JPH01110695A - Amino acid derivative as hypotensive agent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is amino or 5--6-membered saturated heterocyclic ring having 1-2N atoms; n is 1-12, provided that 7-12 only when A is amino; R1 and R2 are H; R3 is 1-6C alkyl or aminoalkyl; W and Z are absent or -CH2- or -CH2-CH2-; B is absent or saturated 5--6-membered ring). EXAMPLE:N-[1(S)-Carboxyl-8-aminooctyl]-L-alanyl-L-proline. USE:A hypotensive agent. PREPARATION:A compound expressed by formula II (X is Cl, Br, I or alkylsulfonyl; R1 is H, 1-4C alkyl or benzyl) with a compound expressed by formula III (R2 is H, 1-4C alkyl or benzyl) to provide a condensation product in a protected form. The protecting groups are then removed.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel amino acid derivatives useful as pharmaceuticals.

[Conventional technology]

U.S. Pat. No. 4,374,829 describes carboxyalkyl dipeptide derivatives and related compounds that are useful as angiotensin converting enzyme inhibitors and therefore effective as antihypertensive agents. Also, U.S. patent cylinder 4,
No. 472,384 and U.S. Pat. No. 4,558,03
No. 7 describes a mixture of a carboxyalkyl dipeptide derivative and a compound having other pharmacological actions.

[Problem of invention]

The present invention provides new amino acid derivatives useful as angiotensin converting enzyme activity inhibitors and as antihypertensive agents. The compound of the present invention has the following formula [■]: C0OR.

(In the formula, A is 5 to 5 having 1 to 2 amino or nitrogen atoms)
It is a 6-membered saturated heterocycle.

n is 1 to 12. However, only if A is amino, 7 to 12
, R1 and R2 are each hydrogen, R1 is C-C6 alkyl or aminoalkyl, and V and 2 are absent or -CH, - or -CH,CH
2-, and B is absent or is a saturated 5- to 6-membered ring. ) and pharmaceutically acceptable salts thereof.

A specific example of the compound of the present invention is a compound represented by the following formula [VI] and a salt thereof.

C0OR.

n is 1 to 12, but 7 to 12 only when A is amino
, R1 and R2 are each hydrogen, R1 is -CH, or -C)I2CH, CH, CH, NH
2, the compound of the present invention is a novel compound, has strong and long-lasting angiotensin-converting enzyme inhibitory activity, and is a pharmaceutical compound useful as some antihypertensive drugs.

One group of compounds of the present invention represented by the general formula (1) includes an alanylproline derivative represented by the following formula (Ia) and a salt thereof.

C0OR.

■ A-(CH,)ncllNHc)IcON-Y
(1a) ~lO and coOR.

R and R2 are each hydrogen. ) Representative compounds of this group include N-(1(S)-ruboxy-
8-Aminooctyl]-L-alanyl-proline, N-(1(S)-hydroxy-9-aminononyl)-L
-Alanyl-shi-proline, N-(1(S)-carboxy-1O-aminodecyl)-
L-alanyl-proline.

N-(1(S)-ruboxy-3-(4-piperidyl)
propyl)-L-alanyl-proline, N-(1(
S)-ruboxy-5-(4-piperidyl)pentyl)
-L-alanyl-L-proline, N-(1(S)-ruboxy-6-(4-piperidyl)hexyl)-L-alanyl-proline, 1-(N-(1(S)-proline) ruboxy-6-(4-piperidyl)hexyl)-L-alanyl]-(2α, 3aβ, 7aβ)-octahydro-IH-
Indole-2(S)-carboxylic acid, 1-(N-(1(
S)-ruboxy-5-(4-piperidyl)pentyl)
-L-alanyl)-(2α, 3aβ, 7aβ)-octahydro-IH-indole-2(S)-carboxylic acid, 2
-(N-(1(S)-carboxy-6-(4-piperidyl)hexyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid, 2-( N-(1(s)-ethoxycarbonyl-6-(4
-piperidyl)hexyl)-L-alanyl)-1,2,
3,4-tetrahydroisoquinoline-3(S)-carboxylic acid.

and its pharmaceutically acceptable salts.

The second group of compounds of the present invention represented by general formula (1) includes lysine derivatives represented by primary formula (Ib) and salts thereof.

n is 3 to 8, provided that it is 7 to 8 only when A is amino, and R1 and R3 are each hydrogen. ) Preferred compounds of the second group include:

Nα-[1(S)-ruboxy-8-aminooctyl]
-1ridyl-1proline, Nα-(1(S)-ruboxy-5-(4-piperidyl)pentyl)-1ridyl-1proline, Nα-(1
(S)-Ruboxy-6-(4-piperidyl)hexyl)-L-lysyl-proline.

and pharmaceutically acceptable salts thereof.

Compound (1) of the present invention has 3 asymmetric carbon atoms, 8
Although certain optical isomers exist, the present invention encompasses any of these compounds. Among these isomers, preferable compounds include compounds in which all three asymmetric carbon atoms have S coordination.

When the compound (1) of the present invention is used as a medicine, it can be used in a free form or in a pharmaceutically acceptable salt form.

Examples of pharmaceutically acceptable salts include sodium salts,
Alkali metal salts such as potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, etc., or lysine salts. , salts with organic bases such as ornithine salts, dicyclohexylamine salts, and organic acid salts such as succinates, maleates, fumarates, methanesulfonates, and the like.

These salts can be formed by conventional means, for example, in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which can be removed by vacuum drying or lyophilization, as the free acid or free base. by reacting the product in the form with one or more equivalents of a suitable base or acid, or by exchanging the cation of the existing salt for another cation in a suitable ion exchange resin. Can be done.

According to the present invention, compound (1) has the formula [II]: (wherein,
X is chlorine, bromine, iodine or alkylsulfonyl, A has the same meaning as in formula (1), A can include appropriately protected amino or imino, R1 is hydrogen, 01-C4 is alkyl or benzyl. ) The compound represented by the following formula [■]: C0OR.

(wherein R,, W, Z and B have the same meanings as in formula (1), R3 can include an appropriately protected aminoalkyl, and R2 is hydrogen, C1-C4 alkyl or benzyl) to obtain a protected form of condensation product, and then the protecting group is removed by an appropriate method.

Alternatively, compound (1) can be expressed by the following formula [■]: (wherein,
A, n and R1 have the same meanings as in formula [■]. ) can also be produced by reacting the above compound (m) in the presence of a reducing agent to obtain a protected form of the condensation product, and then removing the protecting group by a suitable method.

