JPH05504359A - Imidazole angiotensin 2 antagonists containing substituted benzyl moieties - 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] Imidazole containing a substituted pencil moiety Angiotensin antagonist Background of the invention This invention is part of U.S. Application No. 479.780, filed February 13, 1999. This is a continuation application. The renin-angiotensin system (RAS) is responsible for normal blood pressure. It plays a central role in the regulation of congestive cardiac dysfunction and It appears to be involved in the development and maintenance of hypertension in an important manner. Angiote Ancin (A II) is an amino acid localized in the endothelium of blood vessels in some organs such as the lungs and kidneys. During the TA cleavage of angiotensin converting enzyme (ACE), It is an octapeptide hormone produced primarily in the blood. This is Renin Angi It is the final product of the otensin system (RAS) and is a specific substance present in the cell membrane. It is a powerful arterial vasoconstrictor that exerts its action by interacting with receptors. Ru. One of the modes of controlling RAS is angiotensin receptor antagonism. be.

Some peptide homologs of AII may competitively block its receptors. Therefore, it is known to suppress the influence of this hormone.

However, their experimental and clinical applications are limited due to incomplete agent activity and poor oral absorption. Limited due to difficulty etc.

[M, Antona:cio, Cl1n, EXp, Hype+unS, A4. 27-46 (1982): D, H, P, 5ueten and G, H, Anae++on, IT, -Handbook of Hypertensio n, Cl1nical Pharmacology of n1ih7pe+ len+iveDougs, ed, A, E, Doyle, vol. 5. pp, 246-271. EIsevie+5science Publisher, A msterdam, The Netherlands, 1984] How many times have you been lately? Such non-peptide compounds have been described as An antagonists. of such compounds Examples are U.S. Patent 4.207.304; 4, 340.598: 4.576 958+ 4.582. H7 and European patent 02 Otsu, 834; 24 5.637: 253.310 and 291.969 and ~, T, Chiu et al. The paper [Eor, 1. F'ha+, m, EIL Tbe+ap, 157. 13 -21 (1988)) and P, C, Wong et al.'s paper CJ, Pba+m, Erp, The+ap, 247. l-7 (19N)] etc. There is.

All U.S. patents and European patent applications 028.834 and 253, 310 and The two above-mentioned papers contain phenyl groups with substituents through lower alkyl bridges. Discloses substituted imidazole compounds containing

European patent application 245.637 describes 4.5.6.7-tetrahydro-2H- Imidazo[4,5-cl-pyridine-6-carboxylic acid and its analogues are antihypertensive. It is disclosed as an agent.

Any compound in this application may be disclosed or identical in a U.S. patent, European application or article. Not determined. Some of these include novel substituted phenyls through alkyl bridges. There are also types of compounds that contain substituted heterocycles bonded together. The substituted imidazole is D In the patents for uFont (EPO 253,310 and EPO 324,377) , was published for the purpose of designing angiotensin antagonists.

The compounds of the invention possess central nervous system (CNS) activity.

These are used to treat cognitive dysfunctions such as Alzheimer's disease, amnesia, and senile dementia. Effective for treatment.

These compounds also have anxiolytic and antidepressant properties and may therefore be associated with depression and dysphoria. It is effective in relieving the patient's mental state from symptoms of tension and anxiety.

Additionally, these compounds exhibit anti-dopamine properties and may be associated with dopaminergic disorders such as schizophrenia. It is effective in treating disorders including min dysfunction. The compound of this invention is particularly may be useful in treating these conditions in patients who also suffer from hypertension or congestive heart failure. It is for use.

Details of the invention A detailed explanation is for the compound of formula 1. or relating to pharmaceutically acceptable salts.

(ri(C-C)-alkyl, (C2-06)-alkenyl or (C2-C6 )-alkynyl, each unsubstituted or substituted with a group selected from the following group: It is something that (i) an aryl as defined below; (ii) (C3C7)-siluroalkyl, (iii) CI, Br, 1. F.

(b) Aryl, where aryl is defined as phenyl or naphthyl, unsubstituted or is substituted with one or two groups selected from the following groups: (Ma11rihydroxy) (1 amino, Cc) heteroaryl, where heteroaryl is a group consisting of N, O, S unsubstituted, -substituted, disubstituted 5- or 6-membered, which may contain one or two selected from a cyclic heteroaromatic ring in which the substituents are a group consisting of It is selected from.

(d) perfluoro-(C,-C4)-alkyl, and B is: (a) single bond, X is from O to 2: S is from 0 to 5: m is 1 to 5° p is 0 to 3: n is 1 to 10° or (C,-C)-alkynyl 1, 6 (c) CI, Br, I, F.

(d) NO2, tel　(C,-C8)-perfluoroalkyl, (k)NH[CO(C,-C 4)-alkyl], (a+) N (C+ C4)-alkyl-coaryl, (n) N (CC4)-alkyl-so, aryl, (s) phenyl and phenyl -(C,-C3)-alkyl, whose phenyl ring is selected from the following groups: one or (al) (CH2) n F, (ac) (CH2) m-1,2,3-triazole, unsubstituted or Substituted with one or two groups selected from (ad) tetrazol-5-yl, (a e) CON HS O2-aryl, (a f) CON HS O (CICs)-alkyl, where the alkyl group is unsubstituted or from the following groups: OH, -3H, -〇(C-C4) monoalkyl, - substituted with selected groups 3-(C,-C4)-alkyl.

-CF3. CI, Br, F, I, -No2. -Co, H.

(C0NH5OQ-perfluoro-(C-C4')-alkyl, R9 and R10 independently; Substituted with (C3,, Cy)-cycloalkyl, (g) where R and RIG are When on adjacent carbons, they can combine to form a phenyl ring. (h) perfluoro-(C,-C6)-alkyl, (1j (C3C7)- Cycloalkyl, unsubstituted or substituted with (C,-C6')-alkyl (1) single bond, or fffl)-CH=, where if Y and Rl2 are absent, it has Z and R11 to form -C=C-; and Y is: (aj single bond, However, the carbon atom to which Z is bonded also has two heteroatoms (0, N, S , So, So2), except when X and Y are not defined. R11 and R12 are independently: (a) H.

(bl　(C1-C6)-alkyl, unsubstituted or substituted with: What: (aryl, or (ii) (C3-C-cycloalkyl, (C) aryl, unsubstituted or Substituted with 1 to 5 groups selected from the group consisting of: (i) CA ', Br, I, F.

(ii) (CIC6)-alkyl, or substituted with one to five groups selected from the group consisting of: (M1ii)-CF3, R13 is.

(a) H.

Z = (d) -Co-NH (tetrazol-5-yl), 11) CON HS O ( Ct　Cg　)-alkyl, 22-alkyl group is unsubstituted or from the following group No OH, -3H, -0(C, -C4) alkyl group substituted with the selected one. OH, -SH, -0( substituted or substituted with a group selected from the following groups) C, -C4')--CO, -(C,-C4)-alkyl, -NH.

-NH((C-C)-alkyl), -N[(C,-alkyl, (Q)-PO(OH)(OR・); and R14 is (C) (C, -C3)-perfluoroalkyl, Ri5 is - (a) H.

rb) (C,-C6)-alkyl, (Cl (C3-C6)-cycloalkyl, (e) (1-naphthyl)ethyl, or R18 and R19 independently (RiH.

(e) α-methylbenzyl; and (b) heteroaryl, unsubstituted, or one selected from the group consisting of: or substituted with two groups = (iii) B r, CI, 1. F or (+ vj CH2-aryl.

The alkyl substituents mentioned above are, for example, methyl, ethyl, isopropyl, isobutyl. , neopentyl, isopentyl, etc. indicate straight chain and branched hydrocarbons of length.

Alkenyl and alkynyl substituents are each a carbon atom in an alkyl group as described above. - modified to contain carbon double or triple bonds. Each one is vinyl aryl, aryl and 2-butenyl.

Cycloalkyl is a ring consisting of 3 to 8 methylene groups, each of which may be unsubstituted or substituted. is substituted with a hydrocarbon substituent.

and, for example, cyclopropyl, cyclopentyl, cyclohexyl and 4-methyl Contains lecyclohexyl.

Alkoxy substituents are those in which the alkyl groups mentioned above are bonded via an oxygen bridge. to show that

The aryl substituents mentioned above represent phenyl or naphthyl.

The heteroaryl substituents mentioned above represent a 5- or 6-membered aromatic ring, which contains nitrogen, an acid containing one to three heteroatoms selected from the group containing elemental atoms and sulfur. be. They include, for example, pyridyl, chenyl, furyl, imidazolyl, and chiron. Examples include azolyl.

Preferred imidazoles: 2-Butyl-1-C4-(1-carboxy-1-phenyl)methoxyphenylco Methyl-4-chloro-5-hydroxymethylimidazole; 1-[4-C1-carboxy-1-phenyl)methoxyphenylcomethyl-4- Chloro-5-hydroxymethyl-2-propylimidazole; 2-Butyl-5-carboxy-1-C4-(1-carboxy-1-phenyl)methane Toxyphenylcomethyl-4-chloroimidazole; 2-Butyl-5-carbomethoxy-1-C4-(1-carboxy-1-phenyl ) methoxyphenylcomethyl-4-chloroimidazole; 2-Butyl-5-carboxy-1-[4-(1-carboxy-1-phenyl)methyl Toxyphenylcomethyl-4-pentafluoroimidazole; 2-Butyl-5-carboxy-1-C4-(1-carboxy-1-phenyl)methane Toxyphenylcomethyl-4-trifluoromethylimidazole; 2-Butyl-5-carboxy-1-C4-(1-carboxy-1-phenyl)methane Toxyphenylcomethyl-4-ditroimidazole; 2-Butyl-1-(4-(1-carboxy-1-phenyl)methoxyphenylco) Methyl-5-hydroxymethyl-4-ditroimidazole; 2-Butyl-5-carbomethoxy-1-[4-(]-]carboxy-1-phenylene methoxyphenylcomethyl-4-nitroimidazole; 5-carboxy-1-C4-(1-carboxy-1-(2-chloro)phenyl) Methoxyphenyldimethyl-2-propyl-4-trifluoromethylimidazole Le; 5-carboxy-2-propyl-1-[4-(1-carboxy-1-(2-methyl phenyl)methoxyphenylcomethyl-4-trifluoromethylimidazole Le: 5-carboxy-1-[4-(1-carboxy-1-(2,6-dichloro)phene) phenylcomethyl-2-propyl-4-trifluoromethylimi Dazole; 5-carboxy-1-(4-(1-carboxy-1!2-trifluoro) phenyl)methoxyphenyldimethyl-2-propyl-4-triflu Oromethylimidazole; 5-carboxy-1-C4-(1-carboxy-1- (2-methoxy)phenyl)methoxyphenyldimethyl-2-propyl-4-to Lifluoromethylimidazole.

5-carboxy-2-propyl-1-[4-(1-carboxy-1-(2-chloro b) phenyl) methoxy-3-chlorophenylcomethyl-4-trifluoromethyl Imidazole: 5-carboxy-1-(4-(1-carboxy-1-(2-k) lolo)phenyl)methoxy-3,5-dichlorophenyl]methyl-2-propyl -4-trifluoromethylimidazole; 5-carboxy-1-[4-(1-carboxy) ruboxy-1-(2-chloro)phenyl)methoxyphenylcomethyl-4-chloro rho-2-propylimidazole; 5-carboxy-1-[4-(1-carboxy-1-(2-methyl)phenyl) Methoxyphenylcomethyl-4-chloro-2-propylimidazole; 5-carboxy-1-C4-(1-carboxy-1-(2,6-dichloro)phene) methoxyphenylcomethyl-4-chloro-2-propylimidazole: 5-carboxy-1-(4-(1-carboxy-1-(2-trifluoromethyl) ) phenyl) methquin phenyl] methyl-4=chloro-2-propylimidazo Le: 5-carboxy-1-1:4-(1-carboxy-1-(2-methoxy)phenylene) ) Methoxyphenylcomenal-4-chloro-2-propylimidazole: 5-carboxy-1-[4-(1-carboxy-1-(2-chloro)phenyl) Methoxy-3-chlorophenylcomethyl-4-chloro-2-propylimidazole Le.

5-carboxy 1-[4-fX-carboxy-1-(2-chloro)phenyl ) Methoxy-3,5-dichlorophenylamethyl-4-chloro-2-propylene Midazole; 2-butyl-4-chloro-5-hydroxymethyl-1-[4-(1 -(tetrazol-5-yl)-1-phenyl)methoxyphenylcomethylimide Dazole: 4-chloro-5-hydroxymethyl-2-propyl-1-[4-(!-(tetra Zol-5-yl)-1-phenyl)methoxyphenylcomethylimidazole: 2-Butyl-4-chloro-5-carboxy-i-C4-(1-(tetrazole- 5-yl)-1-phenyl)methoxyphenylcomethylimidazole; 2-Butyl-4-chloro-5-carbomethoxy-1-[,4-(1-(tetrazo) (5-yl)-1-phenyl)methoxyphenylcomethylimidazole.

2-Butyl-5-carboxy-4-pentafluoroethyl-1-[4-(1-( Tetrazol-5-yl)-1-phenyl)methoxyphenylcomethylimidazo 2-butyl-5-carboxy-1-C4-(1-(tetrazol-5-y) )-1-phenyl)methoxyphenylcomethyl-4-trifluoroimidazole Le; 2-Butyl-5-carboxy-4-nitro-1-C4-(1-(tetrazole- 5-yl)-1-phenyl)methoxyphenylcomethylimidazole; 2-Butyl-5-hydroxymethyl-4-nitro-1-[4i1-(tetrazo (5-yl)-1-phenyl)methoxyphenylcomethylimidazole: 2-Butyl-5-hydroxymethyl-4-nitro-1-[4-(1-(tetrazo (5-yl)-1-phenyl)methoxyphenylcomethylimidazole; 5-carboxy-4-pentafluoroethyl-2-propyl-1-(4-(1- (tetrazol-5-yl)-1-(2-chloro)phenyl)methoxyphenyl ] Methylimidazole.

5-Carboxy-4-pentafluoroethyl-2-propyl-l-C4-(1- (tetrazol-5-yl)-1-(2-methyl)phenyl)methoxyphenyl Lamethylimidazole: 5-carboxy-2-propyl-1-[4-(1-(te) Torazol-5-yl)-1-(2,6-dichloro)phenyl)methoxyphenyl Lucomethyl-4-pentafluoroethyl imidazole.

5-carboxy-4-pentafluoroethyl-2-propyl-1-(4-fl- (tetrazol-5-yl)-1-(2-trifluoromethyl)phenyl)meth Xyphenylamethylimidazole.

5-Sulfoxy4-pentafluoroethyl-2-propyl-I-C4-(1- (tetrazol-5-yl)-1-(2-methoxy)phenyl)methoxyphenyl luramethylimidazole, 5-carboxy-4-pentafluoroethyl-2-propylene Lopyl-1-[4-(1-(tetrazol-5-yl)-1-12-chloro)ph phenyl)methoxy-3-chlorophenylcomethylimidazole.

5-Carboxy-4-pentafluoroethyl-2-propyl-l-C4-(1- (tetrazol-5-yl)-1-(2-chloro)phenyl)methoxy-3,5 -dichlorophenylcomethylimidazole; 5-carboxy-4-chloro-2-propyl-1-C4-(1-(tetrazole -5-yl)-1-(2-chloro)phenyl)methoxyphenyl lamethylimida Zor.

5-carboxy-4-chloro-2-propyl-1-C4-(1-(tetrazole -5-yl)-1-(2-methyl)phenyl)methoxyphenyl lamethylimida Sol: 5-carboxy-4-chloro-2-propyl-1-(4-(1-(teto) lazol-5-yl)-1-(2,6-dichloro)phenyl)methoxyphenyl Lamethylimidazole: 5-carboxy-4-chloro-2-propyl-1-[: 4-(1-(tetrazol-5-yl)-1-(2-trifluoromethyl)phene methoxyphenylramethylimidazole.

5-carboxy-4-chloro-2-propyl-1-C4-(1-(tetrazole -5-yl)-1-(2-methoxy)phenyl)methoxyphenyl lamethylimi Dazole; 5-carboxy-4-chloro-2-propyl-1-(4-(1-(te) torazol-5-yl)-1-(2-chloro)phenyl)methoxy-3-chloro Phenylcomethylimidazole: 5-carboquine-4-chloro-2-propyl- 1-[4-(1-(tetrazol-5-yl)-1-(2-chloro)phenyl) Methoxy-3,5-dichlorophenylcomethylimidazole; 5-carboxine- 4-chloro-1-C4-fl-((N-phenylsulfonyl)carboxamide )-1-r2-chloro)phenyl)methquinphenylcomethyl-2-propylene midazole.

5-carboxy-1-C4-(1-((N-phenylsulfonyl)carboxy mido)-1-(2-chloro)phenyl)methoxyphenylcomethyl-2-propyl -4-trifluoromethylimidazole; 5-carboxy-1-[4-(1-carboxy-1-(2-chloro)phenyl) Methoxyphenylcomethyl-2-propylimidazole: 5-carboxy-1-[4-(1-carboxy-1-(2-methyl)phenyl) Methoxyphenylcomethyl-2-propylimidazole: 5-carboxy-1-C4-(1-carboxy-1-(2-trifluoromethyl ) phenyl)methoxyphenylcomethyl-2-propylimidazole: 5-carboxy-1-[4-(+-carboxy-1-(2-ethyl)phenyl) Methoxyphenylcomethyl-2-propylimidazole: 5-Sulfomethoxy1-C4-(1-carboxy1-(2-chloro)phenylene ) methoxyphenylcomethyl-2-propylimidazole; 5-carbomethoxy-1-N-(1-carboxy-1-(2-methyl)phenyl ) methoxyphenylcomethyl-2-propylimidazole; 5-Carbomethoxy-1-C4-(1-carboxy-1-12-trifluorome thyl)phenyl)methoxyphenylcomethyl-2-propylimidazole: 5-Carbomethoxy-1-C4-(1-carboxy-1-(2-ethyl)phenyl ) methoxyphenyl]methyl-2-propylimidazole: 5-carboxy-1-C4-(1-carbomethoxy-1-(2-chloro)phenylene ) methoxyphenylcomethyl-2-propylimidazole; 5-carboxy-1-C4-(1-carbomethoxy-1-(2-methyl)phenylene ) methoxyphenylcomethyl-2-propylimidazole.

