyl substituted with 1 to 3 substituents; R1 is hydrogen, C2-1゜alkyl, C3-1゜alkenyl, C3-6 cycloal C11F211-11, or unsubstituted or C1,6 alkyl, Cl-6 alkoxy, cl, Br, F, I, OH, NO2, C+eF2m+l, substituted with 1 to 3 substituents selected from CO, R4 or NR'R' (CH,) -8 phenyl: R3 is R1 optionally substituted; -(CH2), -Y, -CH=CY-(C H2)--7'J-l, CH=CY (CH2)-monoheteroaryl, -(C H2), -C(0)-NH-CH(Y)-(CH2ruaryl, -(CH2) -C(○) N HCH(Y) -(CH2) a-heteroaryl, -(C H2).

-NH-CH(Y)-(CR2), -71J-1L4 Taha-(CH2), , -NH-CH(Y)-(CH2)M-heteroaryl, or I;t R' is -C(0)NH-CH(Y)-(CH2), aryl or -C(0)N When H-CH(Y)(CH2)--heteroaryl, it is H;

Y is CO2R4 or tetrazol-5-yl: X haC1, Br5F, I, Cl2. , , CI-sfurkyl, cl-6 alkoxy, OH.

○-phenyl, C0tR4, tetrazol-5-yl, CN or unsubstituted Gamataha C1, Br, F, I 5C1-6 full kill, C+ -s 7 Lu: + Kishi, OH, C, F2. . 1. By CN, CO2R4, No2 or NR'R' is (CH2)o-4 phenyl substituted; Aryl is phenyl, biphenyl or naphthyl, where each aryl group ( or CI-sfull+ru, CI-e7J'v':Jxi, cl , Br, FS I.

Monoconverted with OH, No2, CF, CO2R4 or NR'RI.

Heteroaryl is 2- or 3-chenyl, 2- or 3-furanyl, 2-13 - or 4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl or tetrazolyl, where each heteroaryl group is unsubstituted or c+-g alkyl, C1-6 alkoxy, C1, Br, FS I, OH, Not , CF3, CO, R4 or NR'R'.

m is each independently 1 to 3; n is each independently O~2, and R4 is each independently hydrogen or C1 A compound represented by -6 alkyl or a pharmaceutically acceptable salt thereof. Ru.

A preferred compound within formula (v) is 2-n-butyl-1-(4-carboxylic acid). ruboquinphenyl)methyl-5-talolo IH-benzimidazole-7-cal Bonic acid or a pharmaceutically acceptable salt thereof.

The compound of formula (V) is disclosed in the Patent Cooperation Treaty published on October 31, 1991. Manufactured according to the method described in No. W○91/16313. A compound of formula (V) , prepared as described in Example 4.

A description of the series of An receptor antagonists used in the present invention can be found in the patent applications and publications. Quoted from the opening. Please refer to such patent applications and publications for their full disclosure. , the entire disclosure of which is hereby incorporated by reference.

The following angiotenoid receptor antagonists are also included within the scope of the invention.

Any An receptor antagonist has the novel utility described herein. As such, the scope of the invention should not be limited to the ranges listed below. .

Ani-like tree A■ Cited example showing receptor blocking activity Sar’ Ala” Linical Science (CIin, Sci,) 57: 71°Sar’ Ile' Endocrinology 107 ( 5) Succ' X'a13 Clinical Science and Molecular ・Medi J, Physiol, ) 236 (3): F252.1976 Sar’ Thr” Clinical Science and Molecular Medicine Sun 51: 3855.1976 Sar' Cys-Me' Journal of Cardiology - Macology (J, Cardiovasc, Pharm,) Dan + 10 25. 1983 Sar' Tyr-Me' Life Sciences Sci, ) 34: 317.1983c1y” Canadian Journal Le of Physiology and '7 Fu 7:)ology (Can J, P hysiol Pharm, )57: 121.1979 11e’ Canadian Journal of Physiology and Fur Macology 57: 121.1979Leu' Canadian Journal Of Physiology and Pharmacology 57: 121.1979 Sar’ Leu” Canadian Journal of Physiology Pharmacology: 121.1979desAsp’Leu” kana Dean Journal of Physiology and Pharmacology 121.1979 Pharmacology 57: 763.1979 Sar' DL-Nipecotamide7 Canadian Journal of Fiery Geology A11e” and Pharmacology 57 + 763.1979 Sar’5ar711e’ Canadian Journal of Physiology - and Pharmacology 57: 763.19798-L-^1a Journal of Furman and Pharma Co., Ltd., Pharm, Pharmacol, ) 32: 232.198ONet' Jhana Le of Mesoinnal Chemist IJ- (JMed, Chem,) 22 ( 9): 1147.1979Thr” Journal of Mesoinnal Ke Mistry 22 (9): 1147, 19790-Me Thr Hatake Jar Nar of Mesoinnal Chemistry 22 (9)・1147.1979 N-Me Ile' Journal of Mesointernal Chemistry 22 ( 9): 1147.1979N-Me Phe’ Journal of Mezoi National Chemistry 22(9)-1147, 1979 Sar’5ar7Leu” Journal of Mesointernal Chemistry 22 (9)・1147.1979 Sar’ Sar’ Thr(Me)” Journal of Mesoinnal Ke Mistry 22 (9) + 1147.1979Sar’ Sar” DLa lle” Journal of Mesointernal Chemistry 22 (9): 1147.1979Me11e' Thr' Journal of Mezzoinal ・Chemistry 20 (2): 253.1977 Me, Gly' Thr' Journal of Mesointernal Chemistry 2 0 (2) ・253.1977 GdnAC' Thr' Journal of Mesointernal Chemistry 20 (2)・253.1977 desAsp' Thr' Journal of Mesointernal Chemistry 2 0 (2): 253.1977 Sar’ Ser(Me)’ Journal of Mesointernal Chemistry 20 (2)・253.1977 Sar' Thr' Journal of Mesointernal Chemistry Sar' Thr(Me)’ Journal of Mesointernal Chemistry 19 ( 2): 244.1976 MeAspNH2' Ile' Journal of Mesointernal Chemistry -19 (2)・244.1976 Sar' MeTyr' Ile' Journal of Mesoinnal Chemistry Tory 19 (2): 244.1976 Sar'　Me11e'　Ile' Journal of Mesoinnal Chemis Tory 19 (2)・244.1976 Sar’ Melle” Journal of Mesointernal Chemistry 19 (2): 244.1976 Sar’　Me11e’　Melle”　Journal of Mesoinnal Ke Mistry 19 (2): 244.1976 Sar’　Thr(0-/-Me)8　Journal of Mesoinnal Chemistry Story Sar' Ser' Journal of Mesointernal Chemistry 19 (2): 244.1976 11e’^la” Journal of Mesointernal Chemistry 13: 181.1970 11e', 8-(3-Amino-4-Journal of Mesoinnal Chemistry Tory 664, 1971 Sar’ Cys(lle)’ Circulation Research 46: 72 0.1980Phe'Tyr' Proceedings of National A Academy 1624, 1970 Octanoyl Leu' Journal of Mesoinnal Chemistry Sentence: 8 98, 1977 Cys’ Circulation Research Day 862.1972Phe’ Ty r” Circulation Research 31: 862.1972desAsp 'Phe' Tyr' Circulation Research 31: 862.1 972 books The abbreviation is angiotensin ■ Sequence Asp-＾rg-Val-Tyr -11e-His -Pro-Phe, substitution position indicated by superscript means exchange.

Other groups of AII receptor antagonists are disclosed in the references below.

U.S. Pat. No. 3,751.404 to Sipos et al. (August 1973) Among these AII receptor antagonists, a particularly preferred compound is Salara Sar-Arg-val-Tyr-V also called Saralasin al-His-Pro-β-Ala-OH.