Furthermore, the compound [I] of the present invention has the formula [■]: 0OR
1 A-(C)Ia)ncHNHcHcOOH(V)■R1 (wherein + A, n, R1 and R1 are formulas (II) and (m
) has the same meaning. ) Carboxylic acid represented by formula [■]: C0OR.

(In the formula, R2, W, Z and B have the same meanings as in formula (Tll).) to obtain a protected condensation product.1 Then, the protecting group is removed by an appropriate method. It can also be manufactured by

The above reaction will be explained in detail below.

The reaction between compound (n) and compound (II) can be carried out in a suitable solvent in the presence of a deoxidizing agent.

Potassium carbonate and sodium carbonate are used as deoxidizing agents.

Alkali carbonates such as sodium hydrogen carbonate, organic tertiary amines such as triethylamine, and N-methylmorpholine can be suitably used, and dimethylformamide, acetonitrile, chloroform, etc. can be used as the solvent. The reaction temperature is preferably about 0°C to 120°C, and is appropriately selected depending on the properties of the raw materials to the produced compounds.

Compound (m) and compound [IV) can be subjected to a condensation reaction under reductive conditions.

Reductive conditions include, for example, catalytic reduction using a metal such as platinum palladium, Raney nickel, rhodium, or a mixture thereof with an arbitrary carrier as a catalyst, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, Reactions such as reduction with metal hydride compounds such as sodium cyanoborohydride, reduction with metal sodium or magnesium metal and alcohols, reduction with metals such as iron or zinc and acids such as hydrochloric acid or acetic acid, electrolytic reduction, and reduction with reductase enzymes. I can give you conditions. The above reaction is usually carried out in the presence of water or an organic solvent (e.g., methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, dimethylformamide, dimethylacetamide, etc.), and the reaction temperature varies depending on the reduction method. Generally, however, a temperature of about 0°C to +100°C is preferable.

Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased pressure or reduced pressure depending on convenience.

In the condensation reaction of compound (V) and (VI), compound [
Examples of reactive derivatives of the carboxyl group of [■] include acid halides such as acid chloride and acid bromide, acid anhydrides obtained by dehydrating one molecule of water from two molecules of the compound [■], and the carboxyl group of the compound [V]. Examples include derivatives such as mixed anhydrides in which hydrogen of is replaced with an ethoxycarbonyl group, isobutyloxycarbonyl group, benzyloxycarbonyl group, etc. The reaction is generally carried out in a suitable solvent, and any solvent can be used as long as it does not inhibit the reaction. When compound (V) is used as it is without converting it into a reactive derivative, it is advantageous to carry out the reaction in the presence of a dehydrating reagent such as dicyclohexylcarbodiimide, carbonyldiimidazole, diethyl cyanophosphate, or diphenylphosphorylatide. . The reaction can also be carried out in the presence of a base such as pyridine, picoline, triethylamine, sodium hydroxide, sodium carbonate, etc. One reaction stage is usually carried out in the range of about -20 to +150°C, and in most cases The reaction proceeds satisfactorily even at room temperature.

The condensate thus obtained can be isolated and purified from the reaction mixture by conventional separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. can. If necessary, the condensate can be treated with acid using hydrochloric acid, trifluoroacetic acid, formic acid, etc., alkaline saponification using an aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., palladium black, palladium/carbon, etc. The desired product (1) or a salt thereof can be obtained by carrying out the deprotection reaction using known techniques in peptide chemistry, including catalytic reduction using a metal catalyst such as platinum oxide.

Since the compound represented by formula (1) has three asymmetric carbon atoms in the molecule, eight optical isomers exist, but as described above, all of these isomers and mixtures thereof are included in the present invention. These isomers can also be produced individually if desired.

That is, when at least one of the starting compounds is a racemate, the two compounds (1) are usually obtained as a mixture of isomers, but this isomer mixture can be separated by conventional separation methods such as fractional recrystallization, various chromatography, Optically active base (
quinine.

quinidine, etc.) or optically active acids (camphorsulfonic acid,
It can be separated into each isomer using a method of generating a salt with tartaric acid, dibenzoyltartaric acid). Further, by carrying out the above reaction using each optical isomer of the raw material compound that has been optically resolved in advance, the optical isomer of compound [I] can be obtained.

The compound of the present invention represented by formula [I] exhibits angiotensin-converting enzyme inhibitory effect and bradykinin-degrading enzyme inhibitory effect, has a long-lasting strong hypotensive effect, and is not only useful as an antihypertensive agent, but also It is also useful in the treatment of glaucoma and urinary heart failure.

Although the evaluation of converting enzyme inhibitors is guided by in vitro enzyme inhibition assays,
-5tein method (Am, J, C11n, Patho
An example of the inhibitory activity of the compounds of the present invention determined by the following method is shown in the table below.

(The following is a blank space) The compound of the present invention can be used as an angiotensin-converting enzyme inhibitor in mammals such as monkeys, dogs, cats, rats, and humans. The compounds of the invention can be conveniently incorporated into pharmaceutical formulations in a conventional manner. These can be in the customary dosage forms such as capsules, tablets, dragees, granules, solutions, syrups, soft drinks, emulsions and/or in depot form.

The active substances can optionally also be present in microencapsulated form. The formulation may contain acceptable organic or inorganic additives, such as granulating agents, adhesive and binding agents, lubricants,
It may contain suspending agents, solvents, antimicrobial agents, wetting agents and preservatives. For injection, oral and topical use forms, a daily dose of about 0.5 to 50 μ is administered in 1 to 3 divided doses. The topical use form can contain from 0.001 to 5% by weight;
Dosage can vary depending on the severity of the disease, the weight of the patient, and other factors recognized by those skilled in the art.

The compounds of the present invention can also be used in combination with other diuretics or antihypertensive agents, such as hydrochlorthiazide, furosemide, and the like. Antihypertensive agents include propranolol, a β-blocker;
Timolol and methyldopa are used.

Specific binders that can be mixed into tablets, capsules, fine granules, etc. are shown below. Binders such as tragacanth, gum arabic, corn starch or gelatin; Excipients such as microcellulose; Leavening agents such as corn starch, pregelatinized starch, alginic acid, etc.; Lubricants such as magnesium nistearate; sweeteners, such as sugar, lactose or saccharin; flavoring agents, such as peppermint, oil of red or cherry; and when the dosage unit form is a capsule, it contains materials of the above type in addition to a liquid carrier such as a base oil. Various other materials can be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

Sterile compositions for injection include the active substance dissolved in a vehicle such as water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil and the like, or a synthetic fatty vehicle such as ethyl oleate and the like. can be formulated according to normal pharmaceutical practice. Buffers, preservatives, antioxidants, etc. can be added as necessary.