5-carboxy-1-(4-(1-carbomethoxy-1-(2-trifluoromethane) thyl)phenyl)methoxyphenylcomethyl-ethyl)phenyl)methoxyphe Nylcomethyl-2-propyl-1-(2-chloro)phenyl)methoxyphenyl comethyl-2-1-(2-methyl)phenyl)methoxyphenylcomethyl-2- I-(2-trifluoromethyl)phenyl)methoxyphenyl2-1-12-e thyl)phenyl)methoxyphenylcomethyl-2-propylimidazole: 5-carboxy-1-(4-(1-(N-methylsulfonylcarboxamide) -1-(2-chloro)phenyl)methoxyphenylcomethyl-2-propylimi Dazole.

5-carboxy-1-[4-(1-(N-methylsulfonylcarboxamide)) -1-(2-methyl)phenyl)methoxyphenylcomethyl-2-propylimi Dazole; 5-sulfoxy1-(4(1(N-methylsulfonylcarboxy) mido)-1-(2-trifluoromethyl)phenyl)methoxyphenylcomethyl -2-Propylimidazole: 5-carboxy-1-[4-(f-(N-methyl) Sulfonylcarboxyamido)-1-(2-ethyl)phenyl)methoxyphenyl Rucomethyl-2-propylimidazole: 5-carbomethoxy-1-C4-(1 -(N-methylsulfonylcarboxamide)-1-(2-chloro)phenyl) Methoxyphenylcomethyl-2-propylimidazole: 5-carbomethoxy- 1-C4-(1-(N-methylsulfonylcarboxamide)-1-(2-methyl phenyl)methoxyphenylcomethyl-2-propylimidazole: 5-ka Rubomethoxy-1-1: 4-(1-(N-methylsulfonylcarboxyamide) )-1-(2-trifluoromethyl)phenyl)methoxyphenylcomethyl-2 -Propylimidazole; 5-carbomethoxy-1-(4-(1-(N-methyl) Sulfonylcarboxamide)-1-(2-ethyl)phenyl)methquinpheni Lucomethyl-2-propylimidazole.

4-acetamido-2-butyl-5-carboxy 1-(4-(1-carboxy -1-(2-chloro)phenyl)methoxyphenylcomethylimidazole.

4-acetamido-2-butyl-5-carboxy-1-[4-(1-carboxy -I-(2-methyl)phenyl)methoxyphenylcomethylimidazole: 4-acetamido-2-butyl-5-carboxy-1-[4=+-carboxy 1-(2-trifluoromethyl]phenyl)methoxyphenylcomethylimide Dazole; 4-acetamido-2-butyl-5-carboxy-1-[4-(1- Carboxy-1-(2-ethyl)phenyl)methoxyphenylcomethylimidazo Rule: 4-(N-acetyl-N-methyl)amino-2-butyl-5-carboxy-1- [4-(1-carboxy-1-(2-chloro)phenyl)methoxyphenyl rice Tylimidazole; 4-(N-acetyl-N-methyl)amino-2-butyl-5 -carboxy-1-[4-(1-carboxy-1-(2-methyl)phenyl)methyl Toxiphenylcomethylimidazole.

4-(N-acetyl-N-methyl)amino-2-butyl-5-carboxy-1- C4-(1-carboxy-1-(2-trifluoromethyl)phenyl)methoxy Phenylcomethylimidazole; 4-(N-acetyl-N-methyl)amino-2-butyl-5-carboxy-1- C4-(1-carboxy-1-(2-ethyl)phenyl)methoxyphenyl rice Tylimidazole: 4-(N-acetyl-N-methyl)amino-2-butyl-5 -carboxy-1-(4-(1-carbomethoxy-1-(2-chloro)phenyl) ) Methoxyphenylcomethylimidazole; 4-(N~ruacetyl N-methyl) Amino-2-butyl-5-carboxy-1-(4-(1-carbomethoxy-1- (2-Methyl)phenyl)methoxyphenylcomethylimidazole: 4-(N- acetyl-N-methyl)amino-2-butyl-5-carboxy-1-C4-(1 -Carbomethoxy-1-(2-trifluoromethyl)phenyl)methoxyphenyl Lucomethylimidazole: 4-(N-acetyl-N-methyl)amino-2-butyl-5-carboxy-1- C4-(1-carbomethoxy-1-(2-ethyl)phenyl)methoxyphenyl Comethylimidazole; 5-carboxine-4-chloro-1-(4-(1-(N- (2-chloro)phenylsulfonyl)carboxyamido-1-(2-chloro)phenyl phenyl)methoxyphenylcomethyl-2-propylimidazole.

5-carboxy-4-chloro-1-C4-(1-(N-phenylsulfonyl)carboxylic acid) Ruboxiamido-1-(2-chloro)phenyl)methoxyphenylcomethyl-2 -pentafluoroethyl imidazole; 5-carboxy-4-chloro-1-C4-(1-(N-methylsulfonyl)car Boxamido-1-(2-chloro)phenyl)methoxyphenylcomethyl-2- Propylimidazole: 5-carboxy-4-chloro-1-C4-(1-(N- methylsulfonyl)carboxydiamido-1-(2-chloro)phenyl)methoxy Phenylcomethyl-4-chloro-2-pentafluoroethyl imidazole.

5-carboxy-4-chloro-2-propyl-1-C4-(1-(N-h rifle (oromethylsulfonyl)carboxamido-1-(2-chloro)phenyl)meth Xyphenylcomethylimidazole: 5-Carboxy-4-chloro-2-pentafluoroethyl-1-C4-(1-( N-trifluoroethylsulfonyl)carboxamide-1-(2-chloro)ph phenyl)methoxyphenylcomethylimidazole; 5-carboxy-4-chloro-2-propyl-1-C4-(1-(N-(pyridi) (4-yl)sulfonyl)carboxamido-1-(2-chloro)phenyl) Methoxyphenylcomethylimidazole; 5-carboxy-4-chloro-2-pentafluoroethyl-1-C4-(1-( N-(pyridin-4-yl)sulbonyl)carboxamide-1-(2-chloro ) phenyl)methoxyphenylcomethylimidazole; General method for preparing compounds of general formula ■ The method described below describes the synthesis of the antagonist angiotensin of formula I. . There are several general methods for synthesizing antagonists of formula ■. The general principle is that one or the other method may be more easily applied to Several methods are accepted as (would not be applicable. An antagonist of formula ■ is denoted by formula T a heterocyclic component (moiety) and a substituted benzyl bonded to the nitrogen atom of the heterocyclic component. It consists of a substituent. Thus, two methods can be generally applied to antagonists of formula 1. is the following 1 Substituted imidazole is synthesized by the method described below. Then, imidazole is , a substituted benzyl giving the alkylated imidazole in the scheme below. Nitrogen atoms are alkylated using halides or pseudohalides, and The alkylating agent is often “A r CH2Q” (where Q is a halide (-C1, Br, I) or pseudo halide (-0Ms).

OTs, 0Tf).

In some cases, alkylation occurs on both nitrogen atoms of the imidazole, and this In these cases, separation by fractional crystallization or chromatographic methods or necessary for the isolation of the product. In some cases, the alkalization step The functional groups in the binding agent or imidazole are protected and the synthesis is completed. The complete version of formula 1, except that a deprotection step is required to achieve form of the antagonist. In other cases, alkylation also involves substituted benzylic halides. This is carried out using a genide or a pseudohalide (A r CH2Q'').

However, this alkylation step assembles the substituted benzylic moiety of the antagonist of formula carried on to the later stages required.

The alkylation step and subsequent steps used to synthesize the antagonist of Formula 1 are described below. Ru.

2 Another approach to antagonists of formula I is that the substituted benzyl moiety is It can be introduced before or during synthesis. This type of route is shown below. has been done. This general method is used in most cases, and is used for the synthesis of heterocycles. The substituted benzyl moiety introduced in order to complete the synthesis of the antagonist of Scheme I Furthermore, the composition transformation above must be followed. As shown in the scheme below, this substitution The benzyl component is referred to as “-CH2Ar” and this substituted benzyl component is commonly Always, A r CH2Q (wherein, Q is, for example, CI, Br, I, F, OTs, 0 M5) Produced by substituted benzyl halide or pseudohalogenation be done. The required substituted benzylamine derivatives can be synthesized by standard methods. Probably. For example, substituted benzyl halokenides or pseudohalides (“Ar- CH,, Q”).As mentioned above, alkylated imidazo Substituted benzyl halides or pseudohalides useful in the synthesis of polymers are shown and described in Table 1. Ru. Substitutions useful in the synthesis of alkyl-introduced heterocycles as mentioned above Benzylamines are shown and described in Table 2 below. These benzyl halides, If pseudohalides and amines are not commercially available, they may be used as described below. or by standard methods of organic synthesis. formula The subsequent steps necessary to complete the synthesis of antagonist No. 1 are described below. of this invention The compounds may be solved using techniques known in the art. enantiomeric dia Stereomeric salts and esters are separated and the desired compound is the more active stereoisomer It is. Compounds of the present invention, their pharmaceutically acceptable salts and their prodrugs The dog type is included within the scope of the present invention.

Table 2 Abbreviations used in the tables and examples are shown in Table 3.

AIBN Azo(bis)isobutyronitrile DDQ Dichlorodicyanoquinone Ac, O acetic anhydride DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine TFA hlifluoroacetic acid TMS-CA' Trimethylsilyl chloride 1m Imidazole Ac5K potassium thioacetate p-TsOHp-toluenesulfonic acid DIPEA diisopropylethylamine TBS-CI h butylsilylchloride Ride TBAF Tetrabutylammonium Fluoride TMSCN Trimethy lucilylcyanide solvent D’vI F Dimethylformamide HOA c (AcOH) Acetic acid E t OA c (E) Ac) Ethyl acetate Hex Hexane THF Tetrahydrofuran DMS O dimethyl sulfoxide Me OH methanol 1prOH isopro/<nol HMPA Hexamethylphosphoramide and others Phe Phenylalanine rt room temperature TBDMS t-butyldimethylsilyl FAB-MS (FSBMS) fur Store Tom Pombardment Mass Spectrometry NOE Nuclear Oberno 1 Uther Effect fNucl+a+　Ove+hau+e+　effect) SIO2 silica gel trityl triphenylmethyl Bn Benzyl Part I - Preparation of imidazoles of formula I The imidazole required for alkylation to the substituted benzyl moiety is known in the literature. It can be prepared in a number of ways.

253.3tQ, 324.30 of EP○ publication by DuPont Including those described in EPO Publication 401.1130 by Merck do.

Part ■2 Synthesis of substituted benzyl derivative of general formula 1 Substituted benzyl shown in formula ■ Synthesis of angiotensin antagonist that incorporates a leaving group has a good leaving group. a benzyl compound represented by formula (1) and appropriate substituents R9, RIO, RII.

Achieved by reaction of imidazole in the presence of a base using R12, X, Y and Z can do. Alternatively, compounds having the structure of formula (1) may also include R9, R10 and From a benzyl-substituted imidazole containing an X substituent, successively R11, R12 and the Z position Intermediates for introducing substituents (esters of substituted alpha bromophenyl acetic acids) can be synthesized in several steps. A benzyl-substituted heterocyclic intermediate was first synthesized. , and an example of the latter method to obtain a compound of structure shown in Formula I. It is shown in Mu n-1, n-2 and If-3. Synthesis of compound 5 of formula I, of which B= The single bond and R12=phenyl group are shown in Scheme 11-1. 20-1 sodium hydride or carbon in DMF at a temperature of 00°C for a period of 1 to 24 hours. Deprotonate substituted imidazoles using a strong base such as t-butoxide and then alkylation with 4-benzyloxybenzyl chloride yields the protected ether. -Tel 2 is obtained. The benzyl ether then combines hydrogen with the intermediate phenol 3. using a suitable catalyst such as Pd/C, Pd(OH)2/C or Pt/C. It is removed by hydrogenolysis. The phenol proton is then abstracted and then The phenolate was then alkylated using methyl 2-bromophenyl acetate. This becomes ester 4. Finally, this ester is hydrolyzed and the free acid 5 is can get.

Scheme ll-1 The synthesis of compound IO of formula ■ is shown in scheme n-2: this compound is a compound of formula I where B= Single bond, R9, R10 and R11 are H, X=O1[2 Y=single bond, Z=COHSR=phenyl. Sodium hydride in DMF Following deprotonation of the substituted imidazole (6) with 4-benzyloxyben Treatment with dil chloride gives compound 7. Benzyl ether is hydrogenolyzed to give phenol 8, which was further removed with potassium hydride in DMF to give phenol 8. Deprotonate with 8-crown-6 and further with methyl 2-bromophenylacetate. Alkylation gives ester 9. Hydrolysis of 9 produces free acid 10.

Alkylating phenol 8 with an ester of substituted 2-bromophenylacetic acid, Subsequent ester hydrolysis yields compounds of formula I in which R12 is a substituted phenyl group. It will be done.

The synthesis of compound 15 of formula I is shown in scheme ll-3, where B=single bond , R, 9, R1 (l and R11 are H, X=O1Y=single bond, 12= z=CO2H, R-2-methylphenyl. Sodium hydride in DMF Deprotonation of imidazole (11) using a strong base such as Treatment with 4-benzyloxybenzyl chloride provides ether 12. Be The phenol ether is removed by hydrogenolysis to yield phenol 13, which is then , this phenol was deprolated with potassium hydride and 18-crown-6 in DMF. Tonization and alkylation using methyl 2-bromo-2'-methylphenylacetate Ester 14 is then obtained. Alkaline hydrolysis of 14 gives 15 free acids. I can do it. Reacting another substituted α-bromophenyl acetate with phenol 13 , followed by alkaline hydrolysis to other derivatives of this imidazole series. is obtained.

Scheme n-3 R12 is a substituted phenyl group, R11 is hydrogen, Y is a single bond, and Z is a carboxylic acid. In the synthesis of compounds of general formula I, substituted 2-bromophenyl acetic acid esters are commonly used. These substituted 2-bromophenyl acetic acids Stell is a Herfuorno 1 Ludose Rinse as shown in Scheme n-4. 7) Reaction to key fHel14o1ha+d-2elin+ substituted phenyl Easily synthesized from acetic acid (16). Also, substituted 2-bromophenyl acetate can also be obtained from henzaldehyde (18) as shown in Scheme II-’5. can get. Reaction of substituted henzaldehyde (18) with trimethyluryl cyanide This gives trimethylsilyl-cyanohydrin 19.

When 19 is treated with acid-containing ethanol, hydroxyester 20 is generated, Subsequent reaction of carbon tetrabromide with triphenylphosphine produces substituted 2-bromophyl Phenyl acetate 17 is produced.

Angiotensin antagonist containing a substituted benzyl component (moiety) defined by the formula ■ The synthesis includes all suitable substituents R9, R10°R11, X, Y and Z in appropriate positions. The alkyl of imidazole by a pencil intermediate with a good leaving group This is accomplished through a chemical reaction. This method is generally used when R or R10 is not hydrogen. The preference is shown in Scheme n-6.

Strong bases such as potassium hydride and potassium ten+-butoxide in DMF Deprotonation of p-cresol (21) by 2-bromo-2-phenylacetic acid Alkylation with methyl provides ether 22. N-bromosuccinic acid Bromination of the benzylmethyl group of 22 with Mido yields the alkylating agent 23. Ru. Deprotonate imidazole (pressure) by sodium hydride in DMF and reaction with bromide 23, followed by hydrolysis of the ester to form acid 24. .

scheme n-6 If substitution of R11 as shown in Scheme n-7 is desired, Scheme n- A method similar to 6 is used. Intermediate products such as 22 in Scheme ■-6 In THF, lithium bis(trimethylsilyl)amide, Deprotonated by strong bases to form alkyl halides or alkyl halides, such as mesylates. It can be reacted with a rkylating agent. In this case, methyl iodide and ether 22 The alkylation product 25 is formed by reaction with an anion derived from . 25 and Bromide 26 is formed from the reaction with N-bromosuccinimide, and this bromide is then Used in imidazole alkylation reactions. Scheme n-7 is based on bromide 26. alkylation of imidazole 6 and subsequent hydrolysis of the ester to form acid 27. It represents growth.

scheme n-7 The synthesis of compound 32 of formula I is shown in scheme n-8 (in formula 1, B is a single bond , R9, R", R"1. tH, X1tO, Y is CH, Z is CoH, R12 is F ). In this example, refluxing with potassium carbonate in acetone and p-hydroxybenzyl alcohol (28) was treated with methyl bromoacetate. The phenolic hydroxyl groups of are selectively alkylated. The remaining hydroxyl group is (c'1- After protection as butyldimethylsilyl ether, this ether (29) Deprotonated by a strong base such as umbis(trimethylsilyl)amide , alkyl in a manner similar to that shown for intermediate 22 in Scheme ■-7. Reacts with oxidizing agents. Alkylation of ether 29 with benzyl bromide gives 30 is generated. Hydrolysis of the silyl ether of 30 and the resulting alcohol The bromination of the imidazole produces an alkylating agent (31), which alkylates the imidazole. Used to kill. Anion alkyl derived from imidazole 11 Following silylization, hydrolysis of the ester results in a Acid 32 is obtained.

Scheme II-,9 depicts the synthesis of antagonists of formula I. However, in the formula ■, B is a single bond, R9, R10, R11 are H, X is a single bond, Y is 0, Z is Co H, R 12 is phenyl. In this example, the Heluforhardoselinski anti- 4'-methylphenylation by reaction (7 to Hell-Volhx+d-2elin+) Nyl acetic acid (33) is converted to alpha bromo ester 34 and then this compound reacts with the potassium salt of phenol to produce 35. Smell similar to benzyl in 35 The alkylating agent 36 is produced by the hydrogenation and is reacted with imidazole. Imi When the sodium salt of dazole is alkylated with bromide 36 in DMF, Ester 37 is obtained. Then, by alkaline hydrolysis of ester 37, acid 38 is generated.

Schemes n-1o and -11 represent the synthesis of analogous compounds. Just mu 9 ShiB is a single knot. , R and RIO are H, Y is a single bond, R12 is a phenyl group, Z is C○2 H,, X is either methine or methylene.

First, methyl 3-hydroxy- Synthesis of 3-(4-methylphenyl)-2-phenyl propanoate (39) The Relo+matsk7 reaction is used for this purpose. 39 When heated in benzene in the presence of p-toluenesulfonic acid, it undergoes a dehydration reaction. The resulting trans-stilbene derivative 40, and the bromination at the benzylic position of 4o As a result, alkylating agent 41 is produced. Heterocycle 6 was removed with sodium hydride in DMF. Rotonization and treatment with 41 yields ester 42. Hydroidize 42 with alkali When solved, the product 43 is obtained, but as shown in scheme n-11, X in 43 is a methine group double bonded to the carbon atom with substituents R12 and Z (R11 is missing) ). When 43 is catalytically hydrogenated, derivative 44 is obtained. however , 44, X is a methylene group, and R11 is a hydrogen atom (Scheme n-11 Scheme ll-12 shows the synthesis of compound 47 of formula 1.

