JPH0125744B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to carbamate derivatives of mercaptoacyl-substituted hydroxyproline, more specifically, novel mercaptoacylhydroxyproline carbamate derivatives useful as antihypertensive agents, stereoisomers thereof, salts thereof, carbamate derivatives of hydroxyproline, and the production of these compounds. Regarding the law. The compound of the present invention has the formula: It includes novel mercaptoacylhydroxyproline carbamate derivatives represented by and salts thereof. In the above formula, R is hydrogen; R ₂ is lower alkyl; R ₃
is hydrogen; R ₀ is hydrogen; R ₁ is lower alkyl; R ₄ is hydrogen or R ₅ CO-; R ₅ is lower alkyl; n represents 1; The * mark in the above formula [] represents the irregular center. The carbons on the aliphatic side chains are each R ₂ and/or
It is asymmetric when R ₃ is a group other than hydrogen. Each asymmetric center forms a D-type and an L-type compound;
These can be separated as their respective isomers by conventional methods. Also,

The carbamate group represented by the formula is a group that causes cis-trans isomerism. [In the formula, R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ and n have the same meanings as above. ] The novel compounds represented by or salts thereof, antihypertensive compositions containing these, and methods for treating hypertension using the above compounds or pharmacologically acceptable salts thereof as antihypertensive agents can be provided. . The groups represented by the symbols in each formula have the following meanings throughout this specification. Lower alkyl is a straight chain or branched hydrocarbon group that does not contain 7 carbon atoms (e.g. methyl, ethyl,
propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, isopentyl, etc.). No more than 4 carbons (especially C ₁ and C ₂ )
Lower alkyl is preferred. Lower alkanoyl represented by _R5 -CO-includes acyl residues of lower ( _C2 - _C7 ) fatty acids (eg, acetyl, propionyl, butyryl, isobutyryl, etc.). The lower alkanoyl has preferably no more than 4 carbon atoms (particularly acetyl). The carbamate group on the pyrrolidine ring is a lower alkylcarbamoyl (e.g. methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, etc.). The carbamate group is located at the 3- or 4-position of the pyrrolidine ring.
Preferably, it is present at the 4th position (particularly the 4th position). Next, the method for synthesizing the compound of the present invention [] and its intermediate (represented by the following formula []) will be described in detail. formula: [In the formula, R ₀ and R ₁ have the same meanings as above. ] The novel hydroxyproline carbamate derivative represented by can be produced by the following method. formula: A hydroxyproline starting material of the formula is protected, for example, with N-protecting groups of the type commonly used in peptide synthesis methods (e.g. carbobenzoxy, p-toluenesulfonyl, acetyl, etc.) to form the formula: [Wherein, Cbz represents a protecting group (preferably carbobenzoxy). ] A protected compound represented by is obtained. This protected compound [] is reacted with a diazoalkane such as diazomethane to give the formula: [In the formula, R' represents lower alkyl (eg methyl or isobutyl, preferably methyl). Cbz has the same meaning as above. ] Obtain the ester compound shown below. Above ester [] and isocyanate: R ₁
By reacting -NCO in an inert organic solvent (such as benzene), the ester [] has a carbamate group:

Introducing [formula], formula: [In the formula, R' and Cbz have the same meanings as above. ] A compound represented by is obtained. The cis isomer of the compound [] can be obtained by allowing this reaction to proceed in the presence of a catalytic amount of a base (eg, pyridine or triethylamine). The compound [] is formed by reacting the protected compound [] with phosgene to form the formula: [In the formula, R' and Cbz have the same meanings as above. ] Obtain a compound of the form (it is not necessary to isolate it) and a suitable amine:

It can also be obtained by reacting [Formula]. By alkaline hydrolysis of these compounds [ ] with a base (for example, sodium hydroxide, barium hydroxide, potassium hydroxide, etc.), the formula: In the formula, R ₀ , R ₁ and Cbz have the same meanings as above. ] An N-protected proline derivative represented by the formula can be obtained. This protected proline derivative [] is then reduced in a conventional manner (e.g., hydrogenated in the presence of palladium/carbon) to remove the protecting group, giving the formula: [In the formula, R ₀ and R ₁ have the same meanings as above. ] A carbamate derivative of hydroxyproline can be obtained. Compound [] is a new compound, and the object compound of the present invention [] can be produced by using compound [] as an intermediate. That is, this intermediate [] and the formula: [In the formula, R ₂ , R ₃ , R ₅ and n have the same meanings as above. ] By reacting an acid represented by the formula or its chemical equivalent (most preferably its acid chloride form), the formula: [In the formula, R ₀ , R ₁ , R ₂ , R ₃ , R ₅ and n have the same meanings as above. ] The product represented by (the compound of the present invention [] in which R ₄ is R ₅ -CO-) can be obtained. The proline derivative [XI] is preferably purified and isolated. Purification is preferred, for example, by forming and crystallizing the corresponding salt (such as the dicyclohexylamine salt) and then converting the salt to the free acid form by treating the salt with an acid (eg, acidic potassium sulfate). The compound [XI] having an acyl group: R ₅ CO- is
