JPH04505625A - Cycloalkyl-substituted glutaramide diuretics - 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] The present invention can be used to treat various cardiovascular disorders, Demonstrated expertise in a wide variety of therapeutic areas including, for example, the treatment of hypertension, heart failure, and renal failure. A series of cycloalkyl-substituted glutaramide derivatives that are diuretics with useful properties. It is something that

Applicant's European Patent Application No. 0274234 and European Patent Application No. 03 No. 43911, the applicant discloses that certain cycloalkyl-substituted glutarates Amide derivatives are described and claimed as diuretics. The present invention Extended into the loalkane carboxylate ring! Provide other related compounds containing substituents This is what we provide.

These compounds are zinc-dependent neutral endopeptidase E, C, 3, 4, 24° 11 inhibitors. This enzyme is a strong vasodilator, diuretic and diuretic secreted by the heart. and atrial natriuretic factor (ANF) with natriuretic activity. Involved in the degradation of peptide hormones in species. The compounds of the invention therefore have a neutral end ANF biology by inhibiting peptidase E, C, 3, 4, 24, 11 In particular, these compounds can enhance the effects of hypertension, heart failure, angina, Renal failure, premenstrual syndrome, periodic edema (drops), Meniere's disease, hyperaldosterone hypercalcemia (primary and secondary), including pulmonary edema, ascites and calcium hyperuria It is a diuretic with utility in the treatment of numerous disorders. Furthermore, these compounds The drug has utility in the treatment of glaucoma because it can potentiate the action of ANF. Sara The compounds of the present invention inhibit neutral endopeptidase E, C, 3, 4, 24, 11. These include asthma, inflammation, pain, epilepsy, affective disorders, dementia and and senile confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome 1!f). Treatment, regulation of gastric acid secretion, and others including treatment of hyperreninemia and leukemia. It is effective in the therapeutic area of

The compound of the present invention has the following formula: (In the formula, A completes a 4-7 carbocyclic ring, which is saturated or monounsaturated. , optionally fused to another saturated or unsaturated 5- or 6-order heterocyclic ring. often; B is (CH2)s, where m is an integer from 1-3; R and R4 are H, C, -C6 alkyl, pencil or biologically unstable (b iolabile) other ester-forming groups.

R1 is H or C1-C4 alkyl; R' is C, -c, alkoxy, ali C, Cg alkyl substituted with aryl or aryloxy.

And R5 is Cl-C87/L/kyl, C2-C, alkenyl, Cz-Ca Fulkynyl, C1Cycycloalkyl or CsCtcycloalkenyl or R5 is halo, hydroxy, CI C6 alco, ClCs alco Kishi (c.

-06) alkoxy, C, -C, cycloalkyl, C3Cy cycloalkenyl, Aryl, aryloxy, heterocyclyl, -NR"R", -NR'COR ’, -N R’S O2R”, -CONR’R’ is also 1., < is R’R’N 01-〇〇alkyl substituted by -(Cl　Cs)alkoxy: or R5 is C, -C, alkyl substituted with a group of the following formula: R1'2 R1 co Here, R6 and R7 are independently H, CI C4 alkyl, C1C7 Chloalkyl, aryl, aryl (Cl C4) alkyl, CzCs alkoxy sialkyl or heterocyclyl: or two groups R6 and R7 together with the nitrogen to which they are bonded forming a radinyl or N-(C,-C<)alkyl-piperazinyl group; RA is H or C, -C, alkyl; R'' is C1C47JLt+ru, CF s, aryl, aryl (CI-C4) 7/l/kyl, aryl (CI-C4) ) alkoxy, heterocyclyl, ClC4 alkoxy or NR"R' , R1 here! and R7 are as defined above: R” is Cl　C4 alkyl, C3Ct chloroalkyl, aryl or heterosa It's Ikryl.

R eyes are H, C, -c, alkyl can be.

R”4;tR”CONR-, R”SO2NH”-, R”R”N- (CH2) , - or R110-, where R'' is each as defined above.

Nl3 and R'' are each independently H or C1-C6 alkyl; Or R'th 3 is H, and R'' is CI Cs alkyl, which is OH , CI　C<alkoxy, SH%SCH3, Nl2, aryl (C, -Cs) a Lucyl 0CONH-5NH2CO-1C02H, guanidino, aryl or substituted by heterocyclyl, or the two groups R'3 and R'' are linked. together to form a 5 or 6 homogeneous heterocyclic ring with the carbon atom to which they are attached , they are saturated or monounsaturated, optionally by CI C4 alkyl Substituted or other saturated or unsaturated 5 or 6 homogeneous heterocycles It may be fused to a ring.

Or R" is H, and R12 and R14 are combined to form 2-(N-COR"- 4-aminopyrrolidinyl) group: Nl5 is R1aR17NC〇-1R”0CO-1R”0CH2*f: Haheteo "j-icryl, where Rl l4 is defined above: R" and R17 are each independently H or CI Cs alkyl.

and p is O or an integer of 1-6, as well as their pharmaceutically acceptable salts, and their bioprecursors. .

Unless otherwise indicated in the definitions above, an alkyl group containing 3 or more carbon atoms may be either straight chain or branched chain. The word aryl used here is , means an aromatic hydrocarbon residue, such as phenyl, naphthyl or biphenyl. , these may optionally contain one or more OTs (, CN5CF!, C, -C4 May be substituted with alkyl, CI C4 alkoxy group or halo atom. C Ro means fluoro, chloro, bromo or iodo.

The term heterocyclyl refers to a 5- or 6-membered nitrogen, oxygen or sulfur containing complex. refers to ring residues, which may be saturated or unsaturated unless otherwise specified. If desired, one additional oxygen atom or 1-3 nitrogen atoms may be added in the ring. optionally benzo-fused, or e.g. or two or more halo, CtC<alkyl, hydroxy, carbamoyl, benzene oxo, amino, or mono or cy(CI C4 alkyl) amino Alternatively, it may be substituted with a (CI　C<alkanoyl)amino group. Hetae Detailed examples of rosyclyl include pyritur, pyrazinyl, pyrimidinyl, pyridadi Nil, pyrrolyl, imidazolyl, biracilyl, l-ryanolyl, tetrazolyl , 7ranyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thi phenyl, oxasilyl, isoxazolyl, thiazolyl, indolyl, isoindo Linyl, quinolyl, quinoxalinyl, quinazolinyl and benzimidazolyl and each of these may be substituted according to the definitions above.

Compounds of formula (+) may contain several asymmetric centers and therefore they are enantiomeric It is possible to exist as both stereoisomers and diastereomers. The present invention applies to mixtures and It includes both the isolated isomers and the separated individual isomers. Substituents R2 and CO2R4 are amino It has a cis or trans geometric isomeric structure with respect to the bond. - Contains an acidic center Pharmaceutically acceptable salts of compounds of formula (I) include bases that form non-toxic salts. It is formed by Examples include alkali metal salts, such as sodium with potassium or calcium salts, or amylamines such as diethylamine. Contains salt. Compounds containing a basic center also form pharmaceutically acceptable acid addition salts with phosphoric acids. can be formed. Examples include hydrochloride, hydrobromide, sulfate or hydrogen sulfate, Phosphates or hydrogen phosphates, acetates, citrates, fumarates, gluconates , lactate, maleate, succinate and tartrate.

In the above definition, the term biological precursor refers to The pharmaceutical composition of a compound of formula (1) that is converted in the body to produce a compound of formula (1) means a biodegradable derivative acceptable to

A preferred group of compounds of formula (I) are those in which A is (CH2)4 and R1 is H. , B is (CH2)2, that is, a compound of the following formula (II), in which R1R2, R4 and R5 are as defined above with respect to formula (1).Similarly Preferred compounds are those of formula (1) and formula (II) in which both R and R1 are H. Compounds (diacids) and their biologically unstable mono- and sea-ester derivatives body (in these, one or the opening of R and R1 is a biologically unstable ester) is a group that forms a terminal).

The term biologically unstable ester-forming group refers to a group that is easily cleaved in the body to form R. and R4 are both H, a corresponding diacid-releasing group of formula (1). is well understood in the art. A large number of these ester-forming groups, even It is well known in the field of penicillins or in the case of antihypertensive drugs that are ACE inhibitors.

In the case of compounds of formula (I) and formula (Ir), biologically unstable proteins of this type Drug esters are particularly advantageous in providing compounds of formula (1) suitable for oral administration. It is. The suitability of individual ester-forming groups is determined by conventional animal or in vitro enzymatic hydration. It can be evaluated by a decomposition test. That is, for optimal effectiveness, it is desirable to Esters should be hydrolyzed only after absorption, so esters should be hydrolyzed before absorption. Resistant to hydrolysis by digestive enzymes, e.g. by liver enzymes It must be easily tlU water cleaved. In this way, after oral absorption, the active diacid released into the bloodstream.

In addition to lower alkyl esters (especially ethyl) and benzyl esters, suitable Biologically unstable esters include alkanoyloxyalkyl esters (those including alkyl, cycloalkyl and aryl substituted derivatives of Sialkyl ester, aroyloxy/alkyl ester, arylalkyloxy Sialkyl esters, aryl esters, aralkyl esters and haloal Kyl esters, in which the alkanoyl or alkyl group is 1-8 contains 4 carbon atoms and can be branched or straight chain; aryl groups include phenyl, naphthi or indanyl, optionally containing one or more 01-0 4 alkyl or substituted by C, -C, alkoxy group or halo atom It's okay.

Therefore, biologically unstable ester-forming groups other than ethyl and benzyl Examples of R and R4 in certain instances include: 1-(2,2-diethylene rubyryloxy)ethyl, 2-ethylpropionyloxymethyl, 1-(2- Ethylbropionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy) ) ethyl, 1-(benzoyloxy)benzyl, 1-(benzoyloxy)ethyl 2-methyl-1-probionyloxyprovir, 2. 4. 6-Trimethy Rubenzoyloxymethyl, 1-(2,4,s-=trimethylbenzyloxy ) Ethyl, pivaloyloxymethyl, phenethyl, fenpropyl, 2. 2. 2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl L, 4-butylphenyl, C5-C4-methyl-1,3-dioxolene-2 -onylcucomethyl and 5-indanyl.