However, 47 is compound 10 (except that Z is a tetrazol-5-yl group) It has the same substituents as in Scheme ■-2). Excess of ester 9 in methanol exposure to ammonia gives the corresponding amide, which is converted to phosphorus oxychloride. Dehydration with triethylamine gives nitrile 45. Nitrile 45 is reacted with trimethylstannyl azide under toluene reflux to induce tetrazole. body 46 is generated.

Scheme ■-12 Scheme ■-13 depicts the synthesis of a tetrazole analogue (52) similar to structure 46. (However, R12 is a 2-chlorophenyl group). This synthetic smell Therefore, the ester group of intermediate product 47 is converted into a substituted imidate by this substituted benzyl component. The sol (Part I) is converted to a nitrile before alkylation. In this way, Reaction of Stell 47 with ammonia in methanol followed by dehydration of amide 48 More nitrile 49 is produced. Bromination at the benzylic position gave 50, then This 50 reacts with the sodium salt of heterocycle 6 in DMF to generate intermediate product 51. do. Finally, trimethylstannyl azide and nitrile 51 were added under refluxing toluene. When reacted, as shown in Scheme ■-13, tetrazole 52 is Similar to tetrazole 47 (Scheme n-12) in that the substitution is a methylene group. The method for synthesizing the derivative of formula 1a is shown in Scheme 1-15. In this synthesis, phenyl Acetonitrile is deprotonated using lithium bis(trimethylsilyl)amide and then bromide 53 (the synthesis method of bromide 53 is shown in Ski, Mull-14). Nitrile 54 is obtained by alkylation using

The silyl ether group of compound 54 is dichloromethane (Matz, H; Venezra, C, Tetrahedron Letter 1987. carbon tetrabromide in (1967), Direct bromide by treatment with triphenylphosphine or acetone (bromide) 55. Nato of imidazole 6 using bromide 55 alkylation of the lithium salt and then using trimethylstannyl azide in refluxing toluene. By reacting with 56, tetrazole 57 is obtained Scheme n-15 The preparation of derivatives of formula Ia in which R is 2-methylphenyl and Z is a monoacid group is as follows. It is shown in scheme n-16. using dimethyl phosphite in the presence of triethylamine When o-trialdehyde 58 is reacted, phosphonate ester 59 is obtained. Ru. Carbon tetrabromide and triphenylphosphine in dichloromethane When the hydroxyl group of 59 is brominated using the hydroxyl group of 59, bromide 60 (4) is obtained.

Depurate p-hydroxybenzyl alcohol using sodium hydride in DMF. Rotonization followed by addition of bromide 60 provides intermediate 61. second smell In the chemical reaction (CBr4゜PPh, CH2CA'2), alcohol 61 is translocates to id 62. Because bromide 62 alkylates imidazole used for. Bromide 62 reacts with imidazole 11 to form a phosphonate. The fact that tomonoester 63 can be obtained is shown in Scheme 1-16.

Phosphonic acid 64 treats trimethylsilyl bromide and ester 63 can be obtained by

Scheme n-16 The synthesis of derivatives of formula 1 with Z or acyl-sulfonamide groups is shown in Schemes 1 to 17. ing. Using bromide 65 (the synthesis method was shown in Experimental Example 28), the heterocycle 1 The anion from which 1 is derived is alkylated, and the resulting ester 66 is subjected to alkaline addition. Acid 67 is obtained by water splitting. 1.1'-carbonyldi in THE at high temperature Reaction of acid 67 with imidazole leads to acylimidazolide and sulfonamide (e.g. benzenesulfonamide) and DBU in THE, Z becomes acyl. The desired compound 68 having a Ru-sulponamide group is obtained.

A incorporating a substituted benzyl component in which the substituent R9 is RH and one of which is not hydrogen Precursors for II antagonists are substituted p-cresols (Scheme rI-6), 4-Human. Kinbencyl alcohol, 4-hydroxybenzyl aldehyde, Scheme m-18ts with i-hydroxybenzoic acid and their esters, etc. It is shown in et al.-20.

Commercially available products such as 3-chloro-4-hydroxyl 5-methoxybennyl alcohol The benzyl alcohol is a-bromophenyl acetate and anhydrous potassium carbonate. selectively alkylated by refluxing together in the presence of a base such as The resulting 2-phenoxynystyl like 69 is shown in Scheme II-r8.

Bromide of benzyl alcohol group in 69 (CBr4).

PPh3. Conversion with CH2(12) gives the alkylated compound TO.

Hydration of intermediate ester alkylated imidazole with bromide 7o 71 is obtained from the decomposition. Alternatively, the Mitsunobu reaction (Mi++uubJrea:ti ofi)-like Qi (; L + Lua sosi'I'7 sil alcohol and imidazo Schemes ll-l5 that can connect tools directly Again, hydrolysis of the ester completes the synthesis.

Scheme ■-19 An antagonist of formula I was prepared with a substituted benzyl moiety and a 3-ethoxy group (R9). Commercially available 3-ethoxy-4-hydroxybenzaldehyde 7 The usage of 2 is shown in Scheme 1-19. Methyl 2-bromophenyl acetate The phenolic group of 72 is alkylated using 72 to give aldehyde 73. That's mail Benzyl alcohol using sodium borohydride in tanol or ethanol will be reduced to The alcohol is converted to bromide 74 and the synthesis of product 75 is as follows. Achieve it using the method mentioned above.

Substituted 4-hydroxybenzoic esters are limited to An antagonists in Bunmu 1. It is an effective precursor for the synthesis of substituted benzyl components. With this approach , the phenolic hydroxy group is usually first protected with a suitable protecting group. beauty salon is reduced with a hydroxymethyl group and deprotected to form a 4-hydroxyalcohol derivative. get. Starting from methyl 3,5-dichloro-4-hydroxybenzoate 76 A method for synthesizing derivative 80 using the reaction described above is shown in Scheme It-20. Debonding Reduction of protective esters and silyl ethers with lithium aluminum hydride 3,5-dichloro-4-hydroxybenzyl from the silylation of phenol 76 Alcohol (77) is obtained. Phenol 77 is methyl 2-bromophenylacetate Selective alkylation was performed using

Synthesis of derivative 80 is accomplished using previously described methods.

Various 2-substituted phenols were hydrogenated with carbon tetrachloride and 50% water. Sodium and copper powder (European patent application = i93.353, :0-5ep-36 ) to give the corresponding substituted 4-hydroxybenzoic acid. silized. This reaction converts the easily obtained 2-substituted phenol into the desired A. This would be an effective synthetic method for inducing the desired substitution at the benlu site of an antidrug.

This method is for the preparation of derivative 84 and is shown in Scheme 11-21.

Carboxylation of 2-ethylphenol to 3-ethyl-4-hydroxybenzo Iic acid 81 is obtained. Acid 81 is esterified, silylated, reduced, and desilylated. , 3-ethyl-4-chodroxybenzyl alcohol 32 is obtained. alcohol 82 is the synthesis of AII antagonist 34 shown in Scheme ■21 from the method based on the previous discussion. can be used to achieve.

Scheme ■-21 The Claisen rearrangement of phenyl-allyl ether is an alkaline rearrangement at the meta position of the substituted benzyl component. One useful method is to introduce a kill substituent (R or RIG). skiing In the program ■-22, allyl ether 85 undergoes a Claisen rearrangement at 185°C. It becomes lylphenol 86. This phenol (86) was silylated and then esterified. Reduction and bromination of the group leads to benzyl bromide 87.

Alkylation of imidazole 11 and removal of the next silyl ether results in a link to 88. A series of intermediate products are formed. 88 with methyl 2-bromophenyl acetate After alkylation, alkali hydrolysis leads to derivatives 89 of formula I (with R9 is a meta-allyl group). After hydrogenation of intermediate 88, the same procedure is followed. When this process is carried out, derivative 90 (where R9 is a methane compound as shown in Scheme ■-22) is obtained. -propyl group) is produced.

When an alkyl substituent is required, the Claisen rearrangement method can be used twice. good. Allylphenol 86 is thus converted to its 0-allyl ether, A second Claisen rearrangement gives rise to phenol as shown in scheme n-23. (91) is generated. Phenol 91 is silylated and hydrogenated by catalytic reaction. , reduction of the ester group by lithium aluminum hydride produces benzyl alcohol Rule 9z is generated. Benzyl Alcohol 92 is a compound described in Part I. The elementary ring (11) causes a Mitsunobu reaction, followed by Deprotection of the silyl ether yields intermediates related to 93. 93 Fe The noric hydroxyl group is alkylated with a substituted alpha bromide ester to form an ester. When hydrolyzed, acid 94 is produced. However, as seen in Scheme ■-23 and Example 52 As such, R9 and R10 in acid 94 are meta-propyl.The synthesis of the compound of formula I is as follows: It is represented in one diagram. However, B is a single bond, R9, R10, R12 are H, Y is a single bond, Z is Co2H, R12 is a phenyl group, and X is NR. these types Imidazole as defined in Part I (e.g. II) to access analogues was alkylated with p-nitrobenzyl bromide to form 95 of Scheme 11-24. produce nitro compounds such as When the nitro group is catalytically hydrogenated with a catalyst, Aniline derivative (96) is formed, which is alkylated with alpha bromide ester. will be converted into a file. Ester 97 is then hydrolyzed, resulting in derivative 98 of formula I (where X (NH) is generated.

Angiotensin ■ antagonist (similar to 98 in Scheme ll-24, but X is NR) The synthesis of ) is carried out by the method shown in Scheme 1-25. mentioned above Substituted aniline (96) is converted to N-t-butylcarbamate (BOC) 99 Converted gradually.

Carbamate esters such as 99 can be prepared with salts such as sodium hydride in DMF. When reacting with the group, deprotonation occurs at the nitrogen atom of the amide, forming an alkyl halide. React with le. Next treatment of this intermediate with trifluoroacetic acid results in BOC groups. is removed to form the mono-alkylated aniline derivative 100. Within 100 The nitrogen of the aniline is again deprotonated with sodium hydride in DMF, and Once alkylated with substituted alpha bromide esters, esters like 101 Generate stealth. Alternatively, the order of introduction of substituents on the nitrogen atom can be reversed. It's okay.

Intermediate 97 (Scheme 11-24) was also prepared by lithium bis(trimethane) in THF. is deprotonated by a strong base such as tylsilyl)amide and reacts with the base alkyl A similar product (101) is obtained by reaction. by either synthetic procedure The synthesized ester +01 is hydrolyzed to produce the desired product 2) angiothene. Synthesize an antagonist (102) (where X is NR).

Scheme ■-25 It has been described. 2.4.Synthetic procedures for 5-trisubstituted imidazoles are described by DuPont (Do Pon+) applications (EPO0324377 and 0253310) and Merck fMe+ ck) application (EPo 0401030), which is hereby incorporated by reference. and incorporate it. The imidazole substituent is the use of t-butyldimethylsilyl group. Appropriately protected as illustrated. Sodium hydride protected imidazole The salt was alkalized with the appropriate 4-methylbromide benzoate. Killing produces a tetrasubstituted imidazole. Hydrogenation reduction with alkyl metals The base produces benzyl alcohol, which is processed by Stun oxidation. This produces aldehyde 104.

Scheme ■-27 Scheme ■-27 includes D Reductive oxidation of aldehydes using both - and L-phenylalanine methyl ester They are hailing minification. Scheme ■-28 shows valeroyl chloride, dihydrosil 105 by acylation reaction with nnamoyl chloride or phenylacetyl chloride. The synthesis route for adducts is explained. Also, an addition product with b-70yl chloride Acylation of 105 is also shown. The formed amide is desilylated and hydrolyzed. Acid is produced.

The preparation of benzylphenylalanine methyl ester is shown in Scheme ■-29. There is. Imine is converted to phenylalanine methyl ester using benzaldehyde. formed by processing and desorbed using lithium hexamethyldisilazide. protonated to yield anion and alkyl bromide using benzyl bromide The l-benzylphenylalanine methylester scheme 11-30 is Amino acid 115 was prepared using sodium cyanoborohydride in ethanol. The reductive amination of aldehyde 104 is shown using Compounds with adducts 116 was desilylated using tetrabutylammonium fluoride and base Hydrolysis to the acid using gives the free acid +18.

Scheme ll-30 In the first anle of Lucrophyte, f mi 1 = l Zυτ earth 夙go - 90-゛ no l substituted ben The synthesis of dilphenyl ester is shown in Scheme 1-32. Protective substitution Dazole was deprotonated with NaH and alkaline with 4-benzyloxybenzyl chloride. Kylation gives 1-substituted and 3-substituted imidazoles. 3- Substitution Imidazole is hydrogenolyzed to free hydroxyl groups to give ether 124. Methyl 2 -bromo-2-phenylacetate it is deprotonated and alkyl It has been transformed into ether! It will be 24.

Silyl ethers are removed using fluoride and ester groups are removed using base. Hydrolysis and protonation of the salt with acid provides the inhibitory compound 125.

Scheme ■-33 The 0-chloro analog was prepared using a similar synthetic procedure, and it is shown in Scheme It is shown in ■-33. The order of these stages has been changed. Substituted phenylbenzi The ether is first prepared and used to alkylate the substituted imidazole. I can stay.

Treatment of 2-(1-(2-chlorophenyl))acetic acid 126 with thionyl chloride then an acid chloride is formed which, when brominated, produces 2-bromo-2-[l-2-chloro Lo-phenylcoacetyl chloride is formed, and this is esterified with methanol. When esterified, methyl 2-bromo-2-CI-(2'-chlorophenyl)]-a Cetate 128 was formed. Deprotonation of p-cresol and bromide 127 Alkylation with gave phenylbenzyl ether 128. 123 odor Reaction gave benzyl bromide 129.

Deprotonation of imidazole and alkylation with 129 protect inhibitor 130 give. Hydrolysis of 130 with base KOH and acidification with HCI Inhibitor 131 is given.

Scheme 1-34 shows the preparation of benzophenone derivative 137. 4-me Tylbenzophenone 132 is combined with N-promosuccinimide and a catalytic amount of AI Halogenation with N gave the 4-bromomethyl derivative 133.

In DMF alkylation with bromide 133, the reaction with sodium hydride Deprotonation of midazole gives imidazole substituted benzophenone 134.

trimethylsilylcyanidin in methylene chloride using a catalytic amount of 13-crown-6. When treated with +34 using hydrogen and potassium cyanide, cyanosilyloxy Addition body 135 is given. The cyan group undergoes 1,3-dipolar cycloaddition of azide, and Substituted methylene using alcohol and tetrazole 136 is obtained. in THF Deprotection of t-butyldimethylsilyloxy using 5N HCl yielded the compound 137 were obtained.

Scheme ■-34 Scheme ■-35 Scheme ■-36 Compounds of formula I prepared from carboxylic acid derivatives corresponding to formula I [z is -CONH 8o R20. (R20 is alkyl, aryl, heteroaryl) thionyl chloride or rather oxalyl chloride and a catalytic amount of dimethylene chloride at low temperature. C, G, converted to the corresponding acid chloride by treatment with chloroformamide. 5haefe+, 57nthesis, 767, (1976)) The compound can be treated with an alkali metal salt of R20S02NH2 to form a claimable acid. Rusulfonamide 143 was formed. Instead, these acylsulfonamides from the carboxylic acid using an N,N-diphenylcarbamoyl anhydride intermediate. is also prepared (F, 1, B "own, el, !+,, Ea+opezn Pzf enj Application, EP 199. 543°K, L, 5h epa+d! od W, Halcxenko, I, Het, Chem, , 16. 321 (1979) Rather, carboxylic acids are acylimidazole intermediates. The intermediate can then be converted to a suitable aryl or alkyl sulfonate. Reeds that can be treated and claimed using mido and diazabicycloundecane (DBU) gives rusulfonamide 45 (1.T.

C+++mmond and G, Iohnson, Tef+xhed+on Left ,,29. 1653 (1988)).

*Other method 1) Import) SOCl2. reflux (ii) R20S02NH2 (M is Na or Li) b) (1) (COCl2 ), DMF, 20'Cc) (i) N-(N,N-diphenylcarbamoy ) Pidgenium chloride, aq, NaOH The compounds of this invention form salts with various inorganic and organic acids and bases. These too Within the scope of the present invention. These salts include ammonium salts, thiorium and potassium salts. alkali metal salts, such as calcium and magnesium salts, Lithium metal salts or salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, or also arginine or sine or such It contains salts with amino acids, etc. Also, salts with organic and inorganic acids can be prepared. good. For example, HCl, HBr, H2SO4, H3PO4, methane-sulfone acid, toluenesulfonic acid, maleic acid, fumaric acid, ginger sulfonic acid, etc. be. Although physiologically acceptable, non-toxic salts are preferred, other salts are also useful. It is. For example, when isolating or purifying a product, salts are used in solvents in which they are insoluble. Alternatively, the free acid of the product is in the medium, or a solvent that is removed in vacuo, such as water. Alternatively, the free base can be reacted with one or more equivalents of a suitable base or acid. or by freeze-drying, or by removing the cations of the salts present with suitable ions. formed by conventional methods such as by exchange with other cations using exchange resins. Achievement.

Angiotensin n (An) is a powerful arterial constrictor, which acts on tissue membranes. It exerts its effect by interacting with specific receptors. mentioned in the present invention The compound acts as a competitive antagonist of An at the receptor. fixing AI antagonists and to determine their efficiency in vitro. established the following two assay methods for ligand-receptor binding.

Receptor Binding Assay Using Rabbit Aortic Membrane Preparation Three Frozen Rabbit Motions Pulse (obtained from Pet-Freeze Biological+) was 5mM Suspended in Tris-025M sucrose, pH 7.4 buffer solution (50 ml) homogenized and then centrifuged.

The mixture was filtered through a coarse cotton cloth, and the supernatant liquid was stored at 4°C and 20°C. ．． Centrifuged for 30 minutes at 000+pm. The pellets obtained in this way are Contains 0.2% bovine serum albumin and 0.2%/ml bacitracin. 5 Resuspend in 30 ml of buffer solution of 0mM) Lis-5mM g Cl2; The suspension was then used in 100 analysis tubes. tested for screening Two samples were created. For membrane preparation (0.25 ml) containing the test sample Contains or does not contain l-3ar' l1e8-angiotensin AII (New English+I (obtained from Nuclear) (10ml; 20. OOO+pm) was added and the mixture was incubated for 90 minutes at 37°C. So A mixture of water-cooled 5Q+M Tris-0,9% NaCl, pH 7,4 (4 m l) and glass fiber filter (GF/B Whatman2 ．． 4'l). The filter has a scintillation capacity of (10 ml). Packard 2660 T+ica+b liquid syn Radioactivity was calculated using a tilation counter. Specific binding 125I-8a r 'I l　C8-Angiotensin ■ Potential A resulting in 50% replacement of the entire The inhibitory concentration (IC5o) of a II antagonist is a measure of the efficacy of compounds such as II antagonists. expressed as a fixed standard.

