JPH06507899A - Compound - 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] Compound The present invention is an angiotensin receptor antagonist; ■ Regulation of hypertension induced or worsened by congestive heart failure, renal Novel N-(heteroaryl)-imidazo useful in the treatment of glaucoma and glaucoma Relating to lyle-alkenoic acids. The invention also relates to pharmaceutical compositions containing these compounds. As an angiotensin H antagonist, as an antihypertensive agent, and as an angiotensin H antagonist. Those using these compounds as a treatment for congestive heart failure, renal failure and glaucoma Regarding the law.

Background of the invention A series of peptide pressor hormones, known as angiotensins, are responsible for high blood pressure in humans. It is a substance responsible for the pressor effect, which is related to the pathogenesis of blood pressure. Lenin Angio Inappropriate activity of the nervous system causes essential hypertension, congestive heart failure, and some forms of It is clearly a key factor in kidney disease. for arteries and arterioles In addition to its direct action, andiamine is one of the most potent exogenous vasoconstrictors known. Otensin IT (All) stimulates the release of aldosterone from the adrenal cortex. Gives strength. Therefore, the renin-angiotenin system is responsible for the renal sodium hand. Plays an important role in cardiovascular hemostasis due to its involvement in ring coordination are doing.

Interfering with the renin-angiotenin system using converting enzyme inhibitors such as captopril clinically useful in the treatment of hypertension and congestive heart failure It has been proven that (Abrams W.B. ) et al. (1984), Federation Proceedings (Feder. ation Proc, ), Dan.

1314). The most direct means of suppressing the renin-angiotenin system is to The goal is to block the action of An at the receptor. Noteworthy evidence is that An further Renal vasoconstriction and characteristic of many disorders such as heart failure, cirrhosis and pregnancy complications (Hollenberg N.K.) (Bollenberg, N., K.), (1984), Journal of ・Cardiovasculi fur Tco0gy (J, Cardiovas, P harmacol, ), Dan, 5176), in addition, recent animal experiments have shown that - Suppression of the angiotensin system halts or slows progression of chronic renal failure (undernon varnish). (1985), Journal of Clinical Investigation Ige-Nogn (J, C11n, Invest,), 76. 612), also A recent patent application (South African Patent Application No. 87101.653) claims that AI I antagonists are particularly useful for the reduction and regulation of high intraocular pressure in mammals. The patent claims that it is useful as a drug for internal disorders.

The compounds of the invention suppress, block and antagonize the action of hormone AII, and tean, nootensin-induced hypertension, congestive heart failure, renal failure and the action of AII. It is useful for adjusting and regulating other disorders resulting from the use of Compounds of the present invention When administered to mammals, AII-induced hypertension is reduced and AI [other mediation-based The appearance of symptoms is minimized and regulated. The compounds of the invention also exhibit diuretic activity. It is considered to indicate.

It is recognized that it is important to block and suppress the effects of Other attempts to synthesize antagonists have been stimulated. The documents listed below are An discovered imidazole derivatives that have been described as having blocking activity and are useful as antihypertensive agents. It shows.

Furukawa et al., U.S. Pat. No. 4,340,598, Discloses zol-5-yl-acetic acid and imidazol-5-yl-propanoic acid There is. In particular, the disclosure discloses that 1-benzyl-2-n-butyl-5-chloroimida sol-4 = acetic acid and 1-benzyl-2-phenyl-5-chloroimidazole -4-propanoic acid.

Furukawa et al., U.S. Pat. No. 4,355,040, discloses that substituted imidazole-5-acetic acid Derivatives are disclosed. Specifically disclosed compounds include 1-(2-chlorobenzyl )-2-n-butyl-4-chloroimidazole-5-acetic acid.

In European Patent No. 253,310, Carini et al. Discloses imidazolylpropenoic acid. Intermediate between the two types described in this patent The body is 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazo ethyl-5-yl]propenoate and 3-[2-butyl-4-chloro-1- Ethyl (4-aminobenflu)imidazol-5-yl]propenoate.

Furthermore, faring is PCT/EP 86100297 disclosed certain imidazolyl propenoate compounds as intermediates in ing.

Formula (CX) on page 62 is 3-[1-(4-fluorophenyl)-4-isopropylene ethyl lopyl-2-phenyl-IH-imidazol-5-yl]-2-propenoate [ During the ceremony, R1 is Het, where Het is either saturated or unsaturated, 1 to 3 heteroatoms selected from the group consisting of carbon atoms and N5OSS A stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic compound consisting of The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen and sulfur atoms may be oxidized. The ro atom may be quaternized if desired (the above heterocycle is fused to a benzene ring). It includes any combined bicyclic group, where Het is unsubstituted or C, -C, Alkyl, CB-C, 7Jvko*shi, C1, Br, FS I, NR'R', A- Co2R7, CONR'R, 5OsH5SOzNHR', OH, Not, W, 5OtC+ C4 alkyl, So! WSSCI Ca alkyl, NR'COW or NR7C0C, -Ca alkyl up to 3 substituents selected from the group consisting of , where W is substituted by any stable combination of is C,F,. , (n is 1 to 3), and A is -CH=CH-1-(CHI).

-4-1-〇-CH(R')- or -Q-(CHz)l-2U　(CHz)+ 4 (where Q is O, S, NH or NC, -.

alkyl, U is absent or O, S, NH or N-Co-a alkyl; and R9 is hydrogen, phenyl or benzyl); m is O~4: R2 is Cm CIG alkyl, Cs Cu alkenyl, Cs Coo alkenyl , C5C6-chloroalkyl or unsubstituted or C,-C,alkyl, nitro, C1, Br, F, T, hydroxy, Co Cs alcoquine, NR'R', C02 R’, CN.

C0NR'R', W, tetrazol-5-yl, NR7C0C, -C, alkyl , NR’C0WXSC+ Ca alkyl, 5O2W or 5ChC+ C6 alkyl Substituted with 1 to 3 substituents selected from (CH2). 1st floor Enil.

Xll+- bond, S, NR'tfi; LO: R3 is hydrogen, C1, Br5F, L CHO, hydroxymethyl, C0OR', C0NR'R, NO2, W, CN, NR'R7 or phenyl.

R4 and R5 are independently hydrogen, C, -C, alkyl, phenyl-Y-, biphenyl phenyl-Y-, naphthyl-)'-12- or 3-thenyl-Y-12- or 3-furyl-Y-12-13- or 4-pyridyl-Y-, pyrazolyl-Y-, imidazolyl-Y-, pyrrolyl-Y-, triazolyl-Y-, oxacylyl-Y -, isoxasilyl-Y-, thiazolyl-Y- or tetrazolyl-Y-. each aryl or heteroaryl group is unsubstituted or C, -C 6 alkyl, C, -C, alcoquine, C1, Br, F, L NR'R', C02 Rfu, SO, NHR', 5o3H, C0NR7R', 0HSNOz, WSSO2 WSSC+ Ca alkyl, S O2C1-CC7) Lt*lLt, NR7C0 C, NR7COCl or NR7C0C+-06 alkyl substituted : Y is a single bond, 0, S, or a straight chain or branched chain, and optionally phenyl or C+-Cs alkyl optionally substituted with benzyl, where phenyl or benzyl groups are each unsubstituted or halo, Not, CF 3, C, -C, alkyl, CTCs alkoxy, CN or Co, by R, 7 It has been replaced with: R’f;! -Z-COORa, -Z-C0NR'R'ma? :Ha-Z--r Tora Zol-5-yl: Z is a single bond, vinyl, CH20CHt-1 optionally C, -C, alkyl, 1 or substituted by two benzyl groups, thenylmethyl or furylmethyl methylene or -C(0) NHCHR, where R9 is H1C + C6 alkyl, phenyl, benzyl, thenylmethyl or furylmethyl can be; W is C-F2-+ (where n is 1 to 3); R7 is each independently hydrogen or is C, -C, alkyl: and R8 is hydrogen, C, -C, alkyl or 2 -di(C,-C,alkyl)amino-2-oxoethyl] or a pharmaceutically acceptable salt thereof.