For the skewers, cacao butter and lytepsol are used as a base, and carbowax is used as a hydrophilic base, and may contain a surfactant, a coloring agent, an antioxidant, and the like.

For topical use in the eye, it is administered in combination with a physiologically acceptable carrier material such as, for example, aqueous methylcellulose. The combination can be present in the form of a suspension, solution, solution, emulsion or ophthalmic insert. They are also produced in combination with compounds such as benzalkonium chloride, which facilitate the penetration of the active substance into the eye and have antiseptic properties.

Hereinafter, particularly preferred embodiments of the present invention will be explained with reference to Examples, but the scope of the present invention is not limited thereto.

Example 1 a) Ethyl N-(1(S)-ethoxycarbonyl-8-phthalimidooctyl)-L-alanyl-proline tertiary butyl ester 2-bromo-9-phthalimidononanoate (Che
m, Pharm, Bull, 34, 2078 (1986
3 g of L-alanyl-monoproline tert-butyl ester and 0.8 mQ of triethylamine are dissolved in acetonitrile 200I1112 and refluxed for 60 hours. The acetonitrile is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. Anhydrous a′N! After dehydration and drying with sodium, an oily substance is obtained when concentrated. The crystals were subjected to silica gel chromatography (ethyl acetate: n-hexane =
3:1), N-(
310 III g of 1(R)-ethoxycarbonyl-8-phthalimidooctyl)-L-alanyl-di-proline tert-butyl ester are obtained as a colorless oil.

Thin layer chromatography (TLC), Rf=0.33
(Developing solvent A, ethyl acetate: n-hexane = 3:1; detection: peptide reagent) NMR (CDC1,') δ: 1.1-2.4 (328, m), 3.05-3.3 (
IH, m).

3.4-3.75 (4H, m), 3.9-4.5 (4
8, m).

7.5 to 7.85 (4H, m) From the further effluent fraction, N-[1(S)-ethoxycarbonyl-8-phthalimidooctyl)-L-alanyl-
300 μl of di-proline tert-butyl ester are obtained as a colorless oil.

TLCRf=0.25 (Developing solvent: A, Detection: Peptide reagent) NMR (CDC1,) δ: 1.1-2.2 (321 Lm), 3.0-3.3 (
18,'m).

3.35-3.75 (4H, m) 3.9-4.5 (4H
, m).

7.5-7.9(41(,m) b) N-(1(S)-Ethoxycarbonyl-8-tert-butoxycarbonylaminooctyl) -L-alanyl-L-proline tert-butyl ester N-( 300 μl of 1(S)-ethoxycarbonyl-8-phthalimidooctyl)-L-alanyl-L-proline tert-butyl ester are dissolved in 8 mQ of absolute ethanol.

Next, a solution of 180 μl of hydrazine hydrate in ethanol
Add mQ dropwise and leave at room temperature overnight.

The reaction mixture was diluted with ethyl acetate (50 mfi) plus water.
゜Wash with an aqueous solution of sodium hydroxide. Then, add a 3% aqueous solution of sodium bicarbonate and (B) to an ethyl acetate solution.
oc), 075■ and stir the working time. The ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 30 g of silica gel.
The fractions eluted with a 3:1) solvent system are collected and concentrated to yield 130 rng of a colorless oil.

TLCRf=0.25 (developing solvent: A, detection: peptide reagent) NMR (CDCI, ) δ: 1.1-1.8 (361 (, m), 1.8-2.0 (5
H, m).

2.8-3.7 (5H, m), 3.9-4.7 (5
)1. m) c) N-(1(S)-Ethoxycarbonyl-8-aminooctyl)-L-alanyl-proline Compound 130 obtained in Example 1b) was dissolved in 99% formic acid 100+++Q and heated at 37°C. Stir for 48 hours.

The formic acid was reduced and distilled off under reduced pressure, washed with ether and dried under reduced pressure to obtain 90 cm of a colorless oil.

TLCRf=0.23 (Developing solvent: B, n-butanol: acetic acid: water = 4:1:2: detection: ninhydrin) d) N-(1(S)-hydroxy-8-aminooctyl)-shi Alanyl-Proline 3 mQ of 1N aqueous sodium hydroxide solution is added to the oil obtained in Example 1e) and stirred for 2 hours.

Next, the reaction solution was mixed with a strongly acidic ion exchange resin DO1ilEX5.
011-X2 (20n+9) and stirred for 30 minutes. Fractions eluted with 2% pyridine are collected and lyophilized to yield 75 cm of a colorless white powder.

TLCRf=0.17 (Developing solvent: B, detection: ninhydrin) NMR (CD, OD) δ: 1.2-2.4 (19H, m), 2.7-3.1 (2
H, m).

3.3-3.8 (3H, m), 3.9-4.7 (21
1,m) Example 2 a) Ethyl N(1(S)-ethoxycarbonyl-9-butylimidononyl)-L-alanyl-di-proline tert-butyl ester 2-bromo-10-phthalimi-1-decanoate ( Ch
sm, Pharm, Bull, 34.2078 (198
Synthesis according to 6)] Using 12 g as the starting material, the reaction and purification were carried out in the same manner as in Example 1a), yielding 1.4 g of an oily product.
get g.

TLCRf=0.31 (developing solvent: A, detection: peptide reagent) NMR (CDC13) δ: 1.1-2.25 (34H, m), 3.0-3.3 (1
)1. m).

3.35-3.8 (4H, m), 3.85-4.5 (
4)1. m).

7.5-7.85 (4) 1. a) b) N-(1(S)-ethoxycarbonyl-9-tert-butoxycarbonylaminononyl]-L-alanyl-
-proline tert-butyl ester 1.3 g of the compound of Example 2a) is reacted and purified in the manner described in Example 1b) to obtain 690 ml of an oil.

TLCRf=0.31 (Developing solvent: A, Detection: Peptide reagent) NMR (CDC1,) δ: 1.1-1.7 (38H, m), 1.8-2.3 (5
H, m).

2.8-3.7(5)1. m), 3.8-4.9 (5
)1. a) c) N-(1(S)-Ethoxycarbonyl-9-aminononyl)-L-alanyl-proline Compound 600 of Example 2b) was deprotected by the method shown in Example 1c). , 440ffIg of oil is obtained.