U.S. Patent No. 3.907.762 (1975) to Regoli et al. (September 23): An example of a suitable compound within this class is ^sp-Arg-Va. l-Tyr-41e-Hls-Pro-Val-OH and Asp-Arg- Val-Tyr-11e-His-Pro-a-amino-n-butyric acid Ru.

U.S. Pat. No. 4.388.304 (June 1983) by Nyeki et al. The compound disclosed in Ko's patent is 5ar-^rg-Val- Tyr-11e-His-Pro-11e-methyl ester and hydroxya Cetyl-Arg-Val-Tyr-11e-Hls-Pro-Thr-Methi including esters. The same or similar compounds are also disclosed in European Patent No. 34.259 Disclosed in the issue.

No. 3,886,134 to Sipos et al. An example of this type of compound is 5ar-^rg-Val-Tyr-Va l-His-Pro-^1a-OH,5er-^rg-Val-Tyr-val -1(is-Pro-^1a-OH, and^sn-Arg-Val-Tyr- 1lal-His-Pro-D-Leu-OH.

U.S. Pat. No. 4,179,43 to Kisfaludy et al. No. 3 (dated December 18, 1979): Compounds of this type include, for example, aminooxy Acetyl-＾rg-Val-Tyr　-1ie-His-Pro-Leu-OH and D-a-aminooxypropionyl-^rg-Val-Tyr-11e- Includes His-Pro-Leu-OH.

U.S. Pat. No. 4.204.991 (19 May 27, 1980); furthermore, West German Publication No. 2846200 (Chemi. Chemical Abstracts, Volume 91, 74989d).

U.S. Patent No. 4.209.442 to Kisfaldi et al. (June 2, 1980) 4 date); for example, hydroxyacetyl-^rg-Val-Tyr-11e-H is-Pro-Leu-OH1 hydroxyacetyl-Arg-val-Tyr- 11e-His-Pro-^1a-OH, and α-hydroxypropionyl- Including Arg-Val-Tyr-11e-His-Pro-11e-OH .

No. 4,330,532 to Niecki et al. (dated May 18, 1982): A typical compound of this type is 5ar-^rg-Val-Tyr-11e-His -Pro-Lac, Sar -Arg-Val-Tyr-11e-His-P ro-Lac (OCJs), and Sar-Arg-Val-Tyr-11e- His-Pro-2-hydroxy-3-methylvaleric acid.

U.S. Patent No. 4.340.598 (19 (dated June 20, 1982); for example, 1-benzyl-4-chloro-2-phenylimi dazole-5-acetamide, and 1-benzyl-2-n-butyl-5-chloro Includes loimidazole-4-acetic acid.

U.S. Pat. No. 4,355,040 to Furukawa et al. (October 19, 1982).

For example, 1-(2-chlorobenzyl)-2-n-butyl-4-taloloimidazo -5-acetic acid and 1-benzyl-4-chloro-2-(4-chloro-3,5-di (nitrophenyl)imidazole-5-acetic acid.

European Patent Publication No. 103 647 (published March 28, 1984) by Furukawa et al. Preferred compounds within the scope of this type of An receptor antagonists include Rollo-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazoe -5-acetic acid or a pharmaceutically acceptable salt thereof. .

European Patent Publication No. 253.310 by Carini et al. (published January 20, 1988) ) and U.S. Patent Application No. 50341 (filed May 22, 1987); A preferred compound included in the class of An receptor antagonists is 2-n-butyl-4- Chloro-1-[(2'-(IH-tetrazol-5-yl)biphenyl-4-y methyl]-5-(hydroxomethyl)imidazole and 2-n-butyl- 4-chloro-1-[(2'-(carboxybiphenyl-4-yl)methyl)-5 -(hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof.

European Patent Publication No. 245 637 by Blankley et al. Published November 19, 1987) and U.S. Patent Application No. 847,067 (No. 1 (filed April 1, 1986); A preferred compound is 1-(2-phenylethyl)-5-phenylacetyl-4,5 ,6,7-titrahydroIH-imidazo[4,5-c]pyridine-6-carbo acid and 1-(4-amino-3-methylphenyl)methyl-5-diphenyla Cetyl-4,5,6,7-titrahydro IH-imidazo[4,5-c]pyridi -6-carboxylic acid or a pharmaceutically acceptable salt thereof.

European Patent Publication No. 323841 by Carini et al. (published July 12, 1989) and U.S. Patent Application No. 07/279,193 (filed December 6, 1988). : This type of AI [preferred compounds included in the receptor antagonist are 5-n-propyl -1-[(2'-carboxybiphenyl-4-yl)methylcopyrrole-2-ka Rubonic acid, 3-methoxymethyl-5-n-propyl-4-[(2'-(LH -tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2,4-t lyazole, and 3-methquinmethyl-5-n-butyl-1-[(2'-cal boxybiphenyl-4-yl)methyl]pyrazole or its pharmaceutically acceptable It's salt.

U.S. Patent No. 4.880.804 to Carini et al. (November 14, 1989) : This kind of AI! A preferred compound included in the receptor antagonist is 2-n-butyl- 1-[(2″-carboxybiphenyl-4-yl)methyl]-5-hydroxymeth Tylbenzimidazole and 2-n-butyl-1-[(2'-carboxybif phenyl-4-yl)methyl]-6-hydroxymethylbenzimidazole or It is a pharmaceutically acceptable salt thereof.

U.S. Patent No. 4.916.129 to Carini et al. (dated April 10, 1990): Preferred compounds included in this type of AII receptor antagonist are 5-[4-(3-( N-isopropylamino)hydroxypropoxy)indole-2-carboxy cyamidomethyl)-2-n-butyl-1-[(2°-carboxybiphenyl-4 -yl)methyl]-4-chloroimidazole or a pharmaceutically acceptable salt thereof. Ru.

U.S. Patent No. 4.857.507 to Rosenberg et al. No. (dated August 15, 1989): For example, (4S)-3-oxo-4-amino- 2,2-difluoro-1-inpropyl-mercapto-5-cyclohexylbene Kung's BoC-Phe-Leu amide and (3R,4S,EZ)-3-hydro xy-4-amino-2-fluoro-1-isopropyl-sulfonyl-5-cyclo Boc-Phe-Leu amide of hexyl-1-pentene or its pharmaceutically acceptable It includes salts that are

U.S. Pat. No. 4.013.791 (1) to Wissmann et al. γ March 22, 977; An example of such a compound is Phegly-OH, L-C-phenylglycine residue, sufcinamoyl-^rg-1'al-T yr-Vat-His-Pro-Pbegly-OH.

U.S. Pat. No. 3,923.769 (1975) by Bumpus et al. (dated December 2, 2013).

U.S. Pat. No. 3,923,770 (December 2, 1975) to Pampas et al. .

U.S. Pat. No. 3,923,771 (December 2, 1975) to Pampas et al. .

, U.S. Pat. No. 3,925,345 to Pampas et al., dated December 9, 1975. ).

No. 3,976,770 to Pampas et al. (August 24, 1976, ft. ).

No. 3,915,948 to Will (October 2, 1975) 8); An example of an AI receptor antagonist included in this reference is 5ar-^rg- val-Tyr-Val-His-Pro-OH.

European Patent Publication No. EP 0 438869 by Lifer et al. Published July 31, 1991) and U.S. Patent Application No. 07/444.456 No. (filed on November 30, 1989), preferred of this type of AIr receptor antagonists. The compound is α-hexyl-4-[(2-carboxy-3-hydroxybenzoyl ) Aminoco-IH-imidazole-1-acetic acid ethyl ester or its pharmaceutically acceptable It is a compatible salt or solvate.

European Patent Publication No. E by Chakravarty et al. P O401030 (published December 5, 1990) and U.S. Patent Application No. 071522, No. 662 (filed May 16, 1990); A preferred example of the antagonist is 2-n-butyl-3-(2°-tetrazol-5-y biphenyl-4-yl)methyl-6,7-cyhydroimidazo[4,5-e] Including [1,4] diazepin-8(3H)-one or a pharmaceutically acceptable salt thereof do.