If necessary, the compound of the present invention [] in which R ₄ is hydrogen can be obtained by hydrolyzing this with ammonia, sodium hydroxide, etc. Other manufacturing methods for the starting materials and intermediates are described in the following documents: U.S. Pat. No. 4,046,889;
No. 4105776, Journal of the Chemical
Society (J.Chem.Soc.) 1945 429-432
Page, Journal of the American Chemical Society (J.Amer.Chem.Soc.) Volume 79 185
~192 pages (1957), Volume 85, pp. 3863-3865 (1963)
Year). Method for producing the compound in the present invention As for the general operation method for conversion to the approximate stereoisomeric form, the methods described in the above-mentioned documents can be utilized. The method for producing the compound of the present invention will be explained in more detail in the Examples below. Examples are representative examples of production methods that can be used as a reference for producing compounds that fall within the scope of the present invention but are not described in the Examples. As mentioned above, the compound of the present invention has several asymmetric centers. The compounds of the invention therefore exist as stereoisomers or racemic mixtures thereof. All different stereoisomers and mixtures thereof are included within the scope of the compounds of the present invention. In the above synthetic methods, racemates or enantiomers of either type can be used as starting materials (including intermediates). When a mixture of stereoisomers is obtained as a product, it can be separated, if necessary, by conventional chromatography or fractional crystallization, or converted into a salt by treatment with an optically active base, and then fractionated. It can be isolated as its individual stereoisomers by separation by crystallization or similar methods. Generally, the compounds of the present invention have an L-configuration in the proline moiety and a cis-configuration in the carbamate group.
Compounds having a D-configuration in the acyl side chain moiety are preferred. The compound of the present invention [] forms a salt with the corresponding base by treating it with various inorganic or organic bases. Examples of salt-forming ions derived from such bases are as follows. metal ions, such as aluminum ions, alkali metal ions (such as sodium or potassium),
Alkaline earth metal ions (such as calcium or magnesium) or the many amine salt ions known for this purpose, such as aralkylamines (dibenzylamine, N,N-dibenzylethylenediamine, etc.), lower alkylamines (methylamine , triethylamine, t-butylamine, etc.), procaine, lower alkylpiperidines (N-ethylpiperidine, etc.), cycloalkylamines (cyclohexylamine, dicyclohexylamine, etc.), 1-adamantanamine, benzathine or amino acids (argin, lysine, etc.)
salts derived from etc. Physiologically acceptable salts (e.g. sodium or potassium salts)
can be used for medical purposes as described below, and such salts are preferred. These or other salts need not be physiologically acceptable and may be used to isolate and purify products suitable for purposes such as those described below, or to isolate intermediates as described in the Examples. Useful for separation and purification. The salt can be obtained by reacting a base that supplies the desired basic ion with an equivalent amount of the acid-form compound of the invention in a medium (medium for precipitating the salt) or an aqueous medium, and freeze-drying the reaction. The free acid form of the salt can be obtained again by conventional neutralization methods (for example, by treatment with potassium hydrogen sulfate or hydrochloric acid). The compounds of the present invention (including stereoisomers and salts thereof) inhibit the conversion of angiotensin (decapeptide) to angiotensin by angiotensin-converting enzyme, and are therefore effective in treating various mammals with hypertension (e.g., cats, dogs,
It is useful in reducing or alleviating hypertension in mice, rats, etc.). Hypertension can be alleviated or cured in mammals by administering an antihypertensive effective amount of a composition containing the compound of the present invention or a mixture of one or more physiologically acceptable salts thereof. . Standard animal experiments [SLEngel, TRSchaeffer, MH
Waugh) and B. Rubin et al.: Proceedings of the Society.