Preferably, one of R4 and R5 is hydrogen or C+-Cs alkyl. Ru.

Preferred RI Not groups are piperidinyl, piperazinyl, 2-oxopiperazi Nyl, 2-oxopiperidinyl, 2-oxazolidinyl, 2-oxoazepinyl , azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyra Zolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, 2-13- or 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxasilyl, Oxazolinyl, imidazolyl, isoxazolidinyl, morpholinyl, thia Zolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl ru, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadia Zolyl, benzopyranyl, benzothiazolyl, benzoxacylyl, 2- or 3-furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, 2-furyl is 3-chenyl, benzothenyl, benzoxacylyl, thiamorpholinyl, Amorpholinyl sulfone, thiamorpholinyl sulfone, benzofuranyl and oxadiazolyl, where the R1 group is unsubstituted or Lucil, C+ -Ca Alcoquine, C1, Br, FS I, NR'R F, A-C O2R7, C0NR'R7, S O3H, S O2N HR', OH, No,, W, 5O2C+ Ca full kill, 5O2W, SC, -C67tL4ru, NR'C up to three selected from the group consisting of OW or NR7COCl-C6furkyl Substituted by any stable combination of substituents, W is CoF2m+1 (n is 1 to 3), A is -CH=CH-1-(CH2 ). -4-1-Q-CH(R')- or -Q-(CHa) l-2U (CH 2) l-2 (where Q is O, S, NH or NC, -.

alkyl, U is absent or OSS, NH or NC, -, alkyl and R9 is hydrogen, phenyl or benzyl).

The most preferred compounds of the invention are: R1 is 2- or 3-chenyl, 2- or 3-furyl, or 2-13- or is 4-pyridyl, and each of the chenyl, furyl or pyridyl groups is unsubstituted. or substituted with CO2R7.

m is O~2° X is a single bond or S.

R2 is C2-C, alkyl.

R3 is hydrogen, chloro, fluoro or trifluoromethyl: R4 is hydrogen or C , -C6 alkyl.

R5 is 2- or 3-thenyl-Y-12- or 3-furyl-Y-1 or 2 -13- or 4-pyridyl-Y-, in which each heteroaryl group is unsubstituted. or substituted with methyl or methoxy/.

Y is a single bond or a linear or branched C, -C, alkyl; R8 is -Z-CO OR’.

Z is a single bond; and A compound represented by formula (1) in which R8 is hydrogen or CoC6 alkyl, or a compound thereof is a pharmaceutically acceptable salt of

Generally, the E isomer (COOR) and the imidazole group have a trans stereochemical relationship. ) is more active and is therefore preferred over the Z isomer (cis).

As used herein, alkyl, alkenyl, alkokene and alkenyl The word ``branched or means an unbranched carbon chain.

Individual compounds of the invention include, but are not limited to, the following compounds: : (E) -3-[2-n-butyl-1-+(5-carboxy-2-chenyl)methyl methyl)-IH-imidazol-5-yl]-2-(2-chenyl)methyl-2 -propenoic acid, (E) -3-[2-n-butyl-1-+(5-carboxy-3-chenyl)methyl methyl)-IH-imidazol-5-yl]-2-(2-chenyl)methyl-2 -propenoic acid, (E) -3-[2-n-butyl-1-t(5-carboxy-2-furyl)methy 1-IH-imidazol-5-yl]-2-(2-chenyl)methyl-2- propenoic acid, and (E) -3-[2-n-butyl-1-+(5-carboxy-2-pyridyl)methyl methyl)-IH-imidazol-5-yl]-2-(3-chenyl)methyl-2 -Propenoic acid.

or a pharmaceutically acceptable salt thereof.

The most preferred compound of the present invention is (E)-3-[2-n-butyl-1-+(5 -carboquin-2-chenyl)methyl)-IH-imidazol-5-yl]-2 -(2-chenyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof. Ru.

The invention further provides a pharmaceutical composition comprising a pharmaceutical carrier and an effective amount of a compound of formula (I). related.

Furthermore, the present invention provides an effective amount of a compound of formula (I) as an angiotensin receptor antagonist. of angiotensin receptors, which consists of administering to a subject in need of an anti-inflammatory effect. Includes antagonistic methods. Methods for forming antihypertensive activity and administration of these compounds Also encompassed by the invention are methods of treating congestive heart failure, glaucoma, and renal failure. It will be done.

The invention also provides treatment for diseases such as hypertension, congestive heart failure, glaucoma and renal failure. The formula (1 ) provides methods for using the compounds.

Compounds of the invention can be prepared by the procedures described herein and illustrated in the Examples. Manufactured by. reagents, protecting groups and imidazole and other fluors in the molecule. The functionality in the segment must be consistent with the proposed chemical transformation.

Steps during synthesis include functional groups and protection at imidazole and other sites in the molecule. It must be compatible with the base.

Is the starting material 2-R'X-imidazole known in the art? -j-roof-. 1- Ganitsuk Chemistry〇, Org, Chem,) 45:4038°1.980) or synthesized by known operations. for example, Reacting imidazole with triethyl orthoformate and p-toluenesulfonic acid. This reaction gave 1-jethoxyorthoamide imidazole, and then n-butyl lithium The 2-lithium derivative of the orthoamide was obtained by treatment with tetrahydrofuran. Alkylation using n-butyl iodide in a suitable solvent such as (THF) By this, imidazole is converted to 2-n-butylimidazole.

The following operation is performed on a compound of formula (1), especially when R1 is carboxy-substituted 2-chenyl. , m is 1-, R2 is n-butyl or n-propyl, and X is a single bond. or S, R3 is hydrogen, chloro or CF, and R4 is hydrogen , R is 2-chenylmethyl, Re is C0OR'', Ra is hydrogen, Useful in producing compounds that are methyl or ethyl.

I R,' (CHI)- group is converted into dimethylforma by known procedures, for example. Sodium alkylate, potassium carbonate in a suitable solvent such as DMF or sodium, or metal halides, preferably sodium hydride. a reaction temperature of about 25°C to about 100°C, preferably in the presence of a suitable acid acceptor. at 50°C, R1-(CH,), -halide, mesylate or acetate, e.g. For example, by reacting with 5-promomethyl-2-carbomethoxythiophene , 2-R”X-imidazole. The resulting 1-R1(CHt), -2 -R2X-imidazole, for example, this compound in acetic acid, sodium acetate The 5-position is converted into hydroxymethylene by reacting with formaldehyde in the presence of to obtain IR’CH22R”X 5-hydroxymethylimidazole intermediate. Ru. With a suitable reagent such as chromic anhydride-silica gel in tetrahydrofuran, or preferably benzene or toluene or preferably methylene chloride using activated manganese dioxide in a suitable solvent such as Hydroxymethyl groups are removed from aldehyde by treatment at oxidized to 1-R1(CH2), -IR"X-imidazole-5-carboxylate Obtain sialdehyde.