European Patent Publication Number EP O400974 (1990) by Chakrabarty et al. No. 071516.286 (Published December 5, 2013) and U.S. Patent Application No. 071516.286 (19 (filed on May 4, 1990); This kind of AI! Examples included within the scope of receptor antagonists are , 5,7-dimethyl-2-ethyl-3-(2'-(tetrazol-5-yl)bi) phenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine or its is a pharmaceutically acceptable salt of

European Patent Publication No. EP O400835 (1990) by Chakrabarty et al. No. 071504,441 (Published December 5, 2013) and U.S. Patent Application No. (Application filed on April 4, 1990): A preferred example of this type of An receptor antagonist is 4,6- Dimethyl-2-ethyl-1-[2-(tetrazol,-5-yl)biphenyl- Includes 4-ylcomethylbenzimidazole or a pharmaceutically acceptable salt thereof .

European Patent Publication Number EP O409332 (1) by Aston et al. Published January 23, 1991) and U.S. Patent Application No. 071503,352 (filed on April 2, 1990), preferred examples of this type of AII receptor antagonist are: 3-n-butyl-4-[4-(2-carboxybenzamido)benyl]-5-( 2-methylbenzylthio)-4-1,2,4-triazole or its pharmaceutical approval Includes salts that can be tolerated.

European Patent Publication No. EP O4071 by Greenlee et al. 02 (published January 9, 1991) and U.S. Patent Application No. 071516.5 No. 02 (filed on April 25, 1990): This type of AI [preferable receptor antagonists] A good example is 2-n-butyl-1,5-dihydro-4,5-dimethyl-1-[(2' -flH-tetrazol-5-yl](1,1-biphenyl)-4-yl)methy ]-pyrrolo[3,4-d]imidazole or a pharmaceutically acceptable salt thereof do.

European Patent Publication No. EP O324377 by Carini et al. (July 19, 1989) No. 07/279.194 (December 1988) A preferred example of this type of An receptor antagonist is 2-n-propyl- 4-pentafluoroethyl-1-[2'-(IH-tetrazol-5-yl)bi phenyl-4-yl)methylcoimidazole-5-carboxylic acid or its pharmaceutical Includes acceptable salts.

European Patent Publication No. EP O3426021 (1991) by Oku et al. (published on May 8): A preferred example of this type of An receptor antagonist is 2-n-butyl -7-methyl-3-[(2-(LH-tetrazol-5-yl)biphenyl-4 -yl)methyl]-3H-imidazo[4,5-b]pyridine or its pharmaceutically acceptable Includes salts that can be tolerated.

European Patent Publication No. EP O412848 by Roberts et al. (Published on February 13, 1991), a preferred example of this type of An receptor antagonist is 2 -Methyl-4-(2'-(LH-tetrazol-5-yl)biphenyl-4-y) methoxy]quinoline or a pharmaceutically acceptable salt thereof.

Patent Cooperation Treaty Application Publication No. WO91107404 (1991) by Roberts et al. A preferred example of this type of AII receptor antagonist is 2-ethyl -4-[(2'-(IH-tetrazol-5-yl)biphenyl-4-yl)methyl Includes toquin-1,5-naphthyridine or a pharmaceutically acceptable salt thereof.

European Patent Publication No. EP O399732 (November 2, 1990) by Roberts et al. 8): A preferred example of this type of An receptor antagonist is 4-[(2-n-butane). methyl-IH-benzimidazol-1-yl)methyl-N-phenylsulfony Includes rubenzamide or a pharmaceutically acceptable salt thereof.

European Patent Publication No. EP 0 420237 by Miyake et al. (published on March 3, 1991); a preferred example of this type of An receptor antagonist is 7- Methyl-2-n-propyl-3-[(2°-(IH-tetrazol-5-yl) biphenyl-4-yl)methyl]-3H-imidazo[4,5-b] or its derivatives Includes pharmaceutically acceptable salts.

European Patent Publication No. EP O392317 (1990) by Narr et al. A preferred example of this type of An receptor antagonist is 4'-[ (6-n-butanoylamino-2-n-butyl-benzimidazol-1-yl ) methyl]biphenyl-2-carboxylic acid or a pharmaceutically acceptable salt thereof. Ru.

2-n-butyl-4-chloro-1-f[3-bromo-2-[2-(tetrazole) -5-yl)phenyl]benzofuranyl-4-yl]methyl)imidazole-5 - Angiotensin ■ receptor antagonist of formula (■) which is acetic acid or its pharmaceutically acceptable form; salt.

A series of descriptions of AII antagonists for use in the present invention are available in pending patent applications, patents and publications. and excerpts from publications or abstracts thereof. of such kind and of such kind; such patents and publications in order to fully disclose the particular compounds within which they fall. Reference should be made to the full disclosure of such patents and publications by attribution. Incorporated into this specification. Furthermore, Examples 1 to 4 are based on general formulas (n) to (V). The present invention teaches methods for making the compounds included herein.

Many An antagonists are known in the art and can be obtained by or by known methods. It can be produced by a modified method. Certain AIl [antagonistic Agents may exist in isomeric forms. The invention can be used both in pure form and in mixed forms. all isomers such as racemic mixtures and their pharmaceutically acceptable This includes salts such as

Angiotensin II antagonist activity is evaluated by an in vitro method. 11~ The antagonist activity in 1tro was determined by +25I- in isolated rabbit aortas. Binding of compounds that compete with angiotensin to vascular angiotensin receptors by its ability to antagonize its contractile response to angiotensin H. Measure again. For purposes of the present invention, preferred An antagonists are 1mM or less. A compound having the ability to inhibit A1 action by at least 50% at a concentration of Preferred An antagonists are 25 nM or less when tested by the standard method below. It is a compound that has a small (up to 50%) ability to inhibit AII action at concentrations below .

money Radioligand binding assays were performed using methods previously detailed (Gunther). et al., Circulation Research (Circ, Res, ), Dan: 278.1980). Specific fractions from rat mesenteric arteries angiotensin in Tris buffer containing 80 pM 125I-angiotensin. Incubate for 1 hour at 25°C with or without tensin antagonist.

The incubation was completed by rapid filtration, and the trapped on the filter Quantify receptor-bound I'1SI-angiotensin ■ with a gamma counter . The efficacy of angiotensin ■ antagonists is determined by the specific total binding of angiotensin H. It is expressed as IC5°, which is the concentration of antagonist required to displace 50%.

The ability of compounds to antagonize angiotensin-induced vasoconstriction was tested in rabbit aortas. . Cut a circular segment from the rabbit thoracic aorta and place the tissue in saline. Hang it inside. The annular segment was fixed on a metal support and connected to a recorder. Install the stress conversion transducer. Cumulative concentration for angiotensin■ The temperature response curves were measured in the absence or with the antagonist for 30 min incubation. Create it after you install it. The dissociation constant (K@) of the antagonist was calculated using the dose proportional method. Calculate using effective concentration.

In therapeutic use for improving cognitive function, the present invention antagonizes AII receptors. The compounds are formulated into standard pharmaceutical compositions. The composition can be administered orally, parenterally, rectally or topically. It can be administered topically or transdermally.

Compounds of the invention and their pharmaceutically acceptable salts that are active when administered orally include , as liquids such as syrups, suspensions or emulsions, tablets, capsules and It can be prescribed as a lozenge.

Liquid formulations generally include a suitable liquid carrier(s), e.g. ethanol, glycerin. , non-aqueous solvents such as polyethylene glycols, oils or suspending agents, preservation the compound or a pharmaceutically acceptable salt in water containing an agent, flavoring agent, or coloring agent. consisting of a suspension or solution of

Compositions in tablet form can be prepared using any suitable pharmaceutical preparation commonly used to produce solid formulations. It can be produced using carrier(s). Such carriers include, for example, stearic acid mag Includes nesium, starch, lactose, sucrose and cellulose.