In the receptor assay using preparations of bovine adrenal cortex, the adrenal cortex is the source of the An receptor. selected as a fee. Weighed tissue (f), required for 1g or 100 analysis tubes ) was suspended in Tris HC1 (50mM), pH 7,7 buffer solution and homogenized. I made it.

The homogenate was centrifuged for 15 minutes at 210 H+pm. The supernatant solution is discarded. , and the pellet was mixed with buffer solution CN　a　HP　O4(IQ;J)-NaCl(1 2[1stli)-phenylmethanesulfonyl fluoride (P　M　F　)　( The suspension was resuspended in EDTA disodium salt (5mM) containing 0.1mM). Test tube replicates were generally used to screen compounds). Membrane preparation (0, 5 ml) with and without the test sample. Contain U (50mM) (iQml) was added and the mixture was incubated for 1 hour at 37°C. So The mixture was then diluted with Tris buffer solution (4 ml) and inserted into glass fibers. It was filtered with a filter (GF/BWha)man 2.4' diameter). the Filters were soaked in scintillation cocktail (10 ml) and Pac Radiation using katd 2660 Trica+b liquid scintillation counter The ability was calculated. Specific binding resulted in 50% overall displacement of 3H-angiotensin H The inhibitory concentration (IC5o) of a potential An antagonist is determined by the effect of a compound such as an An antagonist. It was expressed as a standard for measuring performance.

The possible hypotensive effects of the compounds described in this invention are discussed below. It will be evaluated by using the methods described.

Male Chaplet RiverSprague-Davley Mouse (30 0 to 375 mg) was anesthetized using mesohexial (B+evi+al; 50■/kg: p) Then, a PE2ttS tube was inserted into the trachea. stainless steel Insert a steel puncture rod (thinness: 15m, length: 150m+) into the eye socket of the right eye and under the dorsal pillar. Inserted. The mouse was operated using a Harvard Rodent ventilation system ff1 (6 per minute). 0 stroke rate, volume of 1.1 cc per 100 g of body weight). It was. The right carotid artery was ligated, the left and right vagus nerves were cut, and the left carotid artery was ligated, the left and right vagus nerves were cut, and the left carotid artery was Automatic temperature control that inserts a PE50 tube into the carotid artery and receives input from a rectal temperature probe. Body temperature was maintained at 37°C with a temperature-controlled electric pad. Atropine (1■/kg, i ,v,) was administered, and 15 minutes later, propranolol (1■/kg, i,ma,) was administered. administered. After 30 minutes, administer angiotensin or other antagonist intravenously at 30 minute intervals. injected intravenously and record the increase in diastolic blood pressure before and after administering the drug or vehicle. did.

Using the methods described above, representative compounds of the invention were evaluated to achieve at least ICs. o < 50mM, which makes it an effective An antagonist. The usefulness of the compounds of the present invention as a drug has been demonstrated and confirmed.

The compounds of the invention are thus useful in treating hypertension. They are also acute and treatment of chronic congestive heart failure, accessory hyperaldosteronism, primary and accessory pulmonary hyperaldosteronism. treatment of major and accessory pulmonary hypertension, renal failure and renovascular hypertension, and migraine or It is also useful in the treatment of vascular diseases such as Raynaud's disease.

The applicability of the compounds of this invention for these or similar diseases will be clear to those skilled in the art. It will become clear.

The compounds of the invention are also useful in the treatment of increased intraocular pressure and are available in tablets, capsules, and injections. Typical drug formulations and ophthalmic formulations such as solutions, ointments, inserts, and gels are used. It can be administered to patients in need of treatment.

Pharmaceutical formulations prepared to treat intraocular pressure generally contain about 0% by weight of the compounds of this invention. ．． It contains 1% to 15%, preferably 0.5% to 2.0%.

In the treatment of hypertension and the above-mentioned clinical conditions, the compounds of the present invention are suitable for oral administration. Tablets, capsules or elixirs, suppositories for rectal administration, by parenteral or intramuscular injection Used in compositions such as sterile solutions or suspensions for dosing. Embodiment of the present invention The compound is designed to ensure that a single dose provides optimal drug efficacy for patients in need of treatment. can be administered to (animals or humans). The amount per dose varies depending on the patient and the disease. The characteristics and severity of the treatment, the patient's weight, the special diet that the patient must follow, and the simultaneous use of - times of administration, depending on the drug involved, and other factors recognized by those skilled in the art. The amount ranges from about 1 to 1000 per patient per day, which can be administered twice or multiple times. Can be administered in multiple doses. The dosage range is preferably about 2 doses per person per day. ．． Preferably between 5 and 250 ■, and about 25 ■ per patient per day. It is even more desirable that it be 75■.

The compounds of the invention may also be used as other antihypertensive and/or diuretic agents and/or angiotensin converters. Can be administered with enzyme inhibitors and/or calcium channel blockers. for example , the compounds of this invention can be administered with compounds such as: amiloride, a Tenorol, pendroflumethiazide, chlorothalidone, chlorothiazide, chloro Nigin, cryptenamine acetate, cryptenamine tannate, dizapidine, Diazo oxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide metrazone, metoprolol tartrate, methylclothiazide, methyldopa , methyl dopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, plastic Lazosin, Propranolol, Rauwolfia Serpentina, Ricinamine, Les Serpin, nitropurgide sodium, spironolactone, timolol maleae trichloromethiazide, trimethophane camsylate, benzthiazide, Kinethazone, ticulinaphane, triamterene, acetazolamide, aminophylli cyclothiazide, ethacrynic acid, furosemide, meletoxylin proton, Sodium ethacrylate, captopril, delabril hydrochloride, enalapril, Narapril, Funadinopril Sodium, Lisinopril, Pentopril, Cinchona Prill Hydrochloride, Ramapril, Teprotide, Zofenopril Calcium, Diflu Nisar, diltiazem, felodipine, nicardipine, nifedipine, nildipine Nimodipine, Nisoldipine, Nidrenzipine, etc., and their The same applies to mixtures and formulations.

Generally, an individual's daily dosage for these formulations is the minimum recommended dose. About one-fifth of the bed doses are recommended to the maximum when they are given alone. This ranges from high to high levels.

These formulations will be described. Clinically effective in the range of 2.5 to 500 μ per day. Take one of the effective angiotensin antagonists of this invention at a dose of 0.5 to 2 times a day. The following compounds, at levels in the range of 50 ■, and at the indicated daily doses, are effective. ・Hydrochlorothiazide (15-200μ), chloro Thiacyto (125-2000■), ethacrynic acid (15-200mg), 7 Milo' J Do (5-20 ■), Furosemide (5-80 ■), Propranolol (2 0 to 480 ■), timolol maleic acid (5 to 60 ■), methyldopa (65 to 2000■), felodipine (5-60■), nifedipine (5-60■) and and night range pin (5 to 60 cm). In addition, hydrochlorothiazide (15-2 90 ■) + miloride (5 to 20 ■) + angiotensin ■ antagonist of this invention (3 ~200■) or hydrochlorothiazide (15~200■) + timololma Reate (5~60■) + angiotensin■ antagonist of this invention (0.5~20 0■) or hydrochlorothiazide (15-200■)-nifedipine (5-200■ 20■) + Angiotensin■ antagonist of this invention (0.5-200■) The three drug combinations are effective combinations for regulating blood pressure in hypertensive patients. Of course , these dosage ranges should allow for splitting the daily dose. can be adjusted on a component-by-component basis, and as mentioned above, the dosage depends on the nature and severity of the disease, and on the patient. Varies depending on body weight, special diet and other factors.

Typically, these combinations can be formulated in the following formulation combinations.

About 1 to 100 compounds or mixtures or physiologically acceptable salts of compounds of formula , physiologically acceptable agents, carriers, excipients, binders, prophylactic agents, stabilizers, fragrances. Mix with ingredients, etc. These should be administered in pharmaceutically acceptable dosage units. . With such compositions, the amount of active substance formulated is at an appropriate dosage within the indicated range. Ru.

Tablets, capsules, and related adjuvants include: Gacanth gum, acacia, cornstarch or gelatin; as microcrystalline cellulose Excipients such as cornstarch, pregelatinized starch, alginic acid Lubricants such as decomposers magnesium nistearate; sucrose, lactose, Sweeteners like saccharin: peppermint, koji oil, and cherry. Fragrance. When the dosage unit is a capsule, in addition to the above types of substances fatty oils Contains a transport solution such as Various pond substances, e.g. coatings and dosing units It is also possible to optionally modify the physical shape of. For example, tablets are It can be coated with pickle, sugar or both. Syrup or a mixture of several herbal medicines The (elixir) contains the active compound, sucrose as a sweetening agent, and methyl as a preservative. Contains dyes and fragrances like propylparaben, cherry, and orange. Ru.

Sterile compounds for injections can be prepared by convenient formulation, such as water for injections, naturally obtained. Vegetables (sesame oil, coconut oil, peanut oil, cotton music, etc.), ethiluo Dissolving the active drug in a vehicle such as a synthetic fatty vehicle such as a oleate ester Or it can be disassembled and prepared. Mixtures of buffering agents, preservatives, antioxidants, etc. as necessary can.

The compounds of this invention are also useful in curing increased pressure inside the eye and are available in tablets and capsules. Typical products such as capsules, injections, as well as eye drops in solution form, ointments, inserts, and gels It can also be given to patients in need of treatment with pharmaceutical preparations. internal pressure of the eye Medicinal preparations prepared to cure 0.5 to 2% of the compound of the invention.

The compounds of this invention are thus useful in treating hypertension. Also, they are sudden It is also of value in the treatment of chronic congestive heart failure, secondary hyperaldosteronism, primary and secondary hyperaldosteronism. Pulmonary hypertension, glomerulonephritis, scleroderma and similar conditions, renovascular hypertension, left ventricular function It is also valuable in the treatment of diabetic retinopathy, diabetic retinopathy, and conditions such as migraine and Rainey's disease. It is also of value in the treatment of vascular diseases. For these and similar diseases The applicability of the compounds of the invention will be clearer to those skilled in the art.

The useful central nervous system (CNS) activity of the compounds of this invention is demonstrated by subsequent assays or examples. It is proved.

Test of cognitive function The efficacy of these compounds to enhance cognitive function was demonstrated in a passive avoidance assay in rats. I can testify. This assay uses physostigmine and two-tropic reagents. It is known that such choline manipulations are active. In this assay, rats Train yourself to suppress your natural tendency to go into dark territory. Test equipment used is two small rooms, one brightly lit and the other dark. Rat The target is placed in a lighted cubicle and the elapsed time it takes to enter the dark cubicle. Record. Upon entering the dark room, the rats receive a brief electric shock to their legs. test In animals, scopolamine, a muscarinic antagonist that disrupts learning, is used at 0.2 kg or with scopolamine, which has the opposite effect of scopolamine. and the compound to be tested for its potential. After 24 hours, the rats were illuminated again. I was taken back to my room. When you return to the illuminated room, after receiving this training, Normal young rats treated with control drug only were allowed to enter the dark room again. longer than test animals that were placed in the same apparatus but not given an electric shock. It took time.

Rats treated with scobolamine before the test showed no signs of this 'chip' even when tested 24 hours later. Do not show any hesitation. Potent test compounds inhibit scobolamine-induced learning. Can overcome the effects of confusion. Typically, the compounds of the present invention will have about 0.1 ■/ Doses ranging from approximately 100 μg/kg to approximately 100 μg/kg demonstrated efficacy in this passive avoidance test. It should show.

Anxiolysis test The anxiolytic activity of the compounds of the present invention was determined by the Conditioned Emotional Response (CER) assay. I can testify. Diazepam is a clinically useful anxiolytic agent and is It is active against certain conditions. In the CER observation record, the male Spragae-Dav l+y rats f250-350 g) were subjected to a weekly training period ( Variable interval (VI) 60 seconds to replenish food (5 days per week) They were trained to press a lever on a schedule of All animals are then 1 Subjects undergo a conditioning period of 20 minutes per day. Each period is a 5-minute bright period (L) and a two-minute dark period (D), and these alternate, that is, L It is determined that it is continuous with I　Di　L2　D2　L3. L or D At any time of the day, press the lever to release food pellets on a VI 60 second schedule. will be delivered. However, when playing a dark time CD, if you press the - button, it will feel light on your feet. Electric shock (0.8mA, 0.5sec) or separate VI2Q second shock added on a schedule. Pressing the lever during dark hours is suppressed If so, this represents the formation of a conditioned emotional response (CER). Drugs in this model Physical tests were conducted under extinction conditions. During the extinction period, the animal responds to food in the dark. They learn that they are no longer subject to electric shock. Hence , the reaction rate in the dark period gradually increased, and animals given anxiolytic drugs showed lower response rates than the drug. The response rate is faster than animals given only carrier. The compounds of this invention In the test procedure, the efficacy ranges from about 3.1■/kg to about 1 (IG■/kg). There should be.

depression test method The antidepressant activity of the compounds of the present invention was determined by a tail-pulling test using rats. Therefore, it can be demonstrated. Clinically useful antidepressants to act as positive controls for this analysis is desibramine.

The method involves showing a mouse suspended by its tail alternately in an excited state and an immobile state; We have shown that antidepressants change the balance between these two in response to stimuli in the behavior of mice. This is done through observation. A microcomputer monitors the period of immobility during the 5-minute test period. The experimenter then assigned an individual number to each animal. Calculate the incubation period, duration, and frequency of the period of immobility.

The compounds of the invention showed efficacy in this test at 0.1 to 100 μ/kg. The antidopamine activity of the compound can be demonstrated in an apomorphine-induced stereotypy model.

The clinically useful antispermia used as a reference standard for this assay was haloperidol ( haloperidol). This assay method is based on the accumulative dopane system in mice. This is done by observing the motion behavior of the open-door type when stimulated by

Apomorphine is a classical neuroleptic that prevents stereotypy-type symptoms and symptoms of schizophrenia. There is a strong correlation with the preventive medicine. Apomorphine-induced open-mouth tie Microwave behavior was measured using samples pretreated with the test compound and those not pretreated. It was recorded using a keypad connected to a computer. The compounds of the present invention are The assay showed efficacy in the range of 01 to 1 tlO/kg.

For the treatment of the above-mentioned clinical conditions, the compounds of the present invention may be administered in tablets, capsules or tablets for oral administration. Lixil, suppositories for rectal administration, sterile solutions or suspensions for intravenous or intramuscular administration It can be effectively used for compositions such as Compounds of the invention can be used in patients with diseases in need of treatment. (animals, humans). The amount used depends on the nature of the patient's illness, the severity of the illness, the patient's weight, and the patient's diet. Similarly, drug treatment, generally once or The daily dosage per patient, which can be administered in multiple doses, is about 5-6000 ml. preferable The dosage range is 10 to 4000 μ per patient per day, and more preferably It is 20 to 2000 square meters per patient per day.

In order to maximize sensory function, the compounds of the present invention are incorporated into Ike's sensory enhancement reagents. It is better to combine it with They are hebutylphysostigmine (hept71ph) 7sostigmine), tetrano-1-hydroacridine (tet+ab4dr acetylcholinesterase inhibitors such as oacτ7dine), Muscarinic agonists like morin, octyllamibril, rhinoceros Radepyril, Enalapyril, Lisinopyril, Fuosinopyril, and Zofue Angiotensin-converting enzyme inhibitors such as Nobilyl, which act on central calci um channel inhibitors and nimodipine, and two-tropic drugs like piracetam Contains reagents.

To achieve optimal anxiolytic activity, the compounds of the invention may be combined with other anxiolytic agents. drugs such as Albrasillam, Lorazepam, Deazebam, and Bushipirone. It is better to match.

The combination of the compounds of the present invention with other antidepressants in order to obtain optimal conditions for antidepressant properties. It is effective to carry out a They are Norbutylin, Amidryptyline, and Tolibutyline. Tricyclic antidepressants like lazodone and single amine oxidation like tranylcypromine Also includes enzyme inhibitors.

In order to obtain maximum antipsychotic activity, the compounds of the invention are combined with promethacin, flufe It is better to combine it with antipsychotic drugs such as nagin, haloperidol.

The following example illustrates the preparation of formula I and the combination of compounds and their pharmaceutical components. However, these are not intended to limit the scope of the claims of the present invention.

Special table Hei 5-504359 (36) 1.0 equivalent of 4-(bromomethyl)ammonium in 20 mL of methanol and 50 mL of toluene. Add 2.05 g of trimethylsilyldiazomethane to the solution containing zoic acid with stirring at room temperature. Equivalents were added dropwise. Add excess trimethylsilyldiazomethane to the reactants. It was added dropwise until it turned yellow. The mixture was stirred at room temperature for 1 hour to completely release the nitrogen. Hexa By thin layer chromatography in a solvent of ethyl acetate (11), the substance before the reaction was The presence of the desired ester with an Rf value of 07 was confirmed.

FAB-MS: M+H=230. 228’HNMR (300MH2, CD C13, ppm): δ8.02 (d, 2H); 7.46 (d, 2H) ; 4.50 (+, 2H); 3.93 (s, 3H) 1.2 in 5ml DMF The product of Example 1, Step A (2,0g, 6.57 mm ol) solution was added dropwise at 0℃, the repelled compound immediately turned pale yellow, and the gas disappeared at 0℃. Stir until generation is complete. 11 equivalents of methyl 4-(bromomethyl)benzoate at 0℃ of hexane and ethyl acetate and warm the reaction to room temperature. TLC was performed using the solution. After 2.5 hours, the reaction seemed to be complete. DMF is true The residue was removed in air and dissolved in 100 ml of ethyl acetate with 0.5N citric acid. (Water washing was performed again with saturated NaHC○3 solution) and salt water, dried with MgSO4, Filter and remove solvent. The separated viscous yellow oil (312g) is TL This oil, in which two points were observed according to C, was dissolved in CH, C1, and dimethyl Treated with 0.5 equivalent of aminopyridine (DMAP) and cooled to 0°C under nitrogen atmosphere. Ta.

Then 0.33 equivalents of t-butyldimethylsilyl chloride (G, 33g) was added. I got it. The suspension melted and the solution warmed to room temperature.

The mixture was stirred for 2 hours. The CH2Cl2 was evaporated and the residue, slush, was evaporated with acetic acid ethyl chloride. Dissolved in chill. DMAP-HCI was separated by filtration. D that could not be separated MAP-HCA' was filtered through a silica plug. The residue is 41 hexane, Silicage was purified by medium pressure liquid chromatography (MPLC) using ethyl acetate as the eluent. Separation was performed using a column.