Alternatively, 1-R'(CH2), 2R2-imidazole-5-carboxy The aldehyde is prepared according to the following procedure. Barrel amidine methyl ether Unaimide ether, R2-C(=NH)-0~alkyl, in liquid ammonia , reacted with dihydroxyacetone under pressure to form 2-R2-5-hydroxymethyl Obtain imidazole. The hydroxymethyl group can be chlorinated as described above, e.g. to the corresponding aldehyde using manganese dioxide in a suitable solvent such as methylene. Oxidize. 2-R2-imidazole-5-carboxaldehyde in a suitable solvent such as Lumamide at a temperature of about 208C to about 50C, preferably 2 Chloromethyl pivalate (POM) in the presence of a base such as potassium carbonate at 5 °C -CI) to damage the imidazole nucleus by reaction with an N-alkylating protecting reagent such as N-alkylation (e.g. POM-derivatization) of the least nitrogen atoms of . Said The aldehyde of manufacture is heated, for example, at a temperature of about 0°C to about 125°C, preferably 100°C. to halomethyl such as 5-bromomethyl-2-carbomethoxythiophene at °C. By N-alkylation using a teroaryl compound, IR'(CH 2) Incorporating a -- group into the imidazole. Protection on the 3-nitrogen of the imidazole ring By base hydrolysis, for example, a two-phase mixture of ethyl acetate and an aqueous sodium carbonate solution 1-R'(CHz), 2-R2-imidazole-5-carbo A xaldehyde compound is obtained.

In addition, 1-R' (CHz), 2 R2-imidazole-5-carboxy The aldehyde was converted to 2-R'-5-hydroxymethylimidazole using the following procedure. Manufactured from Le. 5-Hydroxymethyl intermediate, for example in tetrahydrofuran/ in a suitable solvent such as 2-methoquinoethane at a temperature of about 25°C to about 60°C, preferably Halogenate the 4-position using N-chlorosumenimide at 50°C. . The 5-hydroxymethyl group of this intermediate was converted to 5-carboxylate using the method described above. Oxidizes to dehyde. The resulting imidazole intermediate is treated with, for example, dimethylforma In a suitable solvent such as amide, in the presence of a base such as potassium carbonate, 5-bromomethyl Halomethylheteroaryl compounds such as thyl-2-carbomethoquinothiophene The 1-position is selectively N-alkylated using palladium-carbon-like In the presence of a catalyst, the halo group is removed by hydrogenolysis, and I R' (CHz), 2 R' 5-hydroquinomethylimidazole is obtained. 1-R1(CH2), -2 -R2-imidazole-5-carboquinaldehyde is prepared according to the method described above. Manufactured from hydroxymethyl compound.

The compound of formula (1) is IR'(C1h)-2R''X-imidazole-5-carbohydrate Luboquinaldehyde and 3-(2-chenyl)-2-phosphonopropionic acid trime It is prepared by reaction with a suitably substituted phosphonate such as phosphonate. The phosphona A suitable trialkylphosphonoacetate is dissolved in a suitable solvent, preferably a glycerol. Sodium hydride in lime at a reaction temperature of 25°C to 110°C, preferably 55°C. a suitable halide, mesylate or acetate in the presence of a suitable base such as is prepared by alkylation using, for example, a phosphonate. Imi The reaction of dazole-5-carboxaldehyde with phosphonates is hydride, lithium hydride or preferably sodium hydride. In the presence of ethanol, methanol, ether, dioxane, tetrahydrofuran or preferably in a suitable solvent such as glyme at a reaction temperature of about 0°C to about 50°C. temperature, preferably 25°C, and a variable mixture of trans and cis, e.g. (E ) and (Z) I　R'　(CH-2R"X-5CH=C(R')(Co.

alkyl)-imidazole is obtained. These isomers can be isolated in a suitable solvent system, preferably separated by chromatography on silica gel in hexane/ethyl acetate do. The ester is dissolved in a suitable solution such as, for example, aqueous alcohol or diglyme. Salts such as potassium hydroxide, lithium hydroxide or sodium hydroxide in solvent systems group to form an acid, 't1-R'(CHt)-2R''X5-CH=C( R') hydrolyzed to COOH-imidazole. Trans and cis structures of nucleic acids by NMR, by the NOE protocol, and in general by trans(E) Isomeric acids are more potent isomers and are therefore more easily determined by biological activity. It will be done.

The compound of formula (1) is also produced by the following operation. 2-R”X-imidazo reaction of the chloride starting material with trimethylethoxymethyl (SEM) chloride. to obtain 1-(trimethylsilyl)ethoxymethyl-2-R2X-imidazole. . The reaction is carried out, for example, with sodium hydride in a solvent such as dimethylformamide. Conducted in the presence of. The 5-tributyltin derivative can be prepared, for example, in a suitable solvent, preferably Alternatively, lithiation with butyllithium in diethyl ether followed by lithiation with the lithium The midazole derivative is added to tributyltin at about -10°C to about 35°C, preferably at 25°C. Produced by reaction with a halide, preferably tri-N-butyltin chloride be done. 1-5EM-2-R2X-1-5E butyltin-imidazole was Fin ligands, such as bis(diphenylphosphino)prono(n) or 11 ) IJ phenylphosphine and palladium (II) compounds, also (more preferred In the presence of radium(0), tetrakis(triphenylphosphine) Temperatures from about 0°C to about 150°C with or without a base such as ethylamine , preferably 1d at 120°C, halide or trifluoromethane is added to the β-position. α,β-unsaturated acid esters with leaving groups such as /honyloxy groups, e.g. Coupling with BrCR'=C(R') (Coo alkyl). to this method , both (E) and (Z) olefin isomers are produced, and the isomer Es The esters are separated by chromatography on silica gel. (E) and (2) The 11-3E group of the isomer is dissolved in a suitable alcohol such as methanol or ethanol. Hydrolyze with aqueous hydrogen chloride in an aqueous solvent using an acid, e.g. The 1-1- Butokinokal, Bo, Nil (t-BOC) Imida-Nol 1 change (Cylinder) Seiseizu Zaitunju Lift Fuel Physiology Chemie (H oppe-3eyler’s Z, Physiol, Chem, ), (1 976), 35″7. 1651). t-BOC ester is alkylated, e.g. (f, a suitable base, in the presence of 1 Yoshiisopropylethylamine, a suitable solvent, preferably +1 methylene chloride, 2-thenylmethyl-O-MJ'7 1-(hetero-1-nol) methylimidazole derivative (e.g. steal). (E) and (Z) isomers were prepared by the method described above. (Z) Hydrolyze to acid.

The compound of formula (1) can also be produced by the following procedure. Manufactured as described above 1-r' (C1(2)-2R2X-imidazole-5-carboxaldehyde In the presence of a base such as dopiperidino, 2-carbon in a suitable solvent at a temperature of about 50'C to about 110C, preferably iisoC. Malonic acids such as nityl ruboxy-3-(2-chenyl)propionate and Reaction of half-ester substituted derivatives. ii et al h ta I R' (CH2) - 2 R”X 5 CH=C(R5)Coo alkyl-imidazole, The compound is hydrolyzed to the corresponding acid compound of formula (I).

Compounds of formula (I) are also prepared as follows. IR produced as described above '(CH2),,2-R''X-imidazole-5-carboxaldehyde , organometallic derivatives or Grignard in a suitable solvent such as tetrahydrofuran. convert to the corresponding alcohol, preferably using methyllithium. The a The alcohol is oxidized to give the ketone using, for example, manganese dioxide. The ketone is reacted with a suitable phosphonate to produce an olefin ester, which is easily separated. (E) and/or (Z) isomers are obtained. Alkaline hydrolysis as described above An acid is produced from the ester.

Additionally, compounds of formula (I) are prepared as follows. 1-R=(CH,),- 2-R2X-imidazole-5-carboxaldehyde with substituted ethyl or or a lithium derivative of methyl ester. These lithio derivatives are Lithium diisopropylamide in a suitable solvent, preferably tetrahydrofuran. is reacted with an acid ester such as ROOC-CH2-Y- (2-thenyl). α-lithio is produced at about -78°C to about -10°C, preferably -78°C. to form a derivative, which is then reacted with imidazole-carboxaldehyde. let

The β-hydroxy group of the imidazole ester intermediate is mesylate or acetate. The melute or preferably acetate can be replaced with a suitable solution such as toluene. 1 to 2 equivalents of 1,8-diazo-vinchlo[5. 4. 0] Un heating with deca-7-ene at about 50'C to about 110C, preferably 80C; 3-(imidazol-5-yl)-2-(2-chenyl)methyl-2-prope An ester compound of formula (I) such as a phosphoric acid ester is obtained. (E) Predominant isomer It is an olefin isomer. An acid is produced from the ester by the method described above.