Compositions in capsule form can be manufactured using conventional encapsulation techniques. For example, active Pellets containing the ingredients are prepared using standard carriers and then added to gelatin capsules. Alternatively, a dispersion or suspension can be prepared by or a suitable pharmaceutical carrier(s) such as aqueous gums, cellulose, silicates or oils. The dispersion or suspension is then filled into soft gelatin capsules. can do.

of the invention that is active when administered parenterally (i.e., by injection of an injectate) The compounds and their pharmaceutically acceptable salts can be formulated as solutions or suspensions.

Compositions for parenteral administration generally include a sterile aqueous carrier or a parenterally acceptable oil. , such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or consisting of a solution or suspension of the active ingredient in sesame oil. Also, freeze the solution. It can be allowed to dry and then reconstituted with a suitable solvent immediately before administration.

Typical suppository compositions contain a compound of the invention that is active when administered in this manner. is a pharmaceutically acceptable salt thereof and a binder and/or lubricant, such as a polymeric agent. Recall, gelatin or coca butter or other Consists of low melting point vegetable or synthetic oils and fats.

Typical transdermal formulations include conventional aqueous or non-aqueous vehicles, e.g. creams, soft consisting of salves, lotions or pastes, or medicated plasters, batches or is in the form of a membrane.

For topical administration, suitable pharmaceutical compositions include solutions, suspensions, ointments and solid inserts. includes. Typical pharmaceutically acceptable carriers include, for example, water, water and water-miscible solvents. , for example, mixtures with lower alkanols or vegetable oils, and water-soluble ophthalmological a non-toxic polymer that is acceptable for example cellulose such as methylcellulose It is a derivative. Pharmaceutical preparations may also contain emulsifying agents, preservatives, wetting agents and e.g. thickeners such as ethylene glycol, antibacterial ingredients such as quaternary ammonium compounds; minutes, buffering components such as alkali metal chlorides, sodium metabisulfite. such as antioxidants, and other conventional ingredients such as sorbitan monolaurate etc. It may also contain non-toxic auxiliary substances.

Preferably, the composition is in unit dosage form. Compounds of the invention in pharmaceutical dosage units The dose of the product is an efficacious, non-toxic amount, ranging from 0.01 to 200 mg of active compound. /kg, preferably from the range of 01 to 100'mg/kg. that choice dose for human patients requiring angiotensin H-induced improvement in cognitive function. Continuously administered to patients 1 to 6 times a day, orally, rectally, topically, by injection, or by infusion. to be administered. Oral dosage units for human administration preferably contain 10 to 500 active compounds. Contains mg. Lower doses are generally used for parenteral administration. to the patient Oral administration is used when safe, effective and convenient.

When the compounds of the invention are administered according to the invention, unacceptable toxicological effects All (unthinkable)

The following examples illustrate, but do not limit, the invention. 1 to 4 are methods for producing certain compounds encompassed by the general formula (Il[)-, (V) Describe. The remaining examples relate to pharmaceutical compositions of the invention. These disclosed compositions The compounds included therein are representative of the An receptor antagonists included within the scope of the invention. , but with therapeutically effective amounts of other An antagonists as described above. You can change it.

The operations of Examples 1 to 4 are for compounds encompassed by general formulas (II)-(V). This is a synthesis example. Formulas (n)-(v) can be prepared by replacing the starting materials with appropriate known reagents. Further compounds within the range are obtained. Reagents, protecting groups on imidazole and and functional groups as well as other fragments of the molecule consistent with proposed chemical modifications. It must be something that does.

The procedure of Example 1 is an example of the synthesis of compounds encompassed by general formula (n).

(i) 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio IH-imidazole 2-chlorobenzylamine (14°2) in dimethylformamide (100ml) g, 1 mol) and triethylamine (13.9 ml, 0.1 mol). Treated with methyl chloroformate (10.9 g, '0.1 mol). Mixture at 50℃ The mixture was heated for 35 hours. Dilute the cooled reaction mixture with diethyl ether and remove the solids. Protected from electricity, the concentrated filtrate was filtered using 6:4 hexane/ethyl acetate over phosphoric gel. The homogeneous 2-[N-(2-chlorophenyl)methane 15.3 g (71%) of methyl tyrucoaminoacetate was obtained. Kinren (100ml) This product (15.2 g, 1071 mol) was dissolved in 98% formic acid (2.74 ml 1.0 ．． 0711 mol) and the mixture was treated with Dean Stark for 2.5 hours. reflux using a water separator. Evaporate to 2-[N-( 17.1 g of methyl (2-chlorophenyl)methyl]-N-formylcoaminoacetate ( 99%). This formylated product (17, Og, 0.071 mol) was dissolved in formic acid. Sodium metal (1,79 g, 0.0778 gram atom) in tetrahydrofuran (325 ml) and Then methanol (3.15ml 1.0.0778mol) was slowly added. and added dropwise to the sodium methoxide mixture prepared by Bring the combined mixture to room temperature. Stirred for 18 hours and then evaporated to dryness. This crude product was mixed with 50% aqueous methane. (200 ml), treated with charcoal, filtered, and the solution was cooled with water. Ta. Slowly add concentrated hydrochloric acid (14.3 ml of 12N solution, 0.171 mol) to this solution. and then potassium thiocyanate (8.6 g, 0.0 885 mol) was added. The mixture was placed in an oil bath kept at 90°C for 2.5 hours. The mixture was heated for a while and then cooled to -10°C. Filter the precipitated solid and dilute with cold ethanol-water. Washed and dried at 60°C, 5-carboxymethyl-1-(2-chlorophenyl) Obtained 14.7 g (74%) of methyl-2-thio IH-imidazole; melting point 72 -74℃.

(ii) 1-(2-chlorophenyl)methyl-5-chloromethyl-2-propyl Lucio-IH-imidazole 5-Carboxymethyl-1-(2-chlorophenyl)methyl-2-thio IH- Imidazole (2 g, 7.08 mmol), ethyl acetate (20 ml), 5% charcoal of sodium acid solution (40 ml) and propyl bromide (4 ml, 44 mmol). The mixture was heated at 60°C for 18 hours. Separate the organic layer and dry over magnesium sulfate. It was dried and concentrated to 2.23 g of crude product. Triturated with diethyl ether , 5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthi Obtained 1.63 g (71%) of O-IH-imidazole; melting point 68-71°C (hexyl from Sun).

The ester was hydrolyzed with an aqueous sodium hydroxide solution to produce 1-(2-chlorophenyl ) Methyl-2-thiopropyl-IH-imidazole-5-carboxylic acid was obtained.

Melting point 158-159.5°C (from ethanol).

5-carboxymethyl-1-(2-k) in dry tetrahydrofuran (50 ml) lorophenyl)methyl-2-propylthio-IH-imidazole (3,74 g.

A solution of 11.5 mmol) was cooled to −78° C. under argon and diluted with aluminum hydride. A toluene solution of umdiisobutyl (30 ml of LM solution) was added dropwise. Add the mixture Stir at 78°C for 1.5 hours, then slowly warm to room temperature. Cool the reactants in water Quench by pouring into acetic acid and extract the product into methylene chloride to extract the organic The extract was washed with water, 5% sodium carbonate solution and brine. dry and concentrate The product was a pale yellow solid (3.32 g). Crystallized from ethanol/water 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propyl Thio-IH-imidazole was obtained: mp 98-101°C.

1-(2-chlorophenyl)methyl-5-hydroxy in thionyl chloride (1 ml) dimethyl-2-propylthio-IH-imidazole (0,117 g, 0.393 The mixture (mmol) was refluxed for 2 h, evaporated under vacuum to an amorphous solid, 1-(2-chlorophenyl)methyl-5-chloromethyl -2-Propylthio-IH-imidazole hydrochloride (0.13g, 94%) was obtained .

