JPS61210079A - 4-aza-1-thiacycloheptane derivative - Google Patents

Abstract

NEW MATERIAL:4-Aza-5-oxo-1-thiacycloheptane derivative of formula I (R<1> is alkyl, cycloalkyl or aralkyl; R<2> and R<4> are H or carboxyl-protecting group; R<3> is naphthyl; Z is lower alkylene). EXAMPLE:4-Aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenyl propyl) amino-5-oxo-2-(1-naphthyl)-1-thiacycloheptane. USE:It has activity to inhibit angiotensinase, and is useful as a remedy for hypertension. Useful also as an important synthetic intermediate of the remedy. It has long-acting activity and can be administered orally. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II with the compound of formula III (X is halogen or sulfonyloxy) in a solvent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-aza-5-oxo-1-thiacyclohebutane (also known as tetrahydro-1,4-thiazepine-5), which is useful as a drug exhibiting hypotensive action and as an important synthetic intermediate thereof. (2H)-one] derivative.

More specifically, the present invention relates to the general formula (wherein R1 represents an alkyl group, a cycloalkylalkyl group, or an aralkyl group, R2 and R4 are the same or different and represent a hydrogen atom or a protecting group for a carboxy group, and R3 is a naphthyl group). The present invention relates to a novel 4-aza-5-oxo-1-thiacyclohebutane derivative represented by the following formula and a pharmacologically acceptable salt thereof.

The present inventors conducted synthetic research for the purpose of research and development of antihypertensive agents, and found that a novel compound having the general formula CI) has an inhibitory activity against angiotensin converting enzyme, and can be used to treat hypertension by oral administration. The present invention was completed based on the discovery that it is useful as a drug.

Structure of the Invention The compound represented by the above general formula [I] contains a k-asymmetric carbon atom at the position indicated by an asterisk (-1 (in some cases, other positions)), so it is optically There may be pure diastereoisomers, racemates of diastereoisomers or mixtures of diastereoisomers; the invention may encompass any of these stereoisomeric forms.

Second, the chisel substituent B1. B2. in the general formula CI"l.
B! 1゜几1 and A) (will be explained in detail.

The alkyl group in R'&C has 1 to 9 carbon atoms.
alkyl groups, such as methyl.

These include ethyl, n-propyl, inpropyl, n-butyl, inobutyl, tert-butyl, pentyl, neopentyl, hexyl, octyl, nonyl, etc. The cycloalkylalkyl group includes a cycloalkyl group having 5 to 7 carbon atoms. An alkyl group having 1 to 2 carbon atoms, such as cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl, 2-cyclohebutylethyl, etc., and an aralkyl group such as benzyl ,
Examples include phenethyl, 1-naphthylmethyl, 1-naphthylethyl, 2-naphthylmethyl, 2-naphthylethyl, 2-indanyl, and the like. These cycloalkyl groups or aralkyl groups may have a substituent, and such substituents include lower alkyl groups having 1 to 4 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl,
-butyl, inobutyl, tert-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc.), norogens (e.g., fluorine, chlorine, etc.) , bromine, etc.), lower alkylthio groups having 1 to 4 carbon atoms (eg, methylthio, ethylthio, etc.), and these substituents may be the same or in combination and may be substituted with 1 to 3.

The carboxylic acid protecting groups in R2 and aA Vc are generally widely known protecting groups in organic synthetic chemistry, or are ester residues that can be pharmacologically converted into carboxy groups in vivo. be. In addition, such protecting groups include alkyl groups having 1 to 6 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.), aralkyl groups, (e.g. benzyl, diphenylmethyl, 1-indanyl, 2-indanyl, 1-(1,2,L4-tetrahydronaphthyl), 2
-(1,2,14-tetrahydronaphthyl), phthalidyl, etc.), aryl groups (e.g. phenyl, etc.), silyl groups (
Examples include trimethylsilyl, ', 'tert-butyldimethylsilyl, etc.). The above protecting groups include alkyl, halogen, hydroxy, alkoxy, acyloxy, oxo, carboxy, alkoxycarbonyl, alkoxycarbonyloxy, acylamino, nitro, cyano, amino, monoalkylamino, dialkylamino, acylamino, alkylthio, arylthio, alkylsulfonyl , 7lylsulfonyl, 2-oxo-1,
A substituent such as a 3-dioxolen-4-yl group may be present, and 1 to 3 of these substituents may be the same or in combination. Examples of such substituents include, for example, 2. z2-Trichloroethyl, 2-iodoethyl, etc., 2 in hydroxy
-Hydroxyethyl, z3-di-droxypropyl, etc.
For alkoxy, methoxymethyl, 2-
Methoxyethoxymethyl, p-methoxybenzyl, etc., acyloxy such as acetoxymethyl, 1-7cetoxyethyl, pivaloyloxymethyl □, etc., oxo such as phenacyl, alkoxycarbonyl such as methoxycarbonylmethyl, alkoxycarbonyloxy such as ethoxy carbonyloxymethyl,
1-(ethoxycarbonyloxy)ethyl, etc., nitro such as p-nitrobenzyl, cyano such as cyanethyl, alkylthio such as methylthiomethyl, ethylthiomethyl, etc., arylthio such as phenylthiomethyl, alkylsulfonyl such as methane. Sulfonylethyl, etc., arylsulfonyl such as benzenesulfonylethyl, 2-oxo-1,3-dioxolen-4-yl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5
-Phenyl-2-oxo-1,3-dioxolene-4-
(il) methyl, etc. These carboxylic acid protecting groups can be widely varied without changing the gist of the invention as long as the purpose of protection is achieved.