Isomer a, 2-butyl-5-t-butyldimethylsilyloxymethyl-1-(4 -Carbomethoxyphenyl)methyl-4-chloro-imidazole with 80% yield (2.34 g) was isolated.

Isomer 2-butyl-4-tert-butyl-dimethylsilyloxymethyl-1-( 4-Carbomethoxyphenyl)methyl-5-chloroimidazole yield 12.8 % (0.38 g).

FAB-MS: i+omer a M+1 = 451i+omer b M +l = 451-HNMRi+ome+a: (300MHz, CDC A’　3. ppm): 68.00 (d, 2H); 7.06 (d, 2H) H); 5.25 (+, 2H); 4.50 (1, 2H); 3, 9N+ , 3H); 2.50 (L 2H); 1.70~lj5 (m, 2H) ; 1.37-1, 23 (m, 2H) +0.8-0.76 (m, 12H ); 0.02 (s, 6H) isome+b: (300MH2, CD Cl 3. ppm): δ8.00(d, 2H]; 7.08(d, 2H) H); 5.14 (s, 2H); 4.65 (s, 2H); 3, 90 (s, 3H); 2.55ft, 2H); 1.68-1.55 (m, 2H); 1.32 (Ill.

2H); 0.92 (s, 9H); 0.85 (t, 3H); 0.10 (s,6H)Methyl-4-chloro-1-(4-hydroxyphenyl) Example 1, Steps B. Dissolve isomer a (2.22 g, 4.931!1 mol) in ethyl acetate , Mg5O, filtered and the solvent was evaporated in vacuo. dry isomerism Cool 35 ml of THF solution (pale yellow oil) of body a to -50°C under nitrogen atmosphere. , 1. G　M　L　t　A　A'　Add 1.2 equivalents of THF solution of H4 dropwise Ta. The reaction was warmed to -25°C. After 30 minutes, add 243μl of water at -25℃. In addition, H2 was generated. Next, 243 μl of 15% NaOH and 243 μl of water. 1 was added and the mixture was gradually warmed to room temperature. This reaction product becomes a gelatinous precipitate in the form of particles. Stir continuously until the mixture is mixed. Filtration of solid aluminum salt with THF Therefore, it was removed. Filter the filtrate (dried with MgO, filter, and remove the solvent from the filtrate) A colorless oil was obtained in 100% yield (2.1 g).

FAB-MS: M+H=423 'HNMR: (300SIH!, CD C13, ppm): δ7.33 (d, 2H); 7.00 (d, 2tl); 5.20 (s, 2tl) ; 4.68 (+, 2H); 4.50 (s, 2) 1); 2.50 (+ , 2H); 1.7G-1,55 (m, 3H); 1.3Q (m, 2fl ); G, 9 (1-072 (112H); 0.02 (S, 6H) stage 2-butyl-5-t-butyldimethylsilyloxymethyl-1-(4-carboxylic acid) Preparation of ruboxyaldehydophenyl)methyl-4-taloloimidazole dichlorodichloro Solution containing 636 μl of oxalyl chloride in 30 ml of methane (CH2CI2) Cool to -78°C, add 25.0 ml dimethyl sulfoxy Do 1. A solution containing Q3011 was added dropwise.

After 15 minutes at -70°C, 23 Oml of CH2CI was added to the product of Example 1, Step C (22 g , 5.21 mmol) was added dropwise. Stir at -70℃ for 45 minutes After stirring, 3.19 ml of triethylamine was added. It was then warmed to room temperature. reaction When 10Q ml of water was added to the mixture, it was separated into two layers.

The organic layer was then washed with water and brine and dried over MgSO4. Remove solvent in vacuum A viscous pale yellow oil was obtained. When this oil cools, it becomes a crystalline solid. became. To obtain the desired aldehyde, use a mixed solvent of hexane and ethyl acetate as a developing solution. When TLC measurement was performed, an Rf value of 0.35 was obtained.

FAB-MS: M+1 of 421” HNMR: (300MH!, C DCl, ppm): δ10. O(1゜□　3 If(″); a 85(d, 21(); 7.15(d, 21() ; 5.26 (s, 2H); 4.50 (s.

2H); 2.50 (+, 2H); l, 70-1.50 (m, 2H ); 1.40-1.20 (m.

2B); 0.80-0.6Bm, 12B); 0. G2(s, 6H ) Step E 2-butyl-5-t-butyldimethylsilyloxymethyl-1-[: 4-(N-fl(R)-carbomethoxy-1-pencyl)-methyl)ami Preparation of methylphenylcomethyl-4-chloroimidazole 3A Powdered Molecule - HCI-D-phenyl in 10 ml of ethanol dried using sieves. Dissolve 11 equivalents of alanine methyl ester and add to this solution in 10 ml of ethanol. Example 1, adding a solution of the step product (0.81 g, 1.92 mmol) I got it. After stirring for 35 minutes1. 3 equivalents of GM N a B H3CN THF solution Volume (5.8ml.

5.77 mmol) was added. This was stirred at room temperature overnight under nitrogen atmosphere.

The reaction solvent was removed in vacuo, and the residue was purified using an LH-20 column using methanol as the eluent. Chromatographic separation was performed using a chromatographic system. In this way, all TEA-HCA! Since it was not possible to remove H3CN and N a B, 30% ethyl acetate Chromatograph again using a silica gel column with a hexane solution of separated. The product was isolated with a yield of 78% (0.88 g).

FAB-MS: M+l a; 584U HNMR: (3BM) Iz, CD Cl, ppm): δ7J5-7.1□3 (m, finished) 1); 5. INs, 2H); 4.50 (s, 2H); 3 ．． 80 (d, LH); 3.6N+.

3H); 3.60 (d, IH); 3.50 (1, l[l); 2. 95 (m, 2tl) 2.50 (+, 2H); 1, 70-i, 55 (m, 2B); 1.40-1.22(m, 21(); 0.95-0.80 (m.

! 2) 1); 0.02 (i, 6H) Preparation of limidazole (Scheme l l-2, compound 3) THF 1. Example 1, Step E product (53 mg, 1.91 μmol) in a solution. [1M tetrabutylammonium fluoride] 0.11 ml of THF solution was added. Stirred overnight at room temperature under nitrogen atmosphere. reactant was filtered through a silica gel plug using ethyl acetate as the eluent, and then filtered with fluoride tetrabutylene. Thilammonium was removed. The eluate was a solution of hexane and ethyl acetate in a ratio of 32. A pale yellow oil was separated by chromatography using silica gel. Generate The product was isolated with a yield of 76% (32 cm).

"HNMR: (300MHb CD C13, ppm): δ7.30-7. 10 (m, 7H); 6.90 (d, 2 [1): 5.17 (s, 2 H); 4.46 (s, 21(); 3.80 (d.

11 (); 3.64 (s, 3H); 3.60 (d, IH); 3 ．． 5G (1,11(); 2.95(m.

2H); 2.55 (+, 2) 1); 1.65 (m, 211); 1 ．． 35 (m, 2H); 0.90 (t.

Example 2 2-Butyl-1-C4-(Nll(R)-carbomethoxy-1-benzyl)methane methyl)aminomethylphenylcomethyl-4-chloro-5-hydroxymethylimide Dazole Sodium Salt Product of Example 1, Step F in a Solvent with a Methanol to Water Ratio of 31 (37mg, 78μzol) in a solution of 2. ON NaOH47μ/ was added and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was poured into 1.5 ml meta Dissolve in alcohol, filter, and use Sephadex column (L) with methanol as eluent. Chromatographically separated using H-20). two overlapping peaks It was found by mass spectrometry that it was a sodium salt and a free acid. Generate The material was separated and obtained in ~100% yield (35μ).

FAB-MS: M+l is 456 (1+e+ acid) and M+ Na (Na + al+) -LHNMR: (300MHx, CD30D, ppm! 67, 30-7 ．． 10 (m, 7H); 6.98 (d, 2H); 5.3G (+, 2H: ; 4.45 (s, 2H); 3.85-3, 70 (m, IH) + 3. 63-3.50fm, Iff); 3.35 (H for m): 3, +0-2, 9 3 (m, iH); 2.92-2.78 (m, 18); 2.551. 2H); 1.53 (m.

2fl): 1.30 fm, 2H); 0.88 ft, 3H)-be N-methyl)methyl-methyl-N-pentanoyl)aminomethylphenyl Rollo-5-hydroxymethylimidazole Step A: 2-Butyl-5-t-butyldimethylsilioxymethyl-1-C4- (N-(1(R)-carbomethoxy-1-benzyl)methyl-N-pentanoyl ) Preparation of amine methylphenyl]-4-chloroimidazole T of the product of Example 1, Step E (0.12 g, 0.20 mmol) under nitrogen atmosphere TEAl, 5 equivalents, was added to 2.0 ml of HF solution. Then 1.2 equivalents of valero chloride Added ile. Then, TEA-HCA' precipitated. Warm the reaction for 1 hour A subsequent TLC analysis showed that the reaction had completely progressed. TEA-HCA' is a reactant After filtration and evaporation of the filtrate, a yellow oil was obtained. This residue is It is thought to consist of two types: one that is silylated and one that is not.

The residue was purified using silica gel using 30% ethyl acetate in hexane as the eluent. Separated by chromatography.

The product was isolated in 92% yield (124 ■).

F, AB-MS: M+l or 668(m, 7)l); 6.9Nd , 2H); 5.15fs, 2)1); 4.50(+, 2H'); 4.40 (d, IH); 4.30 (m, LH); 3.73 (d, IH ); 3.64 (s, 3tl); 3.4-3.2 (Ill, 2H): 2.5 (+, 2H); 2.24 (m, 2H); 1.6 (m, 4H); 1, 3 (m, 4H); 0.85 (m, 15H); 0.02 (+, 6H) Step B 2-butyl-1-C4-(N-(1(R)-carbomethoxy- 1-benzylmethyl)methyl-N-pentanoyl)-aminomethylphenyl]- Preparation of 4-chlorohydroxymethylimidazole At room temperature, under nitrogen atmosphere, T Dissolve the product of Example 3, Step A (0.ilg, 0.16 mnol) in 2 ml of HF. To the clarified solution was added 12 equivalents of 1M tetrabutylammonium fluoride, and The procedure for floor F was performed. The product was isolated in 73% yield (63■).

(m, 7) l); 6.90 (d, 2) l); 5.15 (s, 2H) : 4.44 (s, 2H); 4.48 (d, 1)l); 4.26 (m, IHI; 3.74 (d, IH); 3.63 (s, 3H) ; 3.4-3.17 (m, 2H); 2.50’t, 2H); 2.2 (m , 2H); 1.6fm, 4H); 1.28 (m, 4H): 0.8 5 (s, 6H) Example 4 2-Butyl-! -C4-(N-(1(R)-carboxy-1-benzyl)methyl -N-pentanoyl)-aminomethylphenyl 3 Following the procedure of Example 2, Step A, Example 3. Hydrolysis of the product of step B yields the sodium salt in 58% yield (24,5■) was gotten.

FAB-MS: M+I at 562 anj M+Na aI584-HN MR: (300Hz, CD30D,!'pln) δ: 7.3-6.82 ( m, 9H]; 5.25 (d, 2H); 5. QO(d, IH); 4J (m, IH); 4.44 (s.

2H); 4.30 (d, IH): 3.4-2.8 (m, 2H): 2. I (m, 2H): 2.44-2 (, 2H); 1.6-1.1 (m, 8 H); 0.9-0.75 (s, 6H) flood 2-Butyl-1-C' 4-(N-(1(R)-carbomethoxy-1-benzi ) Methyl-N-(3-phenyl)propionyl)-aminemethylphenyl rice Tyl-4-chloro-5-hydroxymethylimidazole (Scheme I-3, Compound Product 13) Step A 2-Butyl-5-t-butyldimethyl-silyloxy-chloro Preparation of imidazole Product of Example 1, Step E (0,11 g, O,19 5 mmol) was treated with hydrocinnamoyl chloride and the product was obtained in 78% yield (110 ■) Separated by

FAB-MS: M+l at 716’HNMR: (300!dub CD C13, ppm): δ7.30-68 [m, N); 5.13 (s, :lI); 4.48fd, 2H); 4. '! 5fd, l [I); 4.27(m, Itl: : 3.7(d, IHi); 3.62(+, 3H ); 3.4-3.1 (m, 2H); 2.93 (z, 2H”); 2 ．． 5 (m, 4H!; 1.6!m, 211); 1.3 (m, 2H); 1 , 83 (m, 3H) Step B: 2-Butyl-1-C4-(N-(1(R)-carbomethoxy-l-be (3-phenyl)methyl-N-(3-phenyl)propionyl)aminomethylphenylco Preparation of methyl-4-chloroimidazole The procedure of Example 1, Step F was followed. Using the product of Example 5, Step A as the substrate, the desired The product was isolated with a yield of 61% (55 ■).

FAB-MS・ M+l at 602° M-18at 584 (loft of H,, O) and M-188at 414 (lost of 1m1da+ole!+agme++t)”HN MR: (300MH2, CDCA’ ppm1: δ7.30-6.8□3 ′ (m, 14H); 5.15 (s, 2H1; 4.43 (d, H); 4.32 (d, LH); 4.27 (m, IH); 3. Completed (d, I H>: 3.62 (+, 31 (); 3.4-3.1 (m, 2) 1); 2 ．． 93 (m, 2H”): 2.5 (m, 3H); 2.28 (m, I H); 1.64 (m, 2H); 1, 40 (m, 2 [1); 0.8 8 ft, 3H) The procedure of Example 2, Step A was followed using the product of Example 5, Step B.

This produces two products with slightly different Rf values, which are added to the THF solution of HCI. The free hydrochloride salt was obtained upon treatment with liquid.

FAB-MS: M+l at 588 and M-18at 570’HN MR: (300MHr, CD 30D, ppm) 6 7.3-7.0 ( z, 14t(): 5.5(+, 2H); 4.53(s, 2!(); 4.445-4Ji, 21():3, 9(d, IH); 3.25-3 ．． lfm, IH) +2.95-2.75f, 4H); 2.7-2, 4 (m, 2H): 1.6-1.4 (m, 2H); 1.3g -1,2 ( m, 2H); 0.92~0,78 (m, 3H) Example 7 2-Butyl-1-(4-(N-1i(R)-carbomethoxy-1-benzyl) Methyl-N-phenylacetyl)aminomethylphenylcomethyl-4-chloro- 5-hydroxymethylimidazole Step A 2-butyl-5-t-butyldimethylsilyloxymethyl-1-C4 -(N-(:(R)-carbomethoxy-1-benzyl)methyl-N-phenyl Acetyl)aminomethylphenylcomethyl-4-chloroimidazole The procedure of Example 3, Step A was followed. Example 1, Step E product (012 g, 0.209 mmol) with phenylacetyl chloride, the product was obtained in 57% yield ( 60■).

F　A　B-MS　:　M+l　at　702UHNMR:　(3QQ猜HL　 CD Cl 3. ...); 67, 38-7.15 (m, 9) 1); 7.0-6. 95 (m, 5H); 5.15 (+, 2H); 4.48 (S, 2H); 4.44fd, IH) + 4.15 (m, IH); 3.67 (S, 3 H); 3.63i, 2H); 3, 6G (d, LH); 3.38-3 ．． 13 (m, 2H); 2.5 (t, 2H): 1.6! m.

2H); 1.3 (m, 2H); 0.85 (m, 12) 1); 0.02 ( s, 6H) The procedure of Example 1, Step F was followed. Using the product of Example 7, Step A as substrate The desired product was isolated with a yield of 50% (24).

FAB-MS: M+1 at 558° M-18at 570 (lost of 820) and M-1f18a t 400 (ioft offimidxxole fragment+) (m, 14H); 5.15 (s, 2H); 4.45 (d, 2) 1); 4 ．． 4Hd, IH); 4.15 (m, 1) I); 3.6 (m, 6H ); 3゜4-3.15 (m, 2H); 2.52 (+, 2H); 1 ゜65 (m, 2H); 1.3 (m, 2H); 0.81,3H) butyl) Methyl-N-phenylacetyl)aminomethylphenyl]methyl-4-chloro- 5-Hydroxymethylimidazole (Scheme I-3, Compound 16) Following the procedure of Example 6, Step A and using the product of Example 7, Step B, the desired product is: It was isolated with a yield of 61% (16 ■).

FAB-MS: M+l at 574°M-18at 556 and 2M+l at1148 (mouth, 14H): 5.25 (d, 2H): 5.00 (d, 0.6H) :4.9-4.8(m, 0.4H) :4,7-4.6(m, IH): 4.45 (+, 2H); 4.45-4.3 (m, IH); 3.72-3. 48 (m, 2H): 3.38-3.05 (m, 1.4H); 2.70 (m, 0.6H: ; 2.55 (m, 2H); 1.50 (m, 2H); 1.26 (dt, 2H); 0.85 (+, 3H) 2-butyl-1-C4-N -(1(S)-carbomethoxy-1-benzyl)aminemethylphenylcomethyl -4-chloro-5 one step A, 2-butyl-5-t-butyldimethylsilyloxy Add L-phenylalanine to 2-3 ml ethanol with 3A molecular sieves. 1.1 equivalents (116 mmol, 0.538 mmol) of methyl ester hydrochloride and Example 1, Follow the procedure of Example 1, Step E using a solution containing 1.0 equivalent of the aldehyde synthesized in Step E. I obeyed.

The product was isolated with a yield of 59% (168 ■).

F A B - M S: M+,'at 584U HNMR: (300M Hr, CDCl 3. ppm): δ7.32 7.22 (m, 7H); 6.90 (d, 2H); 5.15 (s, 2H); 4.50 (s, 2H); 3.80 (d, 1) I); 3.65 (S, 3H); 3 ．． 60 (d, IH); 3.50 (t, 1) l); 2.95 (m , 2H); 2.50 (+, 2H); L, S (m, 2fl); 1.30 (dL 2H); 0.85 (I, s, 12H); 0.02 (s, 6H) Step B: 2-butyl-1-[: 4-N-(1(S)-cal Bomethoxy-1-benzyl)aminomethylphenyl]methy Example 9, Product of Step A The product was desilylated according to the procedure of Example 1, Step F using ) was obtained.