Formula (I) in which R is benzyl or t-butyl and R4 is ethyl; and Compounds of formula (Ir) are of value for the production of diacids in which both R and R4 are H. It is an intermediate.

In another preferred group of compounds, R5 is a group of the formula -NHCOCR"R"R" Substituted methylene, especially R" is Nl2, R"CONH- or R"502NH -, R13 is H, and R is -(CHz)4NH2. especially Preference is given to groups derived from S-lysine; therefore particular preference is given to this type. The new substituent R5 includes N2-acetyl-8-lysyl aminomethyl, N''-methane Sulfonyl-8-lysyl-aminomethyl, N2-phenylsulfonyl-8-lysyl -Aminomethyl and N2-cyclobutylcarbonyl-S-lysyl-aminomethyl Includes chill.

In yet another preferred group of compounds, R5 is substituted with CI C6 alkokene. CI Ce alkyl, especially methoxydiethyl, or R5 is CI e alkoxy (CI C6) CI C= substituted with alkoxy, alkyl, esp. is 2-methoxyethoxymethyl: or R5 is -NHCOCR”R13R (wherein R'' is NR2, R13 is CHs, R is H or CH3 C, -C6 alkyl substituted with ), especially R-alanyl-aminomethyl or and (2-amino-2-methylpropanoyl)aminomethyl.

R2 is preferably phenyl, pencil, phenethyl, metquinpropyl or ether. Toquinpropyl.

Particularly preferred individual compounds of the invention include:

2S-(N2-methanesulfonyl-8-lysyl aminomethyl)-3-+1-[( cis-4-carboxy-3-cis(3-ethoxypropyl)-cyclohexyl) Carbamoylcocyclopentyl)propanoic acid, 2-(N”-methanesulfonyl- 8-lysylaminomethyl)-3-(1-[(cis-4-carbocy3-cis phenethyl-cyclohexyl)carbamoylcocyclopentyl)propanoic acid, 2S-(2-methoxyethoxymethyl)-3-fl-[(cis-4-carboxy -3-cis(3-ethoxypropyl)cyclohexyl)carbamoylcocyclo pentyl) propanoic acid and 2S-(2-methoxyethoxymethyl)-3-+1- [(cis-4-carboxy cy-3-cis(3-methoxypropyl)-cyclohexyl)carbamoylcosic Lopentyl) propanoic acid as well as their biologically unstable ester derivatives.

Compounds of formula ([) are prepared in a number of different ways. The basic method is A protected cycloalkyl-substituted glutaric acid derivative was synthesized and conjugated to an amine. and obtain the desired glutaramide. Carboxylic acid residue in amine is released or reactive residues in R5 are not preserved during this binding step. These protecting groups may need to be protected in the final step of the method. removed.

The synthetic route is shown in Reaction Formula 1. Here, A, B, R' and R2 are defined above. , and R5' is defined for R5 above, and its opposite is defined as necessary. Both reactive residues are protected, R11' and Rlg are with the exception of H, or they are normal carboxylic acid It is a protection group.

The reaction of compounds of formulas (r　I　I) and (Iv) is carried out by the usual amide bonding method. be exposed. For example, in one method, the reaction is carried out in an organic solvent, such as dichloromethane. A diimide condensing agent, e.g. 1-ethyl-3,- (dimethylaminopropyl)carbonimide or N, N’-zinchlorohexyl With sylcarbocimite, preferably 1-hydroxybenzotriazole and It is carried out in the presence of an organic base such as N-methylmorpholine. The reaction is generally Completion is completed after 12-24 hours at room temperature, and the product is then washed in conventional manner, e.g. is isolated by filtration to remove the by-product urea and evaporation of the solvent. be done. If necessary, the raw product can be further purified by crystallization or chromatography. It can be made by IR. Compounds of formula (v) include R and R' or C, -C6 a Included are compounds of formula (I) that are alkyl or bennor.

Optionally, the protected form of the coupling product is subjected to conventional chemical transformation reactions, Other compounds of formula (v) can be prepared. For example, R'' contains an ester group. A compound of formula m is hydrolyzed or hydrogenated to form a carboxylic acid, which is then Further, amide derivatives can be obtained by reaction with, for example, amines.

R5' is a substituted or protected amino group (e.g. pensylamino, dibenzyl Amino, benzyloxycarbonylamino or t-butyloxycarbonylamino Similar compounds containing mino groups are liberated by hydrogenation or protonolysis as appropriate. Can be converted to amines. The amine produced can be further reacted. , for example, respectively, by reaction with sulfonyl halides. Acylation with acid chloride or acid anhydride gives the corresponding amide. A urea derivative is obtained by reaction with isocyanate, and a chloroform compound is obtained. Reaction with ester gives alkoxycarbonylamino and product. this All of their conversion methods are conventional methods, and appropriate conditions and reagents are required to carry them out. are well known to those skilled in the art, as are other variants and possibilities.

The diester of formula (V) is further reacted so that one or both of R and R4 is H Monoesters of diacid derivatives of formula m can be obtained. The condition to be adopted is the formula Depending on the exact nature of the groups R'' and RI9 present in the compound of (V), a number of Variations are possible. For example, if R'' and R19 are both pencils, the generation Hydrogenation of the product gives a diacid of formula (I) in which R and R4 are both H.

Alternatively, if one of R18 and R'9 is benzyl and the other is alkyl, In this case, the monoester product is obtained by hydrogenation. Add water to this again if desired. It can be decomposed to obtain the diacid product. One side of Rlg and R+s by treating the compound of formula (V) with trifluoroacetic acid, The corresponding acid is obtained. R” and R” are pencil or lower alkyl; The ester product is treated with trimethylsilyl iosite to release the dicarboxylic acid product. You can also get it. Any other carboxylic acid protecting group for R11' and R'' When using, it is obvious that conditions suitable for its removal are adopted in the final step to obtain the equation An ester or diacid product should be obtained. 18 or substituent R5 is unsaturated In some cases, removal of protecting groups should be carried out by non-reductive methods, e.g. If any of 4 are benol, they are treated with trimethylsilyl iosito It can be removed by

The final monolayer is removed as described above, along with the removal of any protecting groups that may be present in R5'. A number of chemical transformation reactions can be performed on the ster or diacid product. Izu In both cases, the product is obtained as the am carboxylic acid or it is prepared with a suitable base. It can be neutralized and isolated in salt form.

Modification of the above method t6 ``'CC1, R' is -NR'COR', -NR''5Oz R”, -NR1ICOCR12RI!R'4 or -NR"5oICR"R13 The compound of formula (1) which is CI-C6 alkyl substituted with R'' is a compound of the following formula ・(In the formula, R” is the sole of R11 or Rl1, and Rlg and and Rlg are as defined above, and Y is a C,-C6 alkyl group). Formula R'C02H.

R" S Oh H, R' 2R' 3R" CCO2H or R' 2R" R” CS O3H (D acids are acylated by reacting with their activated derivatives) Or produced by sulfonylation. The resulting amide or sulphate is then Optionally remove protecting groups from sulfonamide products and cleave diester products to obtain the carboxylic acid of formula (1) in which R and R4 are each H as described above. Ru.

The compound of formula (VI) can be prepared by the method shown in Scheme 1, except for the protected amine It is produced using a compound of formula (III) containing R5' as a derivative. for example R” may include a bis-(IS)-phenylethylamino substituent. Hydrogenation of the corresponding formula ffI where R2° is H and Y is CH2) of free amine is obtained. This pathway has a 2(S) stereochemistry in the glutaramide backbone. It is particularly useful in the production of compounds containing structures.

Starting cycloalkyl of formula III! The converted glutaric acid monoester is European Patent Application Publication Nos. 0274234.89305180.5 and 893046 No. 98.7.

Amines of formula (v) are generally novel compounds (especially if the substituents have a certain stereochemical configuration). structures), they are manufactured by appropriate synthetic methods according to literature methods. and For example, in one method, the corresponding ketone is converted to an amine by reduction of the oxime. Ru. Alternatively, the corresponding alcohols can be combined with diethyldiazodicarboxylate. reacted with methyl toluenesulfonate in the presence of chloride and triphenylphosphine. Se: The obtained 4-methylbenzenesulfonyloxy derivative was mixed with sodium and React and reduce the product to obtain the amine. These methods are shown in the production examples below. It will be done.

Bonding and protection methods suitable for all of the above processes and variations and alternatives include: This will be apparent to those skilled in the art by reference to the standard literature and the examples below.

As mentioned above, the compounds of the invention are capable of reacting with neutral endopeptidase (E, C, 3,4°2 4.11) is a powerful inhibitor. This enzyme is involved in the breakdown of many peptide hormones. It is particularly involved in the degradation of atrial natriuretic factor (ANF). This hormone It consists of a group of related natriuretic peptides that are secreted by the heart and The main circulating form in humans is a 28-amino acid peptide called α-hANP. It is known to be a chido. Therefore, the compounds of the present invention are useful for endopeptidases. The organism by preventing the degradation of ANF by E, C, 3, 4, 24, 11. and thus these compounds have utility in many of the disorders mentioned above. It is a diuretic and sodium excretor.

Activity against neutral endopeptidase E, C, 3, 4, 24, 11 , Sugyu Tugel, Eltos and Barsh (J, T, Gafford, R, A.

Skidge, E, G, Erdos, L, B, Hersh), Bioche mistry, 1983.1, and the assay method described in 3265-3271. Evaluated using a method based on This method uses neutral endopeptides derived from rat kidney. Release from Hypri-L-Phenylalanyl-L-Arginine by Dase Preparation To determine the concentration of compound required to reduce the release rate of radiolabeled hippuric acid by 50%. It is something that

The activity of these compounds as diuretics was demonstrated in conscious saline-loaded mice. Measuring their efficacy in increasing urine output and sodium ion excretion Determined by. In this study, male mice (Charles River CDI , 22-28g) to acclimatize to the climate, and metaball (met a b ow L) - Fast at night. Mice were given a solution dissolved in saline in a volume equal to 2.5% of their body weight. The test compound is administered intravenously through the tail vein. Preliminarily collect urine samples every hour until the second hour. Collect the sample in a weighed test tube and analyze the electrolyte concentration. Urine volume and volume from test animals and sodium ion concentrations are compared to a control group that received saline alone.