几3 is a 1-naphthyl group or a 2-naphthyl group, and these naphthyl groups may have a substituent, such as an alkyl group having 1 to 4 carbon atoms (
For example, methyl, ethyl, n-propyl, inpropyl,
n-butyl, isobutyl, tert-butyl, etc.), alkoxy groups having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, impropoxy, n-butoxy,
(imbutoxy, tert-butoxy, etc.).

Examples of lower alkylene groups include alkylene groups having 1 to 2 carbon atoms, such as methylene, ethylene, and ethylidene.

Suitable compounds in the general formula CI) include R1
is n-butyl, isobutyl, n-pentyl, impentyl, neopentyl, n-hexyl, isooctyl, n
- Straight chain or branched alkyl groups having 4 to 9 carbon atoms such as octyl and n-nonyl; 5-membered or 6-cycloalkylethyl groups such as 2-cyclopentylethyl and 2-cyclohexylethyl; , benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl,
It is an aralkyl group having 7 to 12 carbon atoms such as 1-naphthylethyl, 2-naphthylethyl, 2-indolyl, and R2 is a hydrogen atom, or methyl, ethyl, n
-provil, inpropyl, n-butyl, isopfk,
Carbon number 1 to 6, such as n-pentyl and n-hexyl
(linear or branched alkyl group having 1!d, aralkyl group such as benzyl, acetoxymethyl,
Can be easily converted into carboxy groups in vivo, such as pivaloyloxymethyl, phthalidyl, 1-(ethoxycarbonyloxy)ethyl, and (5-methyl-2-oquino-1,3-dioxolen-4-yl)methyl. is a protecting group, R3 is a 1-naphthyl group or 2-naphthyl group, human is a methylene group, and R4 is a hydrogen atom, tcrt-butyl, methoxymethy/L
', 12.2-17 chloroethyl, allyl, benzyl,
Protecting groups for carboxyl groups used in organic synthetic chemistry such as p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, or acetoxymethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, phthalidyl, (5- Compounds such as methyl-2-oxo-1,3-dioxolen-4-yl) which are protecting groups that can be easily converted into a carboxy group in vivo can be mentioned.

Such novel compound [I] of the present invention can be converted into a pharmacologically acceptable salt by treatment with an acid or base according to a conventional method. Examples of such acid addition salts include inorganic acids such as hydrohalic acids (e.g. hydrochloric acid,
hydrobromic acid, etc.), sulfuric acid, phosphoric acid, and nitric acid, and organic acids (such as oxalic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and benzenesulfonic acid, etc.). can be given. Examples of base-based salts include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., calcium hydroxide, magnesium hydroxide, etc.),
Examples include various salts such as ammonium hydroxide, aluminum hydroxide and organic bases (eg triethylamine, dicyclohexylamine, cinchonine, quanidine, quinine, etc.), basic amino acids (eg lysine, arginine, etc.).

As specific compounds represented by the general formula (1) of the present invention, the compounds described below can be exemplified.

1 'IL'R' M
R4 (1) 06H5G (2Gi, -HωG12
H (21# 02H.

131 1?04)I? #
it+41' E s50-04
H#z#(5)'
(H204H5# z #R'
32 B5 A
R'+6)06u5co2a("H20H,B1
7) 02H5# (81n-0
4H9# +91 181>(1489jFH
GI204H5# @2 02B5 am (CI(B)2GK) 12-Hz
#aa II o2H5a
1<E)-G12G12- H a@# 02H5#
a fin 0Σ H#I al 02H5#
II #all o4) 15G (2G
I2- # > Gl(G(,)@
II g? 06H17-#m Gl,
.

R' 12 B! A
B'9m ((HB)2(IICH2-0
2H5'00(I(, B5042G(2-z # @ 04H, Gl2- # #
＃＃＠0Σ・
・ (To) ・℃0 ・tn,
-60-Ma■02H.

el # <30#tart-a west (to) ・ ℃O as # G (20000(Gl3)3<C)
＃H(14・・ηO・ro02H56゜I R' B2 B5
A n'@
02H51ejc) CI(2a(2(to)
・ ・ Kinds ・ ・Compounds of the present invention (
1) is a compound having the general formula (wherein, Ha, B4, and Human have the same meanings as above) and a compound having the general formula (wherein, R1 and R2 have the same meanings as above, and represents a halogen atom or a nulfonyloxy group.

), or by reductively condensing the compound [■] with a compound having the general formula (wherein ILl and R2 have the same meanings as described above). can be manufactured.

General formula (the halogen atom of X in IN is chlorine,
Bromine and iodine are mentioned, and sulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy,
Substituted or unsubstituted lower plucansulfonyloxy groups such as trifluoromethanesulfonyloxy and benzenesulfonyloxy, p-)
Substituted or unsubstituted aromatic sulfonyloxy groups such as luenesulfonyloxy are mentioned.

The condensation reaction between compound [l] and compound [■] is carried out in the presence of a base in a suitable solvent that does not inhibit the reaction.

