JPS61115064A - Proline derivative - Google Patents

Abstract

NEW MATERIAL:The proline derivative of formula I (R1 is adamantyl, benzocycloalkyl, and cycloalkyl which may have lower alkyl as substituent group; R2 and R3 are lower alkyl; R4 is H or lower alkyl) and its salt. EXAMPLE:N-[(R)-1-ethoxycarbonyl-2-(1-adamantyl)thioethyl]-alanyl-(S)-p roline t-butyl ester BETA-isomer. USE:Hypotensor, expectrant and remedy for glaucoma. It has angiotensinase- inhibiting activity, expectrant activity and intraocular pressure-depressing activity, and has low toxicity. PREPARATION:The compound of formula 1a which is one of the compound of formula I can be prepared by reacting the cysteine derivative of formula 2 with the compound of formula 3 (R5 is OH, lower alkoxy or group of formula II; X is halogen or alkylsulfonyloxy).

Description

[Detailed description of the invention] Star 1 Yu17) $J f@Ran! The present invention relates to novel proline derivatives and salts thereof.

The proline derivative of the present invention is a new compound that has not been described in any literature.

The objective of the present invention is to provide a compound useful as a pharmaceutical, as described later.

The above object is achieved by a proline derivative represented by the following general formula (1) and a salt thereof.

In the general formula C, R1 represents an adamantyl group, a benzocycloalkyl group, or a cycloalkyl group that may have a lower alkyl group as a substituent. R2 and R3 represent lower alkyl groups. R4 represents a hydrogen atom or a lower alkyl group. ] In the above general formula (1), R+, R2, R3 and R
Each group represented by the symbol is as follows.

Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl groups.

Examples of the cycloalkyl group that may have a lower alkyl group as a substituent include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, and 1-methylcyclopentyl groups. , 1-methylcyclohexyl, 1,3-dimethylcyclohexyl, 1
．． Examples include cycloalkyl groups substituted with the above lower alkyl groups such as 4-dimethylcyclohexyl group.

Examples of the benzocycloalkyl group include 1-indanyl, 2-indanyl, 1,2.3.4-tetrahydro-
Examples include 1-naphthyl and 1.2.3.4-tetrahydro-2-naphthyl groups.

The compound of the above general formula (1) has an asymmetric carbon atom in the molecule, and the present invention includes all optical isomers.

The proline derivatives and salts thereof of the present invention have angiotensin-converting enzyme inhibitory activity, anti-tans effect, and intraocular pressure-lowering effect, and have low toxicity, and are useful as antihypertensive agents, anti-tans agents, and therapeutic agents for glaucoma.

The salts of the proline derivatives of the present invention include pharmaceutically acceptable acid addition salts. Examples of acidic compounds that form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrobromic acid, and oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. For example, organic acids such as

Furthermore, among the proline derivatives of the present invention, those having an acidic group can be made into salts by acting on them with a pharmaceutically unacceptable base, and the present invention also includes such salts.

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium bicarbonate, lysine, arginine, ornithine, morpholine, piperazine, ethylamine, dimethylamine, triethylamine, dicyclohexylamine, etc. Examples include organic bases.

The proline derivative of the present invention can be produced, for example, by various methods shown below.

Reaction formula-1> Word R1-5CH2C1l-NH-C1l-COR50OR
2 (1a) [In the formula, R+, R2 and R3 are the same as above. R5 is a hydroxyl group, a lower alkoxy group, or a group. Moreover, X represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group. ] In the above compound (3), the octarogen atom represented by X is a chlorine atom, a bromine atom, an iodine atom, etc.; Examples of the group include p-toluenesulfonyloxy group.

According to the method shown in Reaction Formula-1 above, compound (1a) is obtained by combining cysteine derivative (2) and compound (3). The condensation reaction is carried out in a suitable solvent, mm
It is carried out in the presence of an agent.

As a solvent, for example, tetrahydrofuran (THF),
Ethers such as dioxane, dimethylformamide (D
MF), dimethyl sulfoxide (DMSO), hexamethyl phosphate triamide (HMPA), and other aprotic polar solvents can be used. Examples of deoxidizers include alkali metal carbonates or alkali metal hydrogen carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, 1.8
Organic tertiary amines such as -diazapisic O(5,4,0)undecane-7-ene (DBLJ) can be used. The deoxidizing agent is usually used in an amount of about 1 to 2 times the amount of cysteine derivative (2), preferably about 1 to 1.2 times the amount of the cysteine derivative (2). Compound (3) is usually used in an amount of at least the same mole, preferably about 1 to 1.2 times the mole of cysteine derivative (2). The reaction is generally carried out at a temperature of about 0-30'C1, preferably at or near room temperature, and is complete in about 3-72 hours.