(m, 7H); 6.9Nd, 2Hj; 5.17 (+, 2H); 4.46 (+, 21 (); 3.80Id, IH); 3.64 (s, 3H); 3.60 (d, IH); 3.50 ft, IH); 2.95In, 2H); 2.55(t, 2H); 1.65(m, 2H ); 1.35 (dt, 2 [1); 0.90 (+, 3H) Example 10 2-Butyl-1-C4-N-jl (S)-carboxy-1-pencyl)amino methylphenyl]methyl-4-chloro-5-hydroxymethylimidazole The hydrolysis described in Example 2, Step A was carried out. The product of Example 9, Step B was used. play The free acid was isolated in 82% yield (12■).

FAB-MS: M+l H456° jrac! ! ll1mount of esut at 470 andM-' , Naat 478 fm, 7H); 7.00 (d, 2H); 5.27 (s, 2H); 4 ．． 45 (S, 2H); 3.75 (d, 1ft); 3.53 (d, LH); 3.02-2.90 (m, IH): 2.87-2.77in , 1)i); 2.55 (+, 2H); 1.53 (m, 2H); 1 ．． 27 (dt, 2H); 0.85 (+, 3 [1; The procedure of Example 3, Step A was followed. Example 9, using the product of Step A), with valeryl chloride Upon acylation, the desired product was obtained in 90% yield (97■).

FAB-MS: M+l al 668-HNMR: (300M+(!, C D C13, ppm): δ7.3-7.0 (m, 7H); 6.90 (d , 2H1; 5.13 (+, 2H); 4.48 (+, 2H); 4 ．． 40 (d, IH); 4.26 (t, IH); 3.75 (d, I H); 3.65fs, 3H1; 3.4-3, 15fm, 2H); 2.480.2H); 2.20 (m, 2H); 1.68-1.46f m.

4H); 1.38-1.18 (m, 4H) + 0.93-0.73 (m , 15H); 0.02(S, 6H) Step B 2-butyl-1-C4-(N-fl (S)-carbomethoxy-1- benzyl)-N-pentanoyl)aminomethylphenyl]-methyl-4-chloro -Preparation of 5-hydroxymethylimidazole Example II, Step A (94 mg, 0.14 mmol) in THF solution at 1.0 M Tetrabutylammonium fluoride 0. +7 ml and follow the procedure in Example 1, Step F. Ta. The product was isolated in 52% yield (4G, 5■).

FAB-MS: M+I at 354 and M-18 at 536 (m, 7Hi; 6.90 (d, 2H); 5.18 (s, 2H); 4.45 (s, 2fl); 4.38 (d, Iff) + 4.27 (m, IH); 3.73 (d, IH): 3.62 (s, 310) ; 3.4-3.15 (m, 2H); 2.53 (1, 2H); 2J -2 , 1 (m, 2H); 1.75-1, 5 (m, 4[1); 1.4-1. 2 (m, 4[1); 0.85 (m, 6H) Follow the procedure of Example 2, Step A. Example 11, Step B hydrolysis of methyl ester yields 73% (23■) So, sodium salt was obtained.

FAB-MS: M+l at 562°M+Na at 584.

2M+l atl124 and 2M+Na at 1145 "HNMR: UOOM+ (2, CD30D, ppm): δ7.28-6. 32 (m, 9H); 5.25 (d, 2H); 5.00 (d, IH) ; 4.6 (m, tH); 4.45 (s, 2H); 4.28 (d, I tl); 3.4-3.2 (m, IH); 3.10-2.98 (m, 0. 4H); 2.85-2.75 (m, 0.6H); 2.55 (m, 2H ); 2.38-1, 95 (m, 2H): 1.6-1. l(m, 8 )1);0.90-0.73(m,6H)2-butyl-5-t-butyldime tylsilyloxymethyl-1-C4-(N-(1-carbomethoxy-1,1-di benzyl)methyl)aminomethylphenylcomethyl-4-chlorimidazole (Fig. Scheme I-5, compound 18) Step A Preparation of N-benzylidene-D-phenylalanine methyl ester D Phenylalanine HC1 (1.6 g, 7.4 mmol) 1.0 equivalent suspension 10 equivalents of triethylamine was added to the cloudy solution to dissolve D-phenylalanine. child Add 1 equivalent of Mg504 to the solution followed by 10 equivalents of benzaldehyde. and stirred overnight at room temperature under nitrogen atmosphere. The solvent was then removed from the reaction mixture. . This residue contained a large amount of triethylamine hydrochloride.

This was removed by dissolving the product in THF. TEA-HCA by filtration ’ was excluded.

This benzylidene was confirmed by NMR. All this was used in the next step.

-HN MR: (300MHb CD C13, l'pm) '67, 90 (s, IH); 7, 68 (d, 2) 1); 7.4 (m, 3H) Ni A, 26-7, 12 (m, 5H); 4.17 (m, 1B); 3, 7 2 (s, 3H); 3.38 (dd, IH); 3.15 (dd, IH ) Step B Methyl-2-amino-3-phenyl-2-phenyl-78°C, dry T A solution of benzylidene (Example 13, Step A) in HF2Sml to 1.0 M A THF solution of lithium hexamethylzincracite (1.05 equivalents f7.8 ml) Added over 10 minutes. After 30 minutes 1805 equivalents of benzyl bromine in 15 ml THF The solution containing the amide was added over 15 minutes. The reaction mixture was incubated at -70 °C for 15 min. Stirred. Then, it was gradually warmed to -40℃ and kept at this temperature for 15 hours with stirring. .

The temperature was further increased to -35°C and the same operation was performed. The reaction seemed to be complete now. . 1 at -35°C. The reaction was quenched by adding 150 ml of ON HC. So The mixture was stirred and warmed to room temperature. The reaction mixture was extracted twice with hexane and the formed Benzaldehyde was removed. The aqueous layer was extracted three times with ethyl acetate. And draw The extracts were combined, washed with saturated NaHCO3 and brine, and dried over MgSO4.

The solvent was removed in vacuo to yield 324 ml of a yellow crystalline solid.

The pH of the aqueous layer was adjusted from 1.4 to 11.8 using 3N NaOH.

The NaOH gives a milky white solution, and when ethyl acetate is added, the boundary becomes clear. did. The basic aqueous layer was extracted two more times with ethyl acetate. Mix the extract and wash with salt water. Dry with MgSO4. Solvent was removed in vacuo. and colorless oil (1,37 g) was obtained, with a total yield of 85%.

FAB-MS: M+H=270 YuHNMR: (300MHz, CDCA’3.ppm): 67.3 -7. +5 (m, l0H); 3.65j+, 3H); 3J7 (d, 2 H); 2.74 (d, 2fl) Step C2-Butyl-5-t-butyldimethyl Silyloxymethyl-1-[:+4-11-carbomethoxy-1,1-dibendi methyl)aminomethylphenylcomethyl-4-chloroimidazole (ski MgSO4 was added to a solution containing 1.1 equivalents of Mg I-5, compound mmol). After 1.0 minutes, Example 1, graded aldehyde (0.46 g, 1.09 mmol) Added equivalent amount. The reaction mixture was stirred for one week at room temperature under nitrogen atmosphere. Then filter, Concentrated in vacuo. The reaction mixture was dissolved in toluene and incubated for 3 hours with a Dean-Stark solution. The mixture was heated to reflux under a cup. Then cool to room temperature under nitrogen atmosphere, 1. OM Na C 3.0 equivalents of N　B　H3 were added. The reaction mixture was stirred overnight at room temperature. The solvent is Removed in vacuo. The residue slowly separates into two layers when dissolved in ethyl acetate and water. It was written. The organic layer was washed with brine and dried over MgSO. Then filter the solvent Excluded. The residue was eluted with a ratio of hexane and ethyl acetate of 41, and was purified using silica gel. It was separated into two components using chromatography. The first component is a Schiff base and The product contained 378 μm, 51%. The second component contains the desired product ( 43■) were included. This mixture was eluted with 15% ethyl acetate and hexane. It was separated again by chromatography. The first component produces the product (1,8■) Separated. The total yield was 20.5% (153■). The second ingredient is ship salt It contained 90 μ of a mixture of radicals and desired product.

FAB-MS: M+H=674 'HNMR: (3QOMH!, CD C1a, I'l1m): 67.3 -7.15 (m, 12H): 6.95 (d, 21 (); 5.17 (s , 21 (); 4.53 (S, 2H); J, 87 (S, 2 ■); 3.6 3(s, 3H); 3.23(d, 21(); 3.(lHd, 21); 2.54(1,2)l); 1.66(m, 2Hi); 1.34ft+, 2H); 0.86 (m, 12H); 0,04 (s, 6H) Example 14 2-Butyl-1-(4-(N-(1-carbomethoxy-1,1-dibenzyl)methyl) methyl)-aminomethylphenylcomethyl-4-lyTHF 2. Qa+1 middle example 13 , 1.0M in a solution of the product of step C (67mg, O, lOmmol) Addition of 1.2 equivalents of tetrabutylammonium fluoride in THE solution followed by Example 1, step The product of stage F was added.

The desilylated product was isolated (65μ, 100%).

FAB-MS: M+H=560 YuHNMR: (300Hz, CDCl 3.ppm): 67.35- 7.15 (m, 12H); 6.90 (d, 2H); 5.20 (s, 2H) H); 4.45 (S, 2H); 3.87 (s, 2H); 3.6 4 (s, 311); 3.20 (d, 2H); 3.05 (d, 2H); 2.55 (+, 28); 1.67 (m, 2[1); l. 35 (m, 2H); 0.88 (+, 3H) Example 14, Step B The product was used to carry out the hydrolysis of Example 2, Step A. The reaction was carried out overnight but did not proceed completely. There didn't seem to be any going there. Thereafter, the mixture was refluxed at 100°C for 4 hours. 2. ON N 2 equivalents of aOH! 0.1 ml) was added and the reaction mixture was refluxed for 2 days. reaction mixture When cooled to room temperature, the mixture became cloudy, acidified by adding concentrated hydrochloric acid, and stirred for 1 hour. solvent was removed in vacuo and water was azeotroped with toluene and acetonitrile. The residue is safe Using an Adex column, methanol, which produces both acids and esters, is used as the eluent. Separated by romatograph. This mixture is 111 CH2Cl2:CH30H The mixture was chromatographed using silica gel as an eluent, and the ester was eluted. that From, elute 111110.5 CH2CI2:CH30H:HOAc The acid was eluted as a liquid in 44% yield (27 mg).

FAB-MS: M+1 at 546 and M-19at 528 (m, 12H); 7.0 (1 (d, 2H); 5.3 [d, :H); 4. 45 (s, 2H); 4.05 (s, 2)l); 3.43 (s, 2H); 3.18 (d, 2+1); 2.52 (L 2)l) ; 1.2 ftB 2H): 1.28 fm, 28); 0.85 (m, 3H) Example 16 ! -C4-(1(N-benzyl)-N-pentanoyl)amino-! −(Tetra sol-5-yl)methylphenyl]methyl-2-butyl-5-t-butyldime Example of 2-3 ml CH2C12 medium with added tylsilyloxymethyl-4-Mg5○ 1. Add 1.7 equivalents of benzylamine to the solution containing the step products and mix the reaction. The mixture was stirred for 2 days. The Schiff base format was not fully developed. (T.L.C. Add trimethylsilyl cyanide (1,1 equivalent) to the reaction mixture (based on measurements) and leave at room temperature. The mixture was stirred overnight. The reaction mixture was filtered, CH2Cl was removed from the filtrate, and ethyl acetate was added. The solution was washed twice with water, once with brine, and dried over MgSO3. solvent is true It was removed in air and the residue was acylated in the next step.

FAB-MS: M+l at 537-! HNMR: (300MH!, CDCl 3. ppm): δ7.50 (d, l’H!; 7, 3-7.2 (m, 5H; Near, 03 (d, 2H); 5.20 (s, 2H:); 4.73 (s, 18): 4, 50 (i, 2H): 4.05fd, I tl): 3.95 (d, IH); 2.50ft, 2fO; 1.65 (m, 2H); 1.30 (d+, 2H); 0.85 (m, 12) 1 ); 0.02 (S, 6H) Step B: l-[4-(1-(N-benzyl )-N-pentanoyl-amino-1-cyan)methylphenylcomethyl-2-butyl Chyl-5-t-butyldimethylsilyloxymethyl-4-chloroimidazole Preparation Example 16, Step A product (132 mg, 0.246 mmol) and chloride barrel 1.2 equivalents of loyl (35 μA, 0.295 mmol) and 1.2 equivalents of triethylamine. Example 3, step A acylation using 5 equivalents (51 μA', 0.368 mmol) I did it.

After several hours of stirring the reaction did not appear to have gone completely. So - continue stirring overnight. I got it. The reaction mixture was filtered and the solvent was removed from the filtrate. The residue is 41. Hexane: It was chromatographed on silica gel eluting with ethyl acetate. two separated The one was a mixture. It contained the acylated product and the original material. this A total of 16 equivalents of valeroyl chloride and 10 g equivalent of triethylamine was reacylated in THF.

This was carried out with stirring overnight at room temperature. The product obtained by the procedure described above was 41. Heki Separation was performed by chromatography using silica gel using ethyl acetate as the eluent.

The product was isolated in 33% yield (50 ■).

-HNMR: (300MHz, CDCl 3.ppm): 67.4- 6.96fm, 9H); 5.15 (+, 2H): 4.55-4. 4 (mouth, 5H); 2.48 (+, 2) 1): 2.28ft, 2H ); 1.63fm, 4)1); 1.3 (m, 4H) + 0.85fm , 12H); 0, 02 (+, 6H) A solution of 1.0 equivalents of the product of Example 16, Step B in 2 ml of dry toluene. Add 1.2 equivalents of triethylstaniazide and gradually warm the mixture to toluene overnight. Reflux occurred inside. It was confirmed by TLC and NMR that the original substance had disappeared. The resulting material was used in the next step.

-HNMR: (300MH!, CDCl 3.ppm): 67.6- 6.6 (m, 9H!; 5. i2 (+, 2M:; 4.95 (d , IH); 4.75 (d, IH); 4.55-4, 37 (m, 3H); 2.5-2.4 (m, 2fl): 2.4-2. l(m, 2H ): 1.7-1, 5 (m, 4H): 1.4-1.2ix, 4H) +1. Go-0,8 (m, 12H); 0.70 (s, 6H): 0 ．． 02 (i, 6Hj stage D・l-[4-(1-(N-pencil-N-pen Example 16, Step C product (theoretically 66 mg, 0.08 m mol) 5 drops of concentrated hydrochloric acid were added to 2 ml. The reaction mixture becomes warm and can be placed on ice. Cooled in bath and stirred. The reaction mixture was then warmed to room temperature and stirred for 1 hour at room temperature. did. The reaction appeared to proceed completely. The solvent was removed in vacuo and the residue was 11011, CHCl 3: CH30H: NH4OH as eluent, silica Chromatographic separation using gel. The product was isolated in 25% yield (10■) did.

FAB-MS: M-i-1at 550゜M+Na 1F 572 xnd M-18a1532 YuHf'iMR: (300MH2, CD30D, ppm): 67.5-6. 7 (m, 9H); 5.25 (s, 2H); 5.0-4.7 (m, 2H ]; 4.35 (s, 21 (); 2, 63 (m, 0. SH); 2. 52 (+, 2H); 2.30 (j, 1.5H); 1.68-1.4 5(m, 41(1; 1.4-1.15(m, 41(): 0.95-0 ．． 75 (m, 6 Hi Kou )) Methylphenylcomethylimidazole (Scheme I-9, Compound 39) Step A, Preparation of 4-bromoethylbenzophenone b 4- in Oml CCl J Add N- to a solution of methylbenzophenone (3,0g, 15.3 mmol). Promosuccinimide (3,0g, 1.1 eq.) and AIBN (30■) were added. . The solution was refluxed for 4.5 hours and then cooled to room temperature.

Succinimide was removed by filtration. The filtrate was dried and concentrated. Recrystallization is A large amount of solvent was used. Chromatography seems to be a good alternative to recrystallization. Ta. The residue was chromatographed on silica gel using 5% nityl acetate/hexane as eluent. Separated by chromatography. (3.44 g, 82% yield) 7.5 jm, 4 fl, 7.6 fm, 1ff), 7.8 (m, 41 () Stage B: l- ! 4-benzoyl)phenylmethyl 1-2-butyl-5-t-butyldimethylsilyl Preparation of lyloxymethyl-4-chloroimidazole Suspended N a H (0.21 g, 6.97 mmol) in 15 ml DMF Add 2-butyl-5-t-butyldimethyl-silyloxymethyl-4-chloro to the suspension. Loimidazole (2,0g, 6.62 mmol) was added. Mote N, lower 45 Stir for a minute. To this solution was added 4-bromomethylbenzophenone (1.82 g, 6 ．． 62 comol) was added and stirred for 4.5 hours. The reaction mixture was made of saturated ammonium chloride. The reaction was quenched with nitrogen and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The mixture was washed with H2C and brine, dried over MgSO4, filtered, and concentrated in vacuo.

The product was purified on silica in two batches using 15% ethyl acetate in hexane as eluent. Separation was performed by chromatography using gel (170 ma + x 50 mm). product was isolated with a yield of 71% (2.36 g).

YuHNMR: (300MHz, CD C13, ppm): δQ, l ( s, 6H); Q, 80-1. Q (m, 12H): 1.3-1.45 (m, 2H!; 1.6-1.75 (m, 2H); 2, 5-2.6ft, 2H); 4.55 (+, 2H); 7. l(d, 2H) Near, 5( d, 2H); 7.6jm, IH): 7.7 7.8 (m, 4H) Preparation of phenylcomethylimidazole Nitrogen atmosphere Example 17, Step B Keto: / (0.50 g, 1. Ommol) Add trimethylsilyl cyanide (TMSCN) (35ml) to 2ml of CH3C12 solution. g,l. 2mt5ol) was added. Followed by KCN (10 mg) and 18-crown -5 (10■) was added. Reactions were checked by TLC. Reaction completed in 3 hours did. The solution was diluted with diethyl ether (~3゜ml) and diluted with dilute NaHC○3 and brine. Washed. The organic extract was dried over Mg5o4, filtered and the solvent was removed in vacuo. Living The product was isolated with a yield of 67% (0.40 g).

-HN MR: (300MH2, CD C13, ppm) +60.05 ( +, 9H); Q, to (+, 6) 1:; 0.8-0.9 (m, 12 H): 1.3-1.45 (m, 211); 1.5-1, 65fm, 2 H): 2.4-2.5 (+, 3H): 4.5 (+, 2H); 5.2 (s, 2H) Near, 0 (d, 2!l) Near 1 7.4 (m, 3B); 4 7ffm, 4H: Step D 2-butyl-5-t-butyldimethyl-silyl xymethyl-4-chloro-1-(4-(1-hydroxy-1-phenyl-1-( Tetrazol-5-yl)) Preparation of methylphenylcomethylimidazole Example 17, step Cto, lg, 0.17 mmol) was dissolved in 500 ml of Add trimethylsufnyl azide (41■, 0.20 mmol) to the cooled solution at room temperature. added. The reaction was warmed to reflux for 24 hours. The reaction product was confirmed by TLC.