Examples of solvents include hydrocarbons such as hexane and benzene, halogenated hydrocarbons such as dichloromethane and 1°2-dichloroethane, ethers such as tetrahydrofuran and dioxane, and esters such as ethyl acetate.
Examples include ketones such as acetone, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylhonuformamide, and dimethylsulfoxide. The base used is not particularly limited, but includes alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, and calcium carbonate, alkali metal bicarbonates such as baking soda and potassium bicarbonate, sodium hydride, and hydride. Examples include alkali metal hydrides such as lithium, and organic bases such as triethylamine, pyridine, picoline, and tetraethylammonium hydroxide. In addition, this reaction is carried out in a two-layer system of water and a water-insoluble solvent such as dichloromethane or chloroform using a phase transfer catalyst such as tetra n-butylammonium bromide or penzyltriethylammonium iodide. Sometimes, the reaction time varies depending on the solvent, type of base, etc., but is usually from 1 hour to 3 days.

After the reaction is completed, the target compound of this reaction can be recovered from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate to the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent. If necessary, recrystallization, column chromatography, etc. It can be refined with

Reductive conditions for the reaction between compound [11] and compound [W] include, for example, catalytic reduction using a metal such as platinum, palladium, Raney nickel, rhodium, or a mixture thereof with an arbitrary carrier, such as hydrogenation. Reduction of lithium aluminum, lithium boron hydride, sodium cyanoborohydride, sodium boron hydride, potassium borohydride with metal hydrides, reduction of sodium metal, magnesium metal, etc. with alcohols such as methanol and ethanol, iron , reaction conditions such as reduction with a metal such as zinc and an acid such as hydrochloric acid or acetic acid. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol,
Tetrahydrofuran, diethyl ether, dioxane,
(dichloromethane, chloroform, ethyl acetate, benzene, toluene, dimethylformamide, dimethylacetamide, acetic acid, etc.), and the reaction temperature varies depending on the reduction means, but is generally preferably about -20 to 100°C.

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 the case.

Among the compounds [1] produced in this way, monoester monocarboxylic acid compounds in which R2 is an ester residue and R4 is a hydrogen atom or a salt, and B2. Dicarboxylic acids in which both B4 are hydrogen atoms or salts are pharmaceutically important compounds. The above monoester monocarboxylic acid compound has the general formula (
I) can be produced by selectively unbinding the ester residue R4 of the diester compound represented by I), or with an amino acid compound and a ketoester [W) (B2 is an ester residue) in which R4 is a hydrogen atom in the general formula C11. It can be produced by the reductive condensation reaction of

In addition, the dicarboxylic compound in which R2 and R4 are both hydrogen atoms can be prepared by hydrolyzing the luciester compound or monoester compound [1) obtained by the above reaction] using an acid or base hydrolysis method or by reducing the ester group using a conventional method. It can also be produced by a removal method. The reaction conditions are the same as those for deprotection of the carboxylic acid protecting group R7 in compound [■] described below.

The raw material compound represented by the general formula [1], that is, the compound represented by the general formula (wherein % "t R' and A have the same meanings as described above)" can be produced, for example, according to the reaction formula shown below.

JH2 [■] [■] (In the formula, 11L3. R', human and X have the same meanings as above, BS, B6. RB and R9 represent a hydrogen atom or a protecting group for an amino group, represents a carboxylic acid protecting group.) In the above formula, the carboxylic acid protecting group represented by R7 is an ester residue generally well known in organic synthetic chemistry, such as methyl, allyl, methoxymethyl. , methylthiomethyl, methoxyethoxymethyl, benzyloxymethyl, phenacyl, p-bromphenacyl, N-
Methyl and substituent methyl groups such as phthalotomethyl, ethyl, 2.2.2-)lychloroethyl, 2-
iodoethyl, 2-trimethylsilylethyl, 2-(p
-) ethyl, lower alkyl group which may have a substituent such as tert-butyl, benzyl,
Examples include benzyl groups which may have substituents such as diphenylmethyl, p-methoxybenzyl, and p-2'trobenzyl, and silyl groups such as trimethylsilyl and tert-butyldimethylsilyl. These carboxylic acid protecting groups are not limited in any way as long as the purpose of protection is achieved.

BS, B4. B8 and 几9? The protecting group for the amino group in IC is a protecting group that is generally well known in organic synthetic chemistry, such as 2,2.2-)lychloroethoxycarbonyl, 2-iodoethoxycarbonyl, and trimethylsilylethoxycarbonyl.

2-(p-)luenesulfonyl)ethyl, tert-butoxycarboel, allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzylcarbonyl,
Alkoxycarbonyl groups such as p-nitrobenzyl, dicarbonyl, formyl, acetyl, benzoyl,
Acyl groups such as chloroacetyl and trifluoroacetyl,
Cyclic diacyl groups such as N-phthaquil and N-2,3-diphenylmaleinyl, substituted methyl groups such as methoxymethyl, benzyloxymethyl, benzyl, 4-dimethoxybenzyl, trityl, isopropylidene, benzylidene,
Alkylidene or aralkylidene groups such as salicylidene, 1-methyl-2-acetylvinyl, 1-methyl-2-
Examples include acylvinyl groups such as benzoylvinyl and silyl groups such as trimethylsilyl and tert-butyldimethylsilyl, but there are no restrictions on the protecting groups for these amino groups as long as the purpose of protection is achieved.

