JPH056544B2 - - Google Patents

Description

[Detailed description of the invention]

Purpose of the Invention The present invention discloses 4-aza-5-oxo-1-thiacycloheptane [also known as tetrahydro-1,4-thiadepine-5-(2H)] which is useful as a medicine exhibiting a blood pressure lowering effect and an important synthetic intermediate thereof. -one] derivative. More specifically, the present invention relates to the general formula (In the formula, R ¹ represents an alkyl group, a cycloalkylalkyl group, or an aralkyl group, and R ² and R ⁴
are the same or different and represent a hydrogen atom or a protecting group for a carboxy group, R ³ represents a naphthyl group, and A
represents a lower alkylene group. ) Novel 4-aza-5-oxo-1-
This invention relates to thiacycloheptane derivatives and pharmacologically acceptable salts thereof. The present inventors carried out synthetic research for the purpose of research and development of antihypertensive agents, and found that a new compound having the general formula [] has inhibitory activity against angiotensin converting enzyme and exhibits long-lasting activity when administered orally. The present invention was completed based on the discovery that the present invention is useful as a therapeutic agent for hypertension. Structure of the Invention The compound represented by the general formula [] contains an asymmetric carbon atom at the position indicated by an asterisk (*) (or at other positions as the case may be), so it is an optically pure diastereomer. Isomers, racemates of diastereoisomers or mixtures of diastereoisomers may be present. The present invention may encompass any of these stereoisomeric forms. Next, the substituents R ¹ , R ² in the general formula [],
R ³ , R ⁴ and A will be specifically explained. The alkyl group for R ¹ is an alkyl group having 1 to 9 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
Isobutyl, tert-butyl, pentyl, neopentyl, hexyl, octyl, nonyl, etc., and the cycloalkylalkyl group has 1 to 2 carbon atoms and has a cycloalkyl group with 5 to 7 carbon atoms.
Examples of aralkyl groups include cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl, 2-cycloheptylethyl, etc. Aralkyl groups include benzyl, phenethyl, 1- Examples include 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, n-
butyl, isobutyl, tert-butyl, etc.), lower alkoxy groups having 1 to 4 carbon atoms (such as methoxy, ethoxy, n-propoxy, isopropoxy,
(n-ptoxy, isobutoxy, etc.), halogen (e.g., fluorine, chlorine, bromine, etc.), and lower alkylthio groups having 1 to 4 carbon atoms (e.g., methylthio, ethylthio, etc.), and these substituents may be the same or have different groups. A total of 1 to 3 may be substituted. The carboxylic acid protecting groups in R ² and R ⁴ are generally widely known protecting groups in organic synthetic chemistry, or are ester residues that can be pharmacologically converted into carboxy groups in vivo. . 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-(1,2,3,4-tetrahydronaphthyl),
2-(1,2,3,4-tetrahydronaphthyl),
phthalidyl, etc.), aryl, etc. (e.g. phenyl, etc.), silyl groups (e.g. 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, arylsulfonyl, 2-oxo-1,3- A substituent such as a 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 2,2,2-trichloroethyl, 2-
Iodoethyl, etc., hydroxy such as 2-hydroxyethyl, 2,3-dihydroxypropyl, etc.
For alkoxy, methoxymethyl, 2-methoxyethoxymethyl, p-methoxybenzyl, etc.
In acyloxy, acetoxymethyl, 1-
Acetoxyethyl, pivaloyloxymethyl, etc.
For oxo, phenacyl etc. For alkoxycarbonyl, methoxycarbonylmethyl etc.
For alkoxycarbonyloxy, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, etc. For nitro, p-nitrobenzyl, etc. For cyano, cyanoethyl, etc. For alkylthio, methylthiomethyl,
Ethylthiomethyl etc., arylthio such as phenylthiomethyl, alkylsulfonyl such as 2-(methanesulfonyl)ethyl, arylsulfonyl such as 2-(benzenesulfonyl)ethyl, 2-oxo-1,3-dioxolene- Examples of 4-yl include (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, etc. It will be done. 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. R ³ is a 1-naphthyl or 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, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), alkoxy groups having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.) can give. The lower alkylene group of A is an alkylene group having 1 to 2 carbon atoms, such as methylene, ethylene, ethylidene, and the like. Suitable compounds in the above general formula [] include those in which R ¹ has 4 to 9 carbon atoms, such as n-butyl, isobutyl, n-pentyl, isobutyl, neopentyl, n-hexyl, isooctyl, n-octyl, and n-nonyl. linear or branched alkyl groups having 5- or 6-membered cycloalkylethyl groups such as 2-cyclopentylethyl, 2-cyclohexylethyl, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl , 1-naphthylethyl, 2-naphthylethyl, 2-indolyl, an aralkyl group having 7 to 12 carbon atoms, and R ² is a hydrogen atom,
or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl,
Straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as n-hexyl, aralkyl groups such as benzyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, 1-(ethoxycarbonyl) oxy)ethyl, (5-methyl-
2-oxo-1,3-dioxolen-4-yl)
It is a protecting group such as methyl that can be easily converted into a carboxy group in vivo, R ³ is a 1-naphthyl group or 2-naphthyl group, A is a methylene group, R ⁴ is a hydrogen atom, a tert- Butyl, methoxymethyl, 2,2,2,-trichloroethyl, allyl,
Protecting groups for carboxyl groups used in organic synthetic chemistry such as benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, or acetoxymethyl, bivaloyloxymethyl, 1-
Compounds that are protective groups that can be easily converted into carboxyl groups in vivo, such as (ethoxycarbonyloxy)ethyl, phthalidyl, and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, are listed. be able to. Such a novel compound 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 salts of inorganic acids such as hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, phosphoric acid and nitric acid, and organic acids (e.g. oxalic acid, maleic acid, etc.). , fumaric acid, tartaric acid,
Examples include addition salts with citric acid, methanesulfone, benzenesulfonic acid, etc.). Salts with bases include alkali metal hydroxides (e.g. caustic soda, potassium hydroxide, etc.), alkaline earth metal oxides (e.g. calcium hydroxide, magnesium hydroxide, etc.), ammonium hydroxide, aluminum hydroxide, Organic bases (e.g. triethylamine, dicyclohexylamine, zinconine,
Examples include salts based on basic amino acids (e.g. lysine, arginine, etc.) and basic amino acids (e.g. lysine, arginine, etc.). As specific compounds represented by the above general formula [] of the present invention, the compounds described below can be exemplified.