TLCRf=0.29 (Developing solvent: A, detection: ninhydrin) d) N-(1(S)-hydroxy-9-aminononyl]-L-alanyl-L-proline Compound 420■ of Example 2c) was carried out The mixture was subjected to alkaline hydrolysis as shown in Example 1d) and treated with a strongly acidic ion exchange resin to obtain 200 cm of white powder.

TLCRf=0.23 (Developing solvent: B, Detection: Ninhydrin) NMR (CD300) δ: 1.1-2.3 (21H, m), 2.6-3.0 (2
H, m).

3.3-3.7 (311, m), 3.8-4.5 (2
, H, m) Example 3 a) N-(1(S)-ethoxycarbonyl-10-
ethyl phthalimidodecyl)-L-alanyl-proline tert-butyl ester 2-bromo-11-phthalimidoundecanoate (
Chem, Phar++, Bull, 34.207g (
1986) was used as the starting material and the reaction and purification were carried out in the same manner as in Example 1a) to obtain 1.4 g of an oily product.

TLCRf=0.36 (developing solvent: A, detection: peptide reagent) NMR (CDC1,) δ: 1.0-2.2 (36H, m), 3.0-3.3 (1
)1. m).

3.3-3.75 (4H, m), 3.9-4.5 (4
1(,m).

7.5-7.8 (4H, m) b) N-(1(S)-ethoxycarbonyl-10-
(tert-butoxycarbonylaminodecyl) -L-alanyl-proline tertiary-butyl ester Compound 900 of Example 3a) is reacted and purified in the manner shown in Example 1b) to obtain 570 of an oil.

TLCRf=0.36 (Developing solvent: A, detection: peptide reagent) NMR (CDC1,) δ: 1.1-1.8 (40) 1. m), 1.9 to 2.2 (
5)1. m).

2.8-3.7 (5H, m), 3.8-4.7 (5
1(,m)c) N-(1(S)-ethoxycarbonyl-10-aminodecyl)-L-7ranyl-L-proline Compound 500 of Example 3b) was deprotected by the method shown in Example 1c) The reaction is carried out to obtain 470 ml of oil.

TLCRf=0.33 (Developing solvent: B, detection: ninhydrin) d) N-[1(S)-ruboxy-10-aminodecyl)-L-alanyl-proline Compound 400 of Example 3c) was carried out Alkali hydrolysis and treatment with a strongly acidic ion exchange resin were carried out in the manner described in Example 1d) to obtain 210 cm of white powder.

TLCRf=0.28 (Developing solvent: B, detection: ninhydrin) NMR (CD, 00) δ: 1.1-2.5 (23) 1. m), 2.6 to 3.1 (2
H, m).

3.1-3.8 (3H, m), 3.8-4.5 (21
1,m) Example 4 a) N-(1(S)-ethoxycarbonyl-3-(
1-Benzyloxycarbonyl-4-piperidyl)propyl)-L-alanine tert-butyl ester 4-(1-benzyloxycarbonyl-4-piperidyl)-2-oxobutyric acid ethyl ester (Chem, Pharm.

Synthesized according to Bull, 34.3747 (1986))
3.1g, L-alanine tert-butyl ester hydrochloride 0.65g, Molecular Sieves 3A 60g and triethylamine 0.36g in ethanol 100II.
In addition to IQ, a solution of 0.45 g of sodium cyanoborohydride dissolved in 10 mQ of ethanol was added dropwise. After stirring overnight at room temperature, molecular sieves 3A
Remove from oven.

Ethanol was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography (n-hexane:ethyl acetate = 2:1), and N-(1(R)-ethoxycarbonyl-3-(1 -benzyloxycarbonyl-4-piperidyl)propyl)-L-alanine tert-butyl ester is obtained as a colorless oil.

TLC, Rf=0.40 (developing solvent C, n-hexane:
Ethyl acetate = 2:1. Detection: Peptide reagent) From the subsequent effluent fraction, N-(1(S)-ethoxycarbonyl-3-(1-benzyloxycarbonyl-4-piperidyl)propyl)-L-alanine tert-butyl ester 670 ) is obtained as a colorless oil.

TLC, Rf=0.29 (Developing solvent C1 detection: peptide reagent) b) N-(1(S)-ethoxycarbonyl-3-(
l-benzyloxycarbonyl-4-piperidyl)propyl)-L-alanyl-prolinebenzyl ester N-(1(S)-ethoxycarbonyl-3-(1-benzyloxycarbonyl-4-piperidyl)propyl)-
After adding formic acid to L-alanine tert-butyl ester (containing an unidentified compound) and allowing it to stand at 40°C for 40 hours, the reaction solution was treated with a strongly acidic ion exchange resin DOWEX 5011-X2 and eluted with 2% pyridine. was freeze-dried. Next, 80 mg of crystal and 53,111 g of proline benzyl ester hydrochloride were dissolved in 5 ffiΩ of dimethylformamide, and 70 μa of triethylamine and 46 μa of diethyl cyanophosphate were added dropwise under water cooling. After leaving it at room temperature for 30 minutes,
100% of water was added to the reaction solution, extracted with ethyl acetate, and further extracted with 10% phosphoric acid aqueous solution (50 mQ x 2), I
N-Sodium hydroxide aqueous solution (50d) and water (10d)
After washing with 0 mQ x 2 ), the ethyl acetate layer was dried using a sieve. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate = 1:10) to obtain 92cm of a colorless oil.

TLC, Rf = 0.28 (Developing solvent: hexane: ethyl acetate = 1: 10. Detection: peptide reagent) NMR (CDCI□) δ: 1.0-2.3 (18)! , +m), 2.4-3.7
(7Lm).

3.8-4.7 (6H, m), 5.1 (4H, s).

7.3(IOH,5) c) N-(1(S)-ethoxycarbonyl-3-(
4-Piperidyl)propyl)-L-alanyl-L-proline The oily substance 92w obtained in Example 4b) was dissolved in 30m of methanol, and catalytic reduction was performed by adding 100m of palladium black.After the reaction, The palladium black was removed in the oven, and the methanol was distilled off under reduced pressure to obtain 62 cm of colorless oil.

TLC, Rf=0.11 (Developing solvent 2B.