The reaction between compound [v], which is a cysteine derivative, and compound CM] is carried out in the presence of a base in a suitable solvent that does not inhibit this reaction. Solvent used, type of base, reaction a
The reaction conditions such as X and reaction time, and the purification, separation, etc. of the reaction product [■] are the same as those for the reaction of compound [13 and compound [11+1], which have already been described in detail.

Deprotection of the carboxylic acid protecting group represented by IIL7 and the amino group protecting groups represented by R8 and R9 in compound [■] is a well-known method in organic synthetic chemistry, but in the case of this reaction, is a protecting group for the amine group of the synutein moiety B5. A method is needed that does not affect R6. Examples of such methods include deprotection by alkaline hydrolysis using lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. (for example, R7 is methyl, ethyl, etc.), hydrochloric acid, trifluoroacetic acid, aluminum chloride, and other acids, and Lewis acid. Deprotection (for example, R7 is methoxymethyl, methoxyethoxymethyl, tert-butyl, diphenylmethyl, p-methoxybenzyl, trimethylsilyl, tert-butyldimethylsilyl, etc.).

R8 is tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, t-11thyl, tert
-butyldimethylsilyl, etc.), m-protected C by fusion reduction
For example, &in' is benzyl, p-nitrobenzyl, etc., R8
capendyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), deprotection by reduction with zinc dust-acid (for example, R7 is 2.2° 2-trichloroethyl, 2-iodoethyl, phenacyl, p-bromphenacyl, etc.),
8 is 2. R2-) +770yloxycarbonyl, 2-
:51-)'ethoxycarbonyl, etc.), tetrakis(triphenylphosphine)palladium (0 is deprotected with a catalyst (for example, R7 is allyl, R8 is allyloxycarbonyl, etc.), deprotection with hydrazines such as hydrazine, methylhydrazine, etc. (eg, Be, R9 is 7 taloyl, etc.).The solvent used varies depending on the deprotection method, but may include water.

Carbonization of acids such as acetic acid and formic acid, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and anisole, ketones such as a7tone, halogenated hydrocarbons such as dichloromethane and chloroform, benzene and toluene, etc. Hydrogens etc. are used. The reaction temperature and reaction time vary depending on the deprotection method, but are generally from -10°C to 100°C for 30 minutes to day and night. Disengagement lol
! The production of amino acid [■] is carried out in two steps, that is, first, the carboxylic acid protecting group R7 is deprotected, and then the amino group protecting group Be, R9 is deprotected, or the amino group protecting group B8 is first deprotected. ．． There is a method of deprotecting R9 and then the carboxylic acid protecting group R7, but there is also a method of deprotecting the two protecting groups R7 and R8゜9. For example, when R7 is tert-butyl, 8 is tert-butoxycarbonyl, and R9 is a hydrogen atom, the compound [■] can be obtained by the deprotection method with [C], and when R7 is 2. R2-) dichloroethyl, R8 is 2.2.2-) dichloroethyl
When carbonyl or R9 is a hydrogen atom, the compound [■] can be obtained by a zinc dust-acid reduction method. Compound [■] can be purified by isoelectric precipitation, recrystallization, column chromatography, etc., but it can also be used as a crude product in the next reaction.

Next, the method for producing the 4-aza-5-okynecyclohebutane ring derivative (K) by intramolecular condensation of the compound [■] is to form an amide bond between an amino group and a carboxyl group, which is widely known in peptide chemistry. This is a condensation method. Generally, this reaction is carried out in the presence of a dehydrating agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethyl cyanophosphate, or phosphorus pentachloride. When using a carbodiimide dehydrating agent, the reaction can be accelerated by adding 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc. to the reaction system.

Also, for example, pyridine, picoline, triethylamine, N
- The reaction can also be carried out in the presence of a base such as methylmorpholine, sodium carbonate, sodium chloride, etc. In general, any solvent can be used for the reaction as long as it does not inhibit the reaction (
For example, dimethylformamide, dimethylacetamide, hexamethylphosphoramide, tetrahydrofuran,
dioxane, methanol, ethanol, acetone, dichloromethane, chloroform, ethyl acetate, benzene, toluene, etc.). The product may be isolated as a crystal from the reaction system, but it can also be purified by column chromatography or the like.

The production of compound (I) by N-alkylation of compound (K) with compound (X) I'c is carried out in a suitable solvent in the presence of a base.As a solvent, hydrocarbons such as hexane and benzene can be used. , dichloromethane, 1,2-dichloroethane, 5tt halogenated hydrocarbons, tetrahydro7rane, ethers such as dioxane, esters such as ethyl acetate, ketones such as acetone, N,N-dimethyl Examples include formamide, amides such as N, N-dimethylacetamide, hexamethylphosphoramide, dimethyl sulfoxide, etc., but there are no restrictions as long as the solvent does not inhibit this reaction.As the base, sodium hydride, lithium hydride, etc. , alkali metal hydrides such as potassium hydride, alkali metal hydrides such as n-butyllithium, alkali metal amides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, sodium carbonate, potassium carbonate, etc. alkali metal carbonates, triethylamine, triethylenediamine, 1,5-diazabicyclo[4,fu0]-5-nonene (DBN), 1.8-
Diazabicyclo(5,4,0)-7-undecene(D
Examples include amines such as BU). In addition, when a phase transfer catalyst such as tetra-n-butylammonium bromide, penzyltriethylammonium iodide, etc. is used, and this reaction is carried out in a two-phase system of water and a water-insoluble solvent such as dichloromethane, chloroform, etc. Alkali metal hydroxides such as hydroxide, hydroxide, and hydroxide may also be used. The reaction temperature and time vary depending on the type of solvent and base, but are usually -20°C to 100°C and 30 minutes to -Starry Night. After completion of the reaction, the target compound of this reaction can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent such as ethyl acetate to the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent. If necessary, it can be purified by recrystallization, column chromatography, etc.