【table】

【table】

[Table] The compound of the present invention [] has the general formula (In the formula, R ³ , R ⁴ and A have the same meanings as described above.) and a compound having the general formula (In the formula, R ¹ and R ² have the same meanings as described above, and X represents a halogen atom or a sulfonyloxy group.)
or the above compound [] and the general formula (In the formula, R ¹ and R ² have the same meanings as those described above.) Examples of the halogen atom of and substituted or unsubstituted aromatic sulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. The condensation reaction between compound [] and compound [] is
This reaction is carried out in the presence of a base in an appropriate solvent that does not inhibit the reaction. As a solvent, hydrocarbons such as hexane, benzene, dichloromethane, 1,2
-Halogenated hydrocarbons such as cycloethane, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, ketones such as acetone, N,N-dimethylformamide, N,N-dimethylacetamide, hexa Examples include amides such as methylphosphoramide, dimethyl sulfoxide, and the like. 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 bicarbonate, sodium hydride, and lithium hydrogen carbonate. and organic bases such as triethylamine, pyridine, picoline, and tetraethylammonium hydroxide. Furthermore, when carrying out this reaction 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 benzyltriethylammonium iodide, Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide can also be used. Reaction temperature is usually 0-120℃
The reaction time varies depending on the solvent, type of base, etc., but is usually 1 hour to 3 days.
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, adding an organic solvent such as ethyl acetate to the reaction mixture;
It can be obtained by washing the organic solvent layer with water, drying, and then distilling off the solvent, and if necessary, it can be purified by recrystallization, column chromatography, etc. Reductive conditions for the reaction between compound [] and compound [] include, for example, catalytic reduction using a metal such as platinum, palladium, Raney nickel, or rhodium, or a mixture of these and an arbitrary carrier, such as lithium aluminum hydride, Reduction with metal hydrides such as lithium borohydride, sodium cyanoborohydride, sodium borohydride, potassium borohydride, reduction with metallic sodium, metallic magnesium, etc. and alcohols such as methanol and ethanol, iron, zinc, etc. Examples of reaction conditions include reduction of the metal with 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 method, 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 [] produced in this way,
A monoester carboxylic acid compound in which R ² is an ester residue and R ⁴ is a hydrogen atom or a salt, and R ² ,
Dicarboxylic acids in which R ⁴ are both hydrogen atoms or salts are important compounds in medical products. The above monoester monocarboxylic acid compound can be produced by selective deprotection of the ester residue R ⁴ of a diester compound represented by the general formula [ ] in which R ² and R 4 are both ester residues, or by selective deprotection of the ester residue R ⁴ of the diester compound represented by the general formula It can be produced by a reductive condensation reaction between an amino acid compound in which R ⁴ is a hydrogen atom and a ketoester [ ] (R ² is an ester residue). In addition, the dicarboxylic acid compound in which R ² and R ⁴ are both hydrogen atoms can be obtained by hydrolyzing the diester compound or monoester compound obtained by the above reaction [ ] with an acid or base according to a conventional method. Alternatively, it can also be produced by a reductive removal method of ester groups. The reaction conditions are as follows:
The same is true for the deprotection of ^R7 . Raw material compound represented by general formula [], i.e. general formula The compound represented by (wherein R ³ , R ⁴ and A have the same meanings as defined above) can be produced, for example, according to the reaction formula shown below. ⁽ In the formula, ^{R 3} , R ^{4 , A and} In the above formula, the carboxylic acid protecting group represented by R ⁷ is an ester residue that is generally well known in organic synthetic chemistry, such as methyl, allyl,
Methyl and substituent methyl such as methoxymethyl, methylthiomethyl, methoxyethoxymethyl, benzyloxymethyl, phenacyl, p-promphenacil, N-phthalimidomethyl, ethyl, 2,2,2-trichloroethyl, 2-iodoethyl, 2 -trimethylsilylethyl, 2-
Lower alkyl group which may have a substituent such as (p-toluenesulfonyl)ethyl or tert-butyl; benzyl group which may have a substituent such as benzyl, diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc. 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. The protecting groups for the amino group in R ⁵ , R ⁶ , R ⁸ and R ⁹ are protecting groups generally well known in organic synthetic chemistry, such as 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxy carbonyl, trimethylsilylethoxycarbonyl, 2-
(p-toluenesulfonyl)ethoxycarbonyl,
Alkoxycarbonyl groups such as tert-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, acyl such as formyl, acetyl, benzoyl, chloroacetyl, trifluoroacetyl, etc. ,
Cyclic diacyl groups such as N-phthaloyl and N-2,3-diphenylmaleinyl, substituted methyl groups such as methoxymethyl, benzyloxymethyl, benzyl, 3,4-dimethoxybenzyl, and trityl, isopropylidene, benzylidene, and salicylidene Examples include alkylidene or aralkylidene groups such as, acylvinyl groups such as 1-methyl-2-acetylvinyl and 1-methyl-2-benzoylvinyl, and silyl groups such as trimethylsilyl and tert-butyldimethylsilyl. There are no restrictions on the protecting group as long as it achieves the purpose of protection. The reaction between compound [] which is a cysteine derivative and compound [] is carried out in the presence of a base in a suitable solvent that does not inhibit the reaction. The reaction conditions such as the solvent used, the type of base, the reaction temperature, and the reaction time, as well as the purification and separation of the reaction product [], are the same as those for the reaction between compound [] and compound [], which have already been described in detail. . Deprotection of the carboxylic acid protecting group represented by R ⁷ and the amino group protecting group represented by R ⁸ and R ⁹ in compound [] is a well-known method in organic synthetic chemistry, but this reaction In some cases, a method is required that does not affect the protecting groups R ⁵ and R ⁶ of the amino group of the cysteine moiety. Examples include deprotection by alkaline hydrolysis with lithium hydroxide, caustic soda, potassium hydroxide, etc. (for example, R ⁷ is methyl, ethyl, etc.), deprotection with Lewis acids such as hydrochloric acid, trifluoroacetic acid, aluminum chloride, etc. Deprotection (e.g. R ⁷ is methoxymethyl, methoxyethoxymethyl, tert-butyl, diphenylmethyl, p-methoxybenzyl, trimethylsilyl,
tert-butyldimethylsilyl, etc., R ⁸ is tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, trityl, tert-butyldimethylsilyl, etc.), deprotection by catalytic reduction (e.g. R ⁷ is benzyl, p-nitrobenzyl, etc.) , R ⁸ is benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.), deprotection by reduction with zinc dust-acid (for example, R ⁷ is 2,2,2-trichloroethyl, 2