Y is a single bond, R5 is aryl or hetero as described in formula (I) The compound of formula (1), which is loweryl and R6 is COOH, is ], R1-( CH2), -2-R2X-imidazole-5-carboxaldehyde, about 0 C. to about 180.degree. C., preferably 140.degree. C., optionally substituted acetic acid, acetic anhydride and charcoal. 3[2-n-butyl-1-(2-chenyl)methyl -1. Formulas such as 8-imidazol-5-yl]-iR5-2-propenoic acid It may be produced by obtaining the unsaturated acid (I). Mainly trans olefinic acids It is a product.

R6 is Z-COOH8, where Z is optionally substituted; The compound of formula (I) which is a tyrene group has a 3-(imidazol-5-yl)-2-propylene group. The trans or (E) isomer of lopenic acid ester (prepared above) is A suitable hydride reagent, preferably a hydrogenated diisobutylene, in a suitable solvent such as furan. Produced by reduction with chillaluminum to obtain an unsaturated alcohol compound Ru. These compounds, for example, together with a base, preferably triethylamine, 5- by reaction with ethyl chloroformate in a suitable solvent such as tetrahydrofuran. EtOOCOCH2CR'=CR'-imidazole was obtained and it was converted into phosphine ligator. preferably in the presence of triphenylphosphine and palladium (IT) acetate. from about 5°C to about 100°C in a suitable solvent, preferably tetrahydrofuran. 5-EtOOCC1hCR by reaction with carbon oxide at a temperature, preferably 40°C. '=CR'-imidazole is obtained. The corresponding acids described above these ethyl esters. It is produced by base hydrolysis as in

When Z is C The compound of formula (I) where H2C000R8 is 5Et000 C H 2 C R' = C R' - imidazole, Lithification of the ester using a kylamide, preferably lithium diisopropylamide. um derivatives, then methyl halides, benyl bromides or heterocyclic halo treatment with an alkylating agent such as methyl genide to produce a monoalkylated product or It is produced by obtaining a rkylated product.

Acid compounds are prepared from the esters by base hydrolysis.

R6 is Z-COOR', where Z is one CH2 0 CH2- (I ) is an unsaturated alkyl compound obtained by reducing the propenoic acid ester of formula (I). Manufactured from coal compounds. the alcohol in a suitable solvent such as glyme. , with a suitable hydride reagent such as sodium hydride, followed by bromo vinegar. 5MeOOCCHtOCH2 by reacting with an alkylating agent such as methyl acid CR'=CR'-imidazole is obtained. The corresponding acids were subjected to base hydrolysis as described above. are prepared from these esters by solution.

Formula (I) where R6 is Z-COOR8 and Z is 1C (0) NHCHR@- The compound is produced from a propenoic acid compound of formula (1). These acids are N- Amino acids such as hydroxysuccinimide and dicyclohexylcarbodiimide In the presence of a de-forming reagent, a base such as triethylamine, tetrahydrofuran in a suitable solvent such as Ran, at a temperature of about 0°C to about 50°C, preferably 35°C; Glycine methyl ester hydrochloride or phenylalanine methyl ester hydrochloride React with an appropriately substituted amino acid such as 5 Cl-4 alkylOOCCH R. *NH C (0) C H 2 C R 5 = C R'-imidazo The alcohol is converted to its corresponding acid by base hydrolysis as shown above.

Compounds of formula (I) in which R6 is Z-tetrazol-5-yl can be substituted with the corresponding 2-C Manufactured from OOH compounds. For example, an acid compound of formula (I) may be dissolved in a suitable solvent, e.g. For example, the corresponding acid halogen is produced by reacting with a halogenating agent such as thionyl chloride in benzene. to obtain the ide compound. The acid halide is then reacted with concentrated ammonia to form a primary Convert to amide compound. The amide was then purified using acetonitrile/dimethylform. Dehydrated with oxalyl chloride/dimethylformamide in amide, the tetra of formula (I) A nitrile compound is obtained which is the immediate precursor of a sol compound. Tetrazole formation convert the nitrile into an azide, preferably in a suitable solvent such as tetrahydrofuran. In the middle, aluminum produced in-house by the reaction between sodium azide and aluminum chloride. This is achieved by reacting with mini-and.

Compounds of formula (I) in which the R1 substituent is substituted by hydroxy are boron tribromide. Using an ether cleaving reagent such as hydrogen or hydrobromic acid, the R1 group is Produced from compounds of formula (1) substituted by coquine.

Compounds of formula (T) in which the R'ffi substituent is substituted by carboxy are methano base solution such as aqueous sodium or potassium hydroxide in alcohol or ethanol. Using water lysis or using acid hydrolysis such as aqueous hydrochloric acid, the R1 group can be converted to C0 Prepared from compounds of formula (I) substituted by 2C,-C-alkyl.

Is R1 substituent C0NR? Compounds of formula (I) substituted by R' include R1 groups is produced from a compound of formula (■) in which is substituted with carboxy. The carbo Reacting the xyl compound with a halogenating agent such as thionyl chloride, followed by appropriate substitution. amine, NR'R (where R7 is the same as described for the compound of formula (I)) and the opposite make them respond.

Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by suitable methods known in the art. formed from suitable organic or inorganic acids. For example, by removing the solvent... IIl in a water-miscible solvent such as ethanol, or in which the acid is soluble. In some cases, the desired salt can be isolated directly or by removing the solvent. base in a water-immiscible solvent such as ethyl ether or chloroform. React with inorganic or organic acids. Representative examples of suitable acids are maleic acid, fumaric acid, Ansin 1, folic acid, ascorbic acid, vermic acid, succinic acid, bismethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid Lucic acid, citric acid, glucoacid, aspartic acid, stearic acid, valmitic acid , itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzene Sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nochlorohexylsulfamic acid, phosphoric acid and and nitric acid.

Pharmaceutically acceptable base addition salts of compounds of formula (I) where R8 is H are non-toxic alkali metals and alkaline earth metal bases, e.g. calcium hydroxide, lithium , detotrium and potassium, ammonium hydroxide, and triethylamine , butylamino, piperazine, meglumine, choline, jetanolamine and More common than organic and inorganic bases, including non-toxic organic bases such as tromethamene. Manufactured by known methods.

The antenone antagonist activity of compounds of formula (I) was determined in vitro. Evaluated by o and il vivo methods. You in vitro agonistic activity, the compound's binding to angiotensin receptors in blood vessels. +11)-angiotensin ■ and isolated rabbit size. It is measured by its ability to antagonize the contractile response to angiotensin H in the arteries. Ru. In vivo activity of exogenous angiotensin in conscious rats against hypotension in a rat model of nonine-dependent hypertension. The efficacy of the compound to suppress pressor response is evaluated.

money Radioligand binding assays were performed using methods previously detailed (Gunther). et al., Circulation Research (Circ, T-ness [), iヱ:278.1 980). Selected fractions from rat mesenteric arteries were collected at 80p Angiotensin in Tris buffer containing 1251-angiotensin of M ■ Incubate for 1 hour at 25°C with or without antagonist. that in The incubation is completed by rapid filtration, and the receptor bonds trapped on the filter are removed. The amount of 1251-angiotensin (2) in the mixture is determined using a gamma counter. Angio Angiotensin that specifically binds the efficacy of tensin antagonist IC, which is the concentration of antagonist required to displace 50% of vinegar. - By way of example, the IC5o of a compound of the invention (E isomer) is about 1.0 nM to about It is 10 μM.

personal grudge The ability of compounds of the invention to antagonize angiotensin-induced vasoconstriction was demonstrated in rabbits. Test in the aorta. Cut the annular segment from the rabbit thoracic aorta and place it in saline. Suspend the tissue in a container filled with water. Fix the annular segment to a metal support and record it. Attach to the stress conversion transducer connected to the transducer. angiotensin H Cumulative concentration-response curves for the absence of antagonist or antagonist This is carried out after incubation for 30 minutes. Antagonist dissociation determination The number (K,) is calculated by the dose proportional method using the effective mean concentration. -As an example , the compound of the present invention (E isomer) is about 0.1. nM to about 20 μM.