The method for deprotecting the amino group from compound (X) to compound (13) is the same as the method for removing the amine protecting group from compound [■] to compound [■], which has already been described in detail.The reaction product is, for example, It can be purified by recrystallization and column chromatography.

It has already been mentioned that the compound represented by the general formula [E] produced in this way has multiple optical isomers because it has an asymmetric carbon atom in the molecule. Isomers can also be prepared separately.

That is, by carrying out the above reaction using each optical isomer of the raw material compound that has been optically resolved in advance, the corresponding optical isomer of compound [I] can be obtained from k.

When at least one of the starting compounds is the race i form, compound CI) is usually obtained as a mixture of isomers, and if desired, this isomer mixture can be separated by a conventional separation method, such as an optically active base (e.g. cinchonine, cinchonidine). , quinine, quinidine, etc.), methods to generate salts with optically active organic acids (e.g., !-camphorsulfonic acid, d-camphorsulfonic acid, etc.), various chromatography, fractional recrystallization, etc. It is also possible to separate each isomer by using and.

The compound [1] of the present invention has an action of inhibiting the activity of an enzyme that converts angiotensin ① to angiotensin I (hereinafter abbreviated as AOlil).

Angiotensin I is an active substance that increases blood pressure and has been implicated as a substance that causes hypertension in mammals, including humans. In addition to being involved in the production of angiotensin I, AOFf is also involved in the metabolism of the vasodilator substance pradikinin, and exhibits the effect of converting bradykinin into an inactive substance.

Evaluation of the physiological activity of the compound [1] of the present invention is carried out in vitro (i.
n vitro), the AO]ij activity was reduced by 50%.
For example, the concentration (l050) of compound CI) required to inhibit W, 0us) unan et al. [:Bioch
chemical pharmacology.

20, p. 1637 (1971)]. That is, solutions of various concentrations of the compound, AOE extracted from rabbit lung, and hipryl histidyl leucine as a substrate were mixed at pH containing salt.
After making an 8.3 boric acid buffer solution and carrying out an enzymatic reaction at 37°C for 30 minutes, the reaction was stopped with 1N hydrochloric acid, the produced hippuric acid was extracted with ethyl acetate, and then the ethyl acetate was distilled off. Dissolve the remaining hippuric acid in water, 228
The amount of hippuric acid is measured from the Uv absorption rate in mμ. 105o can be calculated by displaying this value as a graph against the concentration of the compound, and reading from the graph the concentration of the compound CI"l when half the amount of hippuric acid produced without compound CI" is produced. It was done.

Table 1 shows l05o obtained in this way.

Table 1 Example 3 compound 1.6X10→Example 6 compound 2.0X 1G-9 Therefore AOFi
Compound [I] of the present invention and its pharmacologically acceptable salts which inhibit the activity are useful as agents for diagnosis, prevention or treatment of hypertension. When compound CII and its pharmacologically acceptable salts are used as the above-mentioned medicines, they can be used as such or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., and prepared as powders, granules, etc. It can be administered orally or through a gauze as a pharmaceutical composition such as a tablet, capsule, or injection.

The dosage varies depending on the condition of the target disease and the administration method, but for example, when administering to adult patients for the purpose of treating hypertension,
For oral administration, a single dose is usually 0,S~100 (IIP, especially about 5~100η), and for intravenous administration, the same dose is about 0.
．． 5-10019, especially about 0.5-1011P8
It is preferable to administer these drugs once to three times a day depending on the symptoms.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the scope of the present invention is not limited thereto.

Example 1 Engineering person.

Crude 2-amino- obtained by reducing 1-naphthaldehyde cyanohydrin 44f with lithium aluminum hydride
1-(l-naphthyl)ethanol, methanol 200
g/m, triethylamine 12. sy and tert-
Stir with butyl dicarbonate 201 at room temperature for 1 hour.

The reaction solution was concentrated, the residue was dissolved in ethyl acetate and water, the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate,
The solvent was distilled off. The crystalline residue was purified using diisopropyl ether. Yield 142N, melting point 109-11
0℃.

NMR (oDols) δCppm): 1.44 (
9H,s, tert-Bu).

! 1) 5-3.9 (3H, m, -(3H2+, O
H).

5.011 (IH, br, NH).

5.80 (1M, d, t, J=4.8Hz,
-0H-OH).

7.25-IL25 (7H, m, naphthyl proton)
.

Process B.

2-tart-butoxycarbonylamino-1-(l
-naphthyl) ethanol 13F anhydrous dichloromethane 2
A solution of phosphorus pentachloride 9.4 F in anhydrous dichloromethane 1110 was added dropwise to the 00-solution at 0 to -5°C. After the dropwise addition, the mixture was further stirred for I/C for 5 minutes, 195 ml of 4N sodium hydroxide was added at once, and the mixture was stirred for 30 minutes under water cooling.