The reaction was 60% complete after 7 days. The residue was dissolved in 15% ethyl acetate containing a few drops of methanol. Using hexane solution of 100ml as eluent, chromatography was performed using silica gel (F120 x 15mm). Separated by matograph.

The product was isolated in 15% yield (20 ■).

-LHN MR: (300MH2, CD C13, ppm): 60. t (s, 6H); 0, 8-0.9 (m, 12H); 1.25-1.40 ( m, 2H); 1.6-], 7(m, 2H): 2.5ft, 21() ; 4.5 (s, 2H): 5.25 (s, 2H); 7. l(d,2H)d A, 4-7, 6 (m, 3H) + 7.7-7.8 (m, 4H) 〇-Salt Phenyl acetic acid (5,00 g, 29.3 mmol) and thionyl chloride (2,67 1.36.6 mmol) was refluxed. Kake for more than 10 minutes, remove bromine, 1 Refluxing was continued for 7 hours. Cool the reaction mixture to room temperature and slowly add methanol 3 (1 ml). added. The solvent was removed in vacuo and the residue was eluted with 5% ethyl acetate in hexane. The liquid was separated by chromatography using silica gel. The product has a yield of 28% (2.13 g).

'HNMR: (300jH+, CDCl3.ppm1: δ3.3 (s , 3H); 5.95 (+, lH) +7.25-7.45 (m, 3) 1) ; 7.7-7.8 (m, IH) Step B Methyl 2-(4-methylphenoxy) -Preparation of -Qj2'-chlorophenyl)acetate KH (0.53 g, 4.63 mmol) in DMFS ml under nitrogen atmosphere at 0 °C Add p-cresol (0.5 g, 4.63 mmol) to the suspension of Ta. The reaction mixture was stirred until the evolution of H, was complete. Then 18- of 50■ Example 18, Step A (1,2 2 g, 4.63 mmol) was added.

The reaction mixture was stirred at 0°C for 30 minutes. It was then warmed to room temperature.

The reaction mixture was concentrated in vacuo and silicaed using 5% ethyl acetate in hexane as eluent. It was separated by chromatography using Kagel (130 mm x 30 mm). product was isolated in 77% yield (1.03 g).

FAB-MS: 290. 292 -HNMR: (3QOMH1, CDCl 3.ppz): δ2.25(s , 3Hi; 3, Hs, 3) 1); 1.25-1.40 (m, 21(); 1.6-1.1 (m, 2!l); 6.15ts, II); 6.8- 6.9 (d, 2H); 7.25-7.35 (m, 2H); 7.4-7 , 5(m, 1t();'1. 6-7. 7(m, 1B); Completed 6 -7. 7 (m, 1 ll) Step C Methyl 2-C4-bromomethylphenoxy Preparation of c)-2-(2'-chlorophenyl)acetate in 2 mI CCl 4 , Example 182 Step B product f0.2g, 0.69Dmol), N-promosac A solution of cinimide (l 17 mg, 166 mmoi) and a catalytic amount of AIBN was dissolved. Refluxed for 30 minutes. The reaction was concentrated in vacuo and diluted with 5% ethyl acetate in hexane. Separation was performed by chromatography using silica gel (125×20−) as an eluent. Living The product was isolated in 73% yield (186 µ).

FAB-MS: 368. 370. 372 (10:13:3 chlorine and bromine) isotope ratio by presence) ! , 5(s, 2!() +6.1sfs, II); 6.35-6.9 5 [L 2) 1); 7.25-7.35 (m, 4H); 6.15 (1 , IH: ; 6.85-6.951d, 210; 7.25-7.35 ( z, 4H) near, 4-7.5 (m, IH): 7.6-7, Hz, IH) Chloro)-phenyl)methoxyphenylcomethyl-4-chloroimidazo Preparation of the roll N a H [2.7 mg, 89 mmol) was suspended in 250 μβ DMF 2-Butyl-4-chloro-5-t-butyldimethylsilyloxymethylene is added to the suspension. Added limidazole and stirred for 15 minutes. Add DMF (0,2 5 ml) of the solution containing the product of Example 18, Step C was added and stirred at room temperature for 2 hours. . The reaction mixture was stored at -30'C for one week. It was then warmed to room temperature and stirred for 4 hours. . The reaction mixture was concentrated in vacuo and 15% ethyl acetate in hexane was used as the eluent. It was separated by chromatography using silica gel (13G x 20mm).

The product was isolated with a yield of 65% (31■).

HNMR: (3 [10M) IZ, CD CI 3, ppm) +60.0 5 (s, 6H); 98-0°9tm, 12H): 1.2-1.35fm , ? H); 1.5-1.65 (m, 2H): 1, 95-2. Q5 ( f, 2H); 3.75 (s, 310; 4.5ft, 2); 15.1 (s, 2) 1);o, lf+, i! (i:5,35 6.95'm, 4H) +7.257.35 (m, :!H) Near, 4-7, 5 (m, IH!; 7 ．． 5-7.6 (m, III) Step E 2-butyl-1-(1-carboxy -1-! 2-Chloro)phenyl)methoxyphenylzmethyl-4-chloro=5- Preparation of hydroxymethylimidazole in methanol (0.5 ml) Example 1a 1 stage Add 500 μl of N a OHf to the solution containing the next product until the reaction solution becomes cloudy) added. The reaction mixture was stirred for 1 hour and concentrated in vacuo. The residue has a concentration of 11 Hydrochloric acid (T) (F) was dissolved in 5 ml of solution and stirred overnight.The reaction mixture was diluted with 6N NaO Neutralized with H and concentrated in vacuo. The residue was dissolved in ethyl acetate, filtered and dissolved in vacuo. Concentrated. The product is 100:3:1 CHCl:CHOH:CH3Co Chromatograph using silica gel II (20×1, 5 mm) with 2H as eluent. Separated by f. The product was obtained in a yield of 38% (9■).

-HNMR: (30DMHz, CD30D, ppm): 60.75-0 ．． 85 (+, 3H); 1.2-1.35 (m, 2H); 1.35-1 ．． 5 (m, 2H); 2.5-2, 6 (+, 2H): 4.5 (S, 2[ 11:5.2(s, 2H]:6.l(i, IH); 6.9-7.1 [m, 4H); 7.3-7.4 (m, 2H); 7.4-7.5 (m , IH); 7.55-7.65fm, 1H) 4-Bromomethylbenzoic acid (5.04 mg) in THF (30 ml).

The suspension containing 23.3 mmol) was cooled to 0°C, and the boron/THF (35 mmol), remove the ice bath and warm the mixture to room temperature at 15:00. Stir for a while. Excess boron is quenched with methanol and water, and the reaction mixture is kept in vacuum. It was concentrated with The residue was dissolved in ethyl acetate, 4% HCI, NHCO3, water, salt. Washed with water, dried over MgSO4, filtered and concentrated in vacuo to yield the title compound 4. 44g (94%) was obtained.

-HNMR: (300MHz, CD C13, ppm): δ7.38 (Q , 4H); 4, 70 (s, 2H); 4.51 fs, 2H) FAB MS: m/e=202 (M+H) Step B: 4-(bromomethyl)-1- Preparation of butyl-dimethylsilyloxymethylbenzene In CH2Cl2, the product of Example 19, Step A (4.44 g, 22.I++ mol ), N,N-diisopropylethylamine (1,2 equivalents) and 4-dimethylaminopyridine (0.1 eq.) and t-butyldimethylsilylchloride Light (1.2 eq.) was added. The mixture was stirred at room temperature for 1.5 h and concentrated in vacuo. Shrunk. The residue was dissolved in ethyl acetate, washed with water, brine, dried over MgSO4, Filter and concentrate in vacuo. The residue was silica (ethyl acetate/hexane (2,5/ 97.5)) was separated by chromatography to give 5.0 g of the title compound. (71%) was obtained.

■ -HNMR: (300MH2, CD C13, ppm): δ7.34 (q , 4H); 4, 74 (s, 2H); 4.59 (s, 2H); 0 ．． 95 (s, 9H!: Q, 11 (s, 6H) HMP, A (11ml, benzyl cyanide (1,5 mzol) in THF (40 ml) containing ml, 12.7 mmol) was cooled to -78°C. Richi for this umbis triethyl syriaamide (16 ml, 16 mmol. IM in THF ) was added dropwise to maintain the temperature below -73°C. This reaction product was heated to -78°C for 1 ．． Stirred for 5 hours. To this was added the product of Example 19, Step B, in THF (8 ml). A solution containing (2.0 g, 6.34 mmol) was added and kept at -70°C or below. anti The reaction temperature was kept below -68°C for 3 hours. lN N a HS to the reaction mixture O4 was added to quench the reaction at this temperature. After warming to room temperature, the mixture was diluted with ethyl acetate. The organic layer was washed with water, saturated NaHCO3, brine, and dried with MgSO4. , filtered and concentrated in vacuo. The residue was silica (ethyl acetate/hexane (5/9) When separated by chromatography using 5)), 1.5g (67%) of The product was obtained.

-HNMR: (300MH2, CD C13, ppm+: δ7.40-7. 30fm, 3H); 7.30-7.2gm, 410; 7.10(d , 2H); 4.73 (+, 2H!; 3, 98ft, iH); 3.23 -3.08 (m, 2H); 0.94 (s, 9H); 0.10 (s.

6H) FAB MS: m/e=294 (lossof t-Bu) Stage D+3- Preparation of C4-bromomethyl)phenyl-2-phenylpropionitrile Example 19, Step C product (1.5 g, 4.27 mmol) was mixed with acetone and acetic acid. CB r 4 (l equivalent) and Ph5P (1 equivalent) in a mixture of tonitrile or 11 Treated with the dissolved solution and cleaned using silica (ethyl acetate/hexane (5/95)). Romatograph separation yielded 575 ml (45%) of the title compound.

'HNMR: (300MH2, CD C13, N11ll '67.48-7 ．． 10fz, 9H); 4.50 (s, 2H); 4. OOf! , IH ); 3.26-3.10 (m, 2H!FAB MS: m/e=299/ 30/Step E 4-chloro-2-butyl-5-t-butyl-dimethylsilyloxy cymethyl-1-[4-11-cyano-1-phenyl)methylphenylcomethyl Sodium hydride (1,2 eq. in oil) in Midazole dry DMF (1 ml) Dispersed in N, the concentration is 80%, 16■) was suspended in N, cooled to 0°C, -4-chloro-5-t-butyldimethylsilyloxymethylimidazole D M　F　(1.5ml) solution 1. Equivalents of O were added dropwise and foamed. reaction mixture was stirred for 45 minutes at 0°C. Bromide (Example 19, Step D) in 1.5 ml DMF A solution containing the mixture was added.

The ice bath was removed and the reaction mixture was gradually warmed to room temperature. The color gradually changes and becomes darker. It turned red. No bromide remained by TLC (20% ethyl acetate/hexane). There wasn't. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. residue was dissolved in ethyl acetate and washed with water. The organic layer was extracted with water and brine, and Na2 It was dried with SO4. The product was eluted with 15% ethyl acetate in hexane. , separated by MPLC using silica gel.

69 ml of the desired product (yield 29%) was obtained.

Example 19, dry 2 ml of the graded product (69 mg, 0.1 32 mmol) Dissolve in dry toluene [~2 equivalents of trimethylstaniazide are added and the mixture is purged with nitrogen] It was refluxed under atmosphere. After refluxing for 22 hours the reaction turned brown. TLC (30% (ethyl acetate/hexane), leaving a significant amount of unreacted nitrile. The solvent is It was removed in vacuo and the reactant was examined by NMR, leaving 25% unreacted nitrile. there was. Add the same amount of trimethylstaniazide to the toluene solution of this mixture. The mixture was refluxed for 5 hours. Some nitrile still remains due to TLC I understand. The reaction mixture was slowly cooled to room temperature and stirred overnight. reactant Toluene was removed from the solution, dissolved in THF, cooled with ice, and 3 drops of concentrated hydrochloric acid were added. solvent was removed azeotropically from toluene/CH3CN. The product is a5:13 CF (Cl 3: Silica using 10% ammonium hydroxide/methanol as eluent) It was separated by chromatography using Kagel. The target product is 35■ (60% yield) was obtained.

FAB MS: M”, H=451YHN MR (30Blix, CD 3 0D, ppm): δ7,32 7.18 (m, 5H); 7.09 (d, 2H): 6.90 (d, 2H); 5.21 (+, 2H) ; 4.63 (+, IH) ; 4.42 (+, 2! (! ; 3.63 -3.52 (dd, LH); 3.42-3.31-h I-n TCT :lE f; N vpfu777peh k +LfuTT ml-upper m-(a d, 11(); 2.5(1(+,2)1); 1.52-1.39fm, 21 (); 1.32-1.18 (ω, 2H): Q, 82 (+, 3H)ethyl)aminophenylcomethyl-1-chloro-5-hydroxymethy lumidazole Step A 2-Butyl-1-[4-(N-(1-carboxy-1-(2-phenyl) )ethyl)aminophenylcomethyl-4-chloro-hydroxymethylimidazo Preparation of (4-aminophenyl)methyl-2-butyl-4-chloro-5-butyldimethyl A solution of silyloxymethylimidazole, 204 mmolj (500 mmolj) is Methyl-2-)-2-bromoacetate in 0.25 ml of methanol 132 ■ (0,575 mmol) and 50 ■ (0,595 mmol) sodium bicarbonate 1) and potassium iodide crystals. - After stirring overnight, the reaction mixture is After concentration in air, extraction with 5 ml dichloromethane and removal of solvent in vacuo, 1 m The solution was dissolved in 1 methanol and applied to an LH-2θ column. Products containing impurities are purified. After the solvent was evaporated, the yield was 241cm (87%).

-(Otsu ni 1 yo kouji yo 1~-V1 Mr. Kogisujin' 飄) r/shiko l　L　shi1w　d -Q half-V point was used.

Step B 2-Butyl-5-t-butyldimethylsilyloxymethyl-1-C4- (N-Jl-carboxy-1-phenyl)-methyl)aminophenylcomethyl- Preparation of 4-taloloimidazole Example 20, 1116■ of the product of Step A and 1 ml of IN sodium hydroxide were added to a 2 ml tube. It was dissolved in tanol and stirred for 4 hours. After adding 5ml sodium acetate, 5% It was extracted twice with 5 ml of an aqueous enoic acid solution. Drying and concentrating ethyl acetate yields 221 ■ (90%) of the product citrate was obtained, which showed accurate mass spectra and N I had an MR.

Step C・2-Butyl-! -C4-(N(1-phenyl)-aminophenyl rice) Preparation of thyl-4-chloro-5-hydroxymethylimidazole Formation of Example 20, Step B in 420 ml of 1M tetrabutylammonium fluoride solution The mixture containing Product 212 was allowed to stand at room temperature overnight. Concentrate in vacuo and remove remaining o The mixture was treated with 10ml ethyl acetate.

This was extracted four times with 15 ml of a 5% citric acid aqueous solution. Got more salt. T The structure was confirmed at a single point by LC and by NMR and mass spectra. did.

Step D = 2-butyl-1-(4-(N-(t-carboethoxy)methanol 5 ml of Example 20, Step C product ethyl-2-oxo-4-phenylbutanoe. 429mg (2,081mmal) and 50Q■ 3A molecular sieve The slurry was stirred for 6 hours.

Then, add 2 ml of methanol acyanosodium borohydride to this solution. The solution was added and treated for 30 minutes. After stirring for 41 hours, 165 μm of pyridinium chloride ( 1,42 zmol) and after 1 hour the reaction mixture was stirred and filtered to reduce the viscosity. Concentrate in vacuo to a solid oil. Add the oil to 10ml methanol It was dissolved in Then, pour this into ll (1ml Dowex 50 (H”)) Neutral and basic substances are removed with 200 ml methanol, and the product is 400 ml Elution was performed with 4% pyridine in methanol. The eluate is concentrated to an oil. The solution was dissolved in 1 ml of methanol and applied to an LH-20 column.

The product was evaporated from the solvent and the yield obtained was 122.5 μ (49.9%), TL There was one point in the C measurement, which was confirmed by NMR and mass spectra.

Step E 2-butyl-1-(4-(N-11-carboxy-1-2-phenyl) ethyl)aminophenyl]methyl-4-chloro-5-hydroxymethylimidazo Preparation of the roll Example 2 118 mg (Q, 252 mmol) of 0% grade product and IN sodium hydroxide 0.55ml of thorium solution! , dissolved in 5 ml of methanol and kept at room temperature for 5 hours. Made it react. It was then refrigerated for 16 hours. After adding 5ml ethyl acetate, the reaction mixture The material was extracted twice with 5 ml of 5% aqueous citric acid solution.

When ethyl acetate is dried and concentrated under vacuum, 157μ (96%) of citrate is obtained. The product was obtained. The desired structure was confirmed by NMR and mass spectra. .

Engraving (no changes in content) Summary book Substituents attached via a methylene bridge to the novel substituted phenyl derivatives of formula (I) Imidazole is useful as an angiotensin antagonist.