(U 3-[(2-chlorophenyl)methyl]-2-propylthio-histidine ethyl ester of diisopropylamine (8.4m) in tetrahydrofuran (100ml) The solution was cooled to -78°C under argon and diluted with a solution of n-butyllithium (2,5% 30 ml of a hexane solution of 4) was added. The mixture was heated at -78°C for 30 minutes and at 0°C. Stir for 10 minutes. After recooling to -78°C, add tetrahydrofuran (50ml ), N-(diphenylmethylene)-glycine ethyl ester (tetrahedro Tetra, Lett, (1978), 2541.4625 ) (15.4 g) was added, the mixture was stirred at -78°C for 1 hour, and dried 1-(2-chlorophenyl)methyl-5- in methylformamide (20 ml) Solution of chloromethyl-2-propylthio-IH-imidazole hydrochloride (9.4 g) liquid was added. The mixture was then stirred at ambient temperature for 18 hours and saturated ammonium chloride was added. The aqueous layer was extracted with methylene chloride. Wash the organic extract with water, Dry over magnesium sulfate, concentrate, and dilute on silica gel with 1% methanol/methychloride. 3-[(2-chlorophenyl)methyl Go2-propylthiτ-N-(diphenylmethylene)histidine ethyl ester 6.88g was obtained. The product (2.59 g) was dissolved in methylene chloride (52 ml). Then IN aqueous hydrochloric acid solution (52 ml) was added and the mixture was stirred at 25°C for 18 hours.

The aqueous layer was separated, neutralized with sodium carbonate to pH 10.5, and the product was dissolved in methylene chloride. extracted inside. The organic extract was dried over magnesium sulfate, concentrated, and the 3- [(2-chlorophenyl)methyl]-2-propylthio-histidine ethyl ester 1.29 g (71%) of tel was obtained.

(tv) 3-[(2-chlorophenyl)methyl]-2-propylthio N-butyl Tyrylhistidine ethyl ester 3-(2-chlorophenyl)methyl-2-propylene in methylene chloride (20 ml) Ruthiohistidine ethyl ester Treated with ethylamine (0.17ml) and butyryl chloride (0.12ml) .

The mixture was stirred at 25°C for 18 hours. Partition the reactants between ethyl acetate and water The organic layer was washed with water, dried, concentrated, and diluted with 1-3% methanol on silica gel. /methylene chloride to give 3-[(2-chloro) as an oil. (lophenyl)methyl]-2-propylthio N-butyrylhistidine ethyl ester 0367 g (77%) of tel was obtained.

(v) 3-(2-chlorobenzenemethyl)-2-propylthio-N-butyryl Stidine 3-[(2-chlorophenyl)methyl]-2-propylthio N-butyrylhis Tidine ethyl ester (0.37 g, 0.81 9 mmol), ethanol ( 4 ml), water (4 ml) and potassium hydroxide pellets (0.098 g, 1.7 5 mmol) was stirred at 25° C. for 1 hour. Then, dilute the reactant with water , its pH was adjusted to 4 with IN aqueous hydrochloric acid solution. Extract the product into methylene chloride , washed with water, dried and concentrated to an orange solid. Crystallized twice from chloroform 3-[(2-chlorophenyl)methyl]-2-propylthio N-butyryl Obtained 0.22 g of stidine: melting point 178-181°C.

The procedure of Example 2 is an example of the synthesis of compounds encompassed by the general formula (Ilff) .

(i) 2-n-butyl-l-(2-chlorophenyl)methyl-IH-imidazo le Imidazole, Curtiss and Brown , Journal of Organic Chemistry (J.Org.Chem.) , (19 8 0), Dan.

It was converted into a 1-jethoxyorthoamide derivative by the method of 20. imidazole (12.8 g, 0.19 mol) and triethyl orthoformate 118. 4 g (0.8 mol) was reacted in the presence of 1 g of p-toluenesulfonic acid to form 1- 20.6 (61%) of jetoxyorthoamide imidazole was obtained. Boiling point 65~ 70"C (0.1 mm). This product (24.0 g, 0.14 mol) Dissolve in dry tetrahydrofuran (250 ml) and cool to -40°C. Rulithium (0.

14M, 2.5M hexane solution (56.4ml) was added at -40°C to -35°C. Ta.

After 15 minutes, n-butyl iodide (31.1 g, 0.169 mol) was added at -40°C. , the reaction was stirred at ambient temperature overnight. The reactants were placed between ether and 0.3N hydrochloric acid. The organic layer was extracted repeatedly with dilute hydrochloric acid. The combined aqueous extract was diluted with sodium bicarbonate. Neutralized with sodium chloride solution, extracted with methylene chloride, dried over magnesium sulfate and concentrated. did. Flash distilled on a Kugelrohr apparatus, 2 14.8 g (85%) of -n-butylimidazole was obtained.

2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 ml) and sodium methoxide solution (in methanol (2+Oml), water (prepared from sodium chloride (2.31 g SO.0934 mol)). 1 o'clock After a while, the solution was evaporated to dryness and the sodium salt was dissolved in dry dimethylformamide (1 2-chlorobenzyl bromide (16.3 g, 0.079 mol) added. The mixture was heated at 50 °C under argon for 17 h, poured into cold water, and The product was extracted into ethyl acetate. Wash the extract, dry, and concentrate to obtain the crude product. 185 g of the product was obtained, which was transferred onto silica gel using 2:1 ethyl acetate/hexane. Chromatography yielded 2-n-butyl-1-(2-chlorophenylene) as an oil. 11.9 g (61%) of methyl-IH-imidazole were obtained. on silica gel RfM by thin layer chromatography using 4.1 ethyl acetate/hexane. o. I got 59.

(ii) 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxy Methyl-IH-imidazole Method 1 2-n-butyl-1-(2-chlorophenyl)methyl-IH-imidazole (9 5, 5g, 0.384mol), 37% formaldehyde (500ml), sodium acetate A mixture of thorium (80 g) and acetic acid (60 ml) was heated under argon for 40 hours. The mixture was heated to reflux for a while. The reaction was concentrated under vacuum and the residue was dissolved in 20% sodium hydroxide solution. Stirred with 500 ml for 4 hours, diluted with water and extracted with methylene chloride. extraction The liquid was washed, dried and agglomerated. Crude product (117g) was poured onto 600g of silica gel. Ethyl acetate-10% methanol/ethyl acetate gradient in Franzück 8.3 g of starting material, 24 g of mixture of starting material and product 5g and 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxy 44 g (41%) of dimethyl-IH-imidazole were obtained: melting point 86-88°C (vinegar (from ethyl acid). Furthermore, the bis(4,5-hydroxymethyl) derivative m.p. 138-140°C (from ethyl acetate).

Method 2 Valeramidine methyl ether hydrochloride (250 g, 1 ．． 66 mol) and dihydroxyacetone (150 g, 0.83 mol) Leave it overnight at room temperature in a pressurized container! Then, at 375 ps i and 65°C for 4 hours. It was heated for a while. Evaporate the ammonia and dissolve the residue in methanol (3 liters). did. Acetonitrile (1 liter) was added to the resulting slurry and refluxed.

The solution was decanted from solid ammonium chloride while heating. repeat this operation The combined acetonitrile extracts were treated with charcoal, filtered hot, and the filtrate was vacuum-treated. Concentrate to a dark oil, 2-n-butyl-5-hydroxymethylimidazole (2 53 g, 1.63 mol, 98%) was obtained.

This crude alcohol (253 g) was treated with acetic anhydride (400 ml) at -15°C. The mixture was then warmed to ambient temperature with stirring, and then stirred for an additional 19 hours. The acetic anhydride was evaporated under reduced pressure, the residue was dissolved in methylene chloride, and the organic phase was washed with 5% charcoal. Washed with sodium oxyhydrogen solution and water. Dry the extract over sodium sulfate , -a condensed to give 1-acetyl-4-acetoxymethyl-2-n-butylimidazole 323 g (83%) of the product was obtained.