Experimental Biology &
Medicine (Proc.Soc.Exp.Biol.Med.) Volume 143
483 (1973)],
about 0.1 to 100 of the compound of the present invention to lower blood pressure
The dosage is based on a dosage of mg/Kg/day, preferably about 1 to 50 mg/Kg/day, and is preferably administered in divided doses of once or 2 to 4 times a day. Although oral administration is preferred, the active compounds may also be administered parenterally, such as subcutaneously, intramuscularly, intravenously or intraperitoneally. The compounds of the present invention can also be formulated in combination with diuretics for the treatment of hypertension. An effective amount consisting of about 30 to 600 mg, preferably about 30 to 300 mg of the total amount of the compound of the present invention and about 15 to 300 mg, preferably about 15 to 200 mg of the diuretic, is administered to a mammal in need of the same per day for a mammal weighing 70 kg. A composition comprising the compound of the present invention and a diuretic can be used by administering the compound of the present invention and a diuretic. As diuretics that can be incorporated into the compound of the present invention, thiazide diuretics such as chlorthiazide, hydrochlorthiazide, flumethiazide, hydroglumethiazide,
bendroflumethiazide, methochlorthiazide,
trichlormethiazide, polythiazide or benzthiazide as well as ethacrynic acid, ticlinafene, chlorthalidone, furosemide, bumetanide,
Examples include triamterene, amiloride and spironolactone or salts of these compounds. For use as antihypertensive agents, the compounds of the present invention can be formulated into compositions such as tablets, capsules, or elixirs for oral administration, or sterile solutions or suspensions for parenteral administration. A mixture of one or more compounds of the present invention and physiologically acceptable salts thereof, from about 10 to
It is preferable to formulate a pharmaceutically acceptable unit dosage form by incorporating 500 mg into a physiologically acceptable medium, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. The amounts contained in these compositions should be such that a suitable amount of active ingredient within the ranges described above is contained in a unit dosage form. Examples of adjuvants that can be incorporated into tablets, capsules, etc. are as follows. Binders such as gum tragacanth, gum arabic, cornstarch, gelatin; excipients such as dicalcium phosphate, microcrystalline cellulose; cornstarch,
Disintegrants such as starch, alginic acid, etc.; lubricants such as magnesium stearate;
Sweeteners such as sucrose, lactose, and satsucharin; flavoring agents such as peppermint, oil of wintergreen, and cherries. When the unit dosage form is a capsule,
In addition to materials such as those described above, a liquid carrier such as a fatty oil may also be included. Various materials can be used to coat or modify the external shape of the dosage unit form. For example, Serac
The tablets may be coated with sugar or a mixture of both. A syrup or elixir may contain, in addition to the active compound, a sweetening agent, such as sucrose; a preservative, such as methylparaben or propylparaben; a coloring agent; and flavoring, such as cherry flavor or orange flavor. Sterile injectable compositions can be prepared by dissolving or dissolving the active compound in a carrier such as sterile injectable water, a natural vegetable oil (such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc.) or a synthetic oil (such as ethyl oleate). It can be suspended and formulated according to normal pharmaceutical practice. Next, a method for producing a preferable compound included in the present invention will be specifically explained with reference to Examples. Compounds included in the present invention that are not described in the examples can be produced in the same manner as in each example by appropriately changing the reagents. Example 1 Production of trans-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline: - a N-carbo Preparation of benzyloxy-trans-4-hydroxy-L-proline:- Potassium bicarbonate in 200 ml of water and 100 ml of acetone.