Procedural amendment September 2, 1992 1. Indication of case PCT/US 91101001, title of invention Substituted benzyl Imidazole angiotensin antagonist containing the moiety 3. Person who makes corrections Relationship to the incident: Patent applicant Name: Merck & End Company 5. Date of amendment order: Self-issued (1) Add a clear translation of the specification as shown in the attached sheet. (No change in content) (2 , supplement the translation of the claims as attached. (No change in content) (3) Fresh Add a clear translation of the abstract as shown in the attached sheet. (No change in content) 1st investigation report

Claims (12)

[Claims] 1. Compounds of formula I: ▲Mathematical formulas, chemical formulas, tables, etc. ▼Formula I or pharmaceutically acceptable salts thereof: During the ceremony, R1 is: a) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6) )-alkynyl, each unsubstituted or with a substituent selected from the following group: This is what I replaced: i) an aryl as defined below; ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) COOR2, vii) N[((C1-C4)-alkyl)]2, viii) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and b) Aryl, where aryl is defined as phenyl or naphthyl, unsubstituted or Substituted with one or two substituents selected from the following groups: i) Cl, Br, F, I, ii) (C1-C4)-alkyl, iii) (C1-C4)-alkoxy, iv) NO2, v) CF3, vi) SO2NR2aR2a, vii) (C1-C4)-alkylthio, viii) hydroxy, ix) Amino, x) (C3-C7)-cycloalkyl, xi) (C3-C10)-alkenyl; c) heteroaryl, where heteroaryl is unsubstituted, -substituted or disubstituted 5-membered A cyclic or 6-membered heteroaromatic ring, which is a group containing N, O, S. one or two members selected from the following groups, and the substituents are Selected from: i) Cl, Br, F, I, ii) OH, iii) SH, iv) NO2, v) (C1-C4)-alkyl, vi) (C2-C4)-alkenyl, vii) (C2-C4)-alkynyl, viii) (C1-C4)-alkoxy , or ix) CF3 or d) perfluoro-(C1-C4)-alkyl; B is: (a) single bond, (b) -S(O)x(CH2)s-, or (c) -O-; and x is 0 to 2; s is 0 to 5; m is 1 to 5; p is 0 to 3; n is 1 to 10; and R2 is: (a)H, or (b) (C1-C6)-alkyl, R2a is: (a) R2, (b) CH2-aryl, or (c) aryl; R3 is: (a)H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C 6)-alkynyl, (c) Cl, Br, I, F, (d) NO2, (e) (C1-C8)-perfluorinated alkyl, (f) C6F5, (g)CN, (h) NH2, (i) NH[(C1-C4)-alkyl), (j) N[(C1-C4)-alkyl ]2, (k)NH[CO(C1-C4)-alkyl), (l)N[((C1- C4)-alkyl)-(CO(C1-C4)-alkyl)], (m)N(C1- C4)-alkyl-COaryl, (n)N(C1-C4)-alkyl-SO2 Aryl, (o)CO2H, (P)CO2R2a, (q) phenyl, (r) phenyl-(C1-C3)-alkyl, (s) phenyl or phenyl-( C1-C3)-alkyl, in which the phenyl ring is substituted by one or two substituents; and the substituents are selected from: i) (C1-C4)- alkyl, ii) (C1-C4)-alkoxy, iii) F, Cl, Br, I, iv) hydroxy, v) methoxy; vi) CF3, vii) CO2R2a, or viii) NO2 and R4 is: (a)H, (b)CN, (c) (C1-C8)-alkyl, (d) (C3-C6)-alkenyl, (e) (C1-C8)-perfluoroalkyl, (f) (C1-C8)-perfluoro loalkenyl, (g)NH2, (h) NH(C1-C4)-alkyl, (i) N[(C1-C4)-alkyl] 2, (j) NH(C1-C4)-acyl, (k) N[((C1-C4)-acyl)((C1-C4)-alkyl)], (l) CO2H, (m) CO2R2a, (n) phenyl, (o) Phenyl-(C2-C6)-alkenyl, (p) ▲ Numerical formula, chemical formula, table, etc. Yes ▼ (q) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (r) ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼ (s) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (t) ▲ Mathematical formulas, chemical formulas , tables, etc. ▼ (u) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (v) ▲ Mathematical formulas, chemical formulas, etc. There are scientific formulas, tables, etc.▼(w)▲There are mathematical formulas, chemical formulas, tables, etc.▼(x)▲Mathematical formulas , chemical formulas, tables, etc.▼(y)▲Mathematical formulas, chemical formulas, tables, etc.▼(z)( CH2)nNHSO2R16, (aa)(CH2)nF, (ab) (CH2) m-imidazol-1-yl, (ac) (CH2) m-1, 2,3-triazole unsubstituted or one selected from the following or Substituted with two substituents: i) CO2CH3, ii) (C1-C4)-alkyl, (ad) tetrazol-5-yl, (ae)-CONH-SO2-aryl, (af)-CONH-SO2-(C1 -C8)-alkyl, where the alkyl group is unsubstituted or selected from the group Substituted with a substituent: -OH, -SH, -O(C1-C4)-alkyl, - S-(C1-C4)-alkyl, -CF3,Cl,Br,F,I,-NO2,- CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1- C4)-alkyl], -N[(C1-C4)-alkyl)2; (ag)-CONH-SO2-perfluoro-(C1-C4)-alkyl, (ab)-CONHSO2NR2aR2a; and (ag)3▲mathematical formulas, chemical formulas, tables, etc. There are ▼, (ah) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, or or (al) ▲There are mathematical formulas, chemical formulas, tables, etc.▼; and; R5 is: (a)CN, (b) NO2, or (c) CO2R2a R9 and R10 are respectively: (a)H, (b) Unsubstituted (C1-C6)-alkyl or (C3-C7)-cycloal substituted with kyl, (c)(C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (C1-C6)-alkoxy, (g) When R9 and R10 are adjacent carbons, they form a phenyl ring. may be combined with (h) perfluoro-(C1-C6)-alkyl, (i) (C3-C7)-cyclo Alkyl unsubstituted or substituted with (C1-C6)-alkyl, (j) ali rule and X is: (a) -O-, (b) -S(O)n-, (c) -NR13-, (d) -CH2O-, (e)-CH2S(O)n, (f) -CH2NR13-, (g) -OCH2-, (h) -NR13CH2-, (i) -S(O)nCH2-, (j)-CH2-, (k)-(CH2)2-, (l) a single bond, or (m)-CH=(Here, when Y and R12 do not exist, connect to Z and R11 form -C=C- with carbon), Y is: (a) single bond, (b) -O-, (c)-S(O)n (d) -NR13-, or (e) -CH2- and However, for X and Y, the carbon atom to which Z is bonded simultaneously has two heteroatoms (O, N, S, SO, SO2); R11 and R12 are respectively: (a)H, (b) (C1-C6)-alkyl unsubstituted or substituted with the following: : i) aryl, or ii) (C3-C7)-cycloalkyl, (c) unsubstituted aryl, or is substituted with 1 to 5 substituents selected from the following groups: i) Cl, Br ,I,F, ii) (C1C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)- alkynyl)CH2-, v)(C1-C5)-alkoxy, vi) (C1-C5)-alkylthio, vii)-NO2, viii)-CF3, ix)-CO2R2a, or x)-OH: (d) Aryl-(C1-C2)-alkyl unsubstituted or selected from the following group: Substituted with substituents 1 to 5: i) Cl, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl)CH2-, iv) [(C1-C5)- alkynyl)CH2-, v)(C1-C5)-alkoxy, vi) (C1-C5)-alkylthio, vii)-NO2, viii)-CF3, ix)-CO2R2a, or x)-OH; or (e) (C3-C7)-cycloalkyl; R13 is: (a)H, (b) (C1-C6)-alkyl, (c) aryl, (d) Aryl-(C1-C6)-alkyl-(C=O)-, (e) (C1-C 6)-Alkyl-(C=O)-, (f)[(C2-C5)-alkenyl)CH2 -, (g) [(C2-C5)-alkynyl)CH2- or (h) Aryl-CH2-; and Z is: (a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c)-tetrazol-5-yl, (d) -CO-NH (tetrazol-5-yl), (e) -CONH-SO2-a Ryl, (f)-CONH-SO2-(C1-C8)-alkyl, where alkyl The group is unsubstituted or substituted with a substituent selected from the following groups: -OH, - SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -C F3, Cl, Br, F, I, -NO2, -CO2H-CO2-(C1-C4)- Alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C 4)-alkyl]2; (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, (i) -CONHSO2NR2a R2a, (j)-SO2NHCO-aryl, (k)-SO2NHCO-(C1-C8)-alkyl, where the alkyl group is left unrepresented or substituted with a substituent selected from the following group: -OH, -SH, -O (C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3,Cl ,Br,F,I,-NO2,-CO2H,-CO2-(C1-C4)-alkyl , -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-a Lukiru] 2; (l)-SO2NHCO-perfluoro-(C1-C4)-alkyl, (m)-SO2NHCO-heteroaryl, (n)-SO2NHCONR2aR 2a, (o)-PO(OH)2, (p)-PO(OR2)2 or (q)-PO(OH)(OR2); and R14 is: (a)H, (b) (C1-C8)-alkyl, (c) (C1-C8)-perfluoroalkyl, (d) (C3-C6)-cycloa Lukyl, (e) phenyl, (f) Benzyl; R15 is: (a)H, (b) (C1-C6)-alkyl, (c) (C3-C6)-cycloalkyl, (d) (CH2)p-phenyl, (e) OR17, (f) luforin-4-yl, (g)NR18R19; R16 is: (a) (C1-C8)-alkyl, (b) (C1-C8)-perfluoroalkyl, (c) 1-adamantyl, (d) 1-naphthyl, (e) (1-naphthyl)ethyl, (f)-(CH2)p-phenyl; R17 is: (a)H, (b) (C1-C6)-alkyl, (c) (C3-C6)-cycloalkyl, (d) phenyl, (e) benzyl; R18 and R19 are respectively: (a)H, (b) (C1-C4)-alkyl, (c) phenyl, (d) benzyl, (e) α-methylbenzyl; and R20 is: (a) aryl, or (b) Heteroaryl is unsubstituted or has one or two substitutions selected from the following groups: Substituted with a substituent: i) (C1-C4)-alkyl, ii) (C1-C4)-alkoxy, iii) Br, Cl, I, F, or iv) CH2-aryl It is. 2. Compound represented by the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ or a pharmaceutically acceptable salt thereof: During the ceremony, R1 is (C2-C4)-alkyl or cyclopropyl, R3 is H, Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkyl, aryl, CH2-aryl; R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; R9 and R10 are (C1-C6)-alkyl, (C1-C6)-alke Nyl or (C1-C6)-alkynyl, (C1-C4)alkoxyl, Cl, B r, I, F, (C3-C8)-cycloalkyl, or aryl, where aryl is phenyl or naphthyl, unsubstituted or one of the following groups: or substituted with two selected substituents: Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy ,NO2,CF3,SO2NR2aR2a,(C1-C4)-alkylthio,Ha idroxy, amino, (C3-C7)-cycloalkyl, (C3-C10)-a Lukenil), R11 is unsubstituted phenyl or Br, Cl, F, I, (C1-C4)-alkyl phenyl substituted with (C1-C4)-acyl, Z is tetrazol-5-yl, carboxyl or CO2(C1-C4)-alkyl It is. 3. Compound represented by the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ or a pharmaceutically acceptable salt thereof: During the ceremony, Z is CO2H, CO2-(C1-C4)-alkyl or 1H-tetrazol-5- is il, R9 and R10 are (C1-C6)-alkyl, (C1-C6)-alke Nyl or (C1-C6)-alkynyl, (C1-C4)alkoxyl, Cl, B r, I, F, (C3-C8)-cycloalkyl, or aryl, where aryl phenyl or naphthyl, unsubstituted or selected from the following groups: substituted with one or two substituents; Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy , NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, droxy, amino, (C3-C7)-cycloalkyl, (C3-C10)-al Kenil) and R11 is H or benzyl, R13 is H, CH3(CH2)3C(=O)-, C6H5CH2CH2C(=O )- or C6H5CH2C(=O)-. 4. Compound represented by the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ or a pharmaceutically acceptable salt thereof: During the ceremony, R1 is (C1-C4)-alkyl or cyclopropyl, R2a is H, (C 1-C6)-alkyl, benzyl, or phenyl, R3 is H, Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkyl kylamino, (C1-C4)-acylamino, R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; R9 and R10 are (C1-C6)-alkyl, (C1-C6)-alke Nyl or (C1-C6)-alkynyl, (C1-C4)alkoxy, Cl, Br , I, F, (C3-C8)-cycloalkyl, or aryl, and R11 is a aryl or aryl-CH2- (where the aryl group is unsubstituted or Substituted with one or two substituents selected from: Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy , NO2, CF3, (C1-C4)-alkylthio, OH, -NR2aR2a) and X is O, NR13, CH2, or -CH= (this is the carbon connected to Z and R11 double bond), and R13 is H, (C1-C6)-alkyl, (C1- C6)-alkenyl, aryl, Z is CO2H, CO2-(C1-C4)-alkyl, 1H-tetrazol-5-y -CONHSO2-aryl (where aryl is phenyl or naphthyl) monosubstituted or unsubstituted with substituents selected from the following groups: Disubstituted: H, (C1-C4)-alkyl, (C1-C4)-alkyl Koxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthi H, hydroxy, amino, (C3-C7)-cycloalkyl, (C3-C10 )-alkenyl, or -CONHSO2-heteroaryl (where heteroaryl is a 5- or 6-membered heteroaryl ring) (b) The aromatic part is one or two selected from the group consisting of N, O, and S. may contain the following groups, unsubstituted or mono- or di-substituted: is substituted with a substituent chosen from the group: Br, Cl, F, I, OH, SH, NO2, (C1-C4)-alkyl, (C2 -C4)-alkenyl, (C2-C4)-alkynyl, (C1-C4)alkoxy C or CF3) It is. 5. Compound represented by the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ or a pharmaceutically acceptable salt thereof: During the ceremony, R1 is (C1-C4)-alkyl or cyclopropyl, R2a is H, (C 1-C6)-alkyl, benzyl or phenyl, R3 is H, Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkyl kylamino, (C1-C4)-acylamino, R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; R9 and R10 are (C1-C6)-alkyl, (C1-C6)-a alkenyl or (C1-C6)-alkynyl, (C1-C4)alkoxyl, Cl , Br, I, F, (C3-C8)-cycloalkyl, or aryl, and R1 1 is aryl or aryl-CH2- (here, aryl is unsubstituted or the next group Substituted with one or two substituents selected from the loop: Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy , NO2, CF3, (C1-CR4)-alkylthio, OH, -NR2aR2 a) and R12 is H, OH, or (C1-C4)-alkyl, and Z is CO2H, CO 2-(C1-C4)-alkyl or 1H-tetrazol-5-yl It is. 6. The compound of claim 1, wherein the compound and pharmaceutically acceptable salts thereof are selected from the following groups: 2-butyl-1-[4-(N-(1(R)-ka -bomethoxy-1-benzyl)methyl)aminomethylphenyl]methyl-4-k Lolo-5-hydroxymethylimidazole; 2-butyl-1-[4-(N-(1 (R)-carboxy-1-benzyl)methyl)aminomethylphenyl]methyl- 4-chloro-5-hydroxymethylimidazole; 2-butyl-1-[4-(N -(1(R)-carbomethoxy-1-benzyl)methyl-methyl-N-pentano yl)aminomethylphenyl]-4-chloro-5-hydroxymethylimidazo Le; 2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl)methyl -N-pentanoyl)aminomethyl-phenyl]methyl-4-chloro-5-hydro Roxymethylimidazole; 2-butyl-1-[4-(N-(1-(R)-car) boxy-1-benzyl)methyl-N-(3-phenyl)propionyl)aminomethane tylphenyl]methyl-4-chloroimidazole; 2-butyl-1-[4-N- (1(R)-carbomethoxy-1-benzyl)methyl-N-(phenylacetyl )aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazo Rule; 2-Butyl-1-[4-N-(1(R)-carboxy-1-benzyl)-methyl -N-(phenylacetyl)aminomethylphenyl]methyl-4-chloro-5- Hydroxymethylimidazole; 2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)a Minomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole ; 2-Butyl-1-[4-(N-(1(S)-carboxy-1-benzyl)amino methylphenyl] methyl-4-chloro-5-hydroxymethylimidazole; 2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)- N-pentanoyl)aminomethylphenyl]methyl-4-chloro-5-hydroxy dimethylimidazole; 2-butyl-1-[4-(N-(1(S)-carboxy -1-benzyl)methyl-N-pentanoyl)aminomethylphenyl]methyl- 4-chloro-5-hydroxymethylimidazole; 2-butyl-5-t-butyl Dimethylsilyloxymethyl-1-[4-(1-carbomethoxy-1,1-dibetin) methyl)aminomethylphenyl]methyl-4-chloroimidazole; 2 -butyl-1-[4-(N-(1-carbomethoxy-1,1-dibenzyl)methyl) )-aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimide Dazole; 2-butyl-1-[4-(N-(1-carboxy-1,1-dibenzi) methyl)-aminomethylphenyl)phenyl]methyl-4-chloro-5-hyron Droxymethylimidazole; 1-[4-(1-(N-benzyl-N-pentano) yl)amino-1-(tetrazol-5-ylmethylphenyl]methyl-2-butylene -5-t-butyldimethylsilyl-oxymethyl-4-chloroimidazole; 2-Butyl-4-chloro-5-hydroxymethyl-3-[4-(1-(1'-hydroxymethyl) Droxy-1-phenyl-1-tetrazol-5-yl)methylphenyl]methyl Imidazole; 2-butyl-1-[4-(1-carboxy-1-(2-chloro)) phenyl)methoxyphenyl]methyl-4-chloro-5-hydroxymethylimie Dazole; 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxy-3,5- dipropylphenyl]methyl-4-chloro-5-hydroxymethylimidazole ; 2-Butyl-4-chloro-5-hydroxymethyl-1-[4-(1-phenyl- 1-tetrazol-5-yl)) methylphenyl]methylimidazole; and 2-Butyl-1-[4-(N-(1-carboxy-1-(2-phenyl)ethyl) )amino-phenyl]methyl-4-chloro-5-hydroxymethylimidazole . 7. A pharmaceutical composition effective for the treatment of hypertension, comprising a pharmaceutically acceptable carrier and comprising a therapeutically effective amount of a compound of claim 1. 8. 8. The composition of claim 7, wherein the composition comprises a diuretic, an angiotensin converting enzyme inhibitor, and a drug. Contains antihypertensive agents selected from lucium channel blockers and β-blockers; are selected from the following groups: amiloride, atenolol, pendroflumethiazide, chlorothalidone, chloro Thiazide, clonidine, cributenamine acetate and cributenamine tannin acid salt, desarpidine, diazoxide, guanedine sulfate, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, Pargyline hydrochloride, polythiazide, prazosin, propanol, indojaboku , resinamine, reserpine, sodium nitroprod, spironolactone, Thymol maleate, trichloromethiazide, trimethophane camsylate, Benzthiazide, Quinetazone, Chiculinafan, Triamterene, Asekzo amide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, Rethoxylin procaine, sodium ethacrynate, captopril, cinchona Prill hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, rumapril, teprotide, Zofenopril Calcium, Diflunizal, Diltiazem, Felodipine, Nika Ludipine, nifedipine, nildipine, nimodipine, nisoldipine, nitrendi pins, and combinations or mixtures thereof. 9. A therapeutically effective amount of the compound of claim 1 in a method of treating hypertension in a patient. It is characterized by administering. 10. An ophthalmological prescription drug for the treatment of ocular hypertension in an ophthalmologically acceptable carrier. and an effective ocular anti-ocular hypertension agent in an amount of the compound of claim 1. 11. A treatment for ocular hypertension that is effective for patients requiring such treatment. The anti-ocular hypertension agent is characterized in that the amount of the compound of claim 1 is administered locally to the eye. . 12. A treatment for cognitive dysfunction, anxiety, or depression that requires such treatment. administering a therapeutically effective amount of a compound of claim 1 to a patient who .