Administered to humans for the treatment or prophylaxis of hypertension, congestive heart failure, or renal failure Oral doses of these compounds are generally administered to the average adult patient (70 kg) about 4-800 mg/day. Therefore, individual Tablets or capsules may be administered in single or multiple doses, once or several times a day. , 2-400 mg in a suitable pharmaceutically acceptable vehicle or carrier. Contains active compounds. Doses for intravenous administration are generally 1- It would be 400mg. During implementation, physicians will determine the actual dose that is best for each individual patient. However, it will vary depending on the age, weight and response of the individual. For the above Amounts are examples of average cases; of course there may be higher or lower dosage ranges. There are individual cases that may be beneficial and these are within the scope of the invention.

For use in humans, the compound of formula (1) can be administered alone, but Generally, the selected pharmaceutical carrier is related to the intended route of administration and standard pharmaceutical practice. It will be administered in a mixture with Riya. For example, they may be starch or In the form of tablets containing excipients such as toss, or alone or mixed with excipients. in capsules or ovules, or with flavoring. can be administered orally in the form of an elixir or suspension containing a coloring agent. Wear. They can be injected parenterally, e.g. intravenously, intramuscularly or subcutaneously Can be done. For parenteral administration, they are best used in the form of sterile aqueous solutions. and they contain other substances, such as enough salts or other substances to make the solution isotonic with blood. may contain glucose.

Although the above compounds may be administered alone, optimal regulation of blood pressure may be achieved in accordance with established medical practice. or to treat congestive heart failure, kidney failure, or other disorders. It can also be administered in conjunction with other medications as directed by the physician in this patient. for example These compounds are used in various cardiac treatments to facilitate blood pressure regulation in the treatment of hypertension. ACE inhibitors such as vascular drugs such as captopril or enalapril; , or digitalis or other inotropes for the treatment of congestive heart failure or Can be used in combination with ACE inhibitors. Another possibility is 'calcium antagonism'! ( e.g. nifedipine, amlodopine or diltiazem), beta-blockers ( For example atenolol) or alpha blockade! 5 (e.g. prazosin or xazosine) and these are prescribed by a doctor to treat the patient or the condition involved. should be determined as appropriate.

In addition to the above, these compounds may induce exogenous ANF or diuretic/sodium excretion activity. derivatives thereof or related peptides or peptide fragments with Or other ANF gene-related peptides (e.g. Veese') - (D, L, Me5ely) et al., Biochem, Biophys, Res, Comm, , 1987° 143.186).

Therefore, in another aspect, the present invention provides compounds of formula (1) or their pharmaceutical pharmaceutically acceptable salts or biological precursors, as well as pharmaceutically acceptable diluted A pharmaceutical composition is provided that includes a diluent or carrier.

The present invention provides a drug, particularly for the treatment of hypertension, congestive heart failure or renal failure in humans. Compounds of formula (I) used as diuretics for or their pharmaceutical acceptance Also included are acceptable salts or biological precursors.

The present invention further provides compounds of formula (I) for the treatment of hypertension, heart failure, angina, renal failure, menstruation, etc. Presyndrome, periodic edema (edema), Meniere's disease, hyperaldosteronism, pulmonary edema , ascites, hypercalcemia, glaucoma, asthma, inflammation, pain, epilepsy, emotional disorders damage, dementia and senile confusion, obesity, gastrointestinal disorders (including diarrhea), hyperreninemia, Includes use in the manufacture of drugs used in the treatment of leukemia and the regulation of gastric acid secretion. Contains.

The production of the compounds of the present invention will be explained in more detail with reference to the following experimental examples. below Preparations 1-8 describe the preparation of starting amines of formula (IV) and Example 1 -45 describes the production of the compound of formula (1). Compound purity is determined by Merck Key Cellgel 60F2. ．． Rooti by thin layer chromatography using plates. was closely monitored. Solvent system 5s-1 consists of dichloromethane, methanol and glacial acetic acid. It is a mixture (90:10:1), and 5s-2 is methyl isobutyl ketone, The upper layer is a mixture of glacial acetic acid and water (2:1:1), and 5s-3 is It was a mixture of ethyl acetate and hexane (11). 'H-nuclear magnetic resonance subek was recorded by a Nicolebut QE-300 spectrometer and The structure was also consistent with the proposed structure.

Manufacturing example 1 cm4-amino-c-2-(2-phenylethyl)cyclohedrin-r-1-ka Rubonic acid ethyl ester hydrochloride 80% sodium hydride FH (307 mg, 10 mmol) in oil was added to nitrogen. 3-oxo-5-phenylpenconic acid ethyl ester (28.4 g, 1 Stir in a mixture of 29 mmol (e) and absolute ethanol (Lml) under water cooling. Added with stirring. Then methyl vinyl ketone (10,7 mm 1:9 mmo 1) was added dropwise while cooling with water for half an hour, and after stirring at room temperature for 1 hour, , acetic acid (1.4ml), pyrrolidine (775mg), ethanol (17ml) and water (2 mm) were added. After refluxing for 2 hours, the solvent was evaporated under vacuum. , the residue was dissolved in diethyl ether. Sequentially 2N hydrochloric acid, water, saturated sodium bicarbonate Washed with aqueous Mg solution and water, dried over MgO and evaporated to give a yellow liquid. (34.6 g) was obtained. On silica gel (600 g), diethyl ether and and hexane (1:1, volume ratio). The desired enone was obtained as a transparent liquid (18.54 g). Rfo, 35 (1:1, diethyl ether hexane). Actual value: C, 74, 88: H, 7 , 40; C17H2003 theoretical value C, 74,97; H, 7,40%.

The enone from part (i) (18.44 g, 6.76 mmole) was dissolved in 2N hydrochloric acid (3 5% palladium catalyst on activated carbon (5 mm) in ethanol (80 ml) containing 00 mg) at a pressure of 50 p, s, i, (3,45 bar). did. After 3 hours, an additional amount of catalyst (250 mg) was added and the reduction continued for another 2 hours. continued. The suspension was filtered through Avicel and the filtrate was evaporated under vacuum. remain Dissolve the oil in diethyl ether and wash with saturated aqueous sodium bicarbonate solution and water. It was dried over MgSO4 and evaporated to give a clear liquid (18.52g).

Increase the proportion of diethyl ether in hexane on silica gel (600 g) By chromatography with elution (2:8-4:6), the target of the ketone was obtained as a liquid (16.78 g, 90%). Rfo, 4 (1:1, di ethyl ether (hexane).

The above ketone (3.02g, llmmolle), methoxyl hydrochloride 7mine (1 , 19 g, 14.3 mmol) and sodium acetate (1.17 g, 14 ．． 3 mmole) was refluxed in ethanol (50 ml) for 5 hours. Melt under vacuum The agent was evaporated and the residue was taken up in diethyl ether and dissolved in saturated aqueous sodium bicarbonate. solution and then water. Dry with Mg5O, evaporate under vacuum and obtain the above O-methyloxime was obtained as an oil (3.32g, 99%). RfO, 55 and and 0. 66 (1:1, diethyl ether, hexane). Actual value: (', 71. 23; H, s.

33:N, 4. 88; CI, IHzbNOs theoretical value C, 71, 26: H, 8, 30; N, 4.　62%.

iy, c-4-butoxycarbonylamino-〇-2-(2-phenylethyl)cy Chlorhexane-r-1-carboxylic acid ethyl ester dry tetrahydrofuran (1 Trifluoroacetic acid (4.2 mm, 54 mmole) in 0 ml) was dried under water cooling. Sodium borohydride (2.04 g, 54 mmo) in dry tetrahydropran It was added dropwise to the suspension of le) with stirring. Maintain temperature at 5-10℃ for 15 minutes After stirring for a while, part (iii) was obtained in dry tetrahydrofuran (10 ml). 0-Methyloxime (3.28g, 10.8mmole) over 10 minutes Added dropwise. The temperature rose to 20°C and after 5 hours of stirring the water was poured very carefully under water cooling. and the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated salt solution, dried over MgSO4 and evaporated. A gum (3.25 g) was obtained. This crude amine was dissolved in methylene chloride (50 ml ), N-methylmorpholine (2.2 g, 21.6 mmole) and and sheet t-butyl dicarbonate (4.7 g, 21.6 mm.

Ie) was added and the mixture was left at room temperature for 48 hours. Evaporate the solvent under vacuum; The residue was partitioned between diethyl ether and water, and the organic extract was sequentially treated with 0.5N hydrochloric acid, Washed with water, saturated aqueous sodium bicarbonate solution and water. Dry with M　g　O　 Drying and evaporation gave a gum (3.9 g). The target cis compound is silica Chromatography on gel (400 g) removed the more polar side components. separated from the lance isomer. A mixture of diethyl ether in 3 min. , volume ratio) gave the protected amine as an oil (1.94 g , 48%).

RfO, 35 (3nia, diethyl ether:hexane). Actual value: C, 70, 4 3; H, s, 75; N, 3.45, C2□Hs s N O4 theoretical value C, 70 , 37; H, 8, 86; N, 3.73%.

v, c-4-amino-c-2-(2-phenylethyl)cyclohexane-r-1 -Carboxylic acid ethyl ester hydrochloride Solution of the above ester (1.94 g, 5.17 mmole) in diethyl ether The mixture was saturated with hydrogen chloride while stirring under water cooling. After 3 hours, blow off the solvent with nitrogen. , the residue was triturated with diethyl ether and filtered to give the title amine salt as a white solid. (1.44 g, 89%). Melting point 213-214°C. RfO,5(sS -1). Actual value: C, 65,84; H, 8,74; N, 4.43: C+yHz sNO□・HCI theoretical value C, 65,48; H, s, 40; N, 4.49%.

Manufacturing example 2 cm4-amino-c-2-(3-methoxypropyl)cyclohedox-r-1- Ethyl carboxylic acid) pxz-ful hydrochloride According to the method of Production Example 1, only part i) Using 3-oxo-6-medoxyhexanoic acid ethyl ester as the starting material, The title amine was obtained as a white solid.

Melting point 206-208°C. RfO,2(ss-1), actual value: (', 55.15; H.

9.11; N, 5.34; Cl5fh5NOs・HCI・0.2H20 Theoretical value C155.09, H, 9.39, N, 5.94%.

Manufacturing example 3 C-4-amino-c-2-(3-ethoxypropyl)cyclohedrin-r-1- Carboxylic acid ethyl ester hydrochloride Following the method of Preparation Example 1, but using 3-oxo-6-ethene as the starting material for part i). Using xyhexanoic acid ethyl ester, the title amine was obtained as a white solid.

Melting point 201-203°C. Rf O, 2 (s 5-1), actual value -C, 55, 5 0,H.

9.52; N, 4.33: C++Hz7NO3・HCI・0.5HzO Theory fimf C.

55.52; H, 9.65; N, 4.63%.

Ethyl ester from Preparation Example 1 (1.4 g, 4 , 48 mmol l e) was saturated with hydrogen chloride and heated to 55-60'C for 4 days. Heat and then reflux for an additional 3 days with periodic addition of hydrogen chloride to maintain 6 saturation. It was introduced in The solution was evaporated to dryness under vacuum and the residue was azeotropically dried with methylene chloride. and the residue was triturated with diethyl ether to give the above methyl ester as a white powder. Obtained as a powder (129 g, 97%). Melting point 202-4°C. RfO, L5 (s s-1).

Actual measurement value: C, 63, 70: H, 8, 13; N, 4.74; CHHz x NOz・ HCt・0.25 H2O theoretical value C, 63,56; H, 8,17; N, 4.63 %.

Production Example 1. 1 part of ketone (10.97 g, 40 mmole), ethylene glycol Coal (2,73 g, 44 mmol) and 4-toluenesulfonic acid (1 00 mg) in benzene (80 ml) in a DC Stark water trap. It flowed. After 8 hours, the solution was cooled, diluted with diethyl ether, and successively diluted with saturated carbonate. Washed with aqueous sodium hydrogen solution and water. Dry with MgSO4 and evaporate under vacuum. A clear liquid was obtained (12.22 g, 96%), RfO,32 (3: 7, ethyl ether, hexane). Actual measurement value C, 71,45; H, 8,30; Cl9Hz s O4 theory fIC, 71,67; H, 8,23%.

11, trans-7-(2-phenylethyl)-14-dioxaspiro[4゜7 'Kan-8-Carbon 1 Chirue X? Low potassium t-butoxide (1.9g, 1 7 mmole) of the above ester (12, 17 g, 38.2 mmole) and the mixture was refluxed under nitrogen for 48 h. did. Neutralized with 2N hydrochloric acid and evaporated under vacuum to give a pale brown oil. This is true The solution was dissolved in ether and washed with water. Drying over Mg5o and evaporation gave an oil. (12.09g). This was chromatographed on silica gel (600g). did. Solution using a mixture of diethyl ether and hexane (3 near, volume ratio) The desired trans isomer was obtained as an oil (8.44 g, 69%).

RfO, 29 (3nia, diethyl ether, hexane). Actual value: C, 71, 6 0: H, 8, 14: Cl9H2804 theoretical value C, 7167; H, s, 23%.

The above ester (8.40g, 26.4mmol) was mixed with IN sulfuric acid (50mmol 1) and ethanol (70 ml). Most of the ethanol after 3 hours The solution was evaporated under vacuum, water was added and the suspension was extracted with diethyl ether. . The organic extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and water, and M Dry over gSO2 and evaporate under vacuum to give a clear oil (6.46g, 89 %).

Rfo, 38 (Ni 1, diethyl ether: Hegyu San). Actual value: C, 74, 2 5; H, 8,07; Cl7H2□0. Theoretical value C, 74, 42; H, s, os% .

Three molecular sieves (3 g) were added to the ketone from part iii (3.2 g, 11° 66 mmol　e) and pencil amine (1,27rnl, 11゜66mm ole) in ethanol (15 ml) with stirring. 3 at room temperature ．． After 5 hours, the solution was transferred to a dry hydrogenation reactor using a snake bed and the molecular The sieves were washed with a small amount of ethanol (2×5 ml). Platinum oxide (500mg) was added and the reduction was completed in 3 hours at 50 p, s, i, (3,45 bar). Ta. The mixture was filtered through Albacel, evaporated under vacuum and the remaining liquid was siphoned. Chromatography was performed on Kagel (200 g). diethyl ether Actual value in the sun: C, 78, 85: H, 8, 53: N, 4.86; Cz< HHNO□ Ring 1 logical value C, 78,86; H, a, 55; N, 3.83%.

The above amine (3.13 g, 8.56 mmole) was mixed with IN hydrochloric acid (9.42 ml 1°) 9. A solution in ethanol (80 ml) containing 42 mmol 50 p, s, i, with 0% palladium hydroxide and activated carbon catalyst (600 mg) Hydrogenation was carried out at a pressure of (3°45 bar). Additional doses after 6 and 24 hours of catalyst (500 mg) was added. After another 22 hours, the suspension was transferred to Albacel. The filtrate was evaporated to dryness under vacuum. The residue was dissolved in ethanol and diethyl ether. The desired amine was obtained as a white solid (2.03 g) by recrystallization from a mixture of , 76%). Melting point 175-7°C. Rfo, 25 (ss-1). Actual value: C, 64,42; H, 8,50; N, 4.52; CuHzsNO□・HCI・0. 25H20 theoretical value C, 64, 54; H, s, 44; N, 4. ．． 43%.

Methyl 2-hydroxy-4-oxo-2-phenylcyclohexanecarboxylate 9 2427 (1974) 1 at 80℃ for 15 minutes with polyphosphoric acid (17.5g) Stir for a while. The mixture was cooled and partitioned between ethyl acetate and water. Organic extract Next, wash with water, saturated aqueous sodium bicarbonate solution and water, and dry with MgSO4. The mixture was washed and evaporated to give an oil. Dissolution of ethyl acetate in hexane on silica gel Chromatography eluting with increasing concentration (2:8-3.7, volume ratio) The desired compound was obtained as a golden oil (9.0 g, 56%). Rfo, 5( Noenone (9, Og, 39.08 mmole) was removed from the si part by 2N hydrochloric acid (1,5 5% palladium on activated carbon catalyst (5% palladium on activated carbon) in A ethanol (40 ml) containing 00 mg) at 50 p, s, i, (3,45 bar).

After 3 hours the suspension was filtered through Albacel and evaporated to dryness under vacuum. remain The oil was chromatographed on silica gel (400g). to ethyl acetate Elutes with increasing proportion in xane (2.8-4:6, volume ratio) By doing so, the desired ketone was obtained as a white solid (4.04 g, 49%). R fO55 (ss-3), actual value: C, 72, 39: H, 6, 95: C+<H1 eOs theoretical value C, 72,39: H, 6,94%.

Add sodium borohydride (2.33 g, 61.51 mmol) little by little , Part II of the ketone (3,78g, 16.27mmol) in methanol (80ml) le) was added to the solution under stirring while maintaining the temperature below 5°C. 15 minutes later Evaporate the solvent under vacuum and dissolve the residue in methylene chloride and wash with saturated salt solution. Ta.

Dry with MgSO4 and evaporate under vacuum to give a white solid. Silica gel (2 50 g) with diethyl ether in hexane (1,1, volume ratio). The desired ester was obtained as a form (2.93 ．． 77%). Actual value: C, 7L 84: H, 7, 82: C14H1l103 Theoretical value C171,77; H, 7,74%.

iv, t-4-(4-methylbenzenesulfonyloxy)-c-2-phenyldi Diethyldiazodicarboxylate (4°) in tetrahydrofuran (10ml) 08 g, 23.47 mmole) was added under nitrogen to the ester of part iii (4.4 g , 18.78 mmole), triphenylphosphine (6.16 g, 23.47 mmol　e) and methyl 4-toluenesulfonate (4.37 g, 23.4 7 mmole) in tetrahydrofuran (60 ml) under stirring. Addition was maintained at 5-10°C. After stirring overnight at room temperature, the mixture was heated to 0°C. and an additional amount of triphenylphosphine (L, 23 g 54.7 mmole ) and methyl 4-toluenesulfonate (874 mg, 4.7 mmole) and then diethyldiazodicarboxylate (816 mg, 4.7 mmo le) was added. After stirring for a further 4 hours at room temperature, the mixture was evaporated. Reduce the volume, redissolve the residue in methylene chloride, and chromatize on silica gel (400 g). Loaded directly onto a tography column. Increase the proportion of ethyl acetate in hexane By elution while increasing the volume (19-3:7, volume ratio), the desired 4-torr The ensulfonate was obtained as an oil (3.45g, 47%). Rfo, 45 (4 :1, ethyl acetate, hexane). Actual value: C, 64, 71: H, 6, 26; C z+Hz<OsS Theoretical value C, 64,93; H, 6,23%.

Sodium azide (1.16 g, 17.76 mmole) was dissolved in dimethylforma 4-Toluenesulfonate (3.45 g, 8.88 mmo) from part iv in Mido le) and the mixture was stirred at 60° C. for 18 hours. water once cooled was added and the suspension was extracted with diethyl ether. The organic extract was washed with water and MgS Drying with O4 and evaporation gave a clear oil. Add this to silica gel (300g) Chromatographed above. Increasing the proportion of ethyl acetate in beef starch Filter the AND by eluting it while (1・20-1:4, volume ratio). Obtained as a shell-like solid (2.11 g, 92%). RfO,55 (4:1, hexane ,Ethyl acetate). Actual value: C, 65,20; H, 6,60; N, 15.32; C.

Hl 7 N s O2 theoretical value C, 64,85; H, 6,61; N, 16.20 %.

Acid (2.1 g, 8.1 mmole) from 7 parts in methanol (50 ml) was treated with 5% palladium catalyst (210 mg) on activated carbon at 50 p,s,i,(3,4 5 bar). 21i After 4 hours, the mixture was subjected to a short Albuquerque force. Filtered through ram and evaporated under vacuum. Dissolve the residue in ethyl acetate and dilute with diethyl Acidified with IN hydrochloric acid in ether. Filter the precipitated salt and wash with ethyl acetate. The title amine was obtained as a white solid (1.88 g, 94%). Melting point 255- 6°C (decomposition) a Rfo, 2 (ss-1), actual value: C, 62, 64; H, 7 ゜74; N, 5.74; C14H19NO2"HCI theoretical value C, 62, 33 ;H.

7.47; N, 5.19%.

Manufacturing example 7 cm3-amino-c-5-phenylmethylcyclohexane-r-1-carvone dry t-Butyldimethylsilyl chloride (16°5) in dry methylene chloride (65ml) 8 g, 110 mmole) over half an hour, cis-3-hydroxycyclo Hexane-cis-1,3-dicarboxylic acid dimethyl ester (21.5g, 99m mole) [J, Org, Chem, 38 1726.1973], Torie Thylamine (11,13g, 110mmole) and 4-dimethylaminopyry A stirred solution of gin (488 mg, 4 mmole) in methylene chloride (80 ml) The addition was carried out under stirring, maintaining the temperature at 5-10°C with water cooling. Leave at room temperature overnight After that, an additional amount of t-butyldimethylsilyl chloride (1.6 g), I- Add ethylamine (1.1 g) and dimethylaminopyridine (450 mg). and continued stirring for 68 hours. The mixture was then sequentially mixed with water and saturated ammonium chloride. Washed with aqueous solution and water, dried with MgOs and evaporated under vacuum to form a liquid ( 34.4 g) was obtained. This was chromatographed on silica gel (600 g). I understood. Using a mixture of diethyl ether in Hegyu San (1,3, volume ratio) The desired product was obtained as a liquid (32-6 g, 99 %). RfO.

3 (13, diethyl ether, hexane). Actual value: C, 57, 89; H, 9° 20; C+6IhoOsSi theoretical value C, 58, 15; H, 9, 15%.

IN Sodium hydroxide (94 ml) was added to the above diesel in methanol (500 ml). The mixture was added to a solution of tel (30.87 g, 93.4 mmole) under water cooling. blend The mixture was stirred at 5° C. for 3 hours and then left at room temperature for 18 hours. Most solvents under vacuum Add water and evaporate to! llll! Extract the RI solution with diethyl ether and remove the remaining The diester (3.86 g) of the reaction was recovered. The aqueous phase was acidified with 2N hydrochloric acid and Extracted with methyl ether, washed the organic extract with water, dried over MgSO, and Evaporation under vacuum gave a clear gum (25.5 g). Silica gel (500g) using a mixture of diethyl ether in hexane (7:3, volume ratio) Elution chromatography yielded the desired monoester as a viscous oil. (20.Og.

68%). Rfo, 75 (diethyl ether). Actual value: C, 56,75; H.

8.71: C+5HuOsS i Theoretical value C, 56,93; H, s, 92% .

IM diborane solution M in tetrahydrofuran (59 ml) was added under nitrogen to the tetrahydrofuran solution. Monoester from 1i part in Lofuran (17.0 g, 53.72 mmol It was added dropwise to the solution of e) under stirring while maintaining the temperature at -5°C. Bring mixture to room temperature After 4 hours, an additional amount of 1M diborane solution (10.7 ml) was added. , the mixture was left for 18 hours. Evaporate the solvent under vacuum and add diethyl ether. The solution was sequentially diluted with saturated salt solution, saturated aqueous sodium bicarbonate solution, and then saturated again. Washed with Japanese salt solution. By drying with M g SO< and evaporation under vacuum A clear oil was obtained. This was chromatographed on silica gel (500 g). Ta. Elute with a mixture of ethyl acetate and hexane (1:1, by volume). An oil was obtained (15.18 g, 93%). RfO, 42 (ss-3). Actual measurement Value C, 59° 24; H, 9, 67: C15H5oOsSi Theoretical value C, 59 , 56; H, 10°0%.

iv, c-3-tert-butyldimethylsilyloxy-c-5-(4-methyl Benzenesulfonyloxymethyl) cyclohexyl-1-carboxylic acid methyl ester 4-Methylbenzenesulfonyl chloride (14.18g, 74.39mmole ) and the ester from part iii (15,0g.) in dry pyridine (130ml).

It was added to a solution of 49, 59 mmol e) while stirring under water cooling. at room temperature After stirring for 24 hours, the mixture was poured onto ice and extracted with diethyl ether. was washed successively with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. M Drying over gSO4 and evaporation under vacuum gave an oil (22.0 g). this was chromatographed on silica gel (600 g). ethyl acetate Elute in increasing proportions (1:9-1:4, volume ratio) in the sample. The desired product was obtained as an oil (21.78 g, 96%). Rfo, 3( 4:1, hexane, ethyl acetate). Actual value: C, 57, 66; H, ? , 96; C2°H36Q, SSi theoretical value C, 57,86; H, 7,95%.

2M phenyllithium (24.5mM) in cyclohexane-ether (7:3) l, 49 mmole) in dry diethyl ether (50 ml) under nitrogen. A suspension of cuprous oxide (4.67 g, 24.5 mmol) was heated to a temperature with stirring. The mixture was added while maintaining the temperature below 5°C. The resulting dark green solution was stirred at room temperature for 13i4 h. Stir, cool to -70°C, add ether (10 ml) and cyclohexane (4 Drop a solution of the ester (3.7 g, 8.1 mmole) from part iv in 0 ml) added. The temperature was maintained below -60°C during this addition and then for 15 minutes at -70°C. The temperature was lowered to 0°C. The mixture was then warmed to room temperature, stirred for 1 hour, and cooled with water. The reaction was stopped with a saturated aqueous ammonium chloride solution. Wash the organic phase with saturated salt solution. The sample was washed, dried with MgSO4 and evaporated under vacuum to obtain a sample. on silica gel While increasing the proportion of diethyl ether in hexane (1:20-1 : 10, volume ratio) to generate the desired title by eluting chromatography treatment. A product was obtained (1.4g, 148%). Rfo, 2 (1:9, diethyl ether, hexafluoride) Kisan).

40% hydrofluoric acid aqueous solution (0.5 ml, 10 mmol) was diluted with acetonitrate. A solution of the above ester (3.6 g, 9.93 mmole) in rill (40 ml) Added with stirring. After 1 hour the solution was diluted with diethyl ether and saturated bicarbonate Washed with aqueous sodium solution and water, dried with MgSO4 and evaporated under vacuum. Evaporation gave the desired alcohol as a clear oil (2.36 g, 96%). R fo, 2 (11, diethyl ether, hexane). Product (2.39g, 9.6 2 mmole) as described in Preparation Example 6, part iv to give the title compound t-4- Methylbenzenesulfonate was obtained as a pale yellow gum (2.44 g, 63%).

Rfo.

4 (1:1, diethyl ether, hexane). Actual value: C, 65, 59; H, 6 °54; C2□H2606S theoretical value C, 65,65; H, 6,51%.

Trans-4-methylbenzenesulfonate from part iv (2.41 g, 5° 99 mmol e) was treated with sodium azide as described in Production Example 6.7 parts. and was therefore reduced to obtain the desired amine salt as a form (1.44 g, 99% ).

Rfo, 2 (ss-1), actual value: (:, 63. 31; H, 7, 76: N, 4. 56: Cl5H21NO2・HCl theoretical value C, 63, 48; H, 7 , 81; N, 4°94%.

Production example 8 Ethyl (trimethylsilyl) acetate (16, Olg, 99.9 mmol e) and 3-oxocycloto-beef sancarboxylic acid methyl ester (13,0g , 83°24 mmole) in tetrahydrofuran under nitrogen. A solution of M tetrabutylammonium fluoride (2,78 ml) was heated under stirring to the temperature was gradually added dropwise while maintaining the temperature at 0-10°C. The resulting light brown solution was heated at room temperature for 17 Stir for an hour and add additional amounts of tetrabutylammonium fluoride (0.3 ml) and and ethyl (trimethylsilyl) acetate (5 ml) and reacted after 3 hours. Completion of the reaction was indicated by n, m, r. The mixture was diluted with n-hexane (5 Add benzaldehyde (9.31ml, 191.56mmole) and and titanium tetrachloride (9.15ml) in dry methylene chloride (250ml). ．． It was added dropwise to a suspension of 24 mmole) at -70° C. with stirring. mix for 18 hours The temperature was raised to room temperature over a period of time, and the reaction was stopped with water (100 ml) under water cooling. Ta. The organic layer was washed with water, dried over MgSO4 and evaporated under vacuum. Remove residue On the Kagel, increase the ratio of ethyl acetate in hexane (1:4 -3:7, volume ratio) eluting chromatography process produces the desired product. was obtained as a pale solid (6.89 g, 34%). Melting point 73-5°C. Rfo, 2 5 (4:1, hexane, ethyl acetate). Actual value: C, 73, 20; H, 6, 54: Cl5H160!・0. IH, O theoretical value C, 73, 2L: H, 6, 63 %.

-r-/Lz (6 , 55g, 26. 8 mmol l　e) on activated carbon with 5% palladium catalyst (750 mg) to 20 p, s, i, (1,4 bar). 3 hours Afterwards the suspension was filtered, evaporated under vacuum and the residue was filtered on silica gel (600 g). romatographed. Do not increase the proportion of ethyl acetate in hexane. By eluting the trans isomer (1.4-37, volume ratio), the trans isomer becomes a white solid. obtained as. Melting point 54-5°C. Rfo, 35 (1°4, ethyl acetate, hexane ). Actual value C, 73, 11; H, 7, 46: C + 5H + sO3 theoretical value C, 7 3,15; H, 7,37%. By further elution, more polar cis The isomer was obtained as a white solid. Melting point 71-2°C. Rfo, 25 (1:4, acetic acid ethyl, hexane). Actual value: C, 72, 81: H, 7, 41; Cl5HII IO! Theoretical value C173.15, H, 7.37%.

Production Example 1 The cis isomer (1.9 g, 7.71 mmol) from part ii above was ．． Treat with methoxylamine hydrochloride as described in Part 111 to obtain the desired title O. -Methyl oxime was obtained as a clear oil (2.0 g, 94%). RfO,4 and and 0.45 (4:1, hexane, ethyl acetate). Actual value: C, 69, 53; H, 7゜69; N, 4. 94: C16H21NO! Theoretical value C, 69, 7 9; O-methyl oxime from H, 7,69°iii part (1,97 g, 7.15 mmole) as described in Preparation Example 1, part iv to give the title product as cis and It was obtained as a mixture of trans and trans isomers. Pour this onto silica gel (300g) and add vinegar. While increasing the proportion of ethyl acid in hexane (1.3-37, volume ratio) Chromatography was performed to elute. The trans isomer was obtained as a gum ( 680 mg, 27%). RfO,5 (1:4, hexane, ethyl acetate). Actual value ・C, 68,84; H, 8,17; N, 3.91; CzoHz, NO4 theoretical value C, 69,14; H, 8,41; N, 4. 03%. The cis isomer is also available as gum. (345 mg, 14%). RfO, 45 (1:4, hexane, ethyl acetate ). Actual measurement value C, 67°55; H, 8,08; N, 3.80: CzoHz qNOq・0.5H20 theoretical value C167,39; H, s, 48:N, 3.93% .

Example of manufacturing trans isomer (650mg, 1.87mmol) from 1v part 1, treated with MCI as described in Part V to give the title salt as a gum (533 m g, 99%). RfO, 25 (ss-1). Actual measurement value C, 62, 41; H, 7, 78; N, 4. 77; C+5H+sO3・HCl-0,25H20 theory Values C, 62°49, H, 7,87, N, 4.86%.

The cis isomer (325 mg% 0.94 mmole) from part iv of Production Example 1, V Treatment with HCI as described in the section gave the title salt as a gum (263 mg, 9 9%), Rf 0. 25 (s 5-1), Actual value: (, 59, 45: H, 7,44; N, 4.77; Cl5H21NO2・HCl-H2O theoretical value C, 59, 69; H.

8.01; N, 4.64%.

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 0 mg, 2.4 mmole), 3-(1-carboxycyclopentyl)-2 -(2-methoxyethyl)propanoic acid pencil ester (European Patent Application Publication No. 0) 274234) (401 mg, 12 mmole), c-4-ami No-c-2-(2-phenylethyl)cyclohexane-r-1-carboxylic acid ethyl ester hydrochloride (343 mg, 1.1 mmole, 1-hydroxybenzoto Riazole (162 mg, 2 mmol) and N-methylmorphol / (3541 ng, 3.5 mmol e) of dry methylene chloride (15 ml) The mixture was added to the solution while stirring under water cooling. After half an hour, the mixture was brought to room temperature and 2 Stirred for 0 hours.

The solvent was evaporated under vacuum and the residue was partitioned between diethyl ether and water. organic extraction Wash the effluent sequentially with water, 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water. did. Drying (MgSO+) and evaporation under vacuum gave an oil (640 mg). This was prepared on silica gel (50 g) using diethyl ether and hexane a= Chromatography is carried out to elute with 7.3% by volume to obtain the desired diester. was obtained as a colorless oil (550 mg, 85%). RfO, 32 (7:3, Jie tyl ether, hexane). Actual value: C, 73, 23; H, s, 37; N, 2° 12; C+5H+sO3 theoretical value C, 73,07; H, 8,35; N, 2.3 7%.

Example 2-5 Following the method of Example 1, the following compounds were prepared using the appropriate amine of formula (IV): Built.

Example 6-7 Following the method of Example 1, but using 3-(1-carbohalf-dicycloben as starting material) Chitree 2 (S)-(2-methoxyethoxymethyl)propanoate t-butyl Using ester (European Patent Application No. 89304698.7), formula (I By coupling V) with an appropriate amine, the following compounds were prepared.

Example 8-12 Following the method of Example 1 but using 2S-(N2-benzyloxycarboxylic acid as the starting material) Rubonyl-N'-t-butyloxycarbonyl-8-lysyl aminomethyl) = 3 -[1-(1-carboxycyclopentyl)]-propanoic acid t-butyl ester of formula (IV) using Tel (European Patent Application Publication No. 89305180). The following compounds were prepared by coupling with appropriate amines.

! Burning 1 cyclohexyl) carbamoyl J cyclopentyl 1-propanoate (-butyl) 171-11 Ken -111--Ki-1-1111--1--1--1--11 One-one-one-one-one, -1--one-nee.

luester The diester of Example 8 (734 ml) in methanol (18 ml) and water (2 ml) mg, 0.85 mmole) on activated carbon with a 5% palladium catalyst (7 mg, 0.85 mmole) at room temperature for 3 hours. 5 mg) at a pressure of 50 p, s, i, (3,45 burnt). Ta. The suspension was filtered through an acyl cell and the solvent was evaporated under reduced pressure to give the title compound. (630 mg, ioo%), RfO,66 (ss -1). Actual value: (,63,22:H,9,73:N,7.17; CsgHI aN<0, theoretical value C, 62,78: H, 9,70; N, 7.71%.

Following the method of Example 13, the following compounds were prepared from Examples 9-12.

Example 18 2S-(N''-methanesulfonyl-N'-t-butoquinocarbonyl-8-lysyl Methanesulfonyl chloride (0.14ml 1.1.8mmole) was added to Example [3 amine (601 rng, 0.83 mmole) and N-methylmorphol (0.2 ml, 1.8 mmol) in dry methylene chloride (8 ml). The liquid was lubricated with oil while stirring under water cooling. The solution was stirred at 10°C for 3 hours and then saturated. The reaction was stopped with sodium bicarbonate. Separate the organic layer and dissolve the suiseki in methichloride. The extracts were combined and dried over MgSO4. evaporate under vacuum Got gum. This was applied on silica gel (100 g) to vinegar starting from a 1:1 mixture. Increase the proportion of ethyl acetate in hexane and finally elute with pure ethyl acetate Chromatographed. Evaporate the relevant fractions to obtain the desired product at 7 ohms. Obtained as (576 mg, 87%) o Rfo, 56 (ss-1), actual value: C, 58° 66; H, s, 91: N, 6.65: C5qHt□N4011S Theoretical value C, 58°1B, H, 9,01; N, 6.96%.

Example 19-23 In the same manner as in Example 18, using the appropriate amine of Examples 14-17, an appropriate sulfur N2-substituted-lysyl derivatives by reacting with onyl chloride or acyl chloride The following compound was prepared by doing the following.

Example 24 25-(bis-αl5)-phenylethylcoaminomethyll-3-[1-[( 4-ethoxycarbonylcis-3-(3-methquinpropyl)cyclohe Xanylcarbamoyl]cyclopentyl)propanoic acid t-butyl ester 28 -(bis-[αS)-phenylethyl 1-aminomethyl-3-(1-carboxylic cyclopentyl)propanoic acid and c-4-amino-c-2-(3-methoxy propyl) cyclohexane-r-1-carboxylic acid ethyl ester (from Production Example 2) ) was combined as described in Example 1 to give the title diester as a cam.

RfO,L (4:1, hexane, ethyl acetate). Actual value: C, 73, 19; H.

9.13; N, 4. OL; C+gHa4NzO6 theoretical value C, 73, 26: H, 9°15; N, 3.97%.

Example 25 28-(bis[rlS)-phenylethylcoaminomethyll-3-+1-[ (cis-4-ethoxycarbonyl-cis-3-(2-phenylethyl)cyclohe xyl)carbamoylcocyclopentyl)propanoic acid t-butyl ester above As described in Example 24, c-4-amino-c-2-(2-phenylethyl)cy Clohexane-r-1-carboxylic acid ethyl ester hydrochloride (from Production Example 1) was added to The product was obtained as a white foam. RfO, 55(s s-3), actual measurement value C176°11; H, s, 74; N, 4.25; C4°H 64N20S" 0.25H20 theoretical value C, 76, 12: H, s, 77; N, 3 ゜2S-(Aminomethyl)-3-H-[(cis-4-ethoxycarbonyl-cis -3-(3-methoxypropyl)cyclohexyl)carbamoylcocyclopentyl ) Propanoic acid t-butyl ester ethanol (above Example 24 in 20ml) (992 mg.

1.4 mmol l e) with 60p of 20% palladium hydroxide catalyst on activated carbon, s.

i, (4.1 bar). Shorten the suspension after 24 hours. It was filtered through an Alhacel ram and the solvent was evaporated under vacuum. Dilute the residue with methylene chloride Azeotropic drying with water gave the title amine as a viscous oil (690 mg, 99 %). RfO, 35 (ss-1), actual value: (:, 65.69; H, 9,88: N.

5.19: C27H<aN206 Theoretical value C965°29; H, 9,74: N, 5.2S-(aminomethyl)-3-fl[(cis-4-ethoxycarbonyl -cis-3-[2-phenylethyl-1cyclohexyl)carbamoylcocyclope t-butyl)propanoic acid t-butyl ester The product of Example 25 was hydrogenated as described in Example 26 above to give the title compound was obtained as gum. Rfo, 35 (ss-1), actual value: C, 69,00; H .

2S-(N2-methanesulfonyl-N'-t-butoxycarbonyl-8-lysyl -aminomethyl)-3-[1-[(cis-4~ethoxycarbonyl-cis-3- (3-methoxypropyl)cyclohexyl)carbamoylcocyclopentyl) Propanoic acid t-butyl ester N-methylmorpholine (0.34ml 13.06mmole) was added to the raw material of Example 26. Product (690 mg, 139 mmol), N”-methanesulfonamide -N'-t-butoxycarbonyl-8-lysine (406ing, 1.39mmo le), 1-hydroxybenzotriadulle (188 mg, 1.39 mmo) l e) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (586 mg, 3.06 mmole) in dry methylene chloride (10 ml) The mixture was added to the mixture while stirring under water cooling. After 6 hours, the mixture was diluted with methylene chloride. The mixture was diluted with water (20 ml), washed with water and dried over MgSO4. Evaporate the solvent under vacuum. on silica gel, increasing the proportion of ethyl acetate in hexane (5 0-90%), finally chromatographed with 5% ethanol in ethyl acetate. The desired product was obtained as a cream 7ohm (880mg, 8L%). ). RfO, 2 (s　s　-'3). Actual value C, 58,07; H, 9,06 :N, 6. 74; C31JH7ON4011S Theoretical value C, 58, 33; H , 8,79; N, 6.98%.

Example 1 2S-(N-t-butyloxycarbonyl-R-alanylaminomethyl)-3- H-[(cis-4-ethoxycarbonyl-cis-3-(2-phenylethyl)) Following the method of Example 28, starting from the amine of Example 27, Coupling with cyclocarbonyl-R-alanine gave the title product as a form.

RfO, 5 (ss-1), actual value: C, 67, 22; H, s, 86: N, 5°6 6; CC59H61N30 Theoretical value C, 66, 92; H, a, 78; N, 6 ．． 00%.

Example 30 2-rN-(2-t-butyloxycarbonylamino-2-methylpropanoyl ) aminomethyl] -3-+1- [(cis-4-ethoxycarbonyl-cis -3=(2-phenylethyl)cyclohexyl)carbamoylcocyclopentyl ) Propanoic acid t-butyl ester Following the method of Example 28, starting from the amine of Example 27, 2(-butyl oxycarbonylamino-2-methylpropanoic acid to give the title product as a phosphatide. obtained as a team. Rf 0. 48 (s 5-1), actual value: C, 67, 0 6;H.

8, 94; N, 5. 81: C<aHesNso* Theoretical value C, 67 , 29; H,s.

89; N, 5.89%.

Example 3L ”(cis-4-carboxy-4-2 β-12-sutamyolethyl) Li carbamoyl l cyclopentyl l propanoic acid trifluoroacetic acid (5 ml) , 2S-(N''-methanesulfonyl-N'-t-butoxycarbonyl-8-ly syl-aminomethyl)-3-[1-[(cis-4=ethoxycarbonyl-cis- 3-12-phenylethyl 1 cyclohexyl)carbamoyl 1 cyclopentyl 1 Propanoic acid [-butyl ester (from Example 19) (445 mg, 0.53 m mol e) in dry methylene chloride (5 ml) under water cooling.

The solution was allowed to warm up to room temperature and after 3 hours was evaporated to dryness under vacuum. Toluene the residue It was azeotropically dried twice and dissolved in IN sodium hydroxide.

The solution was stirred at 40-55°C for 68 hours, cooled and applied to a sulfonic acid ion exchange column. Conducted. Elute with 10% aqueous pyridine and evaporate the relevant fractions to obtain the form. Ta. This was triturated under acetonitrile and filtered to give a white powder (279mg).

80%). Rfo, 25 (ss-2), actual value: C, 58, 66: H, '7. 92; N, 8.49: CsC52H5oN40 Theoretical value C, 59,06 ;H,7,74;N,8.　61%.

Examples 32-37 Example 18. The appropriate N'-t-butyloxycarbonyl of 20-23 or 28 From the protected diester, treatment with trifluoroacetic acid according to the method of Example 31 Thereafter, the following compound was produced by alkaline hydrolysis.

Examples 38-39 From the diesters of Examples 29 and 30, trifluoride was prepared according to the method of Example 31. The following compounds are produced by treatment with acetic acid and then alkaline hydrolysis. Ta.

Example 40- 3- +L-[(cis-4-carboxy-cis-3-f2--yaleethyl 1 　Sh’;ia”, -j≦guσthreekafiretonguegorJ’lymi≦2fl　twoAnie 2-methoxyethyl and two brothers Example 1. in ethanol (25 ml) and water (10 ml). diester (5 10 mg, 0-86 mmole) of 10% palladium on activated carbon for 3 hours at room temperature. Catalyst (100 m, g) at a pressure of 50 p, s, i, (3,45 barno) and hydrogenated. The mixture was filtered through a short Avicel column and the solvent was evaporated under reduced pressure. I let it emanate. The monoester thus obtained was dissolved in IN sodium hydroxide, and this solution was The solution was heated to 65° C. for 2 days under nitrogen atmosphere. Once cooled, dilute the solution with diethyl Extracted with ether, acidified the aqueous phase with 2N hydrochloric acid and extracted with diethyl ether. I put it out. The organic phase was washed with water, dried over MgSO4 and evaporated under reduced pressure to obtain the desired (300 mg, 75%), RfO, 62 (ss-1), actual value: (, 68, 17: H, 8, 45: H, 2, 95: CzyHxeN Os Theoretical value C, 68, 47: H, 8, 30; 2.96%.

Examples 41-44 The appropriate diesters of Examples 2-5 were hydrogenated according to the method of Example 4o. The following compound was then produced by alkaline hydrolysis.

Example 45 Trifluoroacetic acid (5 ml) was added to the dichloromethane of Example 6 in dry methylene chloride (3 ml). It was added to a solution of ester (480 mg, 0.77 mmole) under water cooling.

After standing at room temperature for 3 hours, the solution was evaporated to dryness under vacuum and the residue was taken up with toluene. Azeotropically dried. Dissolve the remaining oil in ethyl ether and wash with water to obtain X9L. The resulting monoester was extracted into IN sodium hydroxide solution (2×10 ml).

The aqueous extract was heated to 65-70°C under nitrogen for 24 hours, cooled and saturated with salt. Acidified with hydrochloric acid and extracted with ethyl acetate. Wash the organic extract with water, MgSO It was dried and evaporated to give the diacid as a gum (320 mg, 88 %). Real 2S-(2-methoxyethoxymethyl)-3-fl-[(cis-4-ka Ruboxy-cis-3-(3-ethoxypropyl)cyclohexyl)carbamoy (rucocyclopentyl)propanoic acid The title product was prepared from the diester of Example 7 as described in Example 45 above. , obtained as gum. Actual value: C, 61, 26; H, s, 66: N, 2.83; C zsHlxNOs・O-3H20 theoretical value C, 61, 15: H, s, 95; N, 2 ゜85%.

Submission of translation of written amendment (Article 184-8 of the Patent Law) May 15th, 1992

Claims (22)