Detection: peptide reagent) d) N-(1(S)-hydroxy-3-(4-piperidyl)propyl)-L-alanyl-proline 62■ of the oil obtained in Example 4c) was added with IN -Add 1.5 mm of aqueous sodium hydroxide solution and leave at room temperature for 1 hour. Next, the reaction solution was treated with a strongly acidic ion exchange resin DOVEX.
Lyophilization of the fractions treated with 501-X2 and eluted with 2% pyridine yields 46IIIg of a white powder.

TLC, Rf=0.09 (Developing solvent: B.

Detection: Peptide reagent) NMR (o20) δ: 1.0-2.4 (16H, m), 2.6-3.3 (
611, m).

3.4-4.5 (3) 1. m) Example 5 a) N-[1(S)-ethoxycarbonyl-5-(
1-Benzyloxycarbonyl-4-piperidyl)pentyl)-L-alanine tert-butyl ester 6-(l-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoic acid ethyl ester (Chem.

Pharm, Bull, 34.3747 (1986)) was used as a starting material and the reaction and purification were carried out in the same manner as in Example 4a) to obtain an oily product 1.
Obtain 5g.

TLC, Rf=0.55 (Developing solvent: C9 detection: peptide reagent) b) N-0(S)-ethoxycarbonyl-5-(1
-benzyloxycarbonyl-4-piperidyl)pentyl]-L-alanyl-monoproline benzyl ester The compound obtained in Example 5a) was reacted and purified by the method shown in Example 4b), and 240 mg of an oily product was obtained. obtain.

TLC, Rf=0.38 (Developing solvent: D.

Detection: Peptide reagent) NMR (CDC1,) δ: 1.0-2.4 (22) 1. m), 2.5-3.8(
7H, m).

3.9-4.7(61(,m), 5.1(4H,s
)7.3(IOH,5) c) N-(1(S)-ethoxycarbonyl-5-(
4-Piperidyl)pentyl)-L-alanyl-proline 220 μl of the oil obtained in Example 5b) was reacted and purified by the method of Example 4c), yielding 140 μl of the oil.
get.

TLC, Rf=0.19 (Developing solvent: B.

Detection: peptide reagent) d) N-(1(S)-hydroxy-5-(4-piperidyl)pentyl)-L-alanyl-L-proline using the oil obtained in Example 5c) 90rnr: The reaction and purification were carried out according to the method of Example 4d), and the white powder was obtained at 60 μm.
obtain.

TLC, Rf=0.11 (Developing solvent 2B.

Detection: Peptide reagent) NMR (D, O) δ: 1.0-2.4 (20H, m), 2.6-3.3 (6
H, m).

3.4-4.5 (38, m) Example 6 a) N-(1(S)-ethoxycarbonyl-6-(
1-Benzyloxycarbonyl-4-piperidyl)hexyl)-L-alanine tert-butyl ester 7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoic acid ethyl ester (Chew.

Pharm.
Obtain 5 mg.

TLC, Rf=0.50 (Developing solvent two C2 detection: peptide reagent) b) N-(1(S)-ethoxycarbonyl-6-(
1-Benzyloxycarbonyl-4-piperidyl)hexyl)-L-alanyl-prolinebenzyl ester Using 425 mg of the compound obtained in Example 6a), reaction and purification were carried out by the method shown in Example 4b).

430 ml of oil is obtained.

TLC, Rf=0.50 (Developing solvent: A.

Detection: Peptide reagent) NMR (CDC13) δ: 1.0-2.4 (22H, m), 2.5-3.8 (7
H, m).

3.9-4.7 (6H, m), 5.1 (4H, s) 7
．． 3(10H,5) c) N-(1(S)-ethoxycarbonyl-6-(
4-piperidyl)hexyl]-L-alanyl-L-proline Using 430 μl of the oil obtained in Example 6b), reaction and purification were carried out in the manner described in Example 4c) to obtain 290 μl of the oil.
get.

TLC, Rf=0.30 (Developing solvent 2B.

Detection: peptide reagent) d) N-(1(S)-hydroxy-6-(4-piperidyl)hexyl)-L-alanyl-proline using the oil 29011Ig obtained in Example 6c) The reaction and purification were carried out according to the method of Example 4d), and the pale yellow powder was obtained as 2
Get 20■.

TLC, Rf=0.19 (Developing solvent 2B.

Detection: Peptide reagent) NMR (D, O) δ: 1.0-2.4 (22) 1. m), 2.6-3.3(
6)1. m).

3.4-4.5 (3H, m) Example 7 a) Na-(1-ethoxycarbonyl-8-phthalimidooctyl)-NE-tert-butoxycarbonyl-monolysyl-proline tert-butyl ester 2- Ethyl bromo-9-phthalimidononanoate (Chem, Pha
rm. Reflux for an hour. The acetonitrile is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. After dehydration and drying over anhydrous sodium sulfate, the 6 products, which yield an oily substance when concentrated, were separated by silica gel chromatography (ethyl acetate: n-hexane = 1:1) to obtain a diastereomer mixture 1.1.
get g.

Thin layer chromatography (TLC), Rf=0.22 (
Developing solvent, ethyl acetate:n-hexane=1:1) b)
Na-(1(S)-ethoxycarbonyl-8-tert-butoxycarbonylaminooctyl)-NE-tert-butoxycarbonyl-monolysyl-proline tert-butyl esterNa-(1-ethoxycarbonyl-8-phthalimidooctyl) )-NE-tert-butoxycarbonyl-hydrazine-proline tert-butyl ester (1 g) is dissolved in 30 ml of absolute ethanol.0 then hydrazine hydrate 5
Add 50 ml of ethanol solution 3- dropwise and let it stand overnight at room temperature.The reaction mixture is mixed with ethyl acetate (300 d), water and 0.0 ml of ethanol solution. Wash with IN aqueous sodium hydroxide solution. The ethyl acetate solution was concentrated under reduced pressure (100IIIQ), and 3%
Sodium hydrogen carbonate aqueous solution 60- and (Boa)zo 8
Add 00■ and stir for 3 hours. The ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on 150 g of silica gel (developing solvent, ethyl acetate: n-hexane =
Na-(1(R)
-Ethoxycarbonyl-8-tert-butoxycarbonylaminooctyl)-NE-tert-butoxycarbonyl-1-ridyl-1-proline tert-butyl ester (Rf=0.
65. Developing solvent, ethyl acetate: n-hexane = 2:
1) 500 mg of Na-(1
(S)-Ethoxycarbonyl-8-tert-butoxycarbonylaminooctyl)-NE-tert-butoxycarbonyl-silisudine-L-proline tert-butyl ester (Rf
=0.56, developing solvent, ethyl acetate:n-hexane=
2:1) 510 mg is obtained.

c) Na-(1(S)-ethoxycarbonyl-8-
(aminooctyl)-L-lysyl-proline Example 7
Na-(1(S)-nitoxycarbonyl-8-tert-butoxycarbonylaminooctyl)-N6 obtained in b)
-tert-butoxycarbonyl-cy-lysyl-proline tert-butyl ester (480 mg) and 99% formic acid (100 m
Add and dissolve Q) and stir at 37°C for 48 hours. After distilling off the formic acid and drying under reduced pressure, 320 cm of a colorless oil is obtained.