-iodoethyl, phenacyl, p-bromphenacyl, etc., R ⁸ is 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, etc.),
Deprotection catalyzed by tetrakis(triphenylphosphine)palladium(O) (for example, R ⁷ is allyl, etc.)
R ⁸ is allyloxycarbonyl, etc.), hydrazine,
Examples include deprotection using hydrazines such as methylhydrazine (for example, R ⁸ and R ⁹ are phthaloyl, etc.). The solvents used vary depending on the deprotection method, but include water, acids such as acetic acid and formic acid, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane and anisole, ketones such as acetone, and halogens such as dichloromethane and chloroform. Hydrocarbons such as carbonized hydrocarbons, benzene, and toluene are used. The reaction temperature and reaction time vary depending on the deprotection method, but generally -10
℃ to 100℃ for 30 minutes to one day and night. The production of amino acids [ ] by deprotection involves two steps: first, the carboxylic acid protecting group R ⁷ is deprotected, and then the amino group protecting groups R ⁸ and R ⁹ are deprotected, or the amino group is first deprotected. There is a method of deprotecting the protecting groups R ⁸ and R ⁹ and then deprotecting the carboxylic acid protecting group R ⁷ .
There is also a method of deprotecting two protecting groups R ⁷ and R ⁸ and R ⁹ at once. For example, R ⁷ is tert-butyl, R ⁸ is
When R ⁹ is a hydrogen atom in tert-butoxycarbonyl, the compound [] can be obtained by deprotection with an acid, and when R ⁷ is 2,2,2-trichloroethyl and R ⁸ is 2,2,2-trichloroethoxy carbonyl,
When R ⁹ is a hydrogen atom, the compound [ ] can be obtained by the 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, compound [] is intramolecularly condensed to form 4-aza-
The method for producing the 5-oxocycloheptane ring derivative [] is a method of condensing an amino group and a carboxyl group into an amide bond, which is widely known in peptide chemistry. This reaction is generally carried out in the presence of a dehydrating agent such as N,N'-dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethyl cyanophosphate, or phosphorus pentachloride. When using carbodiimide dehydrating agents, 1-hydroxybenzotriazole, N-
The reaction is accelerated by adding hydroxysuccinimide or the like to the reaction system. Also, for example, pyridine, picoline, triethylamine, N-methylmorpholine,
The reaction can also be carried out in the presence of a base such as sodium carbonate, overlay, etc. In general, any solvent can be used in the reaction as long as it does not interfere with the reaction (e.g., N,N-dimethylformamide, N,N-
Dimethylacetamide, hexamethylphosphoramide, tetrahydrofuran, dioxane, methanol, ethanol, acetone, dichloromethane,
chloroform, ethyl acetate, benzene, toluene, etc.). The product may be isolated as a small sample from the reaction system, but it can also be purified by column chromatography or the like. N- by compound [] for compound []
The production of compound [XI] by alkylation is carried out in a suitable solvent in the presence of a base. 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, esters such as ethyl acetate, and acetone. Ketones, N,
Examples include amides such as N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoramide, dimethyl sulfoxide, etc., but there are no limitations as long as the solvent does not inhibit this reaction.
As the base, alkali metal hydride such as sodium hydride, lithium hydride, potassium hydride, n
- Alkyl alkali metals such as butyl lithium, alkali metal amides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium bis(trimethylsilyl)amide, alkali metal carbonates such as sodium carbonate and potassium carbonate,
Triethylamine, triethylenediamine, 1,
5-Diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]-4-
Examples include amines such as undecene (DBU).
Also, tetra n-butylammonium bromide,
When carrying out this reaction in a two-phase system consisting of a water-insoluble solvent such as dichloromethane, chloroform, etc. and an aqueous phase transfer catalyst such as benzyltriethylammonium iodide, a phase transfer catalyst such as caustic soda or caustic potash is used. Alkali metal hydroxides can also be used. The reaction temperature and time vary depending on the type of solvent and base, but are usually -2°C to 100°C,
It lasts from 30 minutes to a day and 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 [XI] to compound [] is the same as the method for removing the amino protecting group from compound [] to compound [], which has already been described in detail. The reaction product can be purified, for example, by recrystallization, column chromatography, etc. As mentioned above, the compound represented by the general formula [] produced in this way has multiple optical isomers because it has an asymmetric carbon atom in the molecule. The isomers of 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 optical isomer of the reacting compound [ ] can be obtained.
When at least one of the starting compounds is a racemate, the compound [ ] is usually obtained as a mixture of isomers, but this isomer mixture can be separated, if desired, by a conventional separation method, such as an optically active base (such as cinchonine, cinchonidine, etc.). quinine, quinidine, etc.), methods to generate salts with optically active organic acids (e.g. l-carnpharusulfonic acid, d-camphorsulfonic acid, etc.), various chromatography methods, fractional recrystallization, etc. It is also possible to separate each isomer by doing this. Effects of the Invention The compound [] of the present invention is an enzyme that converts angiotensin to angiotensin (hereinafter referred to as
It has the function of inhibiting the activity of ACE (abbreviated as ACE). Angiotensin is an active substance that increases blood pressure and is associated with a substance that causes hypertension in mammals including humans. In addition to being involved in the production of angiotensin, ACE is also involved in the metabolism of bradykinin, a vasodilator, and has the effect of converting bradykinin into an inactive substance. To evaluate the physiological activity of the compound [ ] of the present invention, the concentration (IC ₅₀ ) of the compound [ ] required to inhibit ACE activity by 50% in vitro was determined, for example, by DWCushman et al.
Pharmacology, Vol. 20 , p. 1637 (1971)]. That is, ACE extracted from rabbit lung in various concentrations of the compound and hipryl histidyl leucine as a substrate were used as a borate buffer of PH 8.3 containing salt,
After enzymatic reaction at 37°C for 30 minutes, the reaction was stopped with 1N hydrochloric acid, the generated hippuric acid was extracted with ethyl acetate, the ethyl acetate was distilled off, and the remaining hippuric acid was dissolved in water. The amount of hippuric acid is measured from the UV absorption rate at 228 mμ. This value is graphically displayed as a curve against the concentration of compound [], and the concentration of compound [] when half the amount of hippuric acid produced without compound [] is produced.
The IC ₅₀ was determined by reading the concentration from the graph. The IC ₅₀ thus determined is shown in Table 1.