T! Suppression of pressor responses to angiotensin H in conscious rats prepared using an internal femoral artery and venous catheter and a gastric tube (Ge. Kidney International (Kidney Int.) 1 5:419.1979). Two to three days after surgery, rats were placed in a restrina. blood pressure continuously via an arterial catheter with a pressure transducer. Monitor and record on polygraph. Angiotensin] I250mg/kg Changes in mean arterial pressure in response to intravenous injection of Comparisons are made at various time points after intravenous or oral administration at doses of mg/kg. Ann The compound dose required to inhibit the control response to diotensin by 50% (IC so) to evaluate the efficacy of the compound.

antihypertensive activity The antihypertensive activity of the compound was demonstrated by ligating the left renal artery and renin-dependent hypertension. Measured by the ability to lower mean arterial pressure in conscious rats (Cangiano ((Angiano) et al., National Institute of Pharmacology and Exc. (J, Pharmacol, Exp, T her,) 208: 310. 1979). Rats with renal artery ligation as described above Prepare similarly with an indwelling catheter. Seven to eight days after renal artery ligation, Reni levels in plasma At the point when the concentration of the drug reached a maximum, the conscious rat was placed in a rest liner and the average movement Pulse pressure is recorded continuously before administration and after intravenous or oral administration. 3QmmHg To evaluate efficacy, determine the dose of compound required to lower mean arterial pressure (IC3°) to used for

The intraocular pressure lowering effect used in the present invention was described by Watkins et al. It can be measured by the procedure described (GA Oxy Pharma). Co II = (J, 0cular Pharmacol,), 1 (2): 161 168 (1985)).

Compounds of formula (I) may be formulated into convenient dosage forms such as injectable preparations, or administered orally. In the case of active compounds, they are formulated into capsules or tablets. solid or liquid pharmaceutical carriers use Solid carriers include starch, lactose, calcium sulfate dihydrate, clay, Nycloth, talc, gelatin, agar, beuchi>, acacia, stearic acid Magneto/rum and stearic acid. Liquid carrier is syrup, peanut Including oil, olive oil, saline and water. Similarly, the carrier or diluent is Sustained release substances such as lyceryl monostearate or glyceryl distearate may be included alone or together with wax. The amount of solid carrier incorporated can vary widely. but preferably from about 25 mg to about 1 g per dosage unit. using a liquid carrier If so, the preparation is a syrup, elixir, emulsion, soft gelatin or in the form of sterile injectable solutions or aqueous or non-aqueous liquid suspensions, such as capsules, ampoules; It is a state.

For topical ophthalmic administration, suitable pharmaceutical compositions include solutions, suspensions, ointments and solid forms. Includes inserts. Typical pharmaceutically acceptable carriers include, for example, water, water and lower Water-miscible solvents such as lukanol or mixtures of vegetable oils and water-soluble ophthalmological Non-toxic polymers that are acceptable to It is a conductor. Pharmaceutical preparations may also contain emulsifying agents, preservatives, wetting agents and e.g. Thickeners like tyrene glycol, antibacterial ingredients like quaternary ammonium compounds , buffering components such as alkali metal chlorides, and sodium metabisulfite. like antioxidants, and other conventional ingredients like sorbitan monolaurate. It may also contain non-toxic auxiliary substances.

In addition, suitable ophthalmic vehicles may be used for the purpose, including conventional phosphate buffer vehicle systems. It may also be used as a carrier medium for this purpose.

The pharmaceutical preparation may also be in the form of a solid insert. For example, as a pharmaceutical carrier Solid water-soluble polymers may also be used. From ethylene vinyl acetate copolymer Solid water-insoluble inserts as manufactured can also be used.

The pharmaceutical preparation may be mixed, granulated, compressed if necessary if in tablet form, or mixed with the ingredients. according to conventional means of pharmaceutical chemistry, including mixing, filling and, where appropriate, dissolving the manufactured to obtain the desired oral, parenteral or topical product.

The doses of the compound of formula (I) in the above pharmaceutical dosage units are efficacious and contain 0° of active compound. 01 to 200 mg/kg, preferably (selected from the range of 1 to 100 mg/kg) This is a non-toxic amount. Requires angiotene receptor antagonism in selected doses administered orally, rectally, topically, by injection, or instillation to human patients 1 to 6 times daily. Administer continuously by drops. Oral dosage units for human administration preferably contain 1 to 5 Contains 00 mg of active compound. For parenteral administration, lower doses are preferably used. Use dosage. However, higher doses may be used if safe and convenient for the patient. Oral administration methods can also be used. Topical formulations are 0.0001 to 0.1 ( w/v%), preferably in an amount selected from 0.0001 to 0.01. Contains. As a topical dosage unit form, 50 ng to 0.05 mg, preferably 50 An amount of active compound from ng to 5 μg is applied to the eye.

Methods of the present invention for antagonizing angiothene receptors in mammals including humans administering an effective amount of a compound of formula (I) to a subject in need of such antagonizing effect. It consists of things. The method for producing antihypertensive activity of the present invention and congestive heart failure, Midoriuchi A method for treating renal failure and kidney failure involves administering a compound of formula (I) to a subject in need of such treatment. It consists of administering an effective amount of to obtain its activity.

Equivalents of a compound of formula (I) are those which have the pharmaceutical utility of a compound of formula (I). one substituent is added to any unsubstituted site of the compound of formula (I), provided that and is otherwise considered to be a compound corresponding to formula (I).

The following examples are used to illustrate the preparation of compounds and pharmaceutical compositions of the invention.

The examples do not limit the scope of the invention as claimed above and below. (i) 2-n-butyl-1-bivalyloxymethylimidazole-5-carboxy aldehyde Valeramidine methyl ether hydrochloride (250 g) dissolved in liquid ammonia.

166 mol) and dihydroxyacetone (150 g, 0.83 mol) was left in a pressure vessel at room temperature overnight, then heated at 375 ps i for 4 hours at 65°C. It was heated at Ammonia was evaporated and the residue was dissolved in methanol (3L).

The resulting slurry was refluxed with acetonitrile (IL). solid while warming the solution Decanted from ammonium chloride. Repeat this operation to remove the combined acetonitrile. The extract was treated with charcoal, filtered hot, and the filtrate was concentrated under vacuum to a dark oil, 2 -n-butyl-5-hydroxymethylimidazole (235g, 1.63mol, 98) was obtained.

1 liter of the 5-hydroxymethylimidazole (16.92 g, 0.111 mol) Dissolved in methylene chloride. 45 g of manganese dioxide was added to this solution.

After stirring for 4 hours at room temperature, the solids were filtered and the solvent was removed in vacuo. 2-n-buty Further purification of limidazole-5-carboxaldehyde crude product (16.9 g) to do (used)

In 200 ml of dimethylformamide, 2-n-butylimidazole-5-alde hydride (16.9 g, 0.111 mol), chloromethyl pivalate (21.77 g .

0.145 mol) and potassium carbonate (20.07 g50.145) vftI The solution was stirred at ambient temperature under argon for 4 days. Filter out the solids by filtration and remove the Washed with water. The combined filtrates were partitioned between diethyl ether and water. workman The ether phase was washed successively with water and brine, dried over magnesium sulfate/rum, and dried under vacuum. 1 condense below to give 2-n-butyl-1-bivalyloxymethylimidazole-5-carboxylic acid. 236 g of ruboquinaldehyde was obtained.