This diacetate was N-alkylated by the following procedure. Under argon, -78 triflic anhydride in methylene chloride (200 ml) at °C. methylene chloride (3 50 ml), diisopropylethylamine (128 ml, 0.73 mol) and and 2-chlorobenzyl alcohol (104 g, 0.72 mol) for 20 minutes. added across.

After stirring for a further 20 minutes at -78°C, the solution was then dissolved in methylene chloride (300 1-acetyl-4-acetoxymethyl-2-n-butylimida dissolved in Sol (146 g, 0.61 mol) for 20 minutes. Then, the corresponding The mixture was stirred at ambient temperature for 18 hours and the solvent was evaporated. remaining 2-n-butyl -5-acetoxymethyl-1-(2-chlorophenyl)methyl-IH-imidazo was used without purification for hydrolysis of the acetate group.

In methanol (200 ml), crude 2-. 1-Butyl-5-acetomonmethyl- A solution of 1-(2-chlorophenyl)methyl-IH-imidazole (250 g) treated with 10% sodium hydroxide solution (700 ml) and the mixture was heated on a steam bath. Heated for 4 hours. After cooling, add methylene chloride, separate the organic phase and wash with water, Dry and concentrate. Dissolve the residue in ether, cool, seed and remove the crude product. Obtained. Recrystallized from ethyl acetate to give 2-n-butyl-1-(2-chlorophenyl) 176 g of methyl-5-hydroxymethyl-IH-imidazole was obtained. Melting point 86 -88℃. This material was identical in all respects to the product prepared by method 1. .

(iii) 2-n-butyl-2-(2-chlorophenyl)methyl-5-chloromethane Chill-IH-imidazole 2-n-Butyl-1 prepared in Example 1(u) in thionyl chloride (75 ml) -(2-chlorophenyl)methyl-5-hydroxymethyl-IH-imidazole (10 g, 0.0337 mol) was refluxed for 1 hour and evaporated under vacuum to leave a residue. The residue was azeotroped with toluene three times. Tritnylate the solid with ethyl ether and collected to give 2-n-butyl-1-(2-chlorophenyl)methyl-5-kufuro. 10.4 g (88%) of methyl-IH-imidazole hydrochloride was obtained.

(■) [2-n-butyl-1-+(2-chlorophenyl)methyl)-IH-imi diethyl dazol-5-yl]-2-benzylmalonate, dried under argon. Sodium hydride (053 g, 0.022 mol) in diformamide (50 ml) of benzylmalone in dimethylformamide (10 ml) at 0°C. Diethyl acid (5.51 g, 0.022 mol) was added.

The mixture was stirred at ambient temperature for 1 hour. 2 in dimethylformamide (40ml) -n-butyl-1-(2-chlorophenyl)methyl-5-chloromethyl-IH- A solution of imidazole molten salt (3.5 g, 0.0105 mol) was added over 5 minutes. added. The reaction mixture was stirred at 25°C for 18 hours and then poured between water and methylene chloride. 4.54 g (85%) of the title compound as an oil ) was obtained.

(v) 3-[2-n-butyl-1-((2-ri00phenyl)methyl)-IH- imidazol-5-yl]-2-benzylpropanoic acid [2-n-butyl-1-( (2-chlorophenyl)methyl)-IH-imidazol-5-ylcomethyl-2 - diethyl benzylmalonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 ml) and ethanol (25 ml) was refluxed for 4 hours. Evaporate the ethanol and remove the remaining aqueous layer. Extracted with diethyl ether and adjusted the basic solution to pH 3.75 with concentrated hydrochloric acid. . The precipitated product was extracted into methylene chloride, dried and concentrated. This crude product is Flash chromatography using 10% methanol/methylene chloride on Rica gel 3-[2-n-butyl-1-+(2-chlorophenyl)methyl) -IH-imidazol-5-yl]-2-benzylpropanoic acid 0.51 g (8 6%): mp 118-120°C (acetone/diethyl ether as hydrochloride) from Le).

The procedure of Example 3 is an example of the synthesis of compounds encompassed by general formula (rV).

(i) 2-n-butyl-1-(trimethylsilyl)ethoxymethylimidazole 80% sodium hydride (1,45 g, 0.048 g, washed with hexane under argon) 3 mol)/dimethylformamide (80 ml) at 25°C. 2-n-butylimidazole (5,45 g, 0.0439 mol) of the solution was added dropwise, and the reaction was stirred for an additional hour. Then, 2 -(trimethylsilyl)ethoxymethyl chloride (SEM-C1) (7,68g , 0.0461 mol) and the mixture was stirred at ambient temperature for 18 hours, then poured into ice water. and ethyl acetate. Wash, dry and concentrate the organic solution on a silica gel. Chromatography using 11 hexane/ethyl acetate on a 2-Q -Butyl-1-(trimethylnoryl)ethoxymethylimidazole 10.8g ( 96%).

(ii) 2-n-butyl-5-tributyltin-1-(trimethylsilyl)eth 1,000-methylimidazole 2-n-Butyl-I SEM imidazole ( A solution of (prepared above) (6.37 g, 0.025 mol) was diluted with n- Butyllithium (0,0255 mol, 10.2 ml of 2.5 M hexane solution) It was treated under H. After stirring for an additional 45 minutes, tributyltin chloride (8.83 g, 74ml (1.0.026 mol) was added dropwise. Stir the suspension overnight and add ammonium chloride. Add a saturated solution of ether and separate the ether layer, wash with brine and dry with sodium sulfate. Dry, concentrate and flash on silica gel with 31 hexanes/ethyl acetate. Chromatography was performed to obtain 2-n-butyl-5-tributyltin-1-(tributyltin). 11.3 g (83%) of methylsilyl)ethoxymethylimidazole were obtained.

(th) Methyl 3-trifluoromethanesulfonyloxybenzoate - at 30°C, Methyl 3-hydroxybenzoate (173 g, 11.3 mmol), 4-dimethylaminopyridine (21,img, 1.74 mmol) and 2,6-lutidine (2,0 ml, 16,6 mmol). Oromethanesulfonic anhydride (2.8 ml, 16.6 mmol) was added.

After stirring the reaction mixture at -30°C for 10 minutes, the cold bath was removed and the reactants were transferred to the outside atmosphere. The mixture was stirred for 4 hours at a temperature of 30°C. Then add a saturated aqueous solution of ammonium chloride and separate the layers. , the aqueous layer was back-extracted twice with methylene chloride. The combined organic extracts were diluted with sodium sulfate. Dry and remove methylene chloride under vacuum. Dissolve the residue in ethyl acetate, add water, 1 Washed with 0% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and brine. organic extraction The eluate was dried over magnesium sulfate and the solvent was removed under vacuum. Silica crude product Flash chromatography using diethyl ether/hexane at 11 on gel Methyl 3-trifluoromethanesulfonyloxybenzoate 3.13 (98%).

(iv) 3-[2-n-butyl-1-+(trimethylsilyl)ethoxymethyl )-IH-methyl imidazol-5-ylcobenzoate at room temperature, 1,4-dioxa In 53 ml of 2-n-butyl-5-tributyltin-1-(trimethylsilyl) ) Ethoxymethylimidazole (6.06 g, 11.1 mmol), 3-trif Methyl fluoromethanesulfonyloxybenzoate (3.13 g, 11.0 mmol) ) in a solution of tetrakis(triphenylphosphine)-palladium(0) (25 6 mg, 0.22 mmol) was added. The reaction mixture was incubated at room temperature under argon for 10 min. After stirring for a while, 2,6-di-t-butyl-4-methylphenol (10 mg) was added. added. The reaction was heated at 100°C for 3.5 hours, cooled to room temperature, and diluted with diethyl ether. The mixture was treated with 70 ml of gel and 55 ml of an aqueous potassium fluoride solution. Bring the reaction mixture to the chamber Stir at room temperature for 17 hours, then pass through Celite®. and filtered. The organic layer was washed with water and brine, dried over magnesium sulfate, and reduced. Concentrated under pressure. The crude product was dissolved on silica gel in 3:1 ethyl acetate/hexane. 3-[2-n-butyl-1-+( 1-limethylsilyl)ethoxymethyl)-IH-imidazol-5-yl] rest 2.88 g (67%) of methyl fragrant was obtained.