[Table] Compounds of the present invention that inhibit ACE activity []
and its pharmacologically acceptable salts are useful as diagnostic, preventive or therapeutic agents for hypertension.
When the compound [] and its pharmacologically acceptable salts are used as the above-mentioned medicine, the compound itself or an appropriate pharmacologically acceptable carrier, excipient,
It can be mixed with a diluent and administered orally or parenterally as a pharmaceutical composition such as a powder, granule, 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 0.5 to 1000 mg, especially about 5 to 100 mg, and for intravenous administration, a single dose is about 0.5 mg.
~100mg, especially about 0.5~10mg is preferable,
It is desirable to administer these doses 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 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(1
-naphthyl)-1-thiacycloheptane Step A 2-tert-butoxycarbonylamino-1-
(1-naphthyl)ethanol Crude 2-amino-1-(1-naphthyl)ethanol obtained by reducing 44 g of 1-naphthaldehyde cyanohydrin with lithium aluminum hydride,
12.8 g of triethylamine and 20 g of di-tert-butyl dicarbonate in 200 ml of methanol at room temperature.
Stir for an 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, and then the solvent was distilled off. The crystalline residue was taken up with diisopropyl ether. Yield: 14.2g. Melting point 109-110℃. NMR ( _CDCl3 ) δ (ppm): 1.44 (9H, s, tert-Bu), 3.05-3.9 (3H, m, _-CH2- , OH), 5.60 (1H, d, t, J = 4, 8Hz ,