The dichloromethane layer was washed with a large amount of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate-cyclohexane (1:1) as a solvent system to obtain the target compound in the form of a syrup.
I got oy.

NMR (onoJ3) δ (ppm): 1.43 (
9H,s, tert-nu)t3.3 42 (
2H, m, OH2)t7.2-8.3 (7H,m
, naphthyl proton).

Step 0゜υ To a solution of L-cystine p-toluenesulfonic acid tJ[101 and N-carboethoxyphthalimide r,sy in dimethylformamide 68-, under nitrogen gas, add 16.2F of heavy hydrogen,! The mixture was stirred for 15 hours at 1O-100t.

After cooling the reaction solution, it was dissolved in ethyl acetate and an aqueous potassium bisulfate solution, the aqueous layer was made acidic, and the ethyl acetate layer was separated. After washing with brine and drying over anhydrous magnesium sulfate, 7.4 F of diphenyldiazomethane was added, and the mixture was stirred for 1 hour in a nitrogen stream.

After distilling off the solvent, 60 di'C of dimethylformamide was dissolved, and 9.6 f of this K2-tcrt-butoxycarbonylamino-1-chloro-1-(l-naphthyl)ethane was dissolved.
was added, and the mixture was stirred at 10° C. for 16 hours in a nitrogen stream. Dissolve the reaction solution in ethyl acetate and water, separate the ethyl acetate layer,
After washing with brine, it was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was diluted with ethyl acetate-cyclohexane 1:
The target compound was subjected to silica gel column chromatography (W)K using 4 as a solvent system to obtain 4 as an amorphous solid.

Yield 10.4jF, □ sMn (onoJ3) δ (ppm): 1.35 (9
B, 8. tert-nu).

11518 (4H, tri, 0H2J 0082-
N).

45-5.1 (3H,m, NH,N-0H-00,
8-Oji-naphthyl).

a, l11 and s, ro (total 1B, s, o?h
2) t6.75-8.3 (21H, m, 0H (06
H,,5)2. naphthyl proton, 7thalyl proton)
.

Process.

υ 8-(2-tert-butoxycarbonylamino-""
1-(1-naphthyl)ethyl]-N-phthalyl cysteine diphenyl methyl ester 10.1 anisole 40
50-trifluoroacetic acid was added to the 1t solution, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, ethyl acetate
0m1. Add 30% of water, then add heavy g2oy and stir well, then adjust the pH with 3N hydrochloric acid! Lll VC adjusted. After stirring under water cooling, the precipitated target compound was collected and washed with acetone-diethyl ether 1:1. Yield s, s
y, melting point 195-199°C.

Process B.

S-[2-amino-1-(l-naphthyl)ethyl]-N
- To a solution of 5.5 g of phthalyl cysteine in 110 d of dimethylformamide, 5.1.
Add 2.611 t of N-methyl heptalpholine and stir at room temperature for 15 minutes.
Stir for hours. Approximately 200 gt of water and approximately 500 ml of ethyl acetate were added to the reaction solution and stirred to remove the precipitated target compound.
The mixture was taken and washed with water and ethyl acetate. Yield: 15g. Melting point 3
00℃ or higher.

NM几(DMi90-d6)δ(ppm):5.47
(IH, d, d, J=4.8Hz, N-0H-00
) t7.4-8.5 (11H, naphthyl proton, phthalyl proton).

Process P.

4-aza-5-oxo-2-(l-naphthyl)-B-7
Thalimide 1-thiacyclohebutane 14 g dimethylformamide 34- and hemosamethylhonuformamide 10
d Suspended liquid quote element in the air stream.

25 ml of tart-butyl bromoacetate at an internal temperature of 0 to 5°C.
.

Ethyl acetate and water were added to the reaction solution, and the ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was applied to a cyclosilica gel column using a 2:1 Φsan-ethyl acetate solvent system to obtain crystalline target compound 2.6f. Melting point 211-H2C.

NMR (onoJ3) δ (ppm): 1.47 (
9H,s, tert-Bu).

3.0-4.9 (6H, m, -0H2-8,N-0
H2-00°-O! ,! N).

5.30 (IH, d, J=9H2,N-0H-00
).

~1 5.78 (IH,brd, J=10Hz, 8-0
H-naphthyl).

7.3-8.35 (IIH, naphthyl proton, phthalyl proton).

Process G.

4-aza-4-tert-butoxycarbonylmethyl-
5-oxo-2-(l-naphthyl)-6-phthalimido-1-thiacyclohebutane 2.5f dichloromethane 2
0d and methanol 2-, methylhydrazine 0.
77m? was added and left at room temperature for 2 days. The reaction solution was concentrated, 15-t of dichloromethane was added to the residue, and after thorough stirring, the precipitate was removed. The r solution was concentrated and the residue was subjected to silica gel column chromatography with methanol-ethyl acetate 1:20 to obtain the target compound as an amorphous solid with a yield of $1.92.
I got an F.

NMR (0DOj, )δ (ppm): 1.47 (
IH,s, tert-Bu).

L 11 (2Hv br s t NH2) e2.
45-4.8 (7H, m, N-0H2-00, H2
N-0H-OH2-8°N-0H2-0).

5.15 (IH, d, J=9.5Hz, 8-0H
-naphthyl).

7.2-8.3 (7H, naphthyl proton).

Process ■.