(u) 5-bromomethyl-2-carbomethquine thiophene methanol 500ml Among them, 5-methyl-2-thiophenecarphonic acid (25 g).

A solution of 0176 mol) was saturated with hydrochloric acid gas at 0°C. reaction mixture It was allowed to stir at room temperature for 18 hours, then refluxed for 48 hours. The solvent was removed in vacuo and the 5- The crude methyl methyl-2-thiophenecarboxylate was used without further purification. Puko.

The methyl ester prepared above (11,07 g, 0,071 mol) was added to the Dissolved in 200ml of carbon chloride. Then, N-bromosuccinimide (13゜2 5 g, 0.074 mol) and dibenzoyl peroxide were added. Reaction mixture at 2 hours The mixture was refluxed for 18 hours and left at room temperature for 18 hours. Collect the solids and concentrate the filtrate under vacuum. , 19 g of 5-bromomethyl-2-carbomethquine thiophene was obtained.

(iii) 2-n-butyl-1-[(5-carbomethquine-2-chenyl)methylene Lucoimidazole-5-carboxaldehyde 2-n-butyl-1-bivaliluo xymethylimidazole-5-carboxaldehyde (5.0g50.019mol) ) and 5-bromomethyl-2-carbomethoquinothiophene (4,86 g, 0 ．． 021 mol) was heated to 100° C. for 18 hours under argon. Aete 9.4 g of crystalline salt was obtained by repeating the trituration using the same method. Ethyl acetate 150ml A suspension of this salt was mixed with 150 ml of 5% aqueous sodium carbonate solution for 0.5 hours. Stirred. Separate the layers, wash the aqueous layer with ethyl acetate, and wash the combined organic layers with water. , dried over magnesium sulfate/rum and concentrated to give an oil. This oil was mixed with ethyl acetate/hexyl acetate. Chromatography on silica gel eluting with San (1.1) and 2 -n-butyl-1-[(5-carbomethoxy-2-chenyl)methylcoimidazo 62 g of alcohol-5-carboxaldehyde region was obtained.

(■) Ethyl 2-carboquino-3-(2-thenyl)propionate ethanol In 200ml, diethyl 2-chenylmalonate (16.8g, 0.0655mol) A solution of potassium hydroxide (4.41 g, 0.0786 mol) Stir for 12 days at room temperature under vacuum, then remove the solvent under vacuum and dissolve the residue in water. The aqueous layer was washed with aqueous hydrochloric acid and the product was extracted with diethyl ether. The title compound was prepared. The solvent was removed in vacuo and 2-carboquine-3-(2-che 14 g of ethyl)propionate was obtained.

(v) (E)-3-[2-n-butyl-1-[(5-carbomethquine-2-che methyl)-IH-imidazol-5-ylco-2-(2-chenyl)methy Ethyl-2-propenoate In 50 ml of benzene, 2-n-butyl-1-[(5-carbomethine-2-che methylcoimidazole-5-carboxaldehyde (0.5 g, 1.66 mmol), ethyl 2-carboxy-3-(2-chenyl)propionate (1° 14 g, 4.99 mmol), piperidine (0.155 g, 183 mmol), A mixture of 3.5 ml of pyridine was added to a Dean-8tark ) Refluxed for 18 hours under argon in the presence of plastic wrap. Crude product in acetic acid Fratunoyuchromatog on silica gel eluting with ethyl/hexane (1:1) (E)-3-[2-n-butyl-1-1(5-carbomethoxy) cy-2-chenyl)methyl)-1H-imidazol-5-yl]-2-(2- 0.474 g (49%) of ethyl (chenyl)methyl-2-propenoate was obtained.

(vi) (E) -3-[2-n-butyl-1-1(5-carboxy-2-thi phenyl)methyl)-]]H-imidazol-5-yl]-2-(2-chenyl) Methyl-2-propenoic acid (E)-3-[2-n-butyl-11(5-cal) in ethanol (10 ml) Boquin-2-chenyl)methyl)-IH-imidazol-5-yl]-2- Ethyl (2-chenyl)methyl-2-propenoate (474 mg, 1.0 mmol) ) was treated with 10% potassium hydroxide solution (5 ml) and the solution was heated to 25°C. The mixture was stirred for 18 hours. The ethanol was removed in vacuo and the reaction mixture was diluted with water and diethyl ether. distributed among the tellers. The aqueous layer was washed with diethyl ether (3x), then the pH was adjusted to Adjust to 45 with an aqueous hydrochloric acid solution. The solid was collected to give 0.35 g of crude product. Mail (E)-3-[2-n-butyl-1-1(5-cal) poxy-2-chenyl)methyl)-IH-imidazol-5-yl]-2-( Obtained 0.31 g (72%) of 2-chenyl)methyl-2-propenoic acid; melting point 23 9-240°C (cl).

(i) 2-n-butyl-4-chloro-5-hydroxymethylimidazole tetra 2-n-butylene in 250 ml of hydrofuran and 250 ml of 2-methquinethane -5-hydroxymethylimidazole (25 g, 0.162 mol, Example 1 ( N-chlorosuccinimide (26 g, 0 ．． ], 995 mol were added little by little. The reaction mixture was heated at 50-55°C for 2 hours. It was hot. The solvent was removed in vacuo and the residue was left for 48 hours. Filter the solids and Stirred for 1 hour with 100 ml of ethyl ether. The solid was collected and 2-n- Obtained 16 g (52%) of butyl-4-chloro-5-hydroxymethylimidazole. Ta.

(ii) 2-n-butyl-1-[(5-carbomethoxy-2-pyridyl)methyl ]-4-chloroimidazole-5-carboquinaldehyde methylformamide In 24ml, 2-0-butyl-4-chloroimidazole-5-carboquinalde hydride (17.9 g, 9.6 mmol, oxidized with manganese dioxide to give 2-n-butylene In a solution of Potassium carbonate (1.59 g, 11.5 mmol) was added under argon. at room temperature After stirring for 10 minutes, 2-bromomethyl-5-carbomethoxypyrinone (2,3 2 g, 10 mmol from 6-methylnicotinic acid using the procedure of Example 1(u). (Manufacturing) was added. The reaction mixture was heated at 70°C for 1.5 hours, then at room temperature for 18 hours. Stirred. The reaction was partitioned between water and ethyl acetate. Separate the layers and extract the organic extract. Washed with water and brine and dried over magnesium sulfate. Remove the solvent in vacuo and Flash screen the prepared product on silica gel eluting with 30% ethyl acetate/hexane. 2-n-butyl-1-[(5-carbomethoxy-2- pyridyl)methyl]-4-chloroimidazole-5-carboxaldehyde2. 14g (67%) was obtained.

(5)2-n-butyl-1-[(5-carbomethoxy-2-pyridyl)methyl] Imidazole-5-carbogicaldehyde in 150 ml of methanol, 2-n-butyl Thyl-1-[(5-carbomethoxy-2-pyridyl)methyl]-4-chloroimi Dazole-5-carboxaldehyde (1.6g, 4.furomillimole), acetic acid solution palladium (0,47 g, 4.0 mmol) and 10% palladium/carbon (0. 16 g) of the mixture was hydrogenated at 28 psi for 2 hours. Filter the solids and discard the filtrate. Concentrated under vacuum. Dissolve the residue in ethyl acetate and add 5% aqueous sodium carbonate solution and and washed with brine. The organic extract was dried over magnesium sulfate and concentrated under vacuum. Ta. The crude product (1.2 g) in 200 ml of methylene chloride was dissolved in 30 ml of manganese dioxide. The mixture was stirred with g for 4 hours at room temperature. Filter the solids, concentrate the filtrate, and Chil-1-[(5-carbomethquine-2-pyridyl)methylcoimidazole-5 -1.2 g of carboxaldehyde was obtained.