[Formula], 7.25−8.25 (7H, m, naphthyl proton). Step B 2-tert-butoxycarbonylamino-1-chloro-1-(1-naphthyl)ethane 2-tert-butoxycarbonylamino-1-
A solution of 9.4 g of phosphorus pentachloride in 190 ml of anhydrous dichloromethane was added dropwise to a solution of 13 g of (1-naphthyl)ethanol in 200 ml of anhydrous dichloromethane at 0 to -5°C. After the dropwise addition, stir for another 5 minutes and add 195ml of 4N caustic soda.
was added at once and stirred for 30 minutes under ice 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 1:7 as a solvent system to obtain 9.0 g of the target compound in the form of syrup. NMR ( _CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.3-4.2 (2H, m, _-CH2- ), 5.00 (1H, brt, NH), 5.83 (1H, d, d, J=5.5, 8Hz,

[Formula]), 7.2−8.3 (7H, m, naphthyl proton). Step C S-[2-tert-butoxycarbonylamino-1
-(1-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester L-cysteine p-toluenesulfonate 10g
Add baking soda to a solution of 7.5 g of N-carboethoxyphthalimide in 68 ml of dimethylformamide under nitrogen gas.
6.2g was added and stirred at 90-100°C for 3.5 hours. 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 saline and drying with anhydrous magnesium sulfate, 7.4 g of diphenyldiazomethane was added.
The mixture was stirred for 1 hour in a nitrogen stream. After distilling off the solvent, dissolve in 60 ml of dimethylformamide and add 2-
tert-butoxycarbonylamino-1-chloro-
9.6 g of 1-(1-naphthyl)ethane was added, and the mixture was stirred at 70°C for 16 hours in a nitrogen stream. The reaction solution was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography using ethyl acetate-cyclohexane 1:4 as a solvent system to obtain the target compound as an amorphous solid. Yield 10.4g NMR ( _CDCl3 ) δ (ppm): 1.35 (9H, s, tert-Bu), 3.15-3.8 (4H, m, _CH2S , C- _CH2- N), 4.5-5.1 (3H, m, NH,

【formula】

[Formula] 6.6 and 6.70 (combined 1H, s, CH~ _ph2 ), 6.75-8.3 (21H, m, CH( _C6H ~ ₅ ) ₂ , naphthyl proton, phthalyl proton). Step D S-[2-amino-1-(1-naphthyl)ethyl]-N-phthalylcysteine S-[2-tert-butoxycarbonylamino-
50 ml of trifluoroacetic acid was added to a solution of 10.4 g of 1-(1-naphthyl)ethyl]-N-phthalylcysteine diphenylmethyl ester in 40 ml of anisole, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, 40 ml of ethyl acetate and 30 ml of water were added, followed by 2.0 g of sodium bicarbonate, and after stirring well, the pH was adjusted to 5.8 with 3N hydrochloric acid. After stirring under ice cooling, remove the precipitated target compound,
Washed with acetone-diethyl ether 1:1.
Yield: 5.6g. Melting point 195-199℃. Step E 4-aza-5-oxo-2-(1-naphthyl)-
6-phthalimido-1-thiacycloheptane To a solution of 5.5 g of S-[2-amino-1-(1-naphthyl)ethyl]-N-phthalylcysteine in 110 ml of dimethylformamide were added 5.1 g of diphenylphosphoryl azide and 2.6 ml of N-methylmorpholine, and the mixture was heated at room temperature. Stirred for 15 hours. Approximately 200ml of water to the reaction solution
About 500 ml of ethyl acetate was added and stirred, and the precipitated target compound was collected and washed with water and ethyl acetate. Yield 3.5g. Melting point over 300℃. NMR (DMSO- _d6 ) δ (ppm): 2.7-4.6 (4H, m, CH~-S, N-CH~-C), 4.94 (1H, brd, J=8Hz,

[Formula] 5.47 (1H, d, d, J = 3, 8Hz,

[Formula]), 7.4−8.5 (11H, naphthyl proton, phthalyl proton). Step F 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-6-phthalimido-1-thiacycloheptane 4-Aza-5-oxo-2-(1-naphthyl)-
6-phthalimido-1-thiacycloheptane 3.4
34 ml of dimethylformamide and 10 ml of hexamethylphosphoramide were suspended in a nitrogen stream, and the internal temperature was 0.
At ~5°C, 2.25 ml of tert-butyl bromoacetate was added in portions, followed by 609 mg of 55% oily sodium hydride. After addition, it was stirred at room temperature for 16 hours. 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 silica gel column using a cyclohexane-ethyl acetate 2:1 solvent system to obtain 2.6 g of the crystalline target compound. Melting point 211−
213℃. NMR ( _CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 3.0-4.9 (6H, m, -CH~ _2- S, N- _CH2 ~-
CH~ ₂ -N), 5.30 (1H, d, J=9Hz,