The cysteine derivative (2) used as a starting material in the above reaction is, for example, Che■, Phar■.

Bull, 26 (5), 1576 (1978),
^rch, Phart (Weinheii+) 3
16, 934 (1983).

<Reaction formula-2>(1a')(1a") According to the method shown in the above reaction formula-2, compound (1a')
Compound (1a'') can be obtained by treating with an acid in the presence of a scavenger such as anisole, thioanisole or dimethyl sulfide.

In the liquid treatment reaction, examples of acids include trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, and acetic acid. The reaction may be carried out in a solvent such as ethers such as diethyl ether, THF and dioxane, esters such as methyl acetate and ethyl acetate, and halogenated hydrocarbons such as methylene chloride and chloroform. When using trifluoroacetic acid as the acid, no solvent is required and this method is preferred.

In addition, scavengers such as anisole are usually used for compounds (1
about 1 to 10 times the molar amount of a'), preferably about 3 to 5 times
Used in twice the molar amount. The reaction is carried out at a temperature of about 0 to 50°C, preferably about 0 to 25°C, for about 1 to 10 hours.

Reaction formula-3> (1b) [In the formula, R1, R3 and n are the same as above, R2, and RA
Each M represents a lower alkyl group. ] According to the above reaction formula-3, the compound of the present invention (
1b) is obtained. The reaction is carried out according to the usual amide bond forming reaction by the following various methods.

(b) In the presence of a condensing agent, carboxylic acid (4) and amine (
(b) mixed acid anhydride method, that is, a method of reacting carbon II (4) with a halocarboxylic acid alkyl ester to form a mixed acid anhydride, and reacting this with amine (5); (c) Active ester method, i.e. carvone l! (4) For example, an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and an amine (
(d) Carboxylic acid halide method, that is, carboxylic acid (4)
A method of reacting an amine (5) with a halide of (e) Others, such as carvone I! A method of converting (4) into an acid anhydride using a dehydrating agent such as acetic anhydride and reacting it with amine (5); reacting amine (5) with the ester of carboxylic acid (4) and lower alcohol under high pressure and high temperature. How to do it.

Each of the above methods is carried out under substantially the same conditions as the known secondary method. A particularly preferred method is the method (a) above. To explain the method in detail, the condensing agent specifically includes N,
N-dicyclohexylcarbodiimide (DCC),'
DCC-N-hydroxysuccinimide, DCC-N-
Hydroxybenzotriazole, DCC-N-hydroxy-5-norbornene-2,3-dicarboximide,
Water soluble carbodiimide (WSCD)-N-
Hydroxybenzotriazole, diphenylphosphorylaceto (DPPA)-triethylamine, diethylphosphorylcyanidate (DEPC)-triethylamine, etc. can be used. The reaction is generally carried out in a suitable solvent, and various known solvents that do not adversely affect the reaction can be used. Specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, and THF.
, ethers such as dioxane, esters such as methyl acetate and ethyl acetate, DMF.

Examples include aprotic polar solvents such as DMSOlHMPA. The amount of amine (5) to be used is usually at least about an equimolar amount, preferably 1 to 1.
It is best to use about twice the molar amount, and the condensing agent is carvone!
About 1 to 2 times the molar amount of (4), preferably about 1 to 1
．． The molar amount can be doubled. The reaction is usually -20 ~
About 30°C, preferably about -10'C to room temperature, about 3
It will be completed in ~24 hours.

The target compounds obtained by the reactions shown in each of the above reaction formulas can be easily isolated and purified by conventional separation means. Such means include solvent extraction method, dilution method, distillation method,
Examples include recrystallization method, column chromatography, preparatape thin layer chromatography, ion exchange chromatography, and gel chromatography.

The compound (1) of the present invention and its salts can be administered to humans and animals as is or together with a conventional pharmaceutical carrier. The dosage unit form is not particularly limited (it may be selected and used as required). Examples of such dosage unit form include oral preparations such as tablets, capsules, powders, granules, and oral solutions;
Examples include parenteral preparations such as injections, and parenteral topical preparations such as creams and ointments. Oral preparations are administered orally, topical preparations are administered by application, etc., and injection preparations are administered intravenously or intramuscularly, subcutaneously, subcutaneously, or intraperitoneally, alone or together with normal fluids such as glucose and amino acids. administered. The amount of the active ingredient to be administered is not particularly limited and may be selected from a wide range, but in order to achieve the desired effect,
Daily body m! Approximately 0.1 to 50 ma per kg may be used, which may be administered once to three times per day.

It is also preferred that the dosage unit form contains 1 to 500 cm9 of the active ingredient.

Oral preparations such as tablets, capsules, and oral solutions are manufactured according to conventional methods. That is, tablets contain the compound of the present invention or a salt thereof as an active ingredient, gelatin, starch, lactose,
It is mixed with excipients such as magnesium stearate, talc, and gum arabic, and shaped. Capsules are prepared by mixing the above-mentioned active ingredients with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules, and the like. A syrup or elixir is prepared by mixing the active ingredient with a sweetening agent such as sucrose, a preservative such as methyl- and propylparabens, a coloring agent, a flavoring agent, and the like. For parenteral preparations, the active ingredient is usually dissolved in a sterilized liquid carrier or! ! Manufactured cloudy. The preferred carrier is water or saline. A solution having the desired brightness, stability and suitability for parenteral use is prepared by dissolving the active ingredient with an IQ of about 1-500 in water and an organic solvent and in polyethylene glycol with a molecular weight of 200-5000. be done. Such liquid formulations include sodium carboxymethyl cellulose.

Preferably, a lubricant such as methylcellulose, polyvinylpyrrolidone, or polyvinyl alcohol is contained.

Furthermore, the above liquid preparation contains bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, as well as isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers, etc. as necessary. Good too. To further increase stability, parenterally administered drugs can be machine frozen and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use.

Examples Hereinafter, production examples of the compounds of the present invention will be given as examples. Further, as a reference example, an example of producing a raw material compound for producing the compound of the present invention will be given.

Reference example 1 N-((R)-1-ethoxycarbonyl-2-(1-7
Damantyl)thioethyl]-7ranine-t-butyl ester - Preparation of α and β-producers 5-30m HMPA solution of 10 g of 1-adamantyl-L-cysteine ethyl ester and 7.3 g of 2-bromopropion 1-t-butyl ester triethylamine 4
．． 91111! ? was added and stirred for 36 hours at air temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was thoroughly washed with water and then dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (
The mixture was separated and purified using a solvent (ether: n-hexane (1:3)), and the α-isomer of the target compound was obtained as a colorless oily substance from the preceding fraction. Yield: 13.6g.

) 'HNMR (CDCRt): δ value 1. 1 to 2.4 (22H, m>, 1.45
(981s), 2°81 (28% d, J-61-IZ)
, 3.40 (2H, Ql J-7Hz),
4.20 (28% q, J-7Hz) The β-isomer of the target compound was obtained as a colorless oily substance from the afterflow. Yield i. 9g.

((Z)25--9.1° (C-0,3, ethanol)'H-NMR (COCO2):, δ value 1.2-2.2 (22H, m) 1.47 (9)1 .S), 2.71 (IH, dd, J-14Hz.

8H2), 2.90 (IH, dd, J-1'4Hz.

6H2), 3.19 (IH, Q, J-7H2), 3.43 (I
H, dd, J-6Hz, 8Hz) 4.21 (2H, Q, J-7Hz) Reference Examples 2 to 7 Each compound listed in Table 1 below was obtained in the same manner as in Reference Example 1 above.

Table 1 Co2C2H5 Reference example 8 N-((R)-1-ethoxycarbonyl-2-(1-7
Preparation of N-((R)-1-ethoxycarbonyl-2-(1-7damantyl)thioethyl)-7lanine-t-butyl ester obtained in Reference Example 1 25% β-isomer 1.8Q
The mixture was dissolved in hydrogen bromide-acetic acid and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was poured into ice water, adjusted to pH 4 with a saturated aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was crystallized from methylene chloride to obtain the β-isomer of the target compound. Yield: 11.2o.

mo, 68-72°C.

(a) 25- + 3, 3° (c-0,7, eta/-/I/) Reference Examples 9 to 12 Each compound listed in Table 2 below was obtained in the same manner as in Reference Example 8 above.

Example 1 N-((R)-1-ethoxycarbonyl-2-(1-7
N-([R)-1-ethoxycarbonyl-2-(1-adamantyl) obtained in Reference Example 6 ) Thioethyl)-alanine β-isomer 830 ■ Rito(S)-proline-t-butyl ester 390 ■ To a DMF10111 solution of Q, 418 sa of WSCD-HCl2 and 308 ■9 of N-hydroxybenzotriazole were added under water cooling and stirring. and 0.64111 l of triethylamine were added. After stirring for 2 hours under water cooling, the reaction mixture was roughly stirred at room temperature for 15W, then poured into ice water, made weakly alkaline by adding a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: daloloform:methanol-30:1).
The β-isomer of the target compound was obtained as a colorless oil. Yield 660io.

(α) 25--64.9° (C-0,3, ethanol) 'H-NMR (CDCQs): δ value 1.29 (3H1t, J-7Hz), 1.28 (
3H, d, J-6, 5Hz), 1.44.1.46
(9H, each S), 1.6-2.2 (21H, m), 2.71 (IH, dd, J-6Hz.

13H2), 2.88 (IH, dd, J-7Hz.

13Hz), 3.39 (IH, dd, J-6Hz.

7H2), 3.58 (IH%Q, J-6,5Hz), 4.20
(2H,QlJ-7)-1z), 4°35~4.5
(181m) Example 2 N-((R)-1-ethoxycarbonyl-2-(1-methylcyclohexyl)thioethyltufuranyl-(S)
Production of -proline-butyl ester/β-isomer N-((R)-1-ethoxycarbonyl-2-(1-methylcyclohexyl)thioethyl obtained in Reference Example 9)
-Alanine 2. The target compound was obtained as a colorless oily substance from Og in the same manner as in Example 1.

Yield 2.9Q.

(α) 25--75.1° (C-0,7, ethanol) 'H-NMR (CDC (13): δ value 1.20 (3H, t, J-7Hz), 1.28 (
3H, s), 1.44.1.46 (9H, each S), 1.2-2.4
(17H, m), 2.65 (1H, dd, J-13Hz.

7H2), 2.82 (IH, dd, J-13Hz.

6H2), 3°55 (IH, dd, J-7Hz.

6H2), 3.5-3.8 (3H, m), 4.20 (2H, Ql J-7Hz >, 4.3-4
．． 6 (IHl m) Example 3 Reference for production of N-((R)-1-ethoxycarbonyl-2-(2-indanyl)thioethyl)-alanyl-(S)-proline-1-butyl ester/β-isomer β-isomer of N-((R)-1-ethoxycarbonyl-2-(2-indanyl)thioedyl)-alanine obtained in Example 10 1.2Q, (S)-proline-t-butyl ester 670■O and diethyl cyanophosphate 710
400 mo of triethylamine in DMF5- was slowly added dropwise to a solution of 1H in 20 ml of DMF while stirring under water cooling. After stirring for 15 hours while gradually returning the temperature to room temperature, ice water was added to the reaction mixture, and the mixture was made slightly alkaline with a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with water, then with saturated brine, and dried over anhydrous sodium sulfate. The extract was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: 000 form: methanol - 30: 1) to obtain β of the target compound.
-isomer was obtained as a colorless oil. Yield: 1.7g.

((2) 25--69.7° (C-0,7, ethanol-
)' H-NMR (CD CQ s ): δ value 1.
29 (3H, t, J-7Hz), 1.30 (3H
, d, J-7Hz), 1.44.1°46 (9H,
Each S), 1.6-2.2 (4H, m), 2, 29 (I H, brs), 2, 7-3.
8 (11H, m), 4.21 (2HS Ql
J-7Hz>, 4.4-4.5 (1H, m) 7.15 (4H1s) Example 4 N-((R)-1-ethoxycarbonyl-2-(cyclopentyl)thioethyltufuranyl-( N-((R)-1-ethoxycarbonyl-2-(cyclopentyl)thioethyl)-°alanine β-isomer obtained in Reference Example 12 The β-isomer of the target compound was obtained as a colorless oil from 580sa in the same manner as in Example 3. Yield: 17371L [α) 26--88.1° (C-0,6, ethanol) 'H- NMR (CDC123): δ value 1.29 (3H, tl J-7Hz), 1.2
9 (3H, dl J-7Hz), 1.44.
1.47 (9H, each S), 1.4-2.3 (12
H, m), 2゜65 (I H, dd, J-13H
z.

6Hz), 2.86 (IH, dd, J-13Hz.

6Hz), 3.0-3.3 (IH, m), 3.3-3.7 (4H, m), 4.20 (2H, Ql J-7Hz), 4.3-4
．． 5 (IH,m) Example 5 Production Example 1 of N-((R)-1-ethoxycarbonyl-2-(1-adamantyl)thioethyltualanyl-(S)-proline and its-arginine salt) From 632 parts of N-((R)-1-ethoxycarbonyl-2-(1-adamantyl)thioethyltufuranyl-(S)-proline-t-butyl ester obtained in Example 8), The target compound was obtained as a colorless amorphous substance.Yield: 470.9° To a 5-ethanol solution of compound 470.9 obtained in the above reaction, a 2111fi aqueous solution of 1811 g of fulginine was added with stirring.Water and ethanol was distilled off and dried under reduced pressure to obtain the L-arginine salt of the target compound as a colorless powder. Yield ff13091c1. Colorless crystals, mp 1
Examples 6 to 8 Each compound listed in Table 3 below was obtained in the same manner as in Example 5 above.

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R_1 represents an adamantyl group, a benzocycloalkyl group, or a cycloalkyl group that may have a lower alkyl group as a substituent. R_2 and R_3 represent lower alkyl groups. R_4 represents a hydrogen atom or a lower alkyl group. ] A proline derivative represented by and its salt.