4-af-4-tert-butoxycarbonyl 6-amino-4-aza-4-tcrt-butoxycarbonylmethyl-5-oxo-2-(l-naphthyl)-1-thiacyclohebutane 110319 Add 2, 80 Stirred at ℃ for 15 hours. The reaction solution was dissolved in ethyl acetate and brine, and the ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was dissolved in ethyl acetate-dichloromethane 1
: Subjected to 30 silica gel column chromatography, 7
Two types of isomers derived from the asymmetry of the carbon to which the enethyl group is bonded were separated by B&C.

Isomer A eluting first: oil o, 4sfI.

NMR (oDo15) δ (ppm): 1.24
(3H,t, J-7,5H2,0020H20H,)
.

1.46 (9H, s, tert-Bu).

1, 1 12 (2H, m, Pt1OH20H2)
.

~ 1 2.4-4.7 (13H,m, Ph0H20f(2
0H-NH, T-membered ring 0020H20H3).

5.13 (IH,brd, J=9Hz, 8-0
H-naphthyl).

7.14 (5H,s, phenyl proton).

T, 2-8.2 (7H, m, naphthyl proton).

Isomer B eluting next: oil at 0.46F.

NMR (0DO15) δ (ppm): 1.28 (3
H, t, J==7.511z, 0020H20H
5).

1.411 (9H, s, tert-Bu).

1.8-2.3 (2H, m, Ph0H20H2).

2.5 4.8 (13H, me Pt1OH20H2
0HNH, 7-membered ring 0020H20H5).

5.111 (IH, d, J=9.5H2, S-0H
-naphthyl).

7, old (5H,s, phenyl proton).

7.35-8.3 (711,m, naphthyl proton)
.

Example 2 4-Aza-4-tert produced in Example 1.1 H
-butoxycarbonylmethyl-6-(l-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-
2-(l-naphthyl)-1-thiacyclohebutane isomer B 455w1 with anisole 2d and trifluoroacetic acid j
l! 2sJVc was dissolved and stirred at room temperature for 4 hours. The reaction solution was concentrated, diisopropyl ether was added to the residue and stirred, and a crystalline powder was collected. Yield: 447 capes. This was dissolved in 2 dVC of ethyl acetate and 2 dVC of water, and 20% of the solution was added. After stirring, 3N hydrochloric acid was added to adjust to I) Hls.

The precipitated target compound was collected as P. Yield old 8m1f.

After separating the ethyl acetate layer in Ffi and extracting the aqueous layer with ethyl acetate, all the ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off to precipitate the target compound as crystals. CF was removed using diisopropyl ether.

Yield 17019°, melting point 201-203°C.

NMR (lDMso-ti6) δ (ppm): 1.2
11 (3H, t, J=7.5Hz, 0020H2
0H,).

ton, N-0H2-00,0020H2
0H5).

L12 (SH, s, phenyl proton).

7.2-8.3 (7H, m, naphthyl proton)
.

Example 3 4-Aza-4-carboxymethyl-5-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(l-naphthyl)-1 prepared in Example 2
-Thiacyclohebutane 216119 was mixed with 2 liters of 1N aqueous sodium hydroxide solution and stirred at room temperature for 16 hours. A small amount of insoluble matter was removed, 1N hydrochloric acid was added dropwise to F[, and the pH was adjusted to 2,0
The precipitated powdery target compound was collected and washed with a small amount of water. Yield 201ηO NMR (DM80-d6) δ (ppm): Roton,
N-0H2-00).

7.28 (5H,s, phenyl proton).

7.1-11.3 (7H, naphthyl proton).

Example 4 4-aza-4-tert-butoxycarbonylamino A
.

The crude 2-amino-1-(2-naphthyl)ethanol obtained by hydrogenating 2-nattaldehyde cyanohydrin 261 and reducing it with tium aluminum was used in Example 1. Tert-butoxycarbonylation was performed in the same manner as the engineer, to obtain the crystalline target compound tap. Melting point 99-
100.5℃.

NMR (oDal5) δ (ppm): 1.43
(9H,s, tert-Bu).

3.1 3.75 (3H, m, OH2, OH)
.

4.95 (IH, t)r, Nll).

4.516 (IH, d, d, J=4.8H2
, -0H-OH).

7.4-8.0 (7H, m, naphthyl proton).

Process B.

2-tert-butoxycarbonylamino-1-(2
-Naphthyl) ethanol 16f was chlorinated with phosphorus pentachloride in the same manner as in Example 1, Step B to obtain crystalline target compound 9.14F.

Melting point 97-98°C.

NMR (oDal 5 ) δ (ppm): 1.43
(9H,s, tert-Bu).

3.4 4.0 (2H, m, OH2).

483 (IH, b et al. NH).

5.18 (IH, d, d, J=8.7Hz, -3H
-naphthyl).

7.45-8.0 (7H, m, naphthyl proton).

Step 0゜ L-cysteine p was obtained by the same operation as in Example 1.1 Step 0
-) luenesulfonic acid [1(NF, N-phthalyl-L-cystine diphenylmethyl ester prepared from N-carboethoxyphthalimide 7.51.fluorocarbon 16.21 and diphenyldiazomethane 7.4f and 2-
tert-butoxycarbonylamino-1-chloro-
Sodium carbonate r, 3y was added to a dimethylformamide 8o-solution of 9.6 g of 1-(2-naphthyl)ethane, and the mixture was stirred at 80° C. for 18 hours in a nitrogen stream. The reaction solution was prepared in Example 1.
Treat in the same manner as in step 0 to convert the target compound into an amorphous solid [
Obtained. Yield 12.3F.

NMR (onOJ3) δ (ppm): 1.37 (9
Hts, tert-Bu).

! 2-3.7 (4H, m, CfH2B, 0-0H
2-N).

4.22 (18,t, J=4.5Hz, 8-0H
-naphthyl).

4.87 (IH, br, NH).

s, os (IH@m, N-0H-00)t6.7
9 and 7.112 (total IH,s, 0HPh2).

r,o -a,o (21H,m, 0H(06)2.
naphthyl proton, phthalyl proton).

Engineering 8D.

8-(2-tert-butoxycarbonylamino-1
-(2-naphthyl)ethyl)-N-phthalylcysteine diphenylmethyl ester 12.3f was prepared in Example 1. Deprotection with trifluoroacetic acid was performed in the same manner as in step 3 to obtain powdered target compounds e and ay. Melting point 196-2
00℃.

Process E.

8-[2-amino-1-(2-naphthyl)ethyl]-N
- Using 6.5 g of phthalylcysteine in the same manner as in Example 1, Step E, 47 m of diphenylphosphoryl azide was obtained!
The target compound 4.25N was obtained by condensation and cyclization using the following formula. It softens from a melting point of 270°C and melts at 2113-2115°C.

NMR (DM80-d6) a (ppm) ethyl)
.

5.43 (IH, m, N-0H-Co L7.5-
14 (11H, naphthyl proton, phthalyl proton) 6 Step P.

4-aza-5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacyclohebutane 415II in Example 1. Bromoacetic acid tert was prepared in the same manner as in Step F.
−'jMethyl treatment to obtain crystalline target compound &351
I got it. Melting point 208-209.5°C.

NIJB (oDol g ) δ (ppm): 1.47
(!IH,s, tert-nu).

2.9-4115 (7H, m, N-OH, -03(
Nafuchi Jl/)-8-U, N-0 Seaoo).

5.72 (IH, d, d, J=2.10H
z, N-0H-00L7.3-10 (11H, naphthyl proton, phthalyl proton).

Process G.

4-aza-4=tert-butoxycarbonylmethyl-
3.25f of 5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacyclohebutane in Example 1. By the same treatment as in Step G, the target compound 2.62 was obtained as an amorphous powder by defthalylation with methylhydrazine.

NMR (oncj,) δ (ppm): 1.46 (9
H,S, tert-Bu)t2.26 (2H,59
NH2).

2.45-4.75 (8H, m, 7-membered ring proton, -N-OH2-CO).

7.2-7.9 (IIH, naphthyl proton, phthalyl proton).

Step H9 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oquine-2-(2-naphthyl)-1-
Thiacyclohebutane Q, 85 fl was prepared in Example 1. Process H
N-alkylation was carried out with 1.011 ethyl 2-bromo-4-phenylbutyrate in the same manner as described above. The product was subjected to silica gel column chromatography using ethyl acetate-dichloromethane (1:30) to separate it into two isomers A and B derived from the carbon to which the phenethyl group is attached. The isomer eluting first: Oil Q, 47f.

NMR (onoJ5) δ (ppm): 1.25 (3
H, t, , T near, 5H2, Co20H20H3)v
l, 47 (9H,s, tert-Bu).

Roton, N.ag.co).

4.14 (2H, (1, J=7.5Hz, Co20
! 20H,).

7.20 (5H,s, phenyl proton).

7.1-7.9 (7H, m, naphthyl proton).

The next eluting isomer nO, 50f.

NMR (0DOj 5 ) δ (ppm): 1.27
(3H, t, J=7.5Hz, Co20H20H3
).

1.47 (9H, s, tert-Bu).

ton, N-0Hj-Co).

4.16 (2H, q, J=7.5Hz, oo2c!
! 2ou3).

7.20 (5H,S, phenyl proton).

7.1-7.9 (7H, m, naphthyl proton).

Example 5 1-thiacyclohebutane Example 4. 4-aza-4-tert produced in step H
-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-
The isomer 80.47F of 2-(2-naphthyl)-1-thiacyclohebutane was detert-butylated with trifluoroacetic acid according to the method of Example 2 to obtain the desired product as a crystalline powder. Yield 0.42F, softens around 115℃ and melts at 175-180℃.

NMR (DMSO-L d6) δ (ppm): 1.3
0 (3H,L, J=7.5Hz, Co20!20
H,) e roton, N-aH2-Co, co2o)
12a)(3)e7.33 (5H,S, phenyl proton).

7.2-8.1 (7H, m, naphthyl proton).

Example date 4-aza-4-carboxymethyl-6-(l-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2-naphthyl)-1-thiacyclohebutane 2
00■ was hydrolyzed with sodium hydroxide according to the method of Example 3 to obtain the target compound 133η in powder form.

NMR (1) MSOd6) δ (ppm): Roton,
N-0H2-00).

7.30 (5H, s, 7 any s, proton).

7.2-8.1 (7H, m, naphthyl proton).

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 represents an alkyl group, cycloalkylalkyl group, or aralkyl group, and R^2 and R^4 are the same or different. represents a hydrogen atom or a protecting group for a carboxy group, R^3 represents a naphthyl group, and A represents a lower alkylene group).