The Canadian Journal・Of Biochemistry and Physiology (Can.J.Biochem.&
Treatment with 90 ml of concentrated sulfuric acid is completed according to the procedure described in Physiol.), Vol. 37, p. 584 (1959). The product is reacted with cyclohexylamine to obtain 69 g of its cyclohexylamine salt. Melting point 193-195
℃. 34 g of this salt was neutralized with N-hydrochloric acid to obtain 27 g of colorless glass-like free acid. [α] ²⁶ _D = -70° (in chloroform, concentration c = 1%). b. Preparation of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester: - 12.4 g (0.047 mol) of N-carbobenzyloxy-trans-4-hydroxy-L-proline in dioxane-ether. The Journal of
The American Chemical Society (JAC)
S.) Vol. 79, p. 191 (1957), esterify with diazomethane. During this time, to avoid dioxane freezing, firstly at 10℃ and finally at 0 to 2℃.
Processing is carried out at ℃. N-carbobenzyloxy-trans- as an almost colorless viscous oil
14.6 g (100%) of 4-hydroxy-L-proline methyl ester product was obtained. [α] ²⁶ _D = -62° (in chloroform, concentration c = 1%). c trans-N-carbobenzyloxy-4-
[[(methylamino)carbonyl]oxy]-L-
Production of proline methyl ester: - N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester (J.
To a stirred solution of 6.0 g (0.021 mol) in benzene in 120 ml is added 6 ml (0.10 mol) of methyl isocyanate and the mixture is kept at room temperature overnight. After refluxing for another hour, it was placed on a rotary evaporator and finally under 0.2 mmHg.
Remove the solvent at 50°C. The viscous residue was dissolved in 150 ml of ether, washed three times with 50 ml of water (50 ml x 3), dried over magnesium sulfate, and the ether was evaporated to give a syrupy form of trans-N-carbobenzyloxy-4-[ [(Methylamino)carbonyl]
Oxy]-L-proline methyl ester product
6.5g (90%) was obtained. d trans-N-carbobenzyloxy-4-
[[(Methylamino)carbonyl]oxy-L-
Production of proline: - Dissolve 7.6 g (0.023 mol) of the crude ester obtained in step c above in 60 ml of methanol and heat to 2N at -1 to 4°C.
Add 14 ml (0.028 mol) of sodium hydroxide dropwise;
Keep at 0°C for 1 hour and at room temperature overnight. After removing about half of the solvent on a rotary evaporator, the solution was diluted with 160 ml of water, washed with ether (discard the washing liquid), and while cooling, PH with 5.5 ml of hydrochloric acid (1:1).
2 and extracted four times with 75 ml of ethyl acetate. The extracts were combined and washed with 50 ml of saturated sodium chloride.
After drying over magnesium sulphate, the solvent is evaporated to give 7.2 g of a very sticky syrupy substance. Dissolve this in 30 ml of ethanol and add cyclohexylamine.
Treat with a mixture of 2.3 g and 5 ml of ethanol and dilute with 600 ml of ether. Add seed crystals and stir;
Forms a crystalline cyclohexylamine salt. After cooling overnight, 8.5 g of salt product are obtained. Melting point 172~
174℃. [α] ²⁵ _D = -20° (in ethanol, concentration c =
1%). Trans-N-carbobenzyloxy-4-[(methylamino)carbonyl] crystallized from 25 ml of isopropanol as an almost colorless solid.
7.8 g of oxy]-L-proline cyclohexylamine salt was obtained. Melting point 174-176℃. [α] ²⁵ _D = -18° (in ethanol, concentration c = 1%). Add this cyclohexylamine salt to 60ml of ethyl acetate.
The mixture is suspended in water, stirred and treated with 40 ml of N-hydrochloric acid. When two clear layers were obtained, each layer was separated, the aqueous layer was further extracted three times with 60 ml of ethyl acetate, the organic layers were combined and dried over magnesium sulfate, and the solvent was evaporated to give a glass-like free acid. 5.5 g (81%) of product was obtained. e trans-4-[[(methylamino)carbonyl]
Production of [oxy]-L-proline: - 2.7 g (0.0084 mol) of trans-N-carbobenzyloxy]-4-[[(methylamino)carbonyl]oxy]-L-proline on a Parr hydrogenation apparatus. 100ml methanol-water (2:1) solution of
Shake for 6 hours with 1 g of 5% palladium-carbon and 45b hydrogen. The catalyst was filtered off under a nitrogen atmosphere, washed with methanol, the filtrate and washings were combined, and finally
Evaporate at 0.1-0.2 mm Hg to obtain 1.5 g (96%) of the residue. This stuff gradually crystallizes. Trans-4-[[(methylamino)carbonyl]oxy]-L-proline was obtained as a gray solid. When heated, it gradually turns dark in color and sinters and melts. Melting point 213-215
°C (decomposition). [α] ²⁶ _D = -12° (in ethanol-methanol (1:3), concentration c = 0.25%). f trans-1-[D-(3-acetylthio)-2-
Production of methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline: - trans-4-[[(methylamino)carbonyl]oxy]-L-proline 2.9 g (0.0154 moles) of water 45
Cool the ml solution to 5°C with stirring, add solid sodium carbonate little by little (total approximately 0.4 g is required),
Adjust to PH8.5. Add 25% (W/V) sodium carbonate dropwise to this, maintain the pH at 7.0 to 8.0, and stir.