[Formula]), 5.78 (1H, brd, J=10Hz,

[Formula]), 7.3−8.35 (11H, naphthyl proton, phthalyl proton). Step G 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-1-thiacycloheptane Dissolve 2.5 g of 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-6-phthalimido-1-thiacycloheptane in 20 ml of dichloromethane and 2 ml of methanol, and add 0.77 ml of methylhydrazine. , and left at room temperature for 2 days. Concentrate the reaction solution and add 15 ml of dichloromethane to the residue.
was added, and after thorough stirring, the precipitate was removed. Concentrate the liquid and mix the residue with methanol-ethyl acetate 1:20.
The resulting product was subjected to silica gel column chromatography to obtain 1.92 g of the target compound as an amorphous solid. NMR ( _CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 2.11 (2H, brs, _NH2 ), 2.45-4.8 (7H, m, N-CH~ ₂ -CO,

[Formula], N-CH~ ₂ -C), 5.15 (1H, d, J=9.5Hz,

[Formula]), 7.2−8.3 (7H, m, naphthyl proton). Step H 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-
(1-naphthyl)-1-thiacycloheptane 6-amino-4-aza-tert-butoxycarbonylmethyl-5-oxo-2-(1-naphthyl)-
1-thiacycloheptane 803mg and 2-bromo-4
- Add 0.66 g of soda carbonate to a solution of 1.13 g of ethyl phenylformamide in 10 ml of dimethylformamide and heat at 80℃.
Stirred 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 subjected to silica gel column chromatography using ethyl acetate-dichloromethane (1:30) to separate it into two types of isomers, A and B, which are derived from the chirality of the carbon to which the phenethyl group is bonded. did. Isomer A eluting first:
Oily 0.49g. NMR ( _CDCl3 ) δ (ppm): 1.24 (3H, t, J = 7.5Hz, CO2CH2CH _{~ 3 )} , 1.46 (9H, s, tert-Bu), 1.7-2.2 (2H, m, PhCH ₂ CH ₂ ), 2.4−4.7 (13H, m,

[Formula], 7-membered ring

[Formula], N-CH~ ₂ - _CO , _CO2CH ~ _2CH3 ), 5.13 (1H, brd, J=9Hz,

[Formula]), 7.14 (5H, s, phenyl proton), 7.2−8.2 (7H, m, naphthyl proton). Isomer B eluted next: 0.46 g of oil. NMR ( _CDCl3 ) δ (ppm): 1.28 (3H, t, J = 7.5Hz, CO2CH2CH _{~ 3 )} , 1.48 (9H, s, tert-Bu), 1.8-2.3 (2H, m, PhCH ₂ CH~ ₂ ), 2.5-4.8 (13H, m,

【formula】, 7-membered ring

[Formula], N-CH~ ₂ -CO, _CO2CH ~ _2CH3 ), 5.18 (1H, brd, J=9.5Hz _,

[Formula]), 7.14 (5H, s, phenyl proton), 7.21 (5H, s, phenyl proton), 7.35-8.3 (7H, m, naphthyl proton). Example 2 4-aza-4-carboxymethyl-6-(1-
ethoxycarbonyl-3-phenylpropyl)
Amino-5-osiso-2-(1-naphthyl)-1
-thiacycloheptane 4-Aza-4- produced in Example 1 Step H
455 mg of isomer B of tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(1-naphthyl)-1-thiacycloheptane was added to anisole 2
ml and 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, diisopropyl ether was added to the residue, and the mixture was stirred to obtain a crystalline powder. Yield 447mg. This was dissolved in 2 ml of ethyl acetate and 2 ml of water, 0.2 g of sodium bicarbonate was added, and after stirring, 3N hydrochloric acid was added to adjust the pH to 2.5. The precipitated target compound was collected. Yield 216mg. After separating the ethyl acetate layer in the liquid and extracting the aqueous layer with ethyl acetate, all the ethyl acetate layers were combined and dried over anhydrous magnesium sulfate.
When the solvent was distilled off, the target compound precipitated as crystals. It was extracted using diisopropyl ether. Yield 70mg. Melting point 201-203℃ NMR (DMSO- _d6 ) δ (ppm): 1.28 (3H, t, J=7.5Hz, _{CO2CH2CH ~ 3} ), 2.0-2.4 (2H, m, _phCH2CH ~ ₂ ), 2.5−5.4 (13H, m,

[Formula], 7-membered ring proton, N-CH~ ₂ -CO, CO ₂ CH~
_{2 CH3} ), 7.32 (5H, s, phenyl proton), 7.2-8.3 (7H, m, naphthyl proton). Example 3 4-aza-4-caloximethyl-6-(1
-carboxy-3-phenylipropyl)amino-5-oxo-2-(1-naphthyl)-1-thiacycloheptane 4-aza-4-carboxymethyl-6-(1-ethoxycarbonyl-3-
phenylpropyl)amino-5-oxo-2-
(1-naphthyl)-1-niacycloheptane 216mg
was mixed with 2 ml of 1N aqueous caustic soda solution and stirred at room temperature for 16 hours. Remove a small amount of insoluble matter and add 1N to the liquid.
Hydrochloric acid was added dropwise to adjust the pH to 2.0, and the precipitated powdery target compound was collected and washed with a small amount of water. Yield 201
mg. NMR (DMSO- _d6 ) δ (ppm): 1.7-2.1 (2H, m, _phCH2CH ~ ₂ ), 2.5-5.35 (11H, m,

[Formula], 7-membered ring proton, N-CH~ ₂ -CO), 7.28 (5H, s, phenyl proton), 7.1-8.3 (7H, naphthyl proton). Example 4 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2
-naphthyl)-1-thiacycloheptane Step A 2-tert-butoxycarbonylamino-1-
(2-naphthyl)ethanol Crude 2-amino-1-(2-naphthyl)ethanol obtained by reducing 26 g of 2-naphthaldehyde cyanohydrin with lithium aluminum hydride,
Tert-butoxycarbonylation was performed in the same manner as in Example 1, Step A to obtain 16 g of the crystalline target compound.
I got it. Melting point 99-100.5℃. NMR ( _CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.1-3.75 (3H, m, _-CH2- , OH), 4.95 (1H, br, NH), 4.96 (1H. d, d, J = 4, 8Hz,

[Formula]), 7.4−8.0 (7H, m, naphthyl proton). Step B 2-tert-butoxycarbonylamino-1-chloro-1-(2-naphthyl)ethane 2-tert-butoxycarbonylamino-1-
16 g of (2-naphthyl)ethanol was chlorinated with phosphorus pentachloride in the same manner as in Example 1, Step B to obtain 9.1 g of the crystalline target compound. Melting point 97-98℃ NMR ( _CDCl3 ) δ (ppm): 1.43 (9H, s, tert-Bu), 3.4-4.0 (2H, m, _-CH2- ), 4.93 (1H, br, NH), 5.18 (1H.d, d, J=6,7Hz,

[Formula]), 7.45−8.0 (7H, m, naphthyl proton). Step C S-[2-tert-butoxycarbonylamino-
1-(2-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester N- produced from 10 g of L-cysteine p-toluenesulfonate, 7.5 g of N-carboethoxyphthalimide, 6.2 g of sodium bicarbonate and 7.4 g of diphenyldiazomethane in the same manner as in Step C of Example 1.
Phthalyl-L-cysteine diphenyl methyl ester and 2-tert-butoxycarbonylamino-1
-7.3 g of soda carbonate in a solution of 9.6 g of chloro-1-(2-naphthyl)ethane in 80 ml of dimethylformamide
was added, and the mixture was stirred at 80°C for 18 hours in a nitrogen stream. The reaction solution was treated in the same manner as in Step C of Example 1 to obtain the target compound as an amorphous solid. Yield: 12.3g. NMR ( _CDCl3 ) δ (ppm): 1.37 (9H, s, tert-Bu), 3.2-3.7 (4H, m, _CH2S , C- _CH2 -N), 4.22 (1H, t, J=4.5 Hz,

【formula】), 4.67 (1H, br, NH), 5.05 (1H, m,

[Formula]), 6.79 and 7.82 (combined 1H, s, CH~ _ph2 ), 7.0-8.0 (21H, m, CH( _C6H ~ ₅ ) ₂ , naphthyl proton, phthalyl proton). Step D S-[2-amino-1-(2-naphthyl)ethyl]-N-phthalylcysteine S-[2-tert-butoxycarbonylamino-
12.3 g of 1-(2-naphthyl)ethyl]-N-phthalylcysteine diphenyl methyl ester was deprotected with trifluoroacetic acid in the same manner as in Step D of Example 1 to obtain 6.6 g of the target compound in powder form. Obtained.
Melting point 196-200℃. Step E 4-aza-5-oxo-2-(2-naphthyl)-
6-phthalimido-1-thiacycloheptane 6.5 g of S-[2-amino-1-(2-naphthyl)ethyl]-N-phthalylcysteine was condensed and cyclized using 4.7 ml of diphenylphosphoryl azide in the same manner as in Step E of Example 1. Target compound
4.25g was obtained. Softens from melting point 270℃, 283−285
Melt at °C. NMR (DMSO- _d6 ) δ (ppm): 3.1-4.6 (CH~ ₂ -S,

【formula】, 5.43 (1H, m,

[Formula]), 7.5−8.4 (11H, m, naphthyl proton, phthalyl proton). Step F 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacycloheptane 4-aza-5-oxo-2-(2-naphthyl)-
6-phthalimido-1-thiacycloheptane 4.15
g was treated with tert-butyl bromoacetate in the same manner as in Example 1 Step F to obtain the crystalline target compound.
3.35g was obtained. Melting point 208-209.5℃ NMR ( _CDCl3 ) δ (ppm): 1.47 (9H, s, tert-Bu), 2.9-4.85 (7H, m, N-CH~ ₂ -CH~ (naphthyl) -S-CH~ ₂ , N-CH~ ₂ -CO), 5.72 (1H, d, d, J=2, 10Hz,