(v) 3-[2-n-butyl-1-t-butoxycarbonyl-IH-imidazole Methyl [ru-5-yl]benzoate 3-[2-n-butyl-1-((trimethylsilyl)ethyl) in 35 ml of ethanol. methyl)-IH-imidazol-5-yl]benzoate (2,88 g , 7°, 41 mmol) was added with 35 ml of 5N aqueous hydrochloric acid solution. reaction mixture was heated at 55° C. for 25 hours, and then an additional 20 ml of 5N aqueous hydrochloric acid solution was added. anti The reaction mixture was heated to 70° C. for 1 hour and then stirred at room temperature for 66 hours. ethanol was removed under vacuum, the resulting aqueous layer was neutralized with a saturated aqueous solution of sodium bicarbonate, and added with vinegar. Extracted with ethyl acid. The organic extract was dried over sodium sulfate and the solvent was removed in vacuo. Ta.

The remaining 6i (1.46 g, 5.65 mmol) was dissolved in methanol (40 ml), Triethylamine (L), 2 ml 37.3 mmol) and -t-butylamine Treated for 42.5 hours at room temperature with Katanabonate (8.4 ml, 35.4 mmol). 1 child.

Mixture under vacuum, crude product on silica gel with ethyl acetate/hemosan. Flash chromatography using a gradient of (1:8 to 4.1) and 3-[2-n-butyl-1-t-butoxycarbonyl-IH-imidazole 800 mg (30%) of methyl-5-yl]benzoate was obtained.

(vi) (3-[2-11-butyl-1-f(2-rioo phenyl)methyl 1 -IH-imidazol-5-yl]methylbenzoate held at -78°C under argon. Triflua 0 methanesulfonic anhydride (0, To a stirred solution of 72 ml (1.5.1 mmol) of 2- Benzyl alcohol (748 mg, 525 mmol) and diisopropylene A solution of ruethylamine (810 mg, 6.26 mmol) was added. -78℃ After stirring for 15 minutes, methylene chloride (10 ml) I;, (3-[2-n-butyl- Methyl 1-t-butoxycarbonyl-IH-imidazol-5-yl]benzoate (1.53 g, 4.26 mmol) over 10 minutes.

and the mixture was stirred at room temperature overnight. 5% solution of sodium bicarbonate was added with stirring and the layers were separated, washed and dried. Evaporate the reaction mixture to dryness The residue was triturated with 11 hexane/ethyl acetate and the solid was ! Say, The filtrate was awled and purified on silica gel using 1:1 hexane/ethyl acetate. Subjected to tube chromatography, (3-[2-n-butyl-1-+(2-chloro Methyl (phenyl)methyl)-1-day-imidazol-5-yl]benzoate 600 m g (38%) was obtained.

(vii) 3-[2-n-butyl-1-1(2-rioophenyl)methyl)-I H-imidazol-5-yl]benzoic acid 3-[2-n-butyl-1-+(2-chlorophenyl)methyl)-IH-imida [sol-5-yl] methyl benzoate (600 mgS1.63 mmol) was The mixture was dissolved in 6 ml of aqueous solution, and then 2 ml of a 10% aqueous sodium hydroxide solution was added. anti The reaction mixture was stirred at room temperature overnight, and 10% aqueous hydrochloric acid was added to adjust the pH to 3.5. The resulting solid was filtered, washed with water, and dried to give 3-[2-n-butyl-1-f (2 -chlorophenyl)methyl)-IH-imidazol-5-ylcobenzoic acid 125 mgf: 21) was obtained as the hydrochloride salt: mp 200-202°C.

The procedure of Example 4 is an example of the synthesis of compounds encompassed by general formula (V).

Example 4 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-IH-ben zimidazole-7-carboxylic acid (i) 2,5-dibromo-3-nitrobenzoic acid RK Bentley and F.G. Holliman (R, K, Bentley and F, G, Holiman) liman), Journal of Chemical Society (J, Che The procedure described in M, SOC, ) (c), 2447 (1970) was used. concentrated sulfur A mixture of 2,5-dibromobenzoic acid (50 g, 0.18 mol) in acid was dissolved in fuming glass. Acid (62.5 ml) was added dropwise at a rate that maintained the temperature below 70°C. Stir thoroughly. The reaction mixture was stirred vigorously and heated to 100°C; It was held for 5 hours. Carefully pour the cooled reaction into 2 liters of ice and stir vigorously. , the precipitate was filtered through a sintered glass funnel, and the solids were washed thoroughly with water. the solid Crystallize by dissolving it in acetic acid (150r: +1) and reduce its volume to half. After concentration, crystals were isolated (16.72 g): mp 225-229°C. Sarana A total yield of 7.52 g was obtained, giving a total yield of 24.24 g (41%).

(if) 5-bromo-2-[(2-chlorophenyl)methylcoamino-3-di Trobenzoic acid 2,5-dibromo-3-nitrobenzoic acid (10,7 6g, 0.0331 mol) of 1! Place under argon overnight and add 2-chloroben. and reflux the mixture. Se/:3 A clear red solution was obtained, the solution was refluxed for 24 hours, cooled and diluted with 5% sodium hydroxide. Poured into thorium solution (600ml) and ether (100ml). insoluble The material was filtered off, the layers separated, the aqueous phase added to the insoluble material and acidified with 10% hydrochloric acid solution. It became sexualized.

Collect the separated crystallized product, wash with water, and remove the solid from copious amounts of methanol. Crystallized into yellow crystals of 5-bromo-2-CC2-chlorophenyl)methyl 7.85 g (61.5%) of No-3-Nitroyasu Ekaa was obtained. Melting point 159-16 1℃.

(m) 5-bromo-2-[(2-chlorophenyl)methyl-N-valerylcoami Nor-3-nitrobenzoic acid 5-Bromo-2-CC2-chlorophenyl)methyl in pyridine (100ml) Co-amino-3-nitroan, 1. A solution of aromatic acid (8 g SO, 021 mmol) was added to the It was cooled with water under Rougon and valeryl chloride (5.5 g, 0.046 mol) was added. mixture The mixture was heated at 45 °C for 18 hours, poured into water, acidified with hydrochloric acid, and the oil was dissolved in acetic acid. Extracted into ethyl. The organic extract was washed with 10% hydrochloric acid solution and brine to produce The material was dried and concentrated to obtain a crude oil of 5-bromo-2-[(2-chloro phenyl)methyl-N-valerylcoamimetro-nitrobenzoic acid was obtained and It was used without further purification.

(■) 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-IH -benzimidazole-7-carboxylic acid in tetrahydrofuran (75 mm), 5 -bromo-2-[(2-chlorophenyl)methyl-N-valeryl]amino-3- A solution of nitrobenzoin 12 (9.72 g, 0.0207 mol) was dissolved in 5% sodium bicarbonate. diluted with sodium RG solution (75ml) and then diluted with sodium hydrosulfide (1ml). 2 g) in portions over 2 hours. The pH is further adjusted with solid hydrogen carbonate. W4 adjusted to 7.1 with thorium. After 1 hour tx stirring, additional sodium hydroxide After adding 6 g of sulfide and stirring for an additional hour, the mixture was filtered and diluted with ether. and the layers were separated. The organic phase was condensed to a solid, which was treated with acetic acid (15 mm) and 1 salt! ! (,5ml) and heated on a steam bath for 2 hours. remaining slurry The solution was condensed under vacuum, diluted with water, and the solid was collected. Dissolve the solid in hot methanol. The insoluble matter was filtered off, and the filtrate was condensed to initiate crystallization.