TLC, Rf=0.12 (Developing solvent, n-BuOH:
Acetic acid:water = 4:1:2) d) Na-(1(S)-hydroxy-8-aminooctyl)-L-lysyl-proline 120 mg of the oil obtained in Example 7c) was added with IN water. Add sodium oxide aqueous solution 3- and stir for 2 hours. Then, acetic acid was added to make it acidic, and 5ephadexLH-20
Purify by gel filtration using (0,2N acetic acid).

The eluted fraction is lyophilized to obtain a hygroscopic white powder (58 µ).

TLC, Rf=0.02 (Developing solvent, n-BuOH:
Acetic acid: water = 4:1:2) Example 8 a) Na-(1(S)-ethoxycarbonyl-5-
(1-benzyloxycarbonyl-4-piperidyl)pentyl)-Nε-benzyloxycarbonyl-cy-lysyl-cy-proline benzyl ester 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoic acid ethyl ester (Chew.

Pharm, Bull, 34.3747 (1986)), 7.4 g of
4.6 g of trifluoroacetate was dissolved in 40 mQ of ethanol, the pH was adjusted to 5 with triethylamine, 2 g of molecular sieves was added, and the mixture was stirred for 30 minutes. 1.4g of sodium cyanoborohydride and 40g of ethanol
The solution dissolved in mQ was soaked under stirring for 5 hours, and stirring was continued for another night. After ethanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, the ethyl acetate layer was dried over anhydrous sodium sulfate, and ethyl acetate was distilled off under reduced pressure. Ether was added to the residue, washed with water, the ether was distilled off under reduced pressure, the residue was separated by silica gel chromatography (ethyl acetate:hexane=2:1), and Na-(
1(R)-Ethoxycarbonyl-5-(1-benzyloxycarbonyl-4-piperidyl)pentyl-Nε-penzyloxycarbonyl-hydryl-proline benzyl ester (Rf=0.62.Developing solvent, ethyl acetate :n-hexane=2:1) 1.34 g was also obtained from the subsequent effluent fraction as Na-(1(S)-ethoxycarbonyl-5-(1-benzyloxycarbonyl-4-piperidyl)pentyl-Nε-benzyloxy Carbonyl-L
-IJ lysyl L-proline benzyl ester (Rf=0
．． 52, developing solvent, ethyl acetate:n-hexane=2:
1) 1.15g is obtained.

b) Na-(1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl)-L-lysyl-proline obtained in Example 8a) -(1-benzyloxycarbonyl-4-piperidyl)pentyl-Nε-benzyloxycarbonyl-
1.1 g of di-lysyl-proline benzyl ester was dissolved in methanol, palladium black was added thereto, and catalytic hydrogenation was performed. After 5 hours of reaction, methanol was distilled off under reduced pressure.

1N-NaII LoaQ was added to the residue, dissolved, and left at room temperature for 1 hour, followed by strong acidic ion exchange resin DOWEX 5.
After treatment with 0V-X2 and removal of impurities with 2% pyridine, both fractions eluted with 4% ammonia were lyophilized to form a hygroscopic white powder (Rf=0.08, developing solvent, n-Bu
300 mg of OH:acetic acid:water=4:1:2) was obtained.

Example 9 a) Na-(1(S)-ethoxycarbonyl-6-
(1-benzyloxycarbonyl-4-piperidyl)hexyl)-Nε-benzyloxycarbonyl-cyclolysine tert-butyl ester 7-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohebutanoate (Chem ,Phar
m.

Synthesized according to Bull, 34, 3747 (1986))
A mixture of 7.0 g of III'-benzyloxycarbonyl-diso-lysine tert-butyl ester hydrochloride, 2.1 g of trimethylamine, 5.6 g of potassium bromide and 300 ml of acetonitrile is refluxed for 3 days.

The mixture is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate, dehydrated and dried over anhydrous sodium sulfate, and then concentrated. This residue was purified by silica gel chromatography (hexane:
When separated and purified with ethyl acetate = 2:1), Na-(1(R)-ethoxycarbonyl-6-
(1-benzyloxycarbonyl-4-piperidyl)hexyl)-Nε-benzyloxycarbonyl-cy-lysine tert-butyl ester (Rf=0.31.Developing solvent: C
1 detection: peptide reagent) was obtained as a pale yellow oil, and from the second runoff fraction 2.57 g of Na-(1(S)
)-ethoxycarbonyl-6-(1-benzyloxycarbonyl-4-piperidyl)hexyl)-Nε-benzyloxycarbonyl-cy-lysine tert-butyl ester (
Rf=0.31, developing solvent: C1 detection: peptide reagent)
2.66 g are obtained as a pale yellow oil.

b) Na-(1(S)-ethoxycarbonyl-6-
(1-benzyloxycarbonyl-4-piperidyl)hexyl)-Nε-benzyloxycarbonyl-di-lysyl-di-proline tert-butyl ester 2.5 g of the oil obtained in Example 9a) was dissolved in 50 mA of formic acid. The solution is left at 40°C for 40 hours. After distilling off the formic acid, the oily residue was dissolved in 200 mA of water.

This solution is treated with a cation exchange resin DOWEX 5O-X2. Elution with a 2% aqueous pyridine solution and lyophilization yields 2.0 g of a colorless powder.

Next, while stirring a mixture of 1.9 g of the colorless powder described above, 740 mg of L-proline tert-butyl ester, and 40 mQ of DMA, 59 g of diethyl cyanophosphate was added.
A solution of 0 g dissolved in 15 d of diethylformamide (DMA) is added dropwise to this. After the addition is complete, a solution of triethylamine (510 mg) in DMA (2 mQ) is added to the mixture. After stirring for 3 hours, the mixture is diluted with 300 mQ of water and extracted with 900 mQ of ethyl acetate.

The ethyl acetate layer was diluted with 10% H, PO, (150 mfl
2) Wash with IN NaOH (60 mQ) and water, dry over anhydrous Na2SO4, and then dry under reduced pressure to obtain an oily residue. When this product was purified by silica gel chromatography (hexane:ethyl acetate = 1:3), a pale yellow oil was obtained as Na-(1(S)-ethoxycarbonyl-6-(1-benzyloxycarbonyl-4-piperidyl)). hexyl)-Nε-benzyloxycarbonyl-
Shi-lysyl-shi-proline tert-butyl ester 2.37
g is obtained.

TLC, Rf=0.54 (developing solvent: A, detection: peptide reagent) c) Na-(1(S)-hydroxy-6-(4-piperidyl)hexyl)-L-lysyl-proline Example To a solution of the oil obtained in step 9b) in 10 mQ acetic acid is added 10-30% HBr-acetic acid solution. After the resulting mixture was allowed to stand for 1 hour, ethyl ether 750
- Dilute with -. The precipitate separated out is washed with ethyl ether and dried to obtain the crude dihydrobromide salt.The mixture of this salt and IN NaNaOH5O is then left to stand for 2 hours and treated with a cation exchange resin DOWEX 5O-X2. After removing impurities with 2% pyridine aqueous solution, elution with 4% ammonia aqueous solution and lyophilization yields the desired Na-[1(S)-carboxy-6-(4-) as a white powder.
piperidyl)hexyl)-L-lysyl-proline 7
00 mg is obtained.

TLC, Rf==0.15 (developing solvent: B, detection: ninhydrin) Example 10 a) 1-(N-(1(S)-ethoxycarbonyl-
6-(1-benzyloxycarbonyl-4-piperidyl)hexyl)-L-alanyl)-(2a, 3aβ, 7a
β)-Octahydro-IH-indole-2(S)-carboxylic acid tert-butyl ester N-(1(S)-ethoxycarbonyl-6-(1-benzyloxy, carbonyl-4-piperidyl)hexyl)
-A solution of L-alanine tert-butyl ester dissolved in formic acid 18- is allowed to stand at 40°C for 40 hours. After removing the solvent under reduced pressure, the oil is dissolved in 100 mM water and the solution is treated with a cation exchange resin DOVEX 5O-X2. 2
% pyridine aqueous solution and lyophilized to give a colorless powder 6
Obtain 40 mg.

Next, 640 mg of this powder and (2m, 3aβ, 7aβ)-
Octahydro-IH-indole-2(S)-carboxylic acid tert-butyl ester (J, Med, Chem, 30
1300 mH and 0 M
While stirring the mixture of F20-, a solution of 280 g of diethyl cyanophosphate dissolved in 4 mn of DMA is added dropwise to the mixture. After the addition is complete, a solution of 250 mg of triethylamine in 2 mfi of DMF is added to the mixture. After stirring for 3 hours, the mixture is diluted with 200 mful of water and extracted with 600 mfl of ethyl acetate. Ethyl acetate layer (10%) 12PO-(100mQ x 2), IN
Washed with NaOH (60 mA) and water, anhydrous NaSO
After drying in step 4, drying under reduced pressure yields an oily residue.

This product was subjected to silica gel chromatography (hexane:
When purified with ethyl acetate = 1:3), 1-(N-(1(S)-ethoxycarbonyl-6-
(1-penzyloxycarbonyl-4-piperidyl)hexyl)-L-alanyl]-(2α, 3aβ, 7aβ)
820 mg of -octahydro-ltoindole-2(S)-carboxylic acid tert-butyl ester are obtained.

TLC, Rf = 0,60 (developing solvent: A, detection: peptide reagent) b) 1-(N-(1(S)-ethoxycarbonyl-
6-(4-piperidyl)hexyl)-L-alanyl]-
(2α.

3aβ, 7aβ)-octahydro-IH-indole-
2(S)-Carboxylic acid dihydrobromide Example 10a
) to a solution of the oil obtained in 4-acetic acid, 25
% HBr-acetic acid solution is added. The resulting mixture is left to stand for 1 hour and then diluted with 300 d of ethyl ether. When the precipitate was washed with ethyl ether and dried, the desired 1-(N-(1(S)-ethoxycarbonyl-6-(4-piperidyl)hexyl)-L-alanyl) was obtained.
-(2a, 3aβ, 7aβ)-octahydro-IH-
530 mg of indole-2(S)-carboxylic acid dihydrobromide are obtained as a colorless powder.

TLC, Rf=0.53 (developing solvent 2B, detection: ninhydrin) C) 1-(N-(1(S)-ruboxy-6-(4
-piperidyl)hexyl)-L-alanyl)-(2α,
3aβ, 7aβ)-octahydro-IH-indole-
2(S)-carboxylic acid 400 mg of the monoacid obtained in Example 10b) and IN N
After the mixture of aNaOH5O is allowed to stand for 2 hours, it is treated with a cation exchange resin DOWEX 5O-X2. The desired 1-(
N-(1(S)-ruboxy-6-(4-piperidyl)
hexylco-mono-alanyl)-(2α, 3a p, 7
aβ)-octahydro-IH-indole-2(S)-
250 mg of carboxylic acid are obtained as a white powder.

TLC, Rf=0.33 (developing solvent 2B, detection: ninhydrin) Example 11 Tahydro IH-indole-2(S)-carboxylic acid a
) 1-[N41(S)-ethoxycarbonyl-5-
(1-benzyloxycarbonyl-entyl)-L-alanyl)-(2α, 3aβ, 7aβ)
-Octahydro-IH-indole-2(S)-carboxylic acid tert-butyl ester N-[1(S)-ethoxycarbonyl-5-(1-
300 mg of benzyloxycarbonyl-4-piperidyl)pentyl)-L-alanine in the presence of cyanophosphoric acid diethyl ester according to the method of Example 10a)
2α, 3aβ, 7aβ)-octahydro-IH-indole-2(S)-carboxylic acid (J. Med. Chem.
, 30,999 (1987)) 165 mg
1-(N-(1(S)-ethoxycarbonyl-5-(1-benzyloxycarbonyl-4)
-piperidyl)pentyl)-L-alanyl)-(2 a
, 3aβ, 7aβ)-octahydro-IH-indole-2(S)-carboxylic acid tert-butyl ester 310m
g is obtained as a colorless oil.

TLC, Rf=0.50 (developing solvent: A, detection: peptide reagent) b) 1-(N-('1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl)-L-alanyl]
−(2α.

3aβ,7aβ)-octahydro-111-indole-2(S)-carboxylic acid dihydrobromide Example 10
Deprotection of the oil of Example 11a) was carried out according to the method of b) and the product obtained was purified to give 1-(N-(1
(S)-2I-xycarbonyl-5-(4-piperidyl)pentyl)-L-alanyl]-(2α,3aβ.

7aβ)-octahydro-IH-indole-2(S)
-245 mg of carboxylic acid dihydrobromide are obtained as a colorless powder.

TLC, Rf=0.26 (developing solvent 2B, detection: ninhydrin) c) 1-(N-[1(S)-ruboxy-5-(4
-piperidyl)pentyl)-L-alanyl]-(2 a
, 3aβ,7aβ)-octahydro-IH-indole-2(S)-carboxylic acid Following the method of Example 10c), the monoacid of Example 11b) was saponified and the product was purified to give 1-(N-( 1
(S)-carboxy-5-(4-piperidyl)pentyl)-L-alanyl]-(2α,3aβ,7aβ)-octahydro-IH-indole2(S)-carboxylic acid 1
14 mg are obtained as a white powder.

TLC, Rf=0.19 (developing solvent: B, detection: ninhydrin)

Claims (1)

[Claims] 1. A compound represented by the following formula [I] and a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕
It is a 6-membered saturated heterocycle, where n is 1 to 12, but only when A is amino, 7 to 12
, R_1 and R_2 are each hydrogen, R_3 is C_1 to C_6 alkyl or aminoalkyl, W and Z are absent or -CH_2- or -CH_2
-CH_2-, and B is absent or is a saturated 5- to 6-membered ring. ) 2. A compound represented by the following formula [I'] and a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I ′] (In the formula, A is amino or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and n is 1 to 12, but only 7 if A is amino) ~12
, R_1 and R_2 are each hydrogen, and R_3 is -CH_3 or -CH_2CH_2CH_2C
H_2NH_2, and x is -CH_2- or -CH_
2CH_2- and D does not exist, or ▲ formula,
There are chemical formulas, tables, etc. ▼ forms a condensed ring with ring Q. ) 3. An alanine derivative represented by the following formula [I a] and a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I a] (In the formula, A is amino or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and n is 1 to 10, but only 7 if A is amino) ~10
, Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R_1 and R_2 are each hydrogen. )4, N-[
1(S)-carboxy-8-aminooctyl]-L-alanyl-L-proline, N-[1(S)-carboxy-9-aminononyl]-L
-alanyl-L-proline, N-[1(S)-carboxy-10-aminodecyl]-
L-alanyl-L-proline, N-[1(S)-carboxy-3-(4-piperidyl)
propyl]-L-alanyl-L-proline, N-[1(S)-carboxy-5-(4-piperidyl)
pentyl]-L-alanyl-L-proline, N-[1(S)-carboxy-6-(4-piperidyl)
hexyl]-L-alanyl-L-proline, 1-[N-[1(S)-carboxy-6-(4-piperidyl)hexyl]-L-alanyl]-(2α, 3aβ,
7aβ)-octahydro-1H-indole-2(S)
-carboxylic acid, 1-[N-[1(S)-carboxy-5
-(4-piperidyl)pentyl]-L-alanyl]-(
2α,3aβ,7aβ)-octahydro-1H-indole-2(S)-carboxylic acid, 2-[N-[1(S)-
Carboxy-6-(4-piperidyl)hexyl]-L-
alanyl]-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid, 2-[N-[1(S)-ethoxycarbonyl-6-(4
-piperidyl)hexyl]-L-alanyl]-1,2,
4. The compound according to claim 3, which is any one of 3,4-tetrahydroisoquinoline-3(S)-carboxylic acid. 5. A lysine derivative represented by the following formula [I b] and a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I b] (In the formula, A is amino or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and n is 3 to 8, but only 7 if A is amino) ~8, and R_1 and R_2 are each hydrogen.)6, N^α
-[1(S)-carboxy-8-aminooctyl]-L
-Lysyl-L-proline, N^α-[1(S)-carboxy-5-(4-piperidyl)pentyl]-L-lysyl-L-proline, N^α-[1(S)-carboxy-6 -(4-piperidyl)hexyl]-L-lysyl-L-proline. The compound according to claim 5, which is any one of the following. 7. A pharmaceutical composition useful for the treatment of hypertension, containing the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount. 8. The pharmaceutical composition of claim 7, further comprising a compound selected from the group consisting of: 8. hydrochlorothiazide, chlorothiazide, ethaclinic acid, amiloride, furosemide, propranolol, timolol, and methyldopa; and a pharmaceutically acceptable carrier. 9. A method for treating hypertension, which comprises administering the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount to a patient in need of treatment. 10. Formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, X is chlorine, bromine, iodine or alkylsulfonyl, and A and n have the same meanings as in claim 1. , A can include a suitably protected amino or imino, R_1 is hydrogen, C
It is alkyl or benzyl of _1 to C_4. ) A compound represented by the formula [III]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] (In the formula, R_3, W, Z and B have the same meanings as in claim 1, and R_3 is an appropriate can include a protected aminoalkyl, R_2 is hydrogen, C_1-C_4 alkyl or benzyl) to give the protected form of the condensation product, and then by an appropriate method. A method for producing a compound according to claim 1, which comprises removing the protecting group. 11. Formula [IV]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [IV] (In the formula, n, R_1 and A have the same meanings as in claim 10.) The ketone represented by the above formula [IV] Claim 1, which comprises reacting the compound represented by [III] in the presence of a reducing agent to obtain a protected condensation product, and then removing the protecting group.
Methods for producing the described compounds. 12. Formula [V]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [V] (In the formula, n, R_1, R_3 and A have the same meanings as in claim 10.) A carboxylic acid represented by the formula [VI]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [VI] (In the formula, R_2, W, Z and B have the same meanings as in claim 10.) A method for preparing a compound according to claim 1, comprising obtaining a condensation product of and then removing the protecting group. 13. As the above compound [III], ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_2 has the same meaning as in claim 10, and E is an appropriate 12. The method according to claim 10 or 11, wherein a protecting group is used. 14. A claim to use ▲ there is a mathematical formula, chemical formula, table, etc. ▼ or ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (in the formula, R_2 has the same meaning as claim 10) as the above-mentioned compound [VI] The method according to item 12.