(iv) 3-[2-n-butyl-1-((5-carbomethquine-2-pyridyl ) methyl)-IH-imidazol-5-yl]-3-hydroxy-2-(2-thi methyl)methylpropanoate diluted in dry tetrahydrofuran (20 ml) kept at -78 °C under argon. In a solution of isopropylamine (0.53 g, 4.98 mmol) was added n-butylthi (1.91 ml 1.478 mol, 2.5M solution in toluene) was added. Applicable After stirring the reaction mixture for 30 minutes, 3-(2- Methyl (chenyl)propanoate (0,746 g, 4.38 mol) was added. the mixture The mixture was stirred at -78°C for 30 minutes. 2-n- in tetrahydrofuran (5 ml) Butyl-1-[(5-carbomethyne-2-pyridyl)methyl]-1H-imida Solution of zo-/l/-5-carboxaldehyde (1.2 g, 3.98 mmol) was added and the resulting mixture was stirred at -78°C for 20 minutes. Reactant ammonium chloride Partition the organic extract between a saturated solution of sodium chloride and diethyl ether and wash the organic extract with brine. , dried over anhydrous magnesium sulfate, 3-[2-n-butyl-1i (5-carboxylic acid) Metquin-2-pyridyl)methyl)-IH-imidazol-5-yl]-3-hy Concentrated to 1.8g of methyl droxy-2-(2-chenyl)methylpropanoate .

(v) 3-acetoquine-3-[2-n-butyl-1-((5-carbomethoxy- 2-pyridyl)methyl)-IH-imidazol-5-yl]-2-(2-thi methyl)methylpropanoate In methylene chloride (10 ml), 3-[2-rl-butyl-1-1 (5-carbo methoxy7・-2-pyridyl)methyl)-IH-imidazol-5-yl]-3- Methyl hydroxy-2-(2-chenyl)methylpropanoate (1.8 g, 3.9 A solution of 4-trimethylaminopyridine (0,194 g, 1.59 mmol) mmol). Then acetic anhydride (0.49 g, 4.78 mmol) was added. was added dropwise to the stirred mixture. The mixture was stirred for 18 hours and water (25 ml) was added. , the mixture was stirred for 1 hour, then added with diethyl ether and sodium bicarbonate. Diluted with saturated solution. The ether layer was washed with brine and dried over anhydrous magnesium sulfate. The water was evaporated to give 3-acetoquine-3-[2-n-butyl-1-+(5-carbomethyl). Toxy-2-pyridyl)methyl)-IH-imidazol-5-yl]-2-( 1.99 g of methyl 2-chenyl)methylpropanoate was obtained.

(vi) (E) 3[2-n-butyl-1-1(5-carbomethoxy-2- pyridyl)methyl 1-IH-imidazol-5-yl]-(2-chenyl)methy Methyl-2-propenoate 3-acetoxy-3-[2-n-butyl-1- in dry toluene (150 ml) ((5-carbomethine-2-chenyl)methyl-IH-imidazole-5 -yl]-2-(2-chenyl)methylpropanoate (1,99 g, 3. 88 mmol) of 1,8-diazabicyclo-[5,4,0]undeca -7-ene (DBU) and the resulting solution was stirred at 80°C under argon. It was heated for 1 hour. Evaporate the solvent and triturate the residue with diethyl ether. and activated carbon was added. After filtration, the filtrate was concentrated to obtain 6.29 g of oil, which Chromatography on silica gel using xane/ethyl acetate (11) (E)-:3-[2-n-butyl-1-+(5-carbomethoxy-2 -chenyl)methyl)-IH-imidazol-5-yl]-2-(2-chenyl) 0.43 g (24%) of methyl methyl-2-propenoate was obtained.

(vi) (E) -3-[2-n-butyl-1-+(5-carboxy-2-pi lysyl)methyl)-IH-imidazol-5-ylco-2-(2-chenyl)methyl Chil-2-propenoic acid The above ester prepared according to Example 1 (acceptable) (0.43 g, 0.95 mmol) base hydrolysis of (E)-3-[2-n-butyl-1-[(5-carboxyl)]. -2-pyridyl)methyl]-1H-imidazol-5-yl]-2-(2- 278 g (70%) of chenyl)methyl-2-propenoic acid domain was obtained; melting point 212 ~213℃.

2-n-butyl-1-[(5-carbomethoxy-2-chenyl)methylcoimida Instead of sol-5-carboxaldehyde, (described in Example 2 (i-fit) 2-n-butyl-1-[(5-carbomethoxy-3- Example 1 using chenyl)methylcoimidazole-5-carboxaldehyde The title compound was produced according to the procedure described in (v=vi).

Example 4 (E)-3-[2-n-butyl-11(5-carboxy-2-furyl)methyl 1-IH-imidazol-5-yl]-2-(2-chenyl)methyl-2-p Lope” 2-n-butyl-1-[(5-carbomethquine-2-chenyl)methylloimida Instead of sol-5-carboxaldehyde, (as described in Example 2 (i-5) 2-n-butyl-1-[(5-carbomethquine-2-fur) prepared by Example 1 (V~ The title compound was prepared according to the procedure described in vI).

Example 5 Oral dosage forms for administering orally active compounds of formula (1) include ingredients such as For example, screen and mix in the proportions shown below to form hard gelatin capsules. It is manufactured by filling the

Ingredients/Amount (E) -3-[2-n-butyl-1-+(5-carboquino 100mg-2- chenyl)methyl 1-IH-imidazol-5-yl]-2-(2-chenyl ) Methyl-2-propenoic acid magnesium stearate 10mg Lactose 100mg Example 6 Sucrose, calcium sulfate dihydrate and orally active compounds of formula (I) Mix and granulate with 10% gelatin solution. Screen the wet granules dried, mixed with starch, talc and stearic acid and screened. Press to tablet.

Ingredients/Amount (E) -3-[2-n-butyl-1-((5-carboxy) 75mg-3-thi (phenyl)methyl)-IH-imidazol-5-yl]-2-(2-chenyl) Methyl-2-propenoic acid calcium sulfate dihydrate 1.00mg 　15mg Starch 8mg Stearic acid 2mg Example 7 (E) -3-[2-n-butyl-1-[(5-carboxine-2-thienyl)methyl methyl)-IH-imidazol-5-ylco-2-(2-thenyl)methyl-2- An injection preparation is prepared by dispersing 50 mg of propenoic acid in 25 ml of physiological saline.

Example 8 Topical ophthalmic solutions for administering compounds of formula (I) may be prepared by dissolving the ingredients under sterile conditions, e.g. For example, it is manufactured by mixing in the proportions shown below.

Ingredients: Hei L Sou (mg/m1) (E) -3-[2-n-butyl-1-+ (5-cal 10poquin-2-furo) methyl)-IH-imidazol-5-yl]-2-(2-chenyl)methyl- 2-propenoic acid Dibasic sodium phosphate 10,4 -Basic sodium phosphate 24 Chlorobutanol 5.0 Hydroxybrobanol notylcellulose 5.0 Sterile water Appropriate amount up to 1.0ml 1. ON sodium hydroxide in an appropriate amount up to pH 7.4 The present invention is not limited to the above specific examples. and all modifications within the scope of the specific examples and claims below. It should be recognized that the right to do so is reserved.