While cooling, a solution of 3.1 g (0.017 mol) of D-3-acetylthio-2-methylpropanoyl chloride in 4 ml of ether is added dropwise with a pipette. about
After 10 minutes, the pH becomes stable at 8.1 to 8.3 (approximately 14 ml of sodium carbonate is added in advance to stabilize it). total
After stirring for 1.25 hours and continued cooling, the solution was washed with 50 ml of ethyl acetate, 50 ml of ethyl acetate was added to form an ethyl acetate layer, stirred, cooled, and diluted with hydrochloric acid (1:
After carefully adjusting the pH to 2.0 in step 1) and saturating with sodium chloride, separate each layer. The aqueous layer was further extracted three times with 50 ml of ethyl acetate, and the organic layers were combined and dried over magnesium sulfate to a final concentration of 0.2 mmHg.
Evaporate the solvent under reduced pressure to a glass-like residue at 5.3
get g. Dissolve this in 40 ml of ethyl acetate, and add a solution of 2.8 g of dicyclohexylamine in 15 ml of ethyl acetate. Add seed crystals and stir to obtain crystalline trans
-1-[D-(3-acetylthio)-2-methyl-
1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline dicyclohexylamine salt precipitates. After cooling overnight, 5.8 g of colorless product was obtained. Melting point 187-189℃ (sintering point
183℃). [α] ²⁶ _D = -64° (in methanol, concentration c =
1%). Recrystallization from 15 ml of methanol and 100 ml of ether gave 4.5 g of a colorless solid product. Melting point 190~
192℃. [α] ²⁵ _D = -67° (in methanol, concentration c =
1%). Add this dicyclohexylamine salt to 50% ethyl acetate.
ml, add 50ml of 10% potassium hydrogen sulfate,
Stir until two layers of clear liquid are obtained. The dicyclohexylamine salt is converted to its free acid by separating the layers, extracting the aqueous layer three times with 50 ml of ethyl acetate, and combining the organic layers and drying over magnesium sulfate. The solvent was evaporated and the trans-1-[D-(3-acetylthio)-2
-Methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline 2.8
g (55%) was obtained. Example 2 Preparation of trans-1-(D-3-mercapto-2-methyl-1-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-L-proline: - 6 ml of concentrated ammonium hydroxide Pass argon through the cold 4 ml water solution for 10 minutes. Add this to the product of Example 1 while cooling under an argon atmosphere and stir on an ice bath until the mixture becomes a pale yellow solution (approximately 3 minutes). After stirring for 2 hours at room temperature under an argon atmosphere, the solution is extracted with 20 ml of ethyl acetate (this and subsequent operations are also carried out under an argon atmosphere as much as possible). The aqueous layer is cooled, stirred, extracted with 20 ml of ethyl acetate, and made acidic by adding about 13 ml of hydrochloric acid (1:1) little by little. Each layer was separated, the aqueous layer was further extracted three times with 20 ml of ethyl acetate, the ethyl acetate layers were combined and dried over magnesium sulfate, and the solvent was evaporated to leave a sticky foamy residue. -Mercapto-2-methyl-1-oxopropyl)-
4-[[(methylamino)carbonyl]oxy]-L
- Obtain proline. This was stirred with ether and finally evaporated under reduced pressure to 0.1-0.2 mm Hg to give 2.2 g (90%) of the product as a colorless, somewhat hygroscopic amorphous solid. Melting point 54-57℃ (sintering point 45℃). [α] ²⁶ _D = -53° (in ethanol, concentration c = 1%). D, L-type amino acids were used in place of the L-type amino acids in Examples 1 and 2 above, and the same operations were carried out to obtain racemic products of the respective examples. Similarly, D-type amino acids were used instead of L-type amino acids in Examples 1 and 2, and D-type amino acids were used in place of L-type amino acids in Examples 1 and 2, respectively.
A type product was obtained. Example 3 Production of cis-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]--4-[[(methylamino)carbonyl]oxy]-L-proline: - a N- Production of carbobenzyloxy-cis-4-hydroxy-L-proline methyl ester: - N-carbobenzyloxy-cis-4-hydroxy-L-proline [see JACS Vol. 79, p. 189 (1957)] 6.5 g Dissolve (0.024 mol) in 65 ml of methanol, stir, and add 0.65 ml of concentrated sulfuric acid. After stirring this for 30 minutes at room temperature, the solution is left overnight. Most of the solvent is evaporated off on a rotary evaporator, 13 g of the oily residue is dissolved in 70 ml of ether and washed with 35 ml of 10% sodium bicarbonate. Back-extract the washings with 35 ml of ether. The combined organic layers were dried over magnesium sulfate and the ether was evaporated to give 6.5 g of product as a thick pale yellow oil.
(96%). [α] ²⁵ _D = −24° (in chloroform,
concentration c=1%). b Production of cis-N-carbobenzyloxy-4-[[(methylamino)carbonyl]oxy]-L-proline methyl ester: - N-carbobenzyloxy-cis-4-hydroxy-L-proline methyl ester 5.4g
(0.019 mol) in 120 ml of acetonitrile are added with stirring 5.4 ml of triethylamine and then 5.4 ml of methyl isocyanate. After standing overnight at room temperature and refluxing for 2 hours, the reaction mixture was treated as in Example 1c to give a viscous pale yellow oil.
5.6g (86%) was obtained. c Production of cis-N-carbobenzyloxy-4-[[(methylamino)carbonyl]oxy-L-proline: - 5.6 g (0.017 mol) of the crude ester obtained in step b above was added in the same manner as in Example 1d. 2N in 45ml methanol
saponified with 11 ml (0.022 mol) of sodium hydroxide,
5.1 g of foamy residue are obtained. Add this to 25ml of ethanol
and 1.7 g of siglohexylamine in 400 ml of ether.
4.8 g of colorless cyclohexylamine salt treated with
get. Melting point 171-173℃. [α] ²⁵ _D = -16° (in ethanol, concentration c = 1%). Recrystallization from ethanol-ether gives a salt having the same melting point and specific rotation as above. This cyclohexylamine salt yields the desired free acid as a colorless foamy residue.
g (65%) was obtained. Preparation of d cis-4-[[(methylamino)carbonyl]oxy]-L-proline: - In 130 ml of methanol-water (2:1), cis-N-
Carbobenzyloxy-4-[[(methylamino)
Carbonyl]oxy]-L-proline 3.5g
(0.011 mol) was hydrogenated with 1.3 g of 5% palladium on carbon as in Example 1e to give the product as a gray solid.
1.9g (95%) was obtained. When heated, it gradually becomes dark and sintered. Melting point 232-234°C (decomposition). [α] ²⁵ _D = -42° (in methanol-water (1:1), concentration c = 0.5%). Production of e cis-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline: - cis-4-[[ (Methylamino)carbonyl]oxy]-L-proline 1.85g (0.0098mol) and D-
2.0 g (0.011 mol) of 3-acetylthio-2-methylpropanoyl chloride are reacted as in Example 1f in 30 ml of water in the presence of sodium carbonate to give 3.35 g of a gummy product. Add this to 35ml of ethyl acetate
The mixture was treated with 1.8 g of dicyclohexylamine to obtain 4.0 g of its dicyclohexylamine salt. melting point
177-179℃. [α] ²⁵ _D = -54° (in methanol, concentration c = 1%).
Treated with 20 ml of acetonitrile and cooled to form a colorless solid.
Obtain 3.6g. Melting point 179-181℃. [α] ²⁵ _D = -54° (in methanol, concentration c = 1%).
This salt was treated with 10% potassium hydrogen sulfate and extracted with ethyl acetate to give the desired free acid as a colorless foamy residue.
2.5g (76%) was obtained. Example 4 cis-1-(D-3-mercapto-2-methyl-
1-oxopropyl)-4-[[(methylamino)
Production of carbonyl]oxy]-L-proline:
- treating the product of Example 3 as in Example 2 with a mixture of 5.5 ml of concentrated ammonium hydroxide and 12.5 ml of water;
Desired product as colorless hygroscopic viscous foam 1.8
g (82%). [α] ²⁵ _D = -59° (in ethanol, concentration c = 1%). Example 5 Manufacture of 1000 tablets: - Composition: cis-1-(D-3-mercapto-2-methyl-1-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-L-proline ( Active ingredients) 100g; Cornstarch 50g; Gelatin 7.5
g; Avicel (microcrystalline cellulose) 25
g; 2.5 g of magnesium stearate. The active ingredients and cornstarch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. This is mixed with Avicel and then magnesium stearate to form granules. This was compression molded to produce 1000 tablets containing 100 mg of active ingredient per tablet. Example 6 Manufacture of 1000 tablets: - Composition: trans-1-(D-3-mercapto-1-
oxopropyl)-4-[[methylamino)carbonyl]oxy]-L-proline (active ingredient) 200
g; 100 g of lactose; 150 g of Avicel; 50 g of corn starch; 5 g of magnesium stearate. Mix the active ingredients with the lactose and Avicel, followed by the cornstarch. To this is added magnesium stearate and the dry mixture is compressed to produce 1000 tablets containing 200 mg of active ingredient per tablet and having a weight of 505 mg.
The tablets were coated with a solution of Methocel E15 (methyl cellulose) containing yellow #6 containing lake as a coloring agent to obtain tablets. Example 7 Manufacture of capsules: Composition: trans-1-(D-3-mercapto-2-
Methyl-1-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-L-proline 125
mg; magnesium stearate 3 mg; lactose (USP) 100 mg. #1 gelatin capsules are filled with the mixture having the above composition, and each capsule contains trans-1-(D-3-mercapto-2-methyl-1-oxopropyl)-
4-[[(methylamino)carbonyl]oxy]-L
- Two capsules containing 250 mg of proline were obtained. Example 8 Manufacture of injection: - Composition: trans-1-(D-3-mercapto-2-
Methyl-1-oxopropyl-4-[[(methylamino)carbonyl]oxy]-L-proline 500
g; Methylparaben 5g; Propylparaben 1
g; Sodium chloride 25 g; Sterile water for injection (enough amount to make the total composition 5). The above active ingredient, preservative and sodium chloride are dissolved in 3 parts of water for injections, and the total volume is made up to 5 parts by adding water for injections to prepare an injection solution. The solution is filtered through a sterile filter and aseptically filled into sterile vials. Each vial was filled with 5 ml of the injection solution containing the active ingredient at a concentration of 100 mg per ml of the injection solution and sealed with a sterile rubber stopper, yielding 1000 vials of injections.

Claims (1)

[Claims] 1 Formula: Compounds represented by, stereoisomers thereof, and salts thereof. [In the formula, R is hydrogen; R ₂ is lower alkyl; R ₃ is hydrogen; R ₀ is hydrogen; R _{1 is lower alkyl; R 4 is} hydrogen or R ₅ CO-; R ₅ is lower alkyl; n is 1. ]. 2. The compound according to claim 1, wherein R ₄ is hydrogen. 3 formula: [In the formula, R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ and n have the same meanings as in claim 1.] The compound according to claim 1, represented by the following formula: 4 trans-1-[D-(3-acetylthio)-2-
The compound according to claim 3 having the name methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline. 5 Claim 3 having the name trans-1-(D-3-mercapto-2-methyl-1-oxopropyl)-4-[[(methylamino)carbonyl]oxy]-L-proline compound. 6 Claim 3 having the name cis-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(methylamino)carbonyl]oxy]-L-proline Compounds described in Section. 7 cis-1-(D-3-mercapto-2-methyl-1-oxopropyl)-4-[[(methylamino)
A compound according to claim 3 having the name carbonyl]oxy]-L-proline.