[Claims] 1. A compound of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A completes a 4- to 7-membered carbocyclic ring. and they may be saturated or monounsaturated, optionally containing other saturated or unsaturated optionally fused to a 5- or 6-membered carbocyclic ring; B is (CH2)m, where m is an integer from 1-3; R and R4 are independently H, C1-C6 alkyl, benzyl or other biologically unstable is an ester-forming group; R1 is H or C1-C4 alkyl; R2 is C1 C1-C6 substituted by -C4 alkoxy, aryl or aryloxy is alkyl; and R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl C3-C7 cycloalkyl or C3-C7 cycloalkenyl, or R5 is halo, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6)alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkyl Kenyl, aryl, aryloxy, heterocyclyl, -NR6R7, -NR 8COR9, -NR8SO2R10, -CONR6R7 or R6R7N-( C1-C6) C1-C6 alkyl substituted by alkoxy; or R5 is C1-C6 alkyl substituted with a group of the following formula: ▲ mathematical formula, chemical formula, There are tables etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R6 and R7 are each independently H, C1-C4 alkyl, C3-C7 Cycloalkyl, aryl, aryl(C1-C4)alkyl, C2-C8alkyl coxyalkyl or heterocyclyl; or two groups R6 and R7 together with the nitrogen to which they are attached is pyrrolidinyl, piperidino, morpholino , forming a piperazinyl or N-(C1-C4)alkyl-piperazinyl group ; R8 is H or C1-C4 alkyl; R9 is C1-C4 alkyl, CF3 , aryl, aryl(C1-C4)alkyl, aryl(C1-C4)alco xy, heterocyclyl, C1-C4 alkoxy or NR6R7, where where R6 and R7 are as defined above; R10 is C1-C4 alkyl, C3-C7 cycloalkyl, aryl or hetero It is rosycryl; R11 is H, C1-C6 alkyl, aryl or C3-C7 cycloalkyl can be; R12 is R11CONR11-, R11SO2NR11-, R16R17N-( CH2)p- or R11O-, where R11 is each as defined above. R13 and R14 are each independently H or C1-C6 alkyl; or R13 is H and R14 is C1-C6 alkyl; So, this is OH, C1-C4 alkoxy, SH, SCH3, NH2, aryl ( C1-C6) Alkyl OCONH-, NH2CO-, CO2H, guanidino, a substituted by lyl or heterocyclyl; or two groups R13 and R14 are connected together with the carbon atom to which they are attached to a 5- or 6-membered carbon atom. forming heterocyclic rings, which are saturated or monounsaturated and optionally C1-C 4 substituted by alkyl or other saturated or unsaturated 5 or may be fused to a 6-membered carbocyclic ring; or R13 is H and R12 and and R14 combine to form a 2-(N-COR11-4-aminopyrrolidinyl) group death; R15 is R16R17NCO-, R11OCO-, R11OCH2- or hetero rosyclyl, where R11 is as defined above; R16 and R 17 is each independently H or C1-C6 alkyl; and p is 0 or is an integer from 1 to 6) and their pharmaceutically acceptable salts and Biological precursors of et al. 2. A is (CH2)1, R1 is H, and B is (CH2)2, the claim A compound of the following formula described in item 1 of the range: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (R, R2, R4 and R5 in the formula are defined above). 3. A compound according to claim 1 or 2, wherein R and R4 are both H. thing. 4. one or both of R and R4 is a group forming a biologically unstable ester; and these groups are ethyl, benzyl, 1-(2,2-diethylbutyryloxy) c) Ethyl, 2-ethylpropionyloxymethyl, 1-(2-ethylpropionyl) nyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, 1- (benzoyloxy)benzyl, 1-(benzoyloxy)ethyl, 2-methyl -1-propionyloxypropyl, 2,4,6-trimethylbenzoyloxy Methyl, 1-(2,4,6-trimethylbenzyloxy)ethyl, pivaloyl oxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylphenyl , [5-(4-methyl-1,3-dioxolen-2-onyl)]methyl or 3. A compound according to claim 1 or 2, which is 5-indanyl. 5. R5 is a group of the formula -NHCOCR12R13R14 (wherein R12 is NH2, R 11CONH- or R11SO2NH-, R13 is H, and R14 is -(CH2)4NH2) is a methylene substituted with -(CH2)4NH2 A compound according to any one of Items 1 to 4. 6. R5 is N2-acetyl-S-lysyl aminomethyl, N2-methanesulfonyl -S-lysyl-aminomethyl, N2-phenylsulfonyl-S-lysyl-amino is methyl or N2-cyclobutylcarbonyl-S-lysyl-aminomethyl , a compound according to claim 5. 7. Claims where R5 is methoxyethyl or 2-methoxyethoxymethyl A compound according to any one of items 1 to 4. 8. R5 is -NHCOCR12R13R14 (wherein R12 is NH2 and R 13 is CH5 and R14 is H or CH3) 5. The compound according to any one of claims 1 to 4, which is alkyl. 9. R2 is phenyl, benzyl, phenethyl, methoxypropyl or ethoxy 9. A compound according to any one of claims 1 to 8, which is propyl. 10. The compound according to claim 1, wherein the compound is: 2S-( N2-methanesulfonyl-S-lysyl aminomethyl)-3-(1-[(cis-4 -carboxy-3-cis(3-ethoxypropyl)-cyclohexyl)carbamo yl]cyclopentyl)propanoic acid, 2-(N2-methanesulfonyl-S-lysyl) (aminomethyl)-3-(1-[(cis-4-carboxy-3-cis-phenetyl) -cyclohexyl)carbamoyl]cyclopentyl)propanoic acid, 2S-(2-methoxyethoxymethyl)-3-(1-[(cis-4-carboxy -3-cis-(3-ethoxypropyl)cyclohexyl)carbamoyl]cyclo pentyl) propanoic acid or 2S-(2-methoxyethoxymethyl)-3-(1-[(cis-4-carboxy -3-cis-(3-methoxypropyl)-cyclohexyl)carbamoyl] Lopentyl) propanoic acid or their biologically unstable ester derivatives. 11. In the method for producing a compound of formula (I) according to claim 1, a compound of the following formula thing: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R19 and R19 are R and and R1, except for H, or they are normal is a bonic acid protecting group, R5' is defined for R5, and the reactive residue hydrolysis and/or hydrogenation (both optionally protected) and/or perform other deprotection reactions to remove the protecting groups present in R5'; and one or both of R18 and R19 is removed so that both R and R4 are H. a corresponding dicarboxylic acid of formula (I), or one of R and R4 is H and the corresponding monoester, the other being a biologically unstable ester-forming group and optionally form pharmaceutically acceptable salts of the product. The way it is done. 12. R18 and R19 are selected from t-butyl, ethyl and benzyl; These groups were treated by trifluoroacetic acid, aqueous alkali or catalytic hydrogenation, respectively. removed by treatment to give a compound of formula (I) where R and R4 are both H , the method according to claim 11. 13. Formula (I) or ( II) Compounds or pharmaceutically acceptable salts thereof or living organisms thereof Drugs containing chemical precursors and pharmaceutically acceptable diluents or carriers agent composition. 14. Claims for drugs, especially for use in the treatment of hypertension, heart failure or renal failure A compound of formula (I) or (II) according to any one of paragraphs 1 to 10, or or their pharmaceutically acceptable salts or their biological precursors. 15. In the method for preparing a compound of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A completes a 4- to 7-membered carbocyclic ring. and they may be saturated or monounsaturated, optionally containing other saturated or unsaturated optionally fused to a 5- or 6-membered carbocyclic ring; B is (CH2)m, where m is an integer from 1-3; R and R4 are independently H, C1-C6 alkyl, benzyl or other biologically unstable is an ester-forming group; R1 is H or C1-C4 alkyl; R2 is C1 C1-C6 substituted by -C4 alkoxy, aryl or aryloxy is alkyl; and R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl C3-C7 cycloalkyl or C3-C7 cycloalkenyl, or R5 is halo, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C5)alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkyl Kenyl, aryl, aryloxy, heterocyclyl, -NR6R7, -NR 8COR9, -NR8SO2R10, -CONR6R7 or R6R7N-( C1-C6) C1-C6 alkyl substituted by alkoxy; or R5 is C1-C6 alkyl substituted with a group of the following formula: ▲ mathematical formula, chemical formula, There are tables etc.▼ ▲There are mathematical formulas, chemical formulas, tables, etc.▼or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Here, R6 and R7 are each independently H, C1-C4 alkyl, C3-C7 Cycloalkyl, aryl, aryl(C1-C4)alkyl, C2-C6alkyl coxyalkyl or heterocyclyl; or two groups R6 and R7 together with the nitrogen to which they are attached is pyrrolidinyl, piperidino, morpholino , forming a piperazinyl or N-(C1-C4)alkyl-piperazinyl group ; R8 is H or C1-C4 alkyl; R9 is C1-C4 alkyl, CF3 , aryl, aryl(C1-C4)alkyl, aryl(C1-C4)alco xy, heterocyclyl, C1-C4 alkoxy or NR6R7, where where R6 and R7 are as defined above; R10 is C1-C4 alkyl, C3-C7 cycloalkyl, aryl or hetero It is rosycryl; R11 is H, C1-C6 alkyl, aryl or C3-C7 cycloalkyl can be; R12 is R11CONR11-, R11SO2NR11-, R16R17N-( CH2)p- or R11O-, where R11 is each as defined above. R13 and R14 are each independently H or C1-C6 alkyl; or R13 is H and R14 is C1-C6 alkyl; So, this is OH, C1-C4 alkoxy, SH, SCH3, NH2, aryl ( C1-C6) Alkyl OCONH-, NH2CO-, CO2H, guanidino, a substituted by lyl or heterocyclyl; or two groups R13 and R14 are connected together with the carbon atom to which they are attached to a 5- or 6-membered carbon atom. forming heterocyclic rings, which are saturated or monounsaturated and optionally C1-C 4 substituted by alkyl or other saturated or unsaturated 5 or may be fused to a 6-membered carbocyclic ring; or R13 is H and R12 and and R14 combine to form a 2-(N-COR11-4-aminopyrrolidinyl) group death; R15 is R16R17NCO-, R11OCO-, R11OCH2- or hetero rosyclyl, where R11 is as defined above; R16 and R 17 is each independently H or C1-C6 alkyl; and p is 0 or is an integer from 1 to 6), a compound of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R18 and R19 are R and and R4, except for H, or they are standard is a bonic acid protecting group, R5' is defined for R5, and the reactive residue hydrolysis and/or hydrogenation (both optionally protected) and/or perform other deprotection reactions to remove the protecting groups present in R5'; and one or both of R18 and R19 is removed so that both R and R4 are H. a corresponding dicarboxylic acid of formula (I), or one of R and R4 is H and the corresponding monoester, the other being a biologically unstable ester-forming group and optionally form pharmaceutically acceptable salts of the product. The way it is done. 16. R18 and R19 are selected from t-butyl, ethyl and benzyl; These groups were treated by trifluoroacetic acid, aqueous alkali or catalytic hydrogenation, respectively. removed by treatment to give a compound of formula (I) where R and R4 are both H , the method according to claim 15. 17. A is (CH2)4, R1 is H, B is (CH2)2, and the following A method according to claim 15 for producing a compound of the formula: ▲ Numerical formula, chemical formula, table etc.▼(II) (R, R2, R4 and R6 in the formula are as defined above. ). 18. R5 is N2-acetyl-S-lysyl aminomethyl, N2-methanesulfony -S-lysyl aminomethyl, N2-phenylsulfonyl-S-lysyl aminomethyl or N2-cyclobutylcarbonyl-S-lysyl aminomethyl, The method described in item 15. 19. Claimed R5 is methoxyethyl or 2-methoxyethoxymethyl The method according to scope item 15. 20. R5 is -NHCOCR12R13R14 (wherein R12 is NH2, C1-C substituted with R13 is CH3 and R14 is H or CH3) 16. The method of claim 15, wherein 6-alkyl. 21. R2 is phenyl, benzyl, phenethyl, methoxypropyl or ethoxy 16. The method of claim 15, wherein the method is cipropyl. 22. According to claim 15, the compound of formula (I) prepared is: How to describe: 2S-(N2-methanesulfonyl-S-lysyl aminomethyl)-3-(1-[( cis-4-carboxy-3-cis(3-ethoxypropyl)-cyclohexyl) Carbamoyl]cyclopentyl)propanoic acid, 2-(N2-methanesulfonyl- S-lysylaminomethyl)-3-(1-[(cis-4-carboxy-3-cis- phenethyl-cyclohexyl)carbamoyl]cyclopentyl)propanoic acid, 2S-(2-methoxyethoxymethyl)-3-(1-[(cis-4-carboxy -3-cis-(3-ethoxypropyl)cyclohexyl)carbamoyl]cyclo pentyl) propanoic acid or 2S-(2-methoxyethoxymethyl)-3-(1-[(cis-4-carboxy -3-cis-(3-methoxypropyl)-cyclohexyl)carbamoyl] Lopentyl) propanoic acid or their biologically unstable ester derivatives.