Cooled 1 barley, 5-proso-2-n-butyl-1-(2-chlorophenyl)methyl- 4.26 g (37%) of IH-benzimidazole-7-carboxylic acid was obtained. melting point 25 Oral dosage forms for administering orally acting compounds of formula (I) can be prepared, for example, by Screen and mix the ingredients in the proportions shown below and add hard gelatin. It is manufactured by filling into capsules.

Ingredients Amount (E)-3-[2-n-butyl-1-t(4-carboxy 100mg phenyl ) Methyl 1-IH-imidazol-5-yl]-2-(2-chenyl)methyl- Magnesium 2-propenoic acid stearate 10mg Sucrose, calcium sulfate dihydrate and orally acting compounds of formula (I) The material was mixed with a 10% gelatin solution and granulated. Screening the wet granules mixed with starch, talc and stearic acid, and screened. and tableted.

Ingredients Amount (E)-3-[2-n-propyl-1-+(4-carboxy 75mg naphtho- 1-yl)methyl)-IH-imidazol-5-yl]-2-(2-chenyl) Methyl-2-propenoic acid calcium sulfate dihydrate 100mg Stearic acid 2mg (E)-3-[2-n-butyl-1-f(4-carboxyphenyl)methyl)- IH-imidazol-5-yl]-2-(2-chenyl)methyl-2-propene The injection preparation is prepared by dispersing 50 mg of acid in 25 ml of saline.

The present invention is not limited to the specific examples described above, but includes the specific examples described and the claims below. It is to be understood that the rights to all modifications that fall within the scope of the request are reserved. It is.

international search report Flm-111PeTM OIlmlllllllMml m-mouth 11・Pklt Sl141I proboscis-■-am epilepsy I-m, PCT/GB91102224 international investigation report

Claims (11)

[Claims] 1. Requires an effective amount of angiotensin II receptor antagonist to improve cognitive function A method for improving cognitive function in a mammal, comprising administering to a subject. 2. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1 is adamantyl, phenyl, biphenyl or naphthyl; group is unsubstituted or Cl, Br, F, I, C1-C6 alkyl, nitro B, A-CO2R7, tetrazol-5-yl, C1-C6 alkoxy, hydro xy, SC1-C6 alkyl, SO2NHR7, NHSO2R7, SO3H, C ONR7R7, CN, SO2C1-C6 alkyl, NHSO2R7, PO(OR 7) 2, NR7R7, NR7COH, NR7COC1-C6 alkyl, NR7C 1 to 3 substituents selected from ON(R7)2, NR7COW, W, SO2W is substituted with; m is 0 to 4; R2 is C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl C3-C6 cycloalkyl, or unsubstituted or C1-C6 alkyl Nitro, Cl, Br, F, I, hydroxy, C1-C6 alkoxy, NR7 R7, CO2R7, CN, CONR7R7, W, tetrazol-5-yl, NR 7COC1-C6 alkyl, NR7COW, SC1-C6 alkyl, SO2W or SO2C1-C6 alkyl. is (CH2)0-8 phenyl; X is a single bond, S, NR7 or O: R3 is hydrogen, Cl, Br, F, I, C HO, hydroxymethyl, COOR7, CONR7R7, NO2, W, CN, N R7R7 or phenyl; R4 and R5 are independently hydrogen, C1-C 6-alkyl, thienyl-Y-, furyl-Y-, pyrazolyl-Y-, imidazolyl -Y-, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isooxy sazolyl-Y-, thiazolyl-Y-, pyridyl-Y- or tetrazolyl-Y- (provided that both R4 and R5 are selected from hydrogen and C1-C6 alkyl) ), each heterocyclic ring is unsubstituted or C1-C6 alkyl L, C1-C6 alkoxy, Cl, Br, F, I, NR7R7, CO2R7, S O2NHR7, SO3H or CONR7R7, OH, NO2, W, SO2W, SC1-C6 alkyl, SO2C1-C6 alkyl, NR7COH, NR7CO substituted by W or NR7COC1-C6 alkyl; Y is a single bond, O, S or C1-C6 alkyl, straight or branched or optionally substituted with phenyl or benzyl, where each aryl The groups are unsubstituted or halo, NO2, CF3, C1-C6 alkyl, C1- substituted with C6 alkoxy, CN or CO2R7: R8 is -Z-COO R8 or -Z-CONR7R7; Z is a single bond, vinyl, -CH2-O- CH2-, optionally C1-C6 alkyl, 1 or 2 benzyl groups, thienyl Methylene optionally substituted with methyl or furyl methyl, or -C(O ) NHCHR9- (where R9 is H, C1-C6 alkyl, phenyl, benzyl , thienylmethyl or fluoromethyl): W is CnF2n+1, CnF2n+1 (where n is 1 to 3): A is -(CH2)m-, -CH=CH-, -O(CH2)m- or -S(CH2 )m-; R7 is each independently hydrogen, C1-C6 alkyl or (CH2)mphenyl (where m is 0-4): and R8 is hydrogen, C1-C6 alkyl or 2-di(C1-C6 alkyl)amino-2-oxoethyl] An angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof shown in 2. The method of claim 1, comprising administering. 3. Angiotensin II receptor antagonist (E)-3-[2-n-butyl-1- {(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2 -(2-thienyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. 3. The method according to claim 2. 4. Angiotensin II receptor antagonist (E)-3-[2-n-butyl-1- {(4-carboxyphenyl)methyl}-1H-imidazolyl-5-yl]-2 -(2-thienyl)methyl-2-propenoic acid methanesulfonate Claim 3 Method described. 5. Angiotensin II receptor antagonist (E)-3-[2-n-butyl-1- {(4-carboxynaphth-1-yl)methyl}-1H-imidazol-5-y ]-2-(2-thienyl)methyl-2-propenoic acid or its pharmaceutically acceptable 3. The method according to claim 2, wherein the salt is 6. Angiotensin II receptor antagonist: (E)-3-[2-n-butyl-1 -{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]- 2-n-butyl-2-propenoic acid: (E)-1-[2-n-butyl-1-{(4 -carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(1 H-tetrazol-5-yl)-3-(2-thienyl)-1-propene: or N-[{1-(4-carboxyphenyl)methyl]-2-n-butyl-1H-y midazol-5-yl}methyl]-β-(2-thienyl)alanine; or its The method according to claim 1, which is a pharmaceutically acceptable salt. 7. Angiotensin II receptor antagonist is 2-n-butyl-4-chloro-1-[ (2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]- 5-(Hydroxymethyl)imidazole or a pharmaceutically acceptable salt thereof The method described in claim 1. 8. The angiotensin II receptor antagonist is 2-n-propyl-4-pentufluoro. loethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]imidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof 2. The method of claim 1. 9. Angiotensin II receptor antagonist is 5,7-dimethyl-2-ethyl-3- (2'-(tetrazol-5-yl)biphenyl-4-yl)methyl-3H-y A claim that it is midazole[4,5-b]pyridine or a pharmaceutically acceptable salt thereof The method described in 1. 10. Angiotensin II receptor antagonist is 2-methyl-4-{(2'-(1H -tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline or The method according to claim 1, which is a pharmaceutically acceptable salt thereof. 11. Angiotensin II receptor antagonist is 2-n-butyl-4-chloro-1- {[3-bromo-2-[2-(tetrazol-5-yl)phenyl]benzofura nyl-4-yl]methyl}imidazole-5-acetic acid or its pharmaceutically acceptable 2. The method according to claim 1, wherein the salt is a salt.