[Formula]), 7.3−8.0 (11H, m, naphthyl proton, phthalyl proton). Step G 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-1-thiacycloheptane 3.25 g of 4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-6-phthalimido-1-thiacycloheptane was treated with methylhydrazine in the same manner as in Step G of Example 1. Defthalylated target compound into amorphous powder
2.6g was obtained. NMR ( _CDCl3 ) δ (ppm): 1.46 (9H, s, tert-Bu), 2.26 (2H, s, _NH2 ), 2.45-4.75 (8H, m, 7-membered ring proton, -N-C
H~ ₂ -CO), 7.2-7.9 (11H, m, naphthyl proton, phthalyl proton). Step H 4-aza-4-tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2
-naphthyl)-1-thiacycloheptane Example 1: 0.85 g of 6-amino-4-aza-4-tert-butoxycarbonylmethyl-5-oxo-2-(2-naphthyl)-1-thiacycloheptane
N-alkylation was carried out using 1.08 g of ethyl 2-bromo-4-phenylbutyrate in the same manner as in Step H.
The product was subjected to silica gel column chromatography using ethyl acetate-dichloromethane (1:30) to separate it into two types of isomers A and B derived from the carbon to which the phenethyl group is bonded. Isomer A eluting first: oil
0.47g NMR ( _CDCl3 ) δ (ppm): 1.25 (3H, t, J = 7.5Hz, _{CO2CH2CH ~ 3} ), 1.47 (9H, s, tert-Bu), 1.7-2.2 (2H, m , _PhCH2CH ~ ₂ ), 2.4−4.6(12H, m,

[Formula] 7-membered ring _proton , N -CH~ ₂ ), 4.14 (2H, q, J=7.5Hz, _CO2CH ~ _2CH3 ), 7.20 (5H, s, phenyl proton), 7.1-7.9 ( 7H, m, naphthyl proton). Next, 0.50 g of isomer B is eluted. NMR ( _CDCl3 ) δ (ppm): 1.27 (3H, t, J = 7.5Hz, _{CO2CH2CH ~ 3} ), 1.47 (9H, s, tert-Bu), 1.8-2.25 (2H, m, PhCH ₂ CH~ ₂ ), 2.5−4.6 (12H,

[Formula] 7-membered ring proton, N-CH~ ₂ -CO), 4.16 (2H _{, q, J=7.5Hz, CO2CH~2CH3 ) ,} 7.20 (5H, s, phenyl proton), 7.1- 7.9 (7H, m, naphthyl proton). Example 5 4-aza-4-carboxymethyl-6-(1-
ethoxycarbonyl-3-phenylpropyl)
Amino-5-oxo-2-(2-naphthyl)-1
-thiacycloheptane 4-Aza-4- produced in Example 4 Step H
0.47 g of tert-butoxycarbonylmethyl-6-(1-ethoxycarbonyl-3-phenylpropyl)amino-5-oxo-2-(2-naphthyl)-1-thiacycloheptane isomer B of Example 2 was added. According to the method, the desired product was obtained as a crystalline powder by detert-butylation with trifluoroacetic acid. Yield 0.42
g. It softens around 115℃ and melts at 175-180℃. NMR (DMSO- _d6 ) δ (ppm): 1.30 (3H, t, J=7.5Hz, CO2CH2CH _{~ 3} ), 2.0-2.35 (2H _, m, _PhCH2CH ~ ₂ ), 2.55-5.2 (13H, m,

[Formula] 7-membered ring proton, N-CH~ ₂ -CO, CO ₂ CH~
_{2 CH3} ), 7.33 (5H, s, phenyl proton), 7.2-8.1 (7H, m, naphthyl proton). Example 6 4-aza-4-carboxymethyl-6-(1-
carboxy-3-phenylpropyl)amino-
5-oxo-2-(2-naphthyl)-1-thiacycloheptane 4-aza-4-carboxymethyl-6-(1-ethoxycarbonyl-3-
phenylpropyl)amino-5-oxo-2-
(2-naphthyl)-1-thiacycloheptane 200mg
was hydrolyzed with caustic soda according to the method of Example 3 to obtain 133 mg of the target compound in powder form. NMR (DMSO- _d6 ) δ (ppm): 1.7-2.1 (2H, m, _PhCH2CH ~ ₂ ), 2.5-4.8 (11H, m,

[Formula] 7-membered ring proton, N-CH~ ₂ -CO), 7.30 (5H, s, phenyl proton), 7.2-8.1 (7H, m, naphthyl proton).

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents an alkyl group, a cycloalkylalkyl group, or an aralkyl group, and R ² and R ⁴
are the same or different and represent a hydrogen atom or a protecting group for a carboxy group, R ³ represents a naphthyl group, and A
represents a lower alkylene group. ) A 4-aza-5-oxo-1-thiacycloheptane derivative having the following formula.