Continuation of front page (51) rnt, ct, 5 Identification symbol Internal reference number C07D409/1 4 213 7602-4C (72) Inventor Hill, Dipid Tillame Magnolia Bush, North Wales, Pennsylvania 19454 Wraith No. 109 I (72) Inventor Weinstock, Joseph Pennsylvania, United States 1234 Hothouse Road, Phoenixville, 19406

Claims (15)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1 is Het, where Het is either saturated or unsaturated, A carbon atom and 1 to 3 heteroatoms selected from the group consisting of N, O, and S. A stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic compound consisting of The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen and sulfur atoms may be optionally oxidized. The ro atom may be quaternized if desired, and the above heterocycle is fused to a benzene ring. It includes any combined bicyclic group, where the Het is unsubstituted or C1-C6 Alkyl, C1-C6 alkoxy, Cl, Br, F, I, NR7R7, A-CO 2R7, CONR7R7, SO3H, SO2NHR7, OH, NO2, W, SO 2C1-C6 alkyl, SO2W, SC1-C6 alkyl, NR7COW or The use of up to three substituents selected from the group consisting of NR7COC1-C6 alkyl W is substituted by any stable combination available, where W is C nF2n+1 (n is 1 to 3), A is -CH=CH-, -(CH2)0-4 -, -Q-CH(R9)- or -Q-(CH2)1-2-U-(CH2)1- 2- (where Q is O, S, NH or NC1-6 alkyl and U is present or present as O, S, NH or NC1-6 alkyl, R9 is hydrogen , phenyl or benzyl); m is 0-4: R2 is C2-C10 alkyl, C3-C10 alkenyl, C3-C10 alkenyl C3-C6 cycloalkyl, or unsubstituted or C1-C6 alkyl, Toro, Cl, Br, F, I, hydroxy, C1-C6 alkoxy, NR7R7, CO2R7, CN, CONR7R7, W, tetrazol-5-yl, NR7CO C1-C6 alkyl, NR7COW, SC1-C6 alkyl, SO2W or S substituted with 1 to 3 substituents selected from O2C1-C6 alkyl is (CH2)0-6 phenyl; X is a single bond, S, NR7 or O; R3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR7, C ONR7R7, NO2, W, CN, NR7R7 or phenyl; R4 and R5 are independently hydrogen, C1-C6 alkyl, phenyl-Y-, biphenyl-Y-, naphthyl-Y-, 2- or 3-thienyl-Y-, 2- or 3-furyl-Y- , 2-, 3- or 4-pyridyl-Y-, virazolyl-Y-, imidazolyl-Y -, pyrrolyl-Y-, triazolyl-Y-, oxazolyl-Y-, isoxazo lyl-Y-, thiazolyl-Y- or tetrazolyl-Y-, and each aryl or or heteroaryl group is unsubstituted or C1-C6 alkyl, C1-C 6 alkoxy, Cl, Br, F, I, NR7R7, CO2R7, SO2NHR7 , SO3H, CONR7R7, OH, NO2, W, SO2W, SC1-C6 Al Kyl, SO2C1-C6 alkyl, NR7COH, NR7COW or NR7C substituted with OC1-C6 alkyl; Y is a single bond, O, S, linear or branched, and optionally phenyl or or C1-C6 alkyl which may be substituted with benzyl, phenyl or The benzyl group is each unsubstituted or halo, NO2, CF3, C1- substituted by C6 alkyl, C1-C6 alkoxy, CN or CO2R7 R6 is -Z-COOR6, -Z-CONR7R7 or -Z-tetrazo Lu-5-yl; Z is a single bond, vinyl, -CH2-O-CH2-, optionally C1-C6 alkyl , substituted by one or two benzyl groups, thienylmethyl or furylmethyl methylene or -C(O)NHCHR9, where R9 is H , C1-C6 alkyl, phenyl, benzyl, thienylmethyl or furylmethyl is le; W is CnF2n+1 (where n is 1 to 3); R7 is each independently hydrogen or is C1-C6 alkyl; and R8 is hydrogen, C1-C6 alkyl or 2 -di(C1-C6 alkyl)amino-2-oxoethyl] A compound represented by or a pharmaceutically acceptable salt thereof. 2. R1 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxo Sopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazevinyl, azepinyl , pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, 2-, 3- or 4-pyri Zyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidi Nyl, isorazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thia Zolidinyl, inthiazolyl, quinuclidinyl, isothiazolidinyl, indoli quinolinyl, inquinolinyl, benzimidazolyl, thiadiazolyl, ben zoviranil, benzothiazolyl, benzoxazolyl, 2- or 3-furyl, Pyranyl, tetrahydrofuryl, tetrahydropyranyl, 2- or 3-thienyl benzothienyl, benzoxazolyl, thiamorpholinyl, thiamorpholini Rusulfoxide, thiamorpholinyl sulfone, benzofuranyl and oxadia zolyl and each R1 group is unsubstituted or C1-C6 alkyl, C 1-C6 alkoxy, Cl, Br, F, I, NR7R7, A-CO2R7, SO 2NHR7, SO3H, CONR7R7, OH, NO2, W, SO2W, SC1 -C6 alkyl, SO2C1-C6 alkyl, NR7COH, NR7COW or is up to three substituents selected from the group consisting of NR7COC1-C6 alkyl. W is substituted by any available stable combination, and W is replaced by CnF2 n+1 (n is 1 to 3), and A is -CH=CH-, -(CH2)0-4-, -Q-CH(R9)- or -Q-(CH2)1-2-U-(CH2)1-2- (where Q is O, S, NH or NC1-6 alkyl, and U is absent) or as O, S, NH or NC1-6 alkyl, R9 is hydrogen, 2. The compound according to claim 1, which is phenyl or benzyl. 3. R1 is 2- or 3-thienyl, 2- or 3-furyl, or 2-, 3- or 4-pyridyl, in which each of the thienyl, furyl or pyridyl groups is a non- or substituted with CO2R7, and m is 0 to 2. Compounds listed. 4. X is a single bond or S, R2 is C2-C8 alkyl, and R3 is hydrogen , chloro, fluoro or trifluoromethyl, and R4 is hydrogen or C1 4. A compound according to claim 3, which is -C6 alkyl. 5. R5 is 2- or 3-thienyl-Y-, 2- or 3-furyl-Y-, or is 2-, 3- or 4-pyridyl-Y-, thienyl, furyl or pyridyl Each of the zyl groups is unsubstituted or substituted with methyl or methoxy , Y is a single bond or a linear or branched C1-C6 alkyl, according to claim 4. compound. 6. R6 is -Z-COOR8, Z is a single bond, and R8 is hydrogen or C 6. The compound according to claim 5, which is 1-C6 alkyl. 7. Claim that COOR8 group and imidazole are E isomer in trans position with each other A compound according to item 6. 8. (E)-3-[2-n-butyl-1-{(5-carboxy-2-thienyl) methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2 - The compound according to claim 7, which is propenoic acid or a pharmaceutically acceptable salt thereof. 9. (E)-3-[2-n-butyl-1-{(5-carboxy-3-thienyl) methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2 -propenoic acid; (E)-3-[2-n-butyl-1-{(5-carboxy-2-furyl)methyl }-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-pro Penic acid; or (E)-3-[2-n-butyl-1-{(5-carboxy-2-pyridyl)methy 1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-yl 8. The compound according to claim 7, which is lopenic acid or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a pharmaceutical carrier and a compound according to claim 1. 11. An effective amount of the compound according to claim 1 is used to antagonize the angiotensin II receptor. of the angiotensin II receptor, which is characterized in that it is administered to a subject in need of treatment. Antagonism method. 12. An effective amount of the compound according to claim 1 is administered to a subject in need of antihypertensive treatment. A method for treating hypertension, which comprises administering. 13. An effective amount of the compound according to claim 1 is administered to patients in need of treatment of congestive heart failure. A method for treating congestive heart failure, the method comprising administering it to an elephant. 14. Administering an effective amount of the compound according to claim 1 to a subject in need of treatment for renal failure. A method for treating renal failure characterized by: 15. Administering an effective amount of the compound according to claim 1 to a subject in need of treatment for glaucoma. A method for treating glaucoma characterized by: