JPH0149705B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel organic compound, and more particularly, to a novel organic compound having the following general formula: where n is 0 or 1; R ₁ is hydrogen or alkyl having 1 to 3 carbon atoms;
R ₂ is hydrogen, phenyl or alkyl having 1 to 3 carbon atoms; R ₃ is mercapto, formylthio, benzoylthio, alkanoylthio having 2 to 4 carbon atoms or the formula

[Formula] is a group of -S-CO ₂ R ₅ or -SCH ₂ CO ₂ R ₅ ; R ₄ is hydrogen,
phenyl or alkyl having 1 to 4 carbon atoms; R ₅ is hydrogen or alkyl having 1 to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 4-methoxy-1-naphthyl, 5,6,7,
8-tetrahydro-1-naphthyl, 5,6,7,
8-tetrahydro-2-naphthyl, 4-biphenylyl, 5-acenaphthyl, 5-indanyl, 4-
indanyl and formula selected from the group consisting of, where R ₆ is hydrogen,
Fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, carbon alkylamino having 1 to 4 atoms,
selected from the group consisting of alkanoylamino having 2 to 4 carbon atoms and alkoxycarbonyl having 2 to 4 carbon atoms; R ₇ is chloro, fluoro, bromo, alkyl having 1 to 4 carbon atoms and 1 carbon atom; and m is 0, 1 or 2, and m is 0, 1 or 2.
Aroyl (propionyl or butyryl)-L-
Regarding proline and its ester. Suitable alkyl and alkoxy groups contemplated in the present invention are, for example, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy,
sec-butoxy, etc., while halo is fluoro,
Chloro and bromo are exemplified, and alkanoylthio is exemplified by acetylthio, propionylthio, butyrylthio and isobutyrylthio. The novel compounds of the invention have an asymmetric carbon atom (indicated by an asterisk) and therefore exist in diastereoisomeric forms. The novel substituted ω-aroyl (propionyl or butyryl)-L-prolines and their esters of the present invention are generally obtained as white to yellow crystals with characteristic melting points and absorption spectra; Obtained as a white or yellow glassy substance. The compounds are generally soluble in many organic solvents such as lower alkanols, tetrahydrofuran, dioxane, chloroform, and the like. Also included within the scope of the present invention are cationic salts of compounds of the above general formula where R ₅ is hydrogen. _R5
Useful pharmaceutically acceptable salts of compounds where is hydrogen are salts with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations. Suitable metal cations are those derived from alkali metals such as lithium, sodium and potassium, and alkaline earth metals such as magnesium and calcium, but
Cationic forms of other metals such as aluminum, copper, iron and especially zinc are also within the scope of the invention. Pharmacologically acceptable amine cations include primary, secondary or tertiary amines, such as mono-, di- or trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, allylamine, cyclopentylamine. , dicyclohexylamine, mono- or dididibenzylamine, α- or β-phenylethylamine, ethylenediamine and 18 carbon atoms
Aryl-aliphatic amines and heterocyclic amines containing up to
-dimethylpiperazine, etc., as well as amines containing water-soluble or hydrophilic groups, such as mono-, di- or triethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl- 1,3-propanediol,
Tris(hydroxymethyl)aminomethane, N-
Phenylethanolamine, galatamine, N-
It is derived from methylglucoseamine, efuedrin, phenylephrine, epinephrine, procaine, etc. Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like. Angiotensin is a strong vasoconstrictor nerve agent that has been implicated as the main causative agent in the pathogenesis of renovascular hypertension. Angiotensin is produced from angiotensin by the action of angiotensin converting enzyme. Angiotensin is a physiologically inactive decapeptide degraded from the blood protein angiotensinogen by the action of the enzyme renin [Oparil et al., New, England J. of Med., 291 ，
389-457 (1974)]. Also, angiotensinogen and renin are physiologically inactive. Angiotensinogen convertase also contains bradykinin, a vasodilator associated with the regulation of kidney function.
[Erdos,
Circulation Research 36, 247 (1975)]. Therefore, reagents that inhibit angiotensin converting enzyme interfere with the blood pressure enhancing effects of angiotensin because they only perform its conversion to angiotensin. These agents can be used therapeutically in the treatment of renovascular and malignant hypertension types as well as other types of angiotensin-dependent hypertension [Gavras et al., New England J. of Med. 291, 817
(1974)]. The novel compounds of the present invention inhibit angiotensin converting enzyme and thus inhibit the conversion of angiotensin to angiotensin, and thus have utility in reducing hypertension, particularly in reducing angiotensin-related hypertension in various mammalian species. . The activity of the novel compounds of the present invention as antihypertensive agents was determined by two systems for determining their efficacy as angiotensin converting enzyme inhibitors: spectrophotometric analysis of the compounds in vitro and testing of the compounds in renal hypertensive rats with aortic stenosis. This was demonstrated by measuring the blood pressure lowering effect. Spectrophotometric analysis for angiotensin converting enzyme inhibitors Using benzoyl-glycyl-histidyl-leucine as the receiving medium, Cushman, DW and
Cheung, HS, Biochem. Pharmacol. 20 , 1637
The in vitro activity for inhibiting angiotensin converting enzyme (ACE) was determined by the method of 1648 (1971). The reaction mixture is 50 ml of potassium phosphate.
(500mM., PH10.2), sodium chloride 30ml
(2500mM), 25ml (50mM) of receptor medium, 30-50ml of crude extract of ACE, 10ml (25mM) of test compound or excipients and an appropriate amount of distilled water to bring the total volume to 250ml. This reaction mixture was heated to 37°C.
After incubation for 30 minutes, the reaction was then stopped by addition of 250 ml of 1N hydrochloric acid. Hippuric acid was then extracted with 1.5 ml of ethyl acetate by vortexing for 15 seconds; after centrifugation, 1 ml of the ethyl acetate layer was pipetted into a new tube and evaporated to dryness. The extracted hippuric acid was then dissolved in 1 ml of water and the amount of this acid was determined by absorption at 228 nm. From rabbit lung acetane powder (Pel-Freez, Biol. Inc.),
The powder was added to 50ml of phosphate buffer (50mM, PH8.3).
ACE was extracted by kneading in a medium and then centrifuging at 40000g for 30 minutes. Supernatant liquid at 5℃
and used as an enzyme source. ACE inhibitor activity compared to the control value for that particular assay
Calculated as percentage inhibition of activity. A total dose-response inhibition curve was then drawn and the LC ₅₀ value was determined, which can be defined as the molar concentration of compound that inhibits ACE activity by 50%. Representative compounds of the invention and their corresponding LC ₅₀ values as determined by the method described above are shown in Table 1 below.

【table】

[Table] Arterial blood pressure measurement in rats with aortic stenosis and renal hypertension Male Sprague-Dawley normal catatonic rats weighing 300-350 g (Charles River Breeding Lab. Inc.,
Wilmington, Mass.) and Purina experimental food (Purina
Laboratory Chow) for 1 to 7 days before use.
Provided plenty of tap water. Rojo-Ortega, J.M. and Genest, J., A. Method for Production of
Experimental Hypertension in Rats，in Can.
Hypertension was induced by complete ligation of the aorta between the origins of the renal arteries, following the method of J. Physiol. Pharmacol. 46 , 883-885 (1968), with a modification of the surgical method. Rats were then anesthetized intraperitoneally with methohexitol sodium 66 mg/Kg body weight and placed on their right side. An incision was made just below the ribs on the left side. The left kidney was exposed by gently pushing back the fat with a cotton swab. The kidney was gently held between the thumb and index finger outside the body cavity. The aorta was completely ligated between the origins of the renal arteries with a No.-000 silk suture. Be careful to avoid occlusion of the right renal artery. Using 4-0 polyglycolic acid sutures on the muscle and wound clips on the skin,
The wound was sealed as a layer. Next, No. 3 thimerosal aerosol was sprayed onto the wound. Following the surgical procedure, the rats were returned to their cages and provided with sufficient access to Purina chow and water. Six days after surgery, sane rats were confined to a rat board with elastic tape. The neck area was locally anesthetized by subcutaneous infiltration of 2% lidocaine. After inserting a cannula into the trachea and allowing the rat to breathe naturally, Statham isolated the carotid artery and monitored blood pressure.
P23Gb pressure transmitter − Gold Brush recorder
The cannula was inserted with a nylon catheter (0.015 inch inner diameter, 0.030 inch outer diameter) connected to a (Model 2400). Test compounds were dissolved in a small amount of ethanol and then diluted with saline to the desired concentration. Both test compounds and excipient-only solutions were administered orally in parallel with each experiment. Representative compounds of the invention were deemed active when tested in this manner. Thus, the novel compounds of the present invention can be used in amounts ranging from about 1 mg to about 1000 mg.
It has been found to be extremely useful in lowering elevated blood pressure in mammals when administered in amounts in the range of mg/Kg body weight/day. A suitable dosage for maximum results will be about 10 mg to about 300 mg/Kg body weight/day. This dosage can be adjusted to optimize treatment. For example, several divided doses may be administered during the day, or the dose may be relatively reduced as indicated by the exigencies of the symptoms being treated. The active compounds are preferably administered orally, but in the usual manner.
For example, it can be administered intravenously, intramuscularly or subcutaneously. Preparations according to the invention having the desired clarity, stability and compatibility for parenteral use can be obtained by dissolving or suspending the active compounds in excipients consisting of polyhydric aliphatic alcohols or mixtures thereof. It will be done.
Glycerin, propylene glycol and polyethylene glycol are particularly preferred. Polyethylene glycol consists of a mixture of non-volatile, normally liquid polyethylene glycols that are soluble in both water and organic liquids and have a molecular weight of approximately
Having 200-1500. Although the amount of active compound dissolved or suspended in the above-mentioned excipients can be varied, the amount of active substance in the preparation is such that a dosage in the range of about 10 to 500 mg of compound is obtained. be. Although various mixtures of the non-volatile polyethylene glycols described above may be used, it is preferred to use mixtures having an average molecular weight of about 200 to about 400. In addition to the active compound, parenteral solutions or suspensions can also contain various preservatives, which can be used to prevent bacterial and fungal contamination.
Preservatives that can be used for this purpose are, for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerin ether, methyl and propylparaben and thimerosal.
In certain cases it may also be advantageous to use antioxidants, such as sodium bisulfite, isomeric sodium bisulfite and sodium formaldehyde sulfoxylate. Generally antioxidants about 0.05
~0.2% is used. The active compounds of the invention can be administered orally, for example with an inert diluent or an assimilable edible carrier, or the compounds can be enclosed in hard or soft gelatin capsules or compressed into tablets. , or can be incorporated directly into feed or food. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules, suspensions, syrups, wafers, and the like. Such preparations and preparations should contain at least 0.1% of active compound.
Of course, the percentages of preparations and formulations can vary;
It can advantageously be between about 2 and 60% by weight of the units. The amount of active compound in such therapeutically useful preparations is such that a suitable dosage will be obtained. Tablets, troches, pills, capsules, etc. may also contain: binders such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn. Starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose or lactose or flavor additives such as peas, yam oil, or cherry flavoring can be added. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with syrup, sugar or both. A syrup or suspension may contain the active compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, all materials used in preparing dosage unit forms should be pharmaceutically pure and substantially non-toxic in the amounts used. The novel compounds of formula () of the present invention can be prepared according to the following reaction scheme: where n, R ₃ , R ₄ , R ₅ and ARYL are as defined above; X is chloro, bromo, iodo,
-S-R or -SO ₂ R, where R is alkyl having 1 to 4 carbon atoms, phenyl, p-
tolyl, benzyl, p-methoxybenzyl, etc.; Y is the carbonyl activated residue of the peptide coupling agent or the formula -OR',

[Formula] or

[Formula], where R' is hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, p
-tolyl, p-methoxybenzyl, 2,4,6-
trimethylbenzyl, trimethylsilyl, 2-trimethylsilylethyl, etc. or a suitable carbonyl protecting group; and R ₅ is as defined above. According to the above reaction formula, the carboxyl group of the appropriately substituted ω-aroyl alkanoic acid is changed to a carbonyl activated derivative, or according to the reaction formula, the derivatives (Y=OH) and (Y=
OH) into a carbonyl-activated derivative. Carbonyl activated derivatives of formulas, and are prepared by reaction of the free acid under standard reaction conditions in activating the carboxyl group of an N-protected amino acid. For example, mixed anhydrides can convert free acids into bases such as trialkylamines (such as triethylamine), N-methylmorpholine, pyridine,
An amine salt is generated in situ by treatment with N-methylpiperidine, etc., and this is added to a lower alkyl chloroformate, such as ethyl chloroformate, t
-Produced by reacting with butyl chloroformate, isobutyl chloroformate, benzyl chloroformate, trityl chloroformate, etc. Alternatively, the free acid can be reacted with N,N'-carbonyldiimidazole or a related peptide coupling agent, such as N,N'-carbonyl-1,2,4-triazole, to form an activated carbonyl derivative. Derivatives in which Y is O-hydroxysuccinimide or O-hydroxyphthalimide can be prepared by converting the free acid to N,N-dicyclohexylcarbodiimide in the presence of a carbodiimide such as
- produced by reacting with hydroxysuccinimide or N-hydroxyphthalimide. The derivative in which Y is the residue of a peptide coupling agent or an activated ester is reacted with L-proline or an L-proline derivative under common coupling conditions. Amides are acid halides or preferably carbonyl-activated derivatives of the formula L-proline or esters of L-proline, such as alkyl ( _C1 - _C4 ) esters, benzyl esters, 2,
4,6-trimethylbenzyl ester and other L with protected acid functionality to be removed in a later step.
- Obtained by reaction with proline derivatives. Reaction conditions for producing carboxyl-activated derivatives and conditions for coupling to L-proline or L-proline derivatives, e.g. time, temperature,
Solvents and the like are well known in the art. Generally, this reaction is carried out in a solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, etc.
It is carried out for 1 to 24 hours at ℃ to 50℃. Further explanations of the meanings of terms used herein are provided in the following table; in the table, representative peptide coupling agents are shown in the left column and the corresponding carbonyl active residues are shown in the right column:

Table: Many other peptide coupling agents are available and well known in the art, such as unsaturated ethers, α-chlorovinylethyl ether, ethoxyacetylene, ketene imines and ketenes, inamines, acyloxyphosphonium ions, EEDQ, silicon tetrachloride, 1,2-oxazolium salt, etc. All of these confer a carbonyl active residue and can be easily used in the conversion of the formula to when Y is the "carbonyl active residue of the peptide coupling agent". Reaction conditions for such conversions are well known in the art and are described in the literature, by Klausner & Bodansky.
SYNTHESIS, September 1972, pages 453-463. Conversion of the intermediate to the corresponding 3-(X-substituted) propionic acid or 4-(X-substituted) butyric acid derivative, where X consists of a dissociable group as defined above, is not known in the art. It is easily done by well-known and common methods. For example, the chloro, bromo and iodo derivatives are prepared by preparing a compound of the formula in a solvent such as chloroform, carbon tetrachloride, acetic acid or dioxane with a halogenating agent such as chlorine, bromine, N-
27° to 75°C for 12 to 24 hours with iodosuccinimide, etc.
It can be manufactured by processing. X is -S-R
Compounds can be obtained from halo derivatives by treatment with alkali metal mercaptides under standard conditions. The _{corresponding} derivatives with
It can be obtained by oxidizing with an oxidizing agent such as metaperiodic acid at 100°C for 1 to 24 hours. If necessary, ω-aroyl alkanoic acid is converted into an L-proline derivative.

[expression] or

can be coupled with the formula to form an intermediate, which can then be converted to the product via the intermediate and. Intermediates where Y is a carboxyl protecting group can also be converted to intermediate or , at which point the protecting group is removed and the intermediate or (Y=OH) is coupled to L-proline or an L-proline derivative. be able to. The ω-aroyl alkanoic acids in which R ₄ is other than hydrogen have one asymmetric carbon atom and the D and L isomers can be prepared by resolution of the racemic mixture. Activation of the carboxyl group of the resolved isomer then yields a compound of the structural formula where the carbon atom bearing the R ₄ group is in the D or L configuration. Conversion of compounds of resolved structural formulas to reactive intermediates yields compounds that are diastereoisomers. Each diastereoisomer can then be converted to a compound of structural formula as shown in the reaction scheme. Alternatively, racemic compounds of the structure in which R ₄ is lower alkyl can be coupled with L-proline or L-proline derivatives to produce compounds of the structure, which exist in diastereoisomeric forms and are commonly It can be divided in the following ways. For example, 1-(3-benzoyl-2
-Methylpropionyl)-L-proline can be separated by fractional crystallization of one diastereoisomer and isolation of the other diastereoisomer from the mother liquor. Diastereoisomeric forms of the structural formula type can be prepared in this manner and converted to compounds of the structural formula that are inhibitors of vasotonic convertase. Formula the reactive intermediate

##STR1## where R ₈ is reacted with an anion of phenyl, alkyl having up to 3 carbon atoms, a thioacid, or another thiolating agent (H--R ₃ ).
Suitable anions of the thioacids and thiolating agents used in the substitution reactions are alkali metals (K ⁺ , Na ⁺ ), alkaline earth metals such as calcium and magnesium, organic bases such as ammonia, alkylamines, and the like. Removal of the acyl group by reaction with hydroxylamine, ammonium hydroxide, or a dilute organic base yields compounds of formula where R ₃ is mercapto. Under appropriate conditions, the intermediate and where X is -S-R;
And Y is

The formula can be directly converted by removal of the thio protecting group to the product where R ₃ is -SH. For example, R is a thio-protecting group such as t-butyl, p-methoxybenzyl,
Derivatives such as PhCH ₂ O ₂ CS- etc. [HBr-HOAc,
CF ₃ CO ₂ H, (CF ₃ CO ₂ ) ₂ Hg, etc.] can be deblocked. Derivatives, where Y is

where R ₃ is as defined above and R′ is a carboxyl protecting group, under normal conditions removal of the carboxyl protecting group produces the product (R ₅ =H)
can be converted into. Carboxyl protecting groups that are generally removed under acidic conditions are preferred. For example, t-butyl ester is heated to 0°C to 50°C for 1 to 24 hours.
It is removed by treatment with trifluoroacetic acid or aqueous trifluoroacetic acid. trimethylsilyl and 2-
Trimethylsilylethyl is removed under conventional conditions known in the art. As shown in the reaction scheme, the reaction can be carried out with esters (R ₅ =lower alkyl) to produce products where R ₅ is lower alkyl. In the product where R ₅ is t-butyl, the ester group can be removed in the presence of trifluoroacetic acid to produce the free acid derivative of formula. New compounds of the formula according to the invention can be prepared according to the following reaction scheme: The novel compounds of the formula of the present invention can then be prepared according to the following reaction scheme: Reaction formula, R ₁ , R ₂ , R ₃ , R ₅ , ARYL and Y are as defined above. According to the above reaction formula, appropriately substituted ω-aroyl acrylic acid, ω-
Aroylcrotonic acid XI or 3-aroyl-3-
Converting butenoic acid to the carbonyl activated derivative, XII or. reaction conditions for producing such carbonyl activated derivatives;
For example, times, temperatures, solvents, etc. are well known in the art and are described above for conversion to products of formula. The carboxyl-activated derivative, XII, and the free acid, XI, are prepared by treating the free acid, XI, or with a peptide coupling agent as described above. (See table of carbonyl active residues). Derivatives in which Y is the residue of a peptide coupling agent or an activated ester, XII or the formula

[expression] or

Reaction with L-proline or an L-proline derivative of where R' and R ₅ are as defined above to produce an intermediate containing a double bond in the configuration with the carbonyl group. The intermediate, XII, and is reacted with a thiolating agent to form the product directly or to form an intermediate that can be converted to the product or. The position of the double bond determines the direction of 1,4-addition of the thiolating agent, as shown in the reaction scheme. The thiolating agent produces 1,4 additions to the ketone carbonyls of intermediates, and, while producing 1,4 additions to the carboxyl groups in derivatives XI and XII. Suitable thiolating agents are _H2S , H-S-C( _CH3 ) ₃ and H- _R3 , where _R3 is as defined above. The preferred reagent is hydrogen sulfide or the formula

is a thiolating agent of the formula where R ₈ is hydrogen, phenyl or alkyl having up to 3 carbon atoms. Suitable conditions for the addition of the thiolating agent are 1 at 0°C to 100°C in an inert solvent such as chloroform, dichloromethane, carbon tetrachloride, dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, toluene, lower alkanols, etc.
~24 hour reaction. compound and where Y is the formula

The conversion of a group of formula and R′ is a carboxyl protecting group as defined above is carried out by removing the protecting group to form the product R ₅ =H and . Carboxyl protecting groups that are removed under acidic conditions are preferred.
The reaction shown in the reaction scheme can be carried out with esters of L-proline (R ₅ =lower alkyl) to produce products and where R ₅ is lower alkyl. In products where R ₅ is t-butyl, the ester group can be removed in the presence of trifluoroacetic acid or aqueous trifluoroacetic acid to produce the free acid derivative of formula and. Conversion of compounds of formula and to final products and is carried out as described above for the conversion of formula to. Derivatives containing thio protecting groups are
The protecting group can be removed under conventional conditions and converted to the product where _R3 is -SH. The invention will be described in further detail in connection with the following specific examples. Reference Example 1 2-Methyl-3-(m-trifluoromethylbenzoyl)propionic acid A solution of 60.0 g of α-(m-trifluoromethylphenyl)-4-morpholine acetonitrile in 200 ml of tetrahydrofuran was mixed with 30% water in ethanol. Add 10ml of potassium oxide, then methacrylonitrile
22.0ml was added quickly (exotherm). The mixture was stirred at room temperature overnight and the solvent was removed. Acetic acid in the residue
200 ml and 20 ml of water were added and the mixture was refluxed for 2 hours. The solvent was removed under vacuum and 200ml of 6N hydrochloric acid was added to the residue. This mixture was refluxed for 18 hours,
Cooled and extracted with dichloromethane. The dichloromethane extract was passed through a column of hydrous magnesium silicate. The eluate was concentrated under vacuum and crystallized from dichloromethane-hexane to give 55 g of off-white crystals. The crystals were dissolved in dichloromethane and extracted with saturated sodium bicarbonate solution. The aqueous extract was acidified with hydrochloric acid and extracted with dichloromethane. The organic extract was passed through hydrous magnesium silicate, and the eluate was concentrated. The residue was crystallized from dichloromethane-hexane to give 39 g of the desired product as off-white crystals with a melting point of 90-91°C. Reference example 2 3-(m-fluorobenzoyl)-2-methylpropionic acid α-(m-fluorophenyl)-4-morpholine acetonitrile in 200 ml of tetrahydrofuran
48.0 g of the solution was reacted as described in Reference Example 1 to yield 34 g of the desired product as off-white crystals with a melting point of 192-194°C. Reference Example 3 1-(3-Benzoylpropionyl)-L-proline methyl ester A mixture of 3.56 g of 3-benzoylpropionic acid and 3.24 g of N,N-carbonyldiimidazole in 30 ml of tetrahydrofuran was stirred at room temperature for 30 minutes. 3.32 g of L-proline methyl ester hydrochloride was added and the mixture was stirred at room temperature for 2.5 days. The solvent was removed under vacuum. Water and dichloromethane were added to the residue, and the organic layer was separated, washed with water, then 0.1N hydrochloric acid, and dried over magnesium sulfate. The solvent was removed under vacuum to yield 5.0 g of the desired product as off-white crystals with a melting point of 66-70°C. Reference example 4 3-bromo-3-(p-fluorobenzoyl)
Propionic acid 3-(p-fluorobenzoyl) in 100 ml of acetic acid
16 g of bromine was added to a solution of 19.62 g of propionic acid.
The mixture was stirred for 18 hours, then the solvent was removed. Ice and water were added to the residue and the mixture was filtered. The solid was washed with water and then dissolved in 80 ml of acetone. This solution was diluted with 400ml hexane and evaporated to a volume of 125ml at room temperature. 100 ml of hexane was added and the mixture was filtered to give 24.6 g of the desired product as tan crystals with a melting point of 131-135°C. Reference Example 5 2-Methyl-3-(benzoyl)propionic acid α-(phenyl) in 400ml of tetrahydrofuran
- To a solution of 40.4 g of 4-morpholine acetonitrile was added 10 ml of 30% potassium hydroxide in ethanol. Add 21ml of methacrylonitrile (exothermic),
This mixture was stirred for 18 hours. The solvent was removed under vacuum, the residue was dissolved in ether-acetone and filtered. The liquid was concentrated and the residue was triturated with hexane, cooled and filtered to give 4-methyl-2-morpholine-2- as white crystals with a melting point of 93-98°C.
51.1 g of (phenyl)glutaronitrile was obtained. 4-Methyl-2-morpholine-2-(phenyl)
A mixture of 5.0 g of glutaronitrile, 26 ml of acetic acid and 2.9 ml of water was refluxed for 1 hour. The solvent was removed under vacuum and the remaining gum was partitioned between water and dichloromethane. Separate the dichloromethane, wash with water,
Drying over magnesium sulfate and removal of the solvent gave 2-methyl-3-(benzoyl)propionitrile as a gum. To this gum was added 30 ml of concentrated hydrochloric acid, the mixture was refluxed for 1 hour, cooled, filtered,
The solid was washed with water to give the desired product as white crystals with a melting point of 143-145°C. Reference Example 6 2-Methyl-3-(p-trifluoromethylbenzoyl)propionic acid A solution of 54.0 g of α-(p-trifluoromethylphenyl)-4-morpholine acetonitrile in 400 ml of tetrahydrofuran with 10% water in ethanol 10ml of potassium oxide was added. Methacrylonitrile 28
ml was added dropwise (exothermic) and the mixture was stirred at room temperature for 18 hours. Solvent was removed. The remaining oil was dissolved in ether and the solution was washed with water, sodium chloride solution and dried over magnesium sulfate. The solvent was removed and the residue was crystallized from hexane containing a small amount of ether. The gummy yellow solid was dissolved in acetone, heated to boiling and hexane was added until crystals separated. The crystals were collected by cooling and filtration, recrystallized twice from acetone-hexane,
4-Methyl-2 as white crystals with melting point 156-159℃
16.1 g of -morpholino-2-(p-trifluoromethylphenyl)glutaronitrile was obtained. 4-Methyl-2- in 170 ml acetic acid and 17.5 ml water
A mixture of 35 g of morpholino-2-(p-trifluoromethylphenyl)glutaronitrile was refluxed for 2 hours. The solvent was removed and the residue was triturated with hexane-ether to give an orange solid. This solid was recrystallized from acetone-hexane with a melting point of 94~
2-Methyl-3-(p-trifluoromethylbenzoyl)propionitrile as yellow crystals at 96°C
17.7g was obtained. 2-Methyl-3-(p-trifluoromethylbenzoyl)propionitrile in 130 ml of concentrated hydrochloric acid 13.0
The mixture of g was refluxed for 5 hours, then cooled and filtered. Wash the solid with water, melting point 116-119
Desired product as grayish white crystals at °C
13.7g was obtained. Reference Example 7 2-Methyl-3-(benzoyl)propionic acid hydroxysuccinimide ester 12.86 g of 2-methyl-3-(benzoyl)propionic acid (Reference Example 5) and N in 70 ml of dioxane
- in a mixture of 7.71 g of hydroxysuccinimide,
A solution of 13.8 g of dicyclohexylcarbodiimide in 50 ml of dioxane was added. This mixture at room temperature
Stir for 18 hours, filter, and concentrate the liquid in vacuo to an oil. This oil was crystallized from hexane containing a small amount of ether. The solid was recrystallized from dichloromethane to yield 12.0 g of the desired product as white crystals with a melting point of 112-115°C. Reference Example 9 1-(3-Benzoyl-2-methylpropionyl)-L-proline Hydroxysuccine 2-methyl-3-(benzoyl)propionate is added to a solution of 4.8 g of L-proline and 6.97 g of sodium bicarbonate in 170 ml of water. A slurry of imidoester (Reference Example 7) was added and the mixture was stirred at room temperature for 18 hours. The volume was reduced to 50% under vacuum while acidified with hydrochloric acid while cooling. This mixture was extracted with dichloromethane. The organic extract was washed with sodium chloride solution, dried over magnesium sulfate and the solvent was removed under vacuum to give a gum. Dissolve this rubber in 60 ml of warm acetic acid and 5 ml of concentrated hydrochloric acid.
was added, and while cooling, water was added until the solution became cloudy. Cooling and filtration gave a solid which was recrystallized from acetone-dichloromethane to give the desired product (referred to as isomer A) as white crystals with a melting point of 218-220°C. The mother liquor from which Isomer A was crystallized was concentrated to obtain a glass. This product was purified by chromatography to obtain a glass (referred to as isomer B). These two isomers A and B were two diastereoisomers, and the polarized carbon with the 2-methyl group was in the R or S configuration. Reference example 9 3-acetylthio-3-(4-fluorobenzoyl)propionic acid 3-bromo-3-(p-fluorobenzoyl)
A mixture of 2.75 g of propionic acid (Reference Example 4), 2.3 g of potassium thioacetate and 40 ml of acetonitrile was stirred at room temperature for 6 hours. The mixture was filtered and the liquid was concentrated under vacuum. The residue was mixed with water and extracted with dichloromethane. Wash the organic extract with water,
Drying over magnesium sulfate and removing the solvent under vacuum gave the desired product as a gum. Reference example 10 1-(3-benzoyl-3-bromo-2-methylpropionyl)-L-proline Isomerism of 1-(3-benzoyl-2-methylpropionyl)-L-proline (Reference example 8) in 30 ml of acetic acid Body A) A mixture of 1.25 g of bromine in 10 ml of acetic acid
Added 0.7g. The mixture was stirred at room temperature for 18 hours, the solvent was concentrated under vacuum to 1/2 the volume, and the mixture was poured onto ice and water. The mixture was extracted with dichloromethane. The organic extract was washed with water and then with sodium chloride solution, dried over magnesium sulfate and the solvent was removed under vacuum to give a gum. The gum was dissolved in dichloromethane, hexane was added, and the solvent was removed at room temperature to give a white glass. The glass was chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (75:25:2) to give 1.25 g of the desired product (3-bromo derivative of isomer A) as a white glass. In a similar manner, 1-(3-benzoyl-
2-Methylpropionyl)-L-proline (isomer B of Reference Example 8) was reacted with bromine in acetic acid to obtain a glass (3-bromo derivative of isomer B). Example 1 1-(3-acetylthio-3-benzoyl-2
-(S)-Methylpropionyl)-L-proline 1-(3-benzoyl-3-bromo-
1.25 g of 2-methylpropionyl)-L-proline (Reference Example 10, 3-bromo derivative of isomer A) was added. The mixture was stirred for 18 hours, the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, then with sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under vacuum yielded a yellow glass;
This material was dissolved in 10 ml of ethanol. 0.47 g of potassium thioacetate was added and the above procedure was repeated to obtain a yellow glassy material. This was filtered through a silica gel column using ethyl acetate-hexane-acetic acid (75:
25:2) to give 0.28 g of the desired product as a yellow glass. In a similar manner, 1-(3-benzoyl-
3-Bromo-2-methylpropionyl)-L-proline (Reference Example 10, 3-bromo derivative of isomer B) was reacted with potassium thioacetate to obtain a glassy substance. Reference Example 11 3-(p-chlorobenzoyl)propionic acid hydroxysuccinimide ester 10.3 g of dicyclohexylcarbodiimide was added to a mixture of 10.7 g of 3-(p-chlorobenzoyl)propionic acid and 5.75 g of N-hydroxysuccinimide in 100 ml of dioxane. Mix this mixture at room temperature for 3
Stir for 1 hour and then freeze for 18 hours. Filtration and evaporation of the liquid gave a residue, which was rubbed with petroleum ether (boiling point 30-60°C) to give a gummy tan solid. 50% of this solid in dichloromethane
Dissolved in ml. Petroleum ether (boiling point 30-60℃) 50
ml to make it cloudy. The mixture was cooled and the desired product was recovered by filtration as white crystals with a melting point of 121-123°C. Reference Example 12 3-(p-fluorobenzoyl)propionic acid hydroxysuccinimide ester To a solution of 25.0 g of 3-(p-fluorobenzoyl)propionic acid and 14.7 g of N-hydroxysuccinimide in 140 ml of dioxane, add 100 ml of dioxane.
A solution of 26.4 g of dicyclohexylcarbodiimide was added thereto. This mixture was stirred at room temperature for 18 hours,
and the liquid was evaporated to dryness under vacuum, leaving a red oil. This oil was triturated with hexane to give a red solid. This solid was dissolved in 200 ml of dichloromethane, and 200 ml of hexane was added to make it cloudy. The mixture was cooled in an ice bath for 2 hours to yield the desired product as white crystals with a melting point of 130-132°C. Reference example 13 3-benzoylpropionic acid hydroxysuccinimide ester 53.4 g of 3-benzoylpropionic acid and N-hydroxysuccinimide in 325 ml of dioxane
To the 34.5 g partial solution was added a solution of 61.8 g dicyclohexylcarbodiimide in 225 ml dioxane. The mixture was stirred at room temperature for 18 hours, filtered and the liquid was evaporated to dryness under vacuum. The residue was triturated with hexane and filtered to give a solid, which was dissolved in 700 ml of dichloromethane and filtered. 700 ml of hexane was added to the liquid to make it cloudy.
Freezing produced a solid which was filtered and washed with dichloromethane-hexane (1:1) to give the desired product as white crystals with a melting point of 130-132°C. Reference Example 14 1-(3-Benzoylpropionyl)-L-Proline A solution of 25.5 g of L-proline and 37.3 g of sodium bicarbonate in 800 ml of water is added to 3-benzoylpropionic acid hydroxysuccinimide ester (Reference Example) in 800 ml of ethanol. 13) Added 61.0g of slurry. The mixture was concentrated to 1/2 volume, cooled and
Acidified with concentrated hydrochloric acid. The mixture was extracted with dichloromethane and the extract was washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under vacuum to give an orange gum which was triturated with ether containing a small amount of dichloromethane to give a solid. This solid was recrystallized from 250 ml of acetone instead of hexane. After cooling for 2 hours, 32.6 g of the desired product was obtained as white crystals with a melting point of 95-97°C. Reference example 15 1-[3-(4-fluorobenzoyl)propionyl]-L-proline A solution of 10.6 g of L-proline and 15.5 g of sodium bicarbonate in 370 ml of water is added to 3-(p-fluorobenzoyl) in 370 ml of ethanol. ) Propionic acid hydroxysuccinimide ester (Reference example 12)
26.9g of slurry was added. Reference example 14 using this mixture
13.1 g of the desired product was obtained as white crystals with a melting point of 127-129°C. Reference example 16 1-[3-(4-chlorobenzoyl)propionyl]-L-proline A solution of 2.30 g of L-proline and 3.36 g of sodium bicarbonate in 50 ml of water is added to 3-[3-(4-chlorobenzoyl)propionyl]-L-proline in 60 ml of ethanol.
A partial solution of 5.96 g of (p-chlorobenzoyl)propionic acid hydroxysuccinimide ester (Reference Example 11) was added. Following the method of Reference Example 14, 3.37 g of the desired product with a melting point of 137-138°C was obtained. Reference example 17 1-[3-bromo-3-4-fluorobenzoyl)propionyl]-L-proline 1-[3-(4-fluorobenzoyl)propionyl]-L-proline in 100 ml of acetic acid (Reference example 15)
To the 10.26 g solution were added 3 drops of 30% hydrogen bromide in acetic acid. A solution of 5.6 g of bromine in 20 ml of acetic acid was then added dropwise and the mixture was stirred at room temperature overnight. The mixture was evaporated to 1/3 of its volume, poured onto ice and water and extracted with dichloromethane. The organic extracts were washed twice with water, then brine, dried over magnesium sulfate, and evaporated to dryness under vacuum with moderate heating to give a white glass. The glass was scraped from the flask to obtain 12.2 g of white powder. This powder was mixed with ethyl acetate-hexane-acetic acid (75:25:
2), put into a 11/2 inch x 20 inch silica gel column, elute with the same solvent system, and 300 ml.
A 100 ml fraction and a holding volume of 400 ml were collected along with a pre-distillate. Fractions 2.5 and 6 were combined and applied to the column again in the same manner. Fraction 2 gave 2.0 g of the desired product as a white glass. Reference Example 18 1-(3-Bromo-3-benzoylpropionyl)-L-proline In a solution of 8.25 g of 1-(3-benzoylpropionyl)-L-proline (Reference Example 14) in 80 ml of acetic acid,
Five drops of 30% hydrogen bromide in acetic acid were added followed by 4.80 g of bromine in 20 ml of acetic acid. The mixture was stirred at room temperature for 18 hours, evaporated to 1/3 of its volume, poured onto ice and water and extracted with dichloromethane. The organic extracts were washed with water and brine, dried over magnesium sulfate and evaporated to dryness to give 10.3 g of the desired product as a white glass. Example 2 1-(3-acetylthio-3-benzoylpropionyl)-L-proline 1.25 g potassium thioacetate in 20 ml ethanol
1 in 20 ml of ethanol to the stirred mixture.
-(3-bromo-3-benzoylpropionyl)-
A solution of 3.54 g of L-proline (Reference Example 18) was added. This mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under vacuum and the residue was partitioned between dichloromethane and water. The dichloromethane layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under vacuum to give 2.9 g of product as a glass. A 2.3 g sample was chromatographed on silica gel with the solvent system ethyl acetate-hexane-acetic acid (75:25:2) to give 1.07 g of product as a pale yellow glass. Example 3 1-(3-benzoylthio-3-benzoylpropionyl)-L-proline Sodium hydride (2 in hexane) in oil dispersion
To 440 mg (washed twice) was added a solution of 1.60 g thiobenzoic acid in 25 ml ethanol. The mixture was stirred for 30 minutes, then 3.54 g of 1-(3-bromo-3-benzoylpropionyl)-L-proline was added and the mixture was stirred at room temperature for 18 hours. Following the method of Example 1, the desired product was obtained as a glass. Example 4 1-[3-acetylthio-3-(4-fluorobenzoyl)propionyl]-L-proline 1-[3-bromo-3-(4
-fluorobenzoyl)propionyl]-L-proline (Reference Example 17) 1.37 g of potassium thioacetate was added to a solution of 3.7 g. Following the method of Example 1, 1.02 g of the desired product was obtained as a glass. Example 5 1-[3-benzoylthio-3-(4-fluorobenzoyl)propionyl]-L-proline Sodium hydride (2 in hexane) in an oil dispersion
A solution of 1.60 g of thiobenzoic acid in 25 ml of ethanol was added dropwise to 440 mg (washed twice). The mixture was stirred at room temperature for 1 hour and 1-[3-bromo-3
-(4-fluorobenzoyl)propionyl]-L
- 3.7 g of proline (Reference Example 17) was added. Example
12 to obtain 3.81 g of the desired product as a white glass. Reference example 9 [3-(4-bromobenzoyl)propionyl]
-L-proline t-butyl ester 1.285 g p-bromobenzoylpropionic acid and triethylamine in 25 ml tetrahydrofuran
0.50ml of the solution was stirred at -8°C in an ice-salt bath. A solution of 0.48 ml of ethyl chlorocarbonate in 5 ml of tetrahydrofuran was added dropwise and the mixture was stirred for 30 minutes at -5°C. Tetrahydrofuran 10
Add dropwise a solution of 855 mg of t-butylproline in ml;
The solution was stirred in an ice-salt bath for 30 min, then 30 min.
It was left to come to room temperature for a minute. The mixture was poured onto ice and water, extracted with dichloromethane, and the organic extracts were washed with saturated aqueous sodium bicarbonate, water, then 1N hydrochloric acid, dried over magnesium sulfate, evaporated to dryness under vacuum, and an oil. remained. This oil was crystallized from hexane containing a small amount of ether to give an off-white solid, which was recrystallized from acetone-hexane to give 505 mg of the desired product as white crystals with a melting point of 70-71°C. Ta. Reference example 20 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester 5.14 g of p-bromobenzoylpropionic acid and triethylamine in 50 ml of tetrahydrofuran
2.78ml of the solution was stirred and cooled to -15°C in a methanol-ice-salt bath. A solution of 1.9 ml of ethyl chlorocarbonate in 10 ml of tetrahydrofuran was added dropwise and the mixture was stirred for 30 minutes at -10°C. Methylproline hydrochloride in 50ml of methylene chloride
3.32g of the solution was treated with 2.78ml of triethylamine and then filtered. The liquid was added dropwise to the above solution, and the temperature was maintained below -5°C. The mixture was stirred in the bath for 30 minutes and then brought to room temperature for 1 hour. The mixture was poured into 300ml of water and extracted with dichloromethane. The organic extracts were washed with saturated aqueous sodium bicarbonate, water, then 1N hydrochloric acid, dried over magnesium sulfate, and evaporated to an oil. Tribbing this oil with petroleum ether (boiling point 30-60°C) gave a solid which was recrystallized from acetone-hexane to give 2.09 g of the desired product as white crystals, mp 84-86°C. Reference Example 21 3-(4-bromobenzoyl)propionic acid hydroxysuccinimide ester A solution of 41.2 g of dicyclohexylcarbodiimide in 150 ml of dioxane was mixed with 51.4 g of p-bromobenzoylpropionic acid in 250 ml of dioxane and N
- Added to a partial solution of 23.0 g of hydroxysuccinimide. The mixture was stirred at room temperature for 18 hours, then in an ice bath, filtered and the liquid was evaporated under vacuum to give a residue. This residue was crushed with hexane and rubbed to obtain a solid. Dissolve this solid in 130 ml of dichloromethane and add petroleum ether (boiling point 30~
60℃) was added to make it cloudy. Cool in an ice bath;
Desired product as white crystals with melting point 127-129 °C
31.1g was obtained. Reference example 22 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester 3.54 g of 3-(4-bromobenzoyl)propionic acid hydroxysuccinimide ester (Reference example 21) and methylproline in 10 ml of acetonitrile 1.75 ml of diisopropylethylamine was added to a solution of 1.66 g of hydrochloride. The mixture was stirred at room temperature for 18 hours and evaporated under vacuum to give a residue. This residue was dissolved in dichloromethane, washed with 1N hydrochloric acid,
Drying over magnesium sulfate and evaporation under vacuum gave a rubber. The rubber was rubbed with hexane to give a solid which was recrystallized from acetone-hexane to give 2.01 g of the desired product as a white solid with a melting point of 78-82°C. Reference example 23 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester 21.8 ml of triethylamine was used instead of diisopropylethylamine, and 27.3 g of 3-(4-bromobenzoyl) propionic acid hydroxysuccinimide ester , methylproline hydrochloride 13.0
Reference Example 22 using g and 150 ml of acetonitrile
I repeated the method. 16.6 g of the desired product was recovered as white crystals with a melting point of 83-85°C. Reference example 24 1-[3-(4-bromobenzoyl)-3-bromopropionyl]-L-proline methyl ester 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl in 50 ml of carbon tetrachloride Add carbon tetrachloride to a solution of 3.52 g of ester (Reference Example 23).
A solution of 0.51 ml of bromine in 20 ml was added dropwise. 30 minutes later,
Two drops of 30% hydrobromic acid in acetic acid were added and the mixture was stirred at room temperature for 2 hours. The solvent was decanted from the resulting rubber. This gum was dissolved in dichloromethane, twice with water and once with sodium chloride solution.
Washed twice, dried over magnesium sulfate and clarified with charcoal. The liquid was evaporated to dryness under vacuum to yield 3.87 g of the desired product as a gum. Reference example 25 2-{α-[(2-carboxy-1-pyrrolylcarbonyl)methyl]phenacylthio}-1-methylpyridinium bromide, methyl ester 1-[3-(4-bromobenzoyl-3-) in 50 ml of acetonitrile To a solution of 7.5 g of 1-methyl-2-(1H)-pyridinethione in 30 ml of acetonitrile was added to a solution of 7.5 g of [bromopropionyl]-L-proline. The mixture was stirred at room temperature for 18 h and the solvent was evaporated under vacuum. Removal under 50% yielded a white glass, which was triturated with ether and filtered.
The solid content is converted into ether and petroleum ether (boiling point 30-60
Wash the product as a cream-colored powder (°C)
8.0g was obtained. Example 6 1-[3-(4-bromobenzoyl)-3-thiopropionyl]-L-proline 2-{α-[(2-carboxy-1-pyrrolylcarboxy)methyl]phenacylthio}-1-methylpyridinium 5.2 g of bromide, methyl ester (Reference Example 25) was slurried with 50 ml of water and extracted with chloroform. Evaporation of the extract gave a gum, which was combined with 50 ml of 1N sodium hydroxide solution and stirred at room temperature for 3 hours. The mixture was washed with chloroform and the alkaline solution was made acidic with hydrochloric acid and extracted with chloroform. The extract was dried and then evaporated to dryness under vacuum to yield a glass. This was rubbed with hexane to give a tan amorphous solid. This solid was mixed with heptane-ethyl acetate-methanol-water (55:45:15:
1) system was used for preparative chromatography on Celite. From fraction No. 3, 539 mg of the desired product was obtained in the form of a yellow-brown glass. Example 7 1-[3-acetylthio-3-(4-bromobenzoyl)propionyl]-L-proline methyl ester 1-[3-(4-bromobenzoyl)-3-bromopropionyl)-L- in 35 ml of acetonitrile 1.48 g of potassium thioacetate was added to a solution of 5.28 g of proline methyl ester (Reference Example 24). The mixture was stirred at room temperature for 2 hours, filtered and the liquid was evaporated to dryness under vacuum leaving an amber gum. This was dissolved in ether and chromatographed on a 1 inch x 16 inch silica gel column, eluting with ether and collecting 100 ml fractions. The desired product (1.64 g) was obtained from fraction no. 3 as a glass. Example 8 1-[3-benzoyl-3-thiopropionyl)
-L-Proline Hydroxylamine hydrochloride in 10 ml of methanol
A solution of 65 mg of 1-(3-benzoylthio-3-benzoylpropionyl)- in 10 ml of methanol
A solution of 0.35 g of L-proline was added. 164 mg of sodium acetate was added to this mixture and the mixture was stirred for 2 hours. The solvent was removed and the residue was partitioned between water and dichloromethane. The organic layer was washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under vacuum to obtain 174 mg of rubber.
Ethyl acetate:hexane:acetic acid (75:
25:2) on silica gel to give the title product as a glass. Reference example 26 1-[3-(4-bromobenzoyl)propionyl]-L-proline 1-[3-(4-bromobenzoyl)propionyl]-L-proline methyl ester (Reference example 20)
A mixture of 2.64 g and 26 ml of 1N sodium hydroxide was stirred at room temperature. The solids were collected by decantation and dissolved in tetrahydrofuran to reconstitute the alkaline solution, which was further stirred at room temperature. This alkaline solution was washed with ethyl acetate and poured into ice-cold hydrochloric acid. This mixture was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness under vacuum, leaving a gum. The gum was triturated with ether to give white crystals which were recrystallized from acetone-hexane to give 1.35 g of the desired product as white crystals with a melting point of 138-139°C. Reference example 27 1-[3-(4-bromobenzoyl)propionyl]-L-proline A solution of 12.65 g of proline and 18.5 g of sodium bicarbonate in 390 ml of water is added to 1-[3-(4-bromobenzoyl)propionyl]-L-proline in 390 ml of ethanol.
(3-p-bromobenzoyl)propionic acid hydroxysuccinimide ester (Reference Example 21) 39.0
g slurry was added. The mixture was stirred at room temperature for 18 hours, evaporated to 1/2 its volume and acidified with concentrated hydrochloric acid to give an oil. The oil crystallized out as a solid upon friction, which was recrystallized from acetone-hexane to give 26.3 g of the desired product as tan needles, mp 143-144°C. Reference example 28 1-[3-(4-bromobenzoyl)-3-bromopropionyl)-L-proline 1-[3-(4-bromobenzoyl)-propionyl]-L-proline in 150 ml of acetic acid (Reference example 27) )
A solution of 9.0 g of bromine in 20 ml of acetic acid was added dropwise to the 17.7 g solution, followed by 5 drops of hydrobromic acid in acetic acid. This mixture was stirred for 18 hours and 1/
Evaporated to 2, poured onto ice and water and extracted with methylene chloride. The organic extracts were washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulphate, clarified with charcoal and evaporated to dryness under vacuum. 20.5 g of desired product as a white amorphous solid
I got it. Example 9 1-[3-acetylthio-3-(4-bromobenzoyl)propionyl]-L-proline To a stirred suspension of 469 mg of potassium thioacetate in 10 ml of ethanol is added 1-[3-(4-bromobenzoyl)propionyl]-L-proline. 1.76 g of benzoyl)-3-bromopropionyl]-L-proline (Reference Example 28) was added. The mixture was stirred at room temperature for 18 hours, filtered and the liquid was evaporated to dryness. The residue was dissolved in dichloromethane, washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under vacuum to give 1.68 g of the desired product as a white glass. Example 10 1-[3-(4-bromobenzoyl)-3-benzoylthiopropionyl]-L-proline To 440 mg of sodium hydride in an oil dispersion was added a solution of 1.6 g of thiobenzoic acid in ethanol.
This mixture was stirred for 30 minutes and then 1-[3-(4-
Bromobenzoyl)-3-bromopropionyl]-
4.33 g of L-proline (Reference Example 28) was added, the mixture was stirred at room temperature for 18 hours, the solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and then with sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under vacuum leaving a pink glass. 2.8g of this glass was mixed with ethyl acetate-hexane-acetic acid (75:
25:2) and loaded onto a 1 inch x 15 inch column of silica gel. The column was eluted with the same solvent system (100 ml retention volume) and a 50 ml fraction was collected.
The desired product was recovered from fraction no. 2 as a glass. Reference example 29 4-benzoylbutyric acid hydroxysuccinimide ester 25 g of 4-benzoylbutyric acid in 200 ml of dioxane
N-hydroxysuccinimide in a partial solution of
Added 14.45g. Stir this mixture and add dicyclohexylcarbodiimide in 100 ml of dioxane.
26.8g of solution was added dropwise. The mixture was stirred for 18 hours, filtered and the liquid was evaporated to an oil. This oil was rubbed with hexane to obtain a solid. This solid was recrystallized from dichloromethane-hexane with cooling to yield 24.6 g of the desired product as white crystals with a melting point of 117-120°C. Reference Example 30 1-(4-Benzoylbutyryl)-L-proline To a stirred solution of 9.78 g of proline and 14.3 g of sodium bicarbonate in 340 ml of water is added 340 ml of ethanol.
A partial solution of 24.6 g of 4-benzoylbutyric acid hydroxysuccinimide ester (Reference Example 29) in ml was added. The mixture was stirred for 18 hours, evaporated to 1/2 of its volume and acidified with concentrated hydrochloric acid in an ice bath.
This mixture was extracted with dichloromethane. The organic extract was washed with water and brine, dried over magnesium sulfate and evaporated under vacuum to give a gum. This rubber was rubbed with hexane containing a small amount of dichloromethane to obtain a solid. Dissolve this solid in warm acetone.
Dissolved in 100ml, filtered and added 150ml hexane. This mixture was stirred in an ice bath and had a melting point of 102-105.
14.9 g of the desired product was obtained as white crystals at . Reference example 31 1-(4-bromo-4-benzoylbutyryl)-
L-Proline 1-(4-benzoylbutyryl) in 115 ml of acetic acid
A solution of 6.4 g of bromine in 25 ml of acetic acid was added dropwise to a solution of 11.5 g of -L-proline (Reference Example 30). The mixture was stirred for 18 hours, its volume reduced to 1/3, poured onto ice and water, and extracted with dichloromethane. The organic extracts were washed with water and brine, dried over magnesium sulphate and evaporated under vacuum to give a yellow gum. This gum was dissolved in dichloromethane and placed in a 1 1/2 inch x 24 inch column of silica gel moistened with dichloromethane and treated with ethyl acetate:acetic acid (1:
1), and 100 ml of fraction was collected. Distillate No.7
2.1 g of a solid were obtained which was dissolved in dichloromethane, filtered through Celite and evaporated to dryness to give 2.0 g of the desired product as an orange gum. Example 11 1-(4-Acetylthio-4-benzoylbutyryl)-L-proline 1-(4-bromo-4-benzoylbutyryl)-L-proline in 20 ml of ethanol (Reference Example 31)
To 2.0 g of solution was added 752 mg of potassium thioacetate. The mixture was stirred at room temperature for 18 hours, evaporated to dryness and the residue was partitioned between dichloromethane and water. Separate the dichloromethane layer, wash with brine,
Drying over magnesium sulfate, treatment with charcoal and evaporation gave a rubber. This gum was dissolved in ethyl acetate-hexane-acetic acid (75:25:2) and chromatographed on a 1 inch x 15 inch silica gel column (100 ml retention volume) and a 50 ml fraction was collected.
Fractions 3-6 were combined to obtain the desired product. Reference example 32 1-[3-(3-fluorobenzoyl)-2-
(S)-Methylpropionyl)-L-proline methyl ester A solution of 2.10 g of 3-(4-fluorobenzoyl)-2-methylpropionic acid (Reference Example 2) in 20 ml of tetrahydrofuran is added to Added 1.62g. The mixture was stirred at room temperature for 1 hour, then L-proline methyl ester
1.66g was added and stirring continued for 18 hours. The mixture was evaporated to dryness under vacuum and the residue was partitioned between dichloromethane and water. Separate the organic layer and sequentially
Washed with 1N hydrochloric acid, water, sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to dryness under vacuum to give 1.98 g of the desired product as a gum. Reference example 33 1-[3-(3-fluorobenzoyl)-2-
(S)-Methylpropionyl)-L-proline 1-[3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline methyl ester (Reference Example 32) 1.98 g and 2 ml of tetrahydrofuran
20 ml of 1N sodium hydroxide was added.
The mixture was stirred at room temperature for 4 hours, cooled in an ice bath, acidified with concentrated hydrochloric acid, and extracted with dichloromethane. The organic extract was washed with sodium chloride solution,
Drying over magnesium sulfate and evaporation under vacuum gave a rubber. The gum was triturated with ether to give 500 mg of the desired product as a white solid. Reference example 34 3-(3-chlorobenzoyl)-2-methylpropionic acid α-(3-chlorophenyl)-4-morpholine acetonitrile in 50 ml of tetrahydrofuran 11.8
of potassium hydroxide in methanol to a solution of 30 g
% solution was added. 4.62 ml of methacrylonitrile was added to this solution. After stirring for 1 hour, the mixture was concentrated to dryness and the residue was dissolved in dichloromethane. The solution was passed through a short column of hydrous magnesium silicate and the eluent was concentrated to produce 15.5 g of yellow oil.
I got it. This oil was heated on a steam bath for 1 hour with a mixture of 75 ml acetic acid and 5 ml water. The solvent was removed under vacuum and water was added to the residue. By filtration, 3-(3-chlorobenzoyl)-2-methylpropionitrile was obtained as crystals with a melting point of 72-75°C.
I got g. A mixture of the above compound (7.9 g) and 75 ml of concentrated hydrochloric acid was refluxed for 1 hour. This mixture was cooled and filtered to give the title product as crystals with a melting point of 102-105 °C.
8.5g was obtained. Reference Example 35 3-(4-Chlorobenzoyl)-2-methylpropionic acid To a mixture of 152.2 g of p-toluenesulfonic acid and 148.1 g of morpholine in 700 ml of tetrahydrofuran was added 102 g of 4-chlorobenzaldehyde in 200 ml of tetrahydrofuran. 6 of this mixture
Reflux for an hour, cool and add 65.1 g of potassium cyanide in 100 ml of water. The mixture was refluxed for 18 hours and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and the solution was washed with sodium bisulfite solution and passed through a column of hydrous magnesium silicate. The liquid was concentrated to near dryness and hexane was added. By filtration, 87.5 g of α-(4-chlorophenyl)-4-morpholine acetonitrile was obtained as white crystals with a melting point of 70°C. Tetrahydrofuran
To the above compound (87.8 g) in 500 ml was added 25 ml of a 30% solution of potassium hydroxide in ethanol, and to this mixture was added 33.5 ml of methacrylonitrile.
The mixture was stirred for 5 hours at room temperature and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and passed through a column of hydrous magnesium silicate. The eluate was concentrated and diluted with hexane to obtain 50 g of white crystals with a melting point of 158-160°C. The above compound (50g) in 400ml acetic acid and 100ml water
The mixture was refluxed for 18 hours. The solvent was removed and the residue was dissolved in dichloromethane. This solution was passed through a column of hydrous magnesium silicate, and the eluate was concentrated to give a yellow oil. Crystallization from hexane gave 57 g of 3-(4-chlorobenzoyl)-2-methylpropionitrile as crystals with a melting point of 80-82°C. The above compound was refluxed with concentrated hydrochloric acid, melting point 125
The title product was obtained at ~129°C. Example 12 1-[3-(acetylthio-3-(1-naphthoyl)-2-(S)-methylpropionyl]-L-proline in a mixture of 133.2 g of p-toluenesulfonic acid and 130.7 g of morpholine in 500 ml of tetrahydrofuran) , 98.0 g of 1-naphthaldehyde were added and the mixture was refluxed for 6 hours. 100 g of water was added to the cooled mixture.
48.8 g of potassium cyanide in ml were added and the mixture was refluxed for 18 hours, the solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer and extract were combined, washed with saturated sodium bisulfite solution, and passed through a column of hydrous magnesium silicate. Concentrate the eluent, dilute with hexane,
123 g of α-(1-naphthyl)-4-formoline acetonitrile was obtained as crystals with a melting point of 88-89°C. The above compound (120
g) was added with 35 ml of a 30% solution of potassium hydroxide in ethanol and 43.6 ml of methacrylonitrile.
The mixture was stirred at room temperature for 24 hours and the solvent was removed. Add 600ml of 6N hydrochloric acid to the residue and mix this mixture for 18
Refluxed for an hour. The mixture was extracted with dichloromethane and the organic extract was extracted with sodium bicarbonate solution. The aqueous layer was made acidic with hydrochloric acid and extracted with dichloromethane. The dichloromethane extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed and the residue was triturated with hexane to obtain 19.2 g of 3-(1-naphthoyl)-2-methylpropionic acid as crystals with a melting point of 111-114°C. The above compound (12.0 g) was dissolved in 100 ml of dioxane, and 5.70 g of N-hydroxysuccinimide was added. To this mixture, N in 100 ml of dioxane,
10.2g of N-dicyclohexylcarbodiimide
Added over a period of minutes. The mixture was stirred overnight, filtered, and the filter cake was washed with dioxane. The liquid was concentrated, hexane was added, and filtered. The solid was recrystallized from dichloromethane-hexane to give 3-(1) as white crystals with a melting point of 170℃.
-naphthoyl)-2-methylpropionic acid, hydroxysuccinimide ester was obtained. The above compound (3.4 g) was slurried in 40 ml of ethanol and added to a solution of 2.30 g of L-proline and 1.68 g of sodium carbonate in 40 ml of water. This mixture was stirred at room temperature for one week. The mixture was concentrated to 1/2 volume, cooled and acidified with concentrated hydrochloric acid. The mixture was extracted with dichloromethane, the extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to obtain 1-[3-(1-naphthoyl)-2-methylpropionyl]-L-proline. The above compound was separated into diastereoisomers A and B and each was reacted with bromine as in Reference Example 17 to form a glass of 1-[3-bromo-3-
(1-naphthoyl)-2-methylpropionyl]-
L-proline (brominated isomer A and brominated isomer B) was obtained. Example 2
Reaction with potassium thioacetate as in gave the title product. Example 13 1-[3-acetylthio-3-(3-chlorobenzoyl)propionyl]-L-proline To a cold solution of 76 g of p-toluenesulfonic acid in 500 ml of tetrahydrofuran are added 87 g of morpholine and m
- 50.6 g of chlorobenzaldehyde was added. This mixture was refluxed for 2.5 hours and then diluted with tetrahydrofuran.
100ml was distilled off. The mixture was cooled and a solution of 28.6 g of potassium cyanide in 100 ml of water was added. The mixture was refluxed for 5 hours and concentrated to dryness under vacuum. The residue was dissolved in dichloromethane and the solution was washed with water, sodium bisulfite solution, saturated sodium chloride solution and dried over magnesium sulfate. This solution was passed through a short column of hydrous magnesium silicate. The eluent was refluxed while adding hexane until crystals separated. Cool and filter α-(3-chlorophenyl)-4-morpholine acetonitrile as crystals with a melting point of 72-73°C.
Obtained 78g. The above compound (23.6 g) in 100 ml of tetrahydrofuran was added with potassium hydroxide in methanol.
Added 120 drops of 30% solution. 4.1 ml of acrylonitrile was added to this mixture. After stirring for 1 hour, the mixture was concentrated to dryness under vacuum. The residue was dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. The eluent was concentrated under vacuum to yield 36.6 g of a yellow oil. This oil was washed with acetic acid on a steam bath.
Heat for 1 hour with a mixture of 150ml and 10ml water.
The solvent was removed under vacuum and the residue was treated with water. The mixture is filtered to form 3-
(3-chlorobenzoyl)propionitrile 18.8
I got g. A mixture of the above compound (8.1 g) and 80 ml of concentrated hydrochloric acid was refluxed for 7 hours. Upon cooling, an oil is obtained, which crystallizes out as crystals with a melting point of 105-107°C.
8.8 g of -(3-chlorobenzoyl)propionic acid was obtained. The above compound was prepared as 3- as described in Reference Example 13.
(3-chlorobenzoyl)propionic acid, converted to hydroxysuccinimide ester, Reference Example 14
1-[3-(3-chlorobenzoyl)propionyl]-L-proline coupled with L-proline was produced as described above. The above compound was reacted with bromine in acetic acid as described in Reference Example 18 to produce 1-[3-bromo-3-(3-chlorobenzoyl)propionyl]-L-proline.
The above compound in a mixture of ethanol-water (1:1) was reacted with potassium thioacetate as in Example 2 to give the title product as a glass. Example 14 1-[3-acetylthio-3-(4-t-butylbenzoyl)propionyl]-L-proline 17.0 g of pt-butylbenzene and succinic acid in 340 ml of 1,1,2,2-tetrachloroethane To a stirred mixture of 13.0 g of anhydride was added 36 g of aluminum chloride. This mixture was stirred at room temperature for 3 hours. The mixture was poured into 170 ml of ice-cold 6N hydrochloric acid. The mixture was evaporated overnight at room temperature and the remaining slush was stirred with boiling water, cooled and filtered. The solids were dissolved in 1.55 g of boiling water containing 20 g of sodium carbonate. The hot mixture was filtered and the liquid was acidified with 6N hydrochloric acid. Cooling and filtration gave a tan solid, which was recrystallized from ethanol-water to give 28 g of product, melting point 85-89°C.
I got it. Recrystallized from benzene-petroleum ether,
3-(4-t) as pale yellow crystals with a melting point of 119-121°C.
-Butylbenzoyl)propionic acid (17.0 g) was obtained. The above compound was prepared as 3-
(4-t-butylbenzoyl) propionic acid hydroxysuccinimide ester, which was coupled with L-proline to 1-[3-(4
-t-butylbenzoyl)propionyl]-L-
Got proline. The above compound was reacted with bromine in acetic acid as described in Reference Example 18, and 1-[3-bromo-3-(4
-t-butylbenzoyl)propionyl]-L-
Got proline. The above compound in a mixture of ethanol-water (1:1) was reacted with potassium thioacetate as in Example 2 to give the title product as a glass. Example 15 1-[3-acetylthio-3-(3-trifluoromethylbenzoyl)propionyl]-L-proline α-[3-trifluoromethyl)phenyl]-4 in 200 ml of tetrahydrofuran stirred at room temperature
- To a solution of 5.0 g of morpholine acetonitrile were added 30 drops of a 30% solution of potassium hydroxide in ethanol. After 1 hour, 30 drops of 30% potassium hydroxide in ethanol were added and 10 ml of ethyl acrylate was added. The mixture was stirred for 2 hours and the solvent was removed under vacuum. Toluene was added several times and the solvent was removed. The residue was stirred with ether, filtered, the solvent was evaporated and the ethyl γ-cyano-γ-
[3-(trifluoromethyl)phenyl]-4-morpholine butanoate (5.6 g) was obtained. The oil was heated with 70% glacial acetic acid for 2 hours and the solvent was removed. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (Na ₂ SO ₄ ) and the solvent was removed to give an oil. A mixture of this oil and 300 ml of 6N hydrochloric acid was refluxed for 5 hours, cooled and extracted with dichloromethane. The organic layer was extracted with sodium bicarbonate. The aqueous layer was made acidic with concentrated hydrochloric acid and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and the solvent was removed. The residue was crystallized from hexane, melting point 80-82 °C.
3-(3-trifluoromethylbenzoyl)propionic acid was obtained as crystals. 3-(3-trifluoromethylbenzoyl)propionic acid, hydroxysuccinimide ester was produced as described in Reference Example 13.
It was coupled with L-proline as in . 1-[3-(3-trifluoromethylbenzoyl)propionyl]-L-proline in acetic acid,
By reacting with bromine as in Reference Example 18, 1-
[3-bromo-3-(3-trifluoromethylbenzoyl)propionyl]-L-proline was obtained.
The above compound was reacted with potassium thioacetate in ethanol-water (1:1) as in Example 2 to give the title product as a glass. Example 16 1-[3-acetylthio-3-(3,4-dichlorobenzoyl)propionyl]-L-proline 122 ml of morpholine in 150 ml of tetrahydrofuran
and 124 g of p-toluenesulfonic acid,
106.3 g of 3,4-dichlorobenzaldehyde in 50 ml of tetrahydrofuran were added. This mixture was heated on a steam bath for 2 hours. Add 30% water to this mixture
A slurry of 45 g potassium cyanide in ml was added.
The mixture was refluxed for 2 hours and the solvent was removed under vacuum. Sodium bisulfite solution was added to the residue and the mixture was extracted with dichloromethane. The extract was washed with sodium bisulfite solution and dried over magnesium sulfate. The solvent was removed under vacuum. Dissolve the residue in benzene and dilute with petroleum ether to obtain 122 g of α-(3,4-dichlorophenyl)-4-morpholine acetonitrile as crystals with a melting point of 59-60°C.
I got it. The above compound (11.6g) was added to tetrahydrofuran.
Dissolved in 125 ml and added 60 drops of a 30% solution of potassium hydroxide in ethanol. To this mixture was added 6.8 ml of ethyl acrylate in 50 ml of tetrahydrofuran.
was added dropwise over 10 minutes. After 1.5 hours at room temperature,
The solvent was removed under vacuum. Toluene was added and the solvent was removed. A petroleum ether-ether mixture was added and the mixture was filtered and concentrated to give 12.9 g of a yellow oil. This oil was heated with 70% acetic acid on a steam bath for 2 hours. Remove the solvent and add ethyl 3
-(3,4-dichlorobenzoyl)propionate was obtained. The above compound was heated with 6N hydrochloric acid, and 3-
(3,4-dichlorobenzoyl)propionic acid was obtained. As described in Reference Example 13, 3-(3,4
-dichlorobenzoyl)propionic acid, hydroxysuccinimide ester was prepared and coupled with L-proline as in Reference Example 14. 1-[3-(3,4-dichlorobenzoyl)propionyl]-L-proline in acetic acid is reacted with bromine as in Reference Example 18 to give 1-
[3-Bromo-3-(3,4-dichlorobenzoyl)propionyl]-L-proline was obtained. The above compound was reacted with potassium thioacetate in ethanol-water (1:1) as in Example 2 to give the title product as a glass. Example 17 1-[3-acetylthio-3-(4-chloro-3
-Trifluoromethylbenzoyl)propionyl]-L-proline 48.9 g of a sample of 5-amino-2-chlorobenzotrifluoride was treated with 4- Conversion to chloro-3-trifluoromethylbenzaldehyde yielded 13.9 g of oil. The above compound (13.9g) was added to tetrahydrofuran.
Added to a mixture of 14.3 g p-toluenesulfonic acid and 13.0 g morpholine in 150 ml. This mixture was refluxed for 3 hours and potassium cyanide was dissolved in 25 ml of water.
Added 4.9g. This mixture was refluxed for 18 hours,
The solvent was removed under vacuum. The residue was diluted with water and extracted with dichloromethane. The extract was washed with saturated sodium bisulfite solution and saturated aqueous salt solution and passed through a column of hydrous magnesium silicate. The solution was concentrated in vacuo and the residue was crystallized from dichloromethane-hexane to give α-
(4-chloro-3-trifluoromethylphenyl)
14 g of -4-morpholine acetonitrile was obtained. The above compound (14
g) 30% potassium hydroxide solution in methanol to 1
Added ml. Methyl acrylate 10 in this mixture
ml was added and the mixture was left at room temperature overnight. The solvent was removed under vacuum and the residue was stripped with toluene several times. The residue was dissolved in dichloromethane and passed through a column of hydrous magnesium silicate. The liquid was concentrated to obtain an oil. This oil was heated with 70% acetic acid on a steam bath, hydrolyzed with 6N hydrochloric acid as described in Example 15, and 3-(4-chloro-3-trifluorochloride) as described in Reference Example 13. Methylbenzoyl)propionic acid was obtained. The above compound was prepared as described in Reference Example 14,
3-(4-chloro-3-trifluoromethylbenzoyl)propionic acid, converted to hydroxysuccinimide ester and coupled to L-proline. 1-[3-(4-chloro-3-trifluoromethylbenzoyl)propionyl]-
L-proline was brominated as in Reference Example 18 and the product was reacted with potassium thioacetate in ethanol-water (1:1) as in Example 2 to give the title product as a glass. I got something. Example 18 1-[3-acetylthio-3-(3-fluoro-
4-methoxybenzoyl)propionyl]-L
-proline 3-fluoro-4 as described in Example 16
- Conversion of methoxybenzaldehyde to 3-(3-fluoro-4-methoxybenzoyl)propionic acid, melting point 169-171°C. As described in Reference Example 13, the above compound was added to 3
-(3-fluoro-4-methoxybenzoyl)propionic acid, was converted to hydroxysuccinimide ester and coupled with L-proline as in Reference Example 14. 1- with a melting point of 180-182℃
[3-(3-fluoro-4-methoxybenzoyl)
[propionyl]-L-proline was brominated as in Reference Example 18 and the product was reacted with potassium thioacetate in ethanol-water as in Example 2 to give the title product as a glass. Ta. Example 19 1-[3-acetylthio-3-(3-fluorobenzoyl)-2-(S)-methylpropionyl]-
L-Proline A solution of 6.21 g of proline and 9.07 g of sodium bicarbonate in 220 ml of water contains 1-proline in 220 ml of ethanol.
[3-Bromo-3-(3-fluorobenzoyl)-
A slurry of 2-methylpropionyl]-L-proline was added. This mixture was stirred at room temperature for 18 hours,
And it passed. The liquid was concentrated under vacuum to 1/2 volume, cooled in an ice bath, filtered and acidified with concentrated hydrochloric acid (pH approximately 4). The mixture was extracted with dichloromethane and the extract was washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to obtain 11.8 g of white rubber. This gum was dissolved in 1 ml of ethyl acetate, 10 ml of hexane and 0.2 ml of acetic acid. After cooling and filtering, 3.18 g of white crystals with a melting point of 176-180°C were obtained (referred to as isomer A). Solvent: ethyl acetate-hexane-acetic acid (25:25:1)
Chromatographed twice on silica gel using 3.2 g of rubber (referred to as isomer B). Isomer A was reacted with N,N-dicyclohexylamine in acetone to give the dicyclohexylamine salt of isomer A with a melting point of 164-166°C. Isomer B was reacted with N,N-dicyclohexylamine in acetone to give the dicyclohexylamine salt of isomer B with a melting point of 98-100°C. A 6.8 g sample of isomer B as the dicyclohexylamine salt was dissolved in 50 ml of water, cooled and acidified with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate and
The extract was concentrated to obtain 4.3 g of rubber. This rubber was dissolved in 20 ml of methanol and 20 ml of water, and 4 ml of 1N sodium hydroxide was added. Add 50g of this solution to IR-120 resin (pre-washed with 1N hydrochloric acid and then water).
passed through. The fractions containing solids were combined and the solids were partitioned between dichloromethane and water. The dichloromethane layer was washed with water, saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 3.3 g of rubber, which was crystallized from hexane and a trace of ether, melting point 100-103°C.
3.07 g of white crystals were obtained. Recrystallization from ethyl acetate-hexane gave 1.5 g of crystals with a melting point of 107-108°C (pure isomer B). 4.0 g of isomer A (melting point 184-186°C) in 90 ml of acetic acid
To the solution was added 2.08 g of bromine in 10 ml of acetic acid. After 18 hours at room temperature, the solution was concentrated to 1/3 volume and
Pour over ice and water. This mixture was extracted with dichloromethane, the extract was concentrated to dryness, and a glassy substance was obtained with 1-[3-bromo-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline.
4.78 g were obtained (bromo derivative according to isomer A). 0.82 g of potassium thioacetate to a solution of 2.32 g of the bromo derivative according to isomer A above in 25 ml of ethanol.
was added and the mixture was stirred at room temperature for 42 hours. The solvent was removed and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed to obtain 2.06 g of solid. Purified by chromatography on silica gel using ethyl acetate-hexane-acetic acid (25:25:1) solvent to give a solid
0.52g was obtained. Crystallization from ethyl acetate-hexane gave 0.3 g of the product as crystals with a melting point of 113-115°C. Example 20

[Table] 1-[3-(m-fluorobenzoyl)-2-acetylthiopropionyl]-L-proline, lactose and corn starch (for mixing) were blended together. Corn starch (for paste) and water
It was suspended in 600 ml and heated with stirring to form a paste. This paste was used to granulate the mixed powder. More water was used as needed. Pass the wet granules through a No. 8 hand sieve.
Dry at 120㎓. The dried granules were passed through a No. 16 sieve. The mixture was lubricated with 1% magnesium stearate and compressed into tablets in a suitable tablet machine. Example 21 Manufacture of oral suspension Amount of ingredients 1-[3-(3,4-dimethoxybenzoyl)-
2-benzoylthiopropionyl]-L-proline 500 mg Sorbitol solution (70% NF) 40 ml Sodium benzoate 150 mg Satucharin 10 mg Red dye 10 mg Thierry flavor additive 50 mg Distilled water, enough to make 100 ml Sorbitol solution in distilled water 40 ml In addition to this, 1-[3-(3,4-dimethoxybenzoyl)-2
-benzoylthiopropionyl]-L-proline was suspended. Saccharin, sodium benzoate, flavor additives and dyes were added and dissolved. The volume was adjusted to 100ml with distilled water. Each ml of this syrup contains 5 mg of 1-[3-(3,4-dimethoxybenzoyl)-2-benzoylthiopropionyl]-L-proline. Example 22 Preparation of parenteral solution 700 ml of propylene glycol and 200 ml of water for injection
1-[3-(4-trifluoromethylbenzoyl)-2-mercaptopropionyl]-L-proline, sodium salt 20.0 ml of solution with stirring.
g was suspended. After suspension, adjust the pH value to 5.5 with hydrochloric acid.
The volume was made up to 100ml with water for injection.
Sterilize this preparation and add 2.0 mL each into 5.0 ml ampoules.
ml (equivalent to 40 mg of drug) and sealed under nitrogen. Example 23 1-[3-acetylthio-5-(4-methoxy-
1-naphthoyl)propionyl]-L-proline 3-(4-methoxy-1-naphthoyl)propionic acid was coupled with L-proline as described in Reference Examples 13 and 14 to form 1-[3-(4- Methoxy-1-naphthoyl)propionyl]-L-proline was obtained. The above compound was reacted with bromine in acetic acid as in Reference Example 20 and the product was reacted with potassium thioacetate in ethanol to give the title product as a glass. Example 24 1-[3-acetylthio-3-(3,4,5-trimethoxybenzoyl)propionyl]-L-
Proline As described in Example 16, 3,4,5-trimethoxybenzaldehyde was converted to 3-(3,4,5-trimethoxybenzoyl)propionic acid.
This compound was converted to the hydroxysuccinimide ester as described in Reference Example 13 and coupled with L-proline as described in Reference Example 14. 1-[3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline in Reference Example 18
1 by reacting with bromine in acetic acid as described in
-[3-bromo-3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline was obtained. This compound was reacted with potassium thioacetate in ethanolic water as in Example 2 to give the title product as a glass. Example 25 1-[3-acetylthio-3-(4-biphenylylcarbonyl)propionyl]-L-proline 3-(biphenylylcarbonyl)propionic acid
50.0g, N-hydroxysuccinimide 23.0g,
N,N-dicyclohexylcarbodiimide 41.3g
and dioxane (400 ml) was stirred at room temperature.
The mixture was filtered and the liquid was concentrated to give an oil, which was crystallized from chloroform-hexane to give 38 g of crystals with a melting point of 160-163°C. Recrystallized from chloroform-ethanol, melting point 163-164
32 g of cream-colored crystals were obtained. Above compound (20g), L-proline 9.9g, sodium bicarbonate
A mixture of 14.3 g, 170 ml of water and 200 ml of ethanol was stirred at room temperature and concentrated to 1/2 volume. The mixture was acidified with concentrated HCl and filtered to give 24.0 g of an off-white solid. This solid was dissolved in dichloromethane and extracted with aqueous sodium bicarbonate. The aqueous phase was acidified with concentrated HCl, filtered and the solid was washed with water to give 10 g of off-white crystals with a melting point of 128-131°C. Recrystallization from CH ₂ Cl ₂ -hexane gave white crystals with a melting point of 131-133°C. The above compound (7.0 g) was brominated as described in Reference Example 18, and 1-[3-bromo-3
-(4-biphenylylcarbonyl)propionyl]
-L-proline (2.0 g) was obtained. The above compound was reacted with sodium thioacetate in 5 ml of ethanol to give the title product as white crystals with a melting point of 173-176°C. Example 26 1-{3-acetylthio-3-[4-(4-chlorophenoxy)benzoyl]propionyl}-
L-proline 3-(4-fluorobenzoyl)propionic acid
9.8g, p-chlorophenol 6.5g, potassium carbonate 13.8g and N,N-dimethylacetamide 120ml
The mixture was heated to 135° C. for 16 hours under argon. The mixture was cooled and poured into 1 part water. The mixture was filtered through Celite and the liquid was acidified with concentrated hydrochloric acid. This mixture was diluted to 2, filtered,
The solid content was recrystallized from ethanol-water (1:1) to obtain 12.2 g of colorless needle-like crystals with a melting point of 148-150°C. The above compound was prepared as described in Reference Example 13.
-[4-(4-chlorophenoxy)benzoyl]propionic acid hydroxysuccinimide ester is converted to hydroxysuccinimide ester, which is coupled to L-proline to produce 1-{3-[4-(chlorophenoxy)benzoyl]propionyl} -L-proline was obtained.
The above compound was reacted with bromine in acetic acid as described in Reference Example 18 to give 1-{3-bromo-3-[4-
(4-chlorophenoxy)benzoyl]propionyl}-L-proline was obtained. The above compound in an ethanol-water mixture was reacted with potassium thioacetate as in Example 2 to give the title product as a glass. Example 27 1-[3-acetylthio-3-(4-chlorobenzoyl)-2-(S)-methylpropionyl]-L
-Proline 3-(4-chlorobenzoyl)-2-methylpropionic acid in 150 ml of dioxane (Reference Example 35) 14.3
A solution of 7.26 g of N-hydroxysuccinimide and 13 g of dicyclohexylcarbodiimide was stirred overnight at room temperature and then filtered. Concentrate the solution under reduced pressure to remove 7.25 g of L-proline and sodium bicarbonate.
It was taken into 100 ml of water containing 10.58 g. The mixture was stirred at 25-35°C overnight and passed through Celite. The liquid was concentrated to remove ethanol. Concentrated hydrochloric acid was added and the mixture was extracted several times with dichloromethane. The extract was washed with water and dried (Na ₂ SO ₄ ). Evaporation of the solvent gave an amber colored gum which was dissolved in ethyl acetate. Hexane was added and white crystals separated. Recrystallization from ethyl acetate gave colorless needle-like crystals with a melting point of 177.5-179.5°C, which was designated as isomer A. The above compound was brominated as in Reference Example 18 and the product was brominated as in Example 2.
Reaction with potassium thioacetate in water gave the title product as a glass. Example 28 1-[3-acetylthio-3-(3-fluorobenzoyl)propionyl]-L-proline 3-(3-fluorobenzoyl)propionic acid was produced from 3-fluorobenzaldehyde as in Reference Example 35. , yellow needles with a melting point of 97-99°C were obtained. Above compound (9.8g) in 80ml dioxane
and 5.75 g of N-hydroxysuccinimide were added to a solution of 10.3 g of N,N-dicyclohexylcarbodiimide in 40 ml of dioxane. The mixture was stirred at room temperature for 18 hours, filtered and the solvent removed under vacuum. Disintegrate the residue with hexane,
13.7 g of off-white crystals with a melting point of 115 DEG -122 DEG C. were obtained. Recrystallized from CH ₂ Cl ₂ -hexane, melting point 130
11 g of white crystals of ~133°C were obtained. ethanol 210ml
The above compound (11g) as a slurry in water
Added to a solution of 9.24 g sodium bicarbonate and 6.33 g L-proline in 210 ml. After stirring at room temperature for 18 h, the solution was concentrated to 1/2 volume under vacuum and
Cool and acidify with concentrated hydrochloric acid. The mixture was extracted with dichloromethane and the extracts were washed with water and brine and dried (MgSO ₄ ). The solvent was removed under vacuum to obtain 10.8 g of rubber. When crushed with hexane containing a trace amount of ether, white crystals with a melting point of 84-89℃ are produced.
8.6g was obtained. Example of the above compound (6.42g)
Bromination as in 20 gave 1-[3-(fluorobenzoyl)propionyl]-L-proline (7.9 g) as a white glass. The above compound (3.72 g) was reacted with 1.48 g of potassium thioacetate in 35 ml of ethanol for 18 hours, yielding 3.4 g of rubber.
This rubber was mixed with ethyl acetate-hexane as a solvent.
Chromatography on silica gel using acetic acid (75:25:2) gave 2.6 g of the title product as a tan glass. Example 29 1-[3-acetylthio-3-(2-naphthoyl)propionyl]-L-proline To a solution of 46.8 g of 2-naphthaldehyde and 57.5 g of p-toluenesulfonic acid in 300 ml of tetrahydrofuran was added 52.5 ml of morpholine. The mixture was refluxed for 1 hour, cooled and a slurry of 19.5 g of potassium cyanide in 15 ml of water was added. The mixture was stirred and refluxed for 1 hour, cooled and poured into 600 ml of 10% potassium carbonate solution. The mixture was extracted with dichloromethane and the extract was washed with water, sodium bisulfite solution and brine solution. The solvent was removed under vacuum and the residue was triturated with hexane to give 61 g of a yellow solid.
I got it. The above compound (61 g) in 400 ml of tetrahydrofuran was mixed with 15 ml of a 30% KOH solution in ethanol.
added to. Add tetrahydrofuran to this mixture.
24ml of acrylonitrile in 150ml was added. After stirring for 24 hours, the solvent was removed. _Residue in _CH2Cl2
The solution was washed with water and the solution was dried (MgSO ₄ ). Remove the solvent under vacuum and leave a dark colored rubber.
Obtained 65g. Add 230 g of acetic acid to the above compound (65 g)
ml and 38 ml of water were added. The mixture was refluxed for 1 hour and the solvent was removed. Dissolve the residue _{in CH2Cl2} ,
Washed with water and brine and dried (MgSO ₄ ). The solvent was removed to obtain 60 g of dark colored rubber. A mixture of the above compound (60 g) and 200 ml of 6N hydrochloric acid was refluxed for 1.5 hours. The mixture was cooled, filtered, and the solid was washed with water, yielding 49.6 g of 3-(2-naphthoyl)propionic acid, melting point 147-155°C. By recrystallization,
Crystals with a melting point of 168-170°C were obtained. Add dioxane to a slurry of the above compound (9.12 g) in 60 ml of dioxane.
8.24 g of N,N-dicyclohexylcarbodiimide and 4.6 g of N-hydroxysuccinimide in 40 ml
g solution was added. The mixture was stirred at room temperature for 18 hours and filtered. The liquid was concentrated under vacuum. The residue was triturated with hexane-ether to obtain 13.0 g of a solid with a melting point of 153-160°C. This solid
Dissolved in _CH2Cl2 and added hexane ( _160ml ).
Filtration gave 9.8 g of white crystals with a melting point of 162-165°C. The above compound (9.8 g) as a slurry in 160 ml of ethanol was mixed with 5.18 g of L-proline in 160 ml of water.
and 7.58 g of NaCO ₃ . The mixture was stirred at room temperature for 18 hours and the solution was concentrated to 1/2 volume. The solution was extracted with ethyl acetate, cooled and acidified with concentrated HCl. The mixture was extracted with CH ₂ Cl ₂ and the extracts were washed with H ₂ O and brine and dried (MgSO ₄ ). The solvent was removed and 9.5 g of rubber was obtained, which was chromatographed on silica gel using ethyl acetate-hexane-acetic acid solvent.
5.5 g of crystals with a melting point of 115-118°C were obtained. The above compound, 3-(2-naphthoyl)propionyl-L-
Proline (3.24 g) was brominated as in Reference Example 18 and 1-[3-bromo-
3-(2-naphthoyl)propionyl]-L-proline (2.55 g) was obtained. The above compound (2.55 g) in ethanol was reacted with sodium thioacetate for 18 hours to give the title product as a white glass. Example 30 1-[3-acetylthio-3-(4-chlorobenzoyl)propionyl]-L-proline 1-[3-(4-chlorobenzoyl)propionyl]-L-proline in 300 ml of acetic acid (Reference Example 16)
To 34 g of solution was added 17.5 g of bromine. The mixture was stirred for 24 hours and the solvent was removed under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous layer was separated and poured onto a mixture of ice and concentrated hydrochloric acid. The mixture was extracted with dichloromethane and the extract was dried (Na ₂ SO ₄ ). The solvent was removed to obtain 44 g of a yellow glass. ethanol15
0.54g sodium methylate and thioacetic acid in ml
Add 2.0 g of the above compound to 1.14 g of the mixture,
This mixture was stirred for 2 hours. The mixture was poured onto crushed ice and extracted with dichloromethane. The extract was dried (Na ₂ SO ₄ ) and the solvent removed under vacuum to give 1.5 g of the title product as a yellow glass. Example 31 1-[3-benzoylthio-3-(3-fluorobenzoyl)propionyl]-L-proline 2.44 g of sodium hydride (60% oil dispersion) was washed with hexane. Add ethanol to this hydride.
1.6 g of thiobenzoic acid in 25 ml was added. To this mixture was added 3.7 g of 1-[3-bromo-3-(3-fluorobenzoyl)propionyl]-L-proline, and the mixture was stirred for 18 hours. The solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. Separate the organic layer and wash with water and brine;
Dried (MgSO ₄ ). Remove the solvent and remove 4.5 g of rubber.
I got it. This gum was chromatographed on silica gel using ethyl acetate-hexane-acetic acid as solvent to give 2.5 g of glassy product. Example 32 1-[3-(acetylthio)-3-(2-naphthoyl)propionyl]-L-proline To a solution of 46.8 g of 2-naphthaldehyde and 57.5 g of p-toluenesulfonic acid in 300 ml of tetrahydrofuran is added 52.5 ml of morpholine. The mixture was then refluxed for 1 hour, cooled and a slurry of 19.5 g of potassium cyanide in 15 ml of water was added. 1 of this mixture
Reflux for an hour, cool, 10% sodium carbonate 600
Pour into ml. This mixture was extracted with dichloromethane, and the extract was mixed with water and 10% sodium bisulfite 600g.
ml and brine. The extract was dried (MgSO ₄ ) and the solvent was removed. The residue was crushed with hexane to obtain 61.7 g of α-(2-naphthyl)-4-morpholine acetonitrile as a yellow solid. To the above solid (61.7 g) in 400 ml of tetrahydrofuran was added 15 ml of 30% KOH in ethanol. To this mixture was added 24 ml of acrylonitrile in 150 ml of tetrahydrofuran (exotherm 20°C → 38°C).
℃). The mixture was stirred at room temperature for 18 hours and the solvent was removed. The residue was dissolved in dichloromethane and washed with water. The solvent was removed to obtain 65 g of dark colored rubber. Above compound (65g), acetic acid 230ml and water 38ml
The mixture was refluxed for 1.5 hours. remove the solvent,
The residue was dissolved _{in CH2Cl2} . The extract was washed with water, brine, dried (MgSO ₄ ), the solvent removed, and the rubber
Obtained 60g. A mixture of the above compound and 200 ml of 6N HCl was refluxed for 1.5 hours. The mixture was cooled and filtered to give crude 3-(2-naphthoyl)propionic acid as a tan solid with a melting point of 147-155°C.
49.6g was obtained. This solid was extracted with 500ml of hot ethyl acetate. 24.3 g of crystals were obtained as a second product from the ethyl acetate extract. Recrystallized from ethyl acetate (twice) to give yellow-brown crystals with a melting point of 168-170°C10.5
I got g. To a slurry of 9.12 g of 3-(2-naphthoyl)propionic acid and 4.5 g of N-hydroxysuccinimide was added 8.24 g of N,N-dicyclohexylcarbodiimide in 40 ml of dioxane. The mixture was stirred at room temperature for 18 hours and filtered. The liquid was concentrated to dryness and the residue was triturated with hexane-ether to obtain 13.0 g of solid. This solid was dissolved in 150 ml of dichloromethane and hexane (160 ml) was added. 9.8 g of N-hydroxysuccinimide of 3-(2-naphthoyl)propionic acid having a melting point of 162-165°C was obtained. The above compound (9.77 g) as a slurry in 160 ml of ethanol was mixed with 5.18 g of L-proline in 160 ml of water.
and 7.58 g of sodium bicarbonate. The mixture was stirred at room temperature for 18 hours and the mixture was concentrated to 1/2 volume. The mixture was extracted with ethyl acetate, the mixture was cooled in an ice bath and acidified with concentrated hydrochloric acid.
The acidified mixture was extracted with dichloromethane and the extract was washed with water, brine and dried (MgSO ₄ ).
The solution was removed to obtain 9.5 g of 1-[3-(2-naphthoyl)propionyl]-L-proline as a rubber. This rubber was chromatographed on an 18 inch by 1.5 inch column of silica gel (60-200 mesh) using ethyl acetate-hexane-acetic acid (1:1:0.4) as the solvent, yielding 5.5 g of crystals. This product was recrystallized from dichloromethane-hexane to obtain 4.9 g of white crystals with a melting point of 116-118°C. To 3.24 g of the above compound in 35 ml acetic acid was added 1.6 g bromine in 10 ml acetic acid. The mixture was stirred at room temperature for 18 hours, concentrated under vacuum to 1/2 volume, and poured onto ice and water. The mixture was extracted with dichloromethane and the extract was washed with water, brine and dried (MgSO ₄ ).
The solvent was removed under vacuum to obtain 4.0 g of rubber. This gum was chromatographed on silica gel using ethyl acetate-hexane-acetic acid (1:1:0.4) as solvent. Concentrate the column fraction to obtain 1-[3-
Bromo-3-(2-naphthoyl)propionyl]-
2.6 g of L-proline was obtained. To 30 ml of ethanol cooled in an ice bath were added 380 mg of sodium hydride (60% dispersion in oil) and 0.67 ml of thiol acetic acid. After stirring for 30 minutes, 1-
2.55 g of [3-bromo-3-(2-naphthoyl)propionyl]-L-proline was added and the mixture was stirred for 18 hours. The solvent was removed under vacuum. The residue was chromatographed on a silica gel column using ethyl acetate-hexane-acetic acid (7.5:2.5:0.2) as solvent to give the title product as a white glass; [α] _D -36(c , 0.96 ethanol). Example 33 [S-(R ^* ,S ^* )]-1-(3-acetylthio-
3-benzoyl-2-methylpropionyl)-
L-proline and [S-(R ^* ,R ^* )]-1-(3
-acetylthio-3-benzoyl-2-methylpropionyl)-L-proline (S)-1-(3-benzoyl-2-methylpropionyl)-L-proline in 400 ml of acetic acid as described in Reference Example 10. , melting point 216-219°C (isomer A) was brominated with 12.5 g of bromine by adding hydrogen bromide gas as a catalyst. After 2 hours, the solvent was concentrated to 1/3 volume and poured onto ice and water. This mixture was extracted with dichloromethane, and the extract was mixed with water and
Washed with brine and dried (MgSO ₄ ). The extract was concentrated and a white glassy substance was obtained [[S-R ^* ,
S ^* )]-1-(3-bromo-3-benzoyl-2-
methylpropionyl)-L-proline and [S-
(R ^* ,R ^* )]-1-(3-bromo-3-benzoyl-2-methylpropionyl)-L-proline mixture]. As described in Example 1, 23.9 g of the above compound (diastereomeric mixture) was dissolved in acetonitrile.
2.2 (prepared from 9.0 ml of thiol acetic acid and 2.92 g of NaH (60% oil dispersion)). Mix this mixture at room temperature for 18
After stirring for an hour, 90 ml of acetic acid was added. The solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO ₄ ) and the solvent removed under vacuum, yielding 23 g of rubber. The gum was dissolved in hot ethyl acetate and the solution was cooled and filtered (2.7 g solids). 70 ml of hexane was added to the liquid and the solvent was decanted from the gum. Concentrate the decanted solution and make a rubber
19.1 g was obtained, which was chromatographed on a 25 inch by 2 inch column of silica gel (60-200 mesh) using ethyl acetate-hexane-acetic acid (5:5:0.2). The first fraction gave 4.53 g of solid, which was crystallized from ethyl acetate-hexane to give 3.14 g of white crystals with a melting point of 123 DEG -125 DEG C. Recrystallized from acetone-hexane to give [S-(R ^* ,S ^* )]-1-(3-acetylthio-3-benzoyl-2-methylpropionyl).
-L-proline white crystals with a melting point of 160-161℃ 3.0
g; [α] ²³ ° _D +275±1 (c, 0.956 ethanol). The fractions from the column, which were found to be a mixture of diastereomers by thin layer chromatography, were rechromatographed. 1
The latter fractions showing the components were combined to form a white glassy substance, [S-(R ^* ,R ^* )]-1-(3-
4.1 g of acetylthio-3-benzoyl-2-methylpropionyl)-L-proline was obtained; [α] ²³ ° _D −
91°±1 (c, 1.08 ethanol). Example 34 [S-(R ^* ,S ^* )]-1-[3-acetylthio-
3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline and [S-(R ^* ,
R ^* )]-1-[3-acetylthio-3-(3-
Fluorobenzoyl)-2-methylpropionyl]-L-proline (S)-1-[3-
(3-fluorobenzoyl)-2-methylpropionyl]-L-proline (isomer A; melting point 182-185
℃) was brominated to give the promo derivative of isomer A [S-(R ^* ,S ^* )]-1-[3-bromo-3-(3-
fluorobenzoyl)-2-methylpropionyl]
-L-proline and [S-(R ^* ,R ^* )]-1-[3
-bromo-3-(3-fluorobenzoyl)-2-
A mixture of methylpropionyl]-L-proline was obtained. This mixture was prepared in a preparative manner using hexane-ethyl acetate-acetic acid (75:25:2) as a solvent.
Chromatography on a LC/500 column yielded 1.68 g of pure diastereomer designated as X and 0.74 g of pure diastereomer designated as Y. The diastereomer designated X with potassium thioacetate in ethanol
After reacting for 1 day, the title product (mixture of diastereomers) was obtained. The diastereomer designated Y was reacted with potassium thioacetate in ethanol for 4 days to give the title product (mixture of diastereomers). This mixture was chromatographed on a silica gel column using ethyl acetate-hexane-acetic acid (5:5:0.2) and [S-
(R ^* ,S ^* )]-1-[3-acetylthio-3-(3-
fluorobenzoyl)-2-methylpropionyl]
-L-proline, melting point 158°-159°C; [α] _D +252° ± 3 (c, 0.318 ethanol) and as a white glass [S-R ^* ,R ^* )]-1-[3-acetylthio- 3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline, [α] _D −147°±1
(c, 0.834 ethanol) was obtained. Example 35 [R-(R ^* ,S ^* )]-1-[3-acetylthio-
3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline and [R-(R ^* ,
R ^* )]-1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]
-L-proline (R)-1-[3-
(3-fluorobenzoyl)-2-methylpropionyl]-L-proline (isomer B; melting point 107-108
°C) was separated from the (S) diastereomer (isomer A). The above compound (isomer B;
2.48 g of bromine in 25 ml of acetic acid was added to 4.76 g of bromine (melting point 107-108 DEG C.). This mixture was stirred at room temperature for 18 hours. The mixture was filtered and the solids were washed with petroleum ether (boiling point 30-60°C) to give 3.26 white crystals with a melting point of 128-135°C (decomposition). More solid from mother liquor
2.9g was obtained. This solid is [R-(R ^* ,S ^* )]-1
-[3-bromo-3-(3-fluorobenzoyl)
-2-methylpropionyl]-L-proline and [R-(R ^* ,R ^* )]-1-[3-bromo-3-(3-
fluorobenzoyl)-2-methylpropionyl]
-L-proline. A sample (5.7 g) of the above mixture was heated at room temperature for 5 minutes.
Reacted with sodium thioacetate (prepared from 1.8 ml of thiol acetic acid and 0.885 g of NaH (60% dispersion in oil)) in 150 ml of acetonitrile.
15 ml of acetic acid were added to this mixture and the solvent was removed under vacuum. The residue was partitioned between dichloromethane and water and the organic layer was separated, washed with water, brine and dried (MgSO ₄ ). The solvent was removed to obtain 5.9 g of rubber.
This rubber was mixed with ethyl acetate-hexane as a solvent.
Chromatographed on silica gel with acetic acid (5:5:0.2) to give [R-(R ^* R ^* )]-1-[3-acetylthio-3-
(3-fluorobenzoyl)-2-methylpropionyl]-L-proline 1.5 g, [α] _D +18° ± 1 (c,
1.075 ethanol) and [R-(R ^* ,S ^* )]-1-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline as white crystals with a melting point of 86-98°C. 0.45g was obtained. Recrystallization from dichloromethane-petroleum ether (boiling point 30-60°C) gave white crystals; mp 91°-93°C.
[α] _D −325±2 (c, 0.649 ethanol). Example 36 [S-(R ^* ,S ^* )]-1-[3-acetylthio-
3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline and [S-(R ^* ,
R ^* )]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-
L-Proline To a solution of 100 g of 4-bromobenzaldehyde in 400 ml of tetrahydrofuran was added 104 g of p-toluenesulfonic acid hydrate. A solution of 94.5 ml of morpholine in 100 ml of tetrahydrofuran was added dropwise to this solution. The mixture was refluxed for 1 hour, cooled and a slurry of 35.2 g of potassium cyanide in 27 ml of water was added. The mixture was refluxed for 18 hours, cooled and poured into 1 10% potassium carbonate. The mixture was extracted with dichloromethane and the extract was washed with water, 10% sodium bisulfite, brine and dried ( _MgSO4 ). The solvent was removed under vacuum and the residue was triturated with hexane and filtered to give 136.2 g of white crystals with a melting point of 88-90°C. To the above α-(4-bromophenyl)-4-morpholine acetonitrile (136.2 g) in 800 ml of tetrahydrofuran was added 25 ml of 30% potassium hydroxide in ethanol. To this stirred mixture was slowly added 42.5 ml of methacrylonitrile in 200 ml of tetrahydrofuran (exothermic,
17° to 34°C). This mixture was stirred at room temperature for 18 hours,
The solution was concentrated to 200ml. ether 100ml
was added, cooled and filtered to obtain 113.7 g of white crystals with a melting point of 170-175°C. Above compound, acetic acid 500ml
and 58 ml of water was refluxed for 1 hour and the solvent was removed. The residue was dissolved in dichloromethane, washed with water, brine and dried (MgSO ₄ ). The solvent was removed to obtain 83 g of 2-methyl-3-(4-bromobenzoyl)propionitrile having a melting point of 101° to 103°C.
A mixture of the above compound (83 g) and 400 ml of 6N HCl was refluxed for 18 hours. The mixture was cooled in an ice bath and filtered. The solid was washed with water and dissolved in 400 ml of dichloromethane. The dichloromethane was dried (MgSO ₄ ) and concentrated on a steam bath while adding hexanes. Cool and filter, melting point 124-125℃
72.0 g of white crystals of 3-(4-bromobenzoyl)-2-methylpropionic acid were obtained. The above compound (72g) was converted to N-hydroxysuccinimide ester having a melting point of 99-104°C as in Reference Example 7, and this activated ester (94.6g) was converted to L-hydroxysuccinimide ester as in Reference Example 8. proline
44.9g and 1-[3
70.7 g of -(4-bromobenzoyl)-2-methylpropionyl)-L-proline (mixture of diastereomers) was obtained. This gum was dissolved in hot ethyl acetate (200ml) and hexane (250ml) was added.
Cooling gave 19.3 g of a solid, which was recrystallized from ethyl acetate to give (S) with a melting point of 165-167°C.
-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline (isomer A)
10.3g was obtained. Further isomer A is obtained from the mother liquor,
This was purified by chromatography on silica gel. (R)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L- from the column
Proline (isomer B) was obtained. A mixture of 10.2 g of isomer A in 125 ml of acetic acid was added with bromine in 20 ml of acetic acid.
Added 4.43g. Anhydrous hydrogen bromide was added and the mixture was stirred for 3 hours. The mixture was concentrated to 1/3 volume and poured onto ice and water. The mixture was extracted with dichloromethane and the extract was washed with water, brine and dried (MgSO ₄ ). The solvent was removed under vacuum to obtain 12.7 g of a glass (mixture of diastereomers). 10.5 of the above glass in 150ml of acetonitrile
A mixture of sodium thioacetate [2.9 ml of thiol acetic acid and NaH (60
% oil dispersion) prepared from 1.4 g]. This mixture was stirred at room temperature for 18 hours,
30ml of acetic acid was added and the solvent was removed under vacuum. The residue was partitioned between dichloromethane and water. The dichloromethane layer was separated, washed with water, brine and dried (MgSO ₄ ). The solvent was removed and the residue was dissolved in ethyl acetate-hexane-acetic acid (5:5:0.2) as the solvent.
Chromatographed on a silica gel column using The first fractions containing mainly one component were combined and chromatographed on silica gel to give 5.1 g of solid. Crystallized from ethyl acetate-hexane as white crystals [S-(R ^* ,S ^* )]
3.5 g of -1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline was obtained; melting point 136° to 138°C; [α] _D +211°±
1 (c, 0.971 ethanol). By thin-layer chromatography, the subsequent fractions from the column chromatography containing one component were combined to form a white glassy substance [S-(R ^* ,R ^* )]-1-[3-acetylthio-3 1.2 g of -(4-bromobenzoyl)-2-methylpropionyl]-L-proline was obtained; [α] _D
−69±1 (c 0.983 ethanol). Example 37 1-[3-acetylthio-3-(2-naphthoyl)-2-(S)-methylpropionyl]-L-proline As in Example 12, 2-naphthaldehyde was
It was converted to -(2-naphthoyl)-2-methylpropionic acid and coupled to L-proline. 1
-[3-(2-naphthoyl)-2-methylpropionyl]-L-proline was separated into isomers A and B. Isomer A, (S)-1-[3-(2-naphthoyl)-2-methylpropionyl]-L-proline, is reacted with bromine in acetic acid and the product is prepared in Example 36.
Reaction with sodium thioacetate in acetonitrile gave the title product (mixture of diastereomers) as a glass. Example 38 1-[3-benzoyl-2-(S)-methyl-3
-(2-pyrimidinylthio)propionyl]-L
-Proline A sample of (S)-1-(3-benzoyl-2-methylpropionyl)-L-proline was reacted with bromine in acetic acid and 1-(3-bromo-3-benzoyl-2-methylpropionyl)- 1.84 g of L-proline (mixture of diastereomers) was obtained. A solution of the above compound in 20 ml of acetonitrile was mixed with a mixture of sodium salts of 2-thiopyrimidine (0.20 g of NaH (60% oil dispersion) and 2-thiopyrimidine in 30 ml of acetonitrile).
(prepared from 0.56 g of thiopyrimidine). The mixture was stirred for 18 hours and 0.4 ml of acetic acid was added. The mixture was filtered and the liquid was concentrated under vacuum. The residue was dissolved in dichloromethane, washed with water, brine and dried (MgSO ₄ ). The solvent was removed and the residue (2.0 g) was chromatographed on a column of silica gel using ethyl acetate-hexane-acetic acid (75:25:2) as the solvent to give [S-( R ^* ,S ^* )]-1-[3-benzoyl-2-methyl-3-(2-pyrimidinylthio)
Propionyl]-L-proline (after precipitation from ether-hexane) 0.32 g, [α] _D +233° ± 2 (c,
0.489 ethanol) and as a glassy substance [S-
(R ^* ,R ^* )]-1-[3-benzoyl-2-methyl-3-(-2-pyrimidinylthio)propionyl]
-L-proline was obtained. Example 39 1-[3-acetylthio-3-benzoyl-2
(S)-Phenylpropionyl]-L-proline 0.01 mol of a sample of 3-benzoyl-2-(phenyl)propionic acid was dissolved in tetrahydrofuran, and 0.01 mol of N,N-carbonyldiimidazole was added. After stirring at room temperature for 3 hours, 0.01 mol of L-proline t-butyl ester was added. After 24 hours, the solvent was removed and 1-[3-benzoyl-2-
(Phenyl)propionyl]-L-proline t-butyl ester was isolated. This compound was reacted with trifluoroacetic acid to remove the t-butyl group.
Separation of isomers A and B was carried out as described in Example 33. Reaction of the isomer with bromine in acetic acid and 1-[3-bromo-3-benzoyl-2-(phenyl)propionyl]-L- as in Example 33
Reaction of the proline isomer with sodium thioacetate in acetonitrile gave the title product.
The products of isomer A are separated by chromatography, [S-(R ^* , R ^* )] and [S-(R ^* , S ^* )]
-1-[3-acetylthio-3-benzoyl-2
-(phenyl)propionyl]-L-proline was obtained. Example 40 1-[3-acetylthio-3-(4-chlorobenzoyl)-2-methylpropionyl]-L-proline 14.3 g of 3-(4-chlorobenzoyl)-2-methylpropionic acid in 150 ml of dioxane and N - To a slurry of 7.26 g of hydroxysuccinimide, N,
13 g of N-dicyclohexylcarbodiimide was added. After stirring overnight, the mixture was filtered and the solids were washed with ether. The combined liquid and washing liquid were concentrated under vacuum to obtain 20.1 g of oil. This oil was added to a solution of 7.25 g L-proline and 10.58 g sodium bicarbonate in 200 ml 50% ethanol. The mixture was stirred overnight and passed through diatomaceous earth.
The solution was made acidic with concentrated hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried (MgSO ₄ ),
The solvent was removed under vacuum to give an amber colored rubber.
This rubber was dissolved in ethyl acetate-hexane and the mixture was allowed to stand for several days, with a melting point of 170-
3.23 g of crystals at 179°C were obtained. Recrystallization from ethyl acetate-hexane yielded 2.81 g of (S)-1-[3-(4-chlorobenzoyl)-2-methyllpropionyl]-L-proline as colorless needle-like crystals with a melting point of 177.5-179.5°C. Obtained. The above compound was dissolved in 50 ml of acetic acid and 1.27 g of bromine was added. The mixture was stirred overnight and the mixture was concentrated under vacuum and poured onto ice and water. The mixture was extracted with dichloromethane and the extract was washed with water and dried (MgSO ₄ ). The solvent was removed to obtain 3.15 g of white glass. Sodium methylate in 40ml methanol
To 0.454 g of solution was added 0.684 g of thiol acetic acid.
3.07 g of the above glass was added to this solution and the mixture was stirred for 3 days. Pour the mixture onto ice and water;
Extracted with dichloromethane. The extract was concentrated to obtain 2.85 g of product (diastereomer mixture) as a white glassy substance. Reference Example 36 1-[3-(4-t-Butylbenzoyl)propionyl]-L-proline As in Example 40, 14 g of 3-(4-t-butylbenzoyl)propionic acid was mixed with N,N-dicyclohexyl It was reacted with 6.9 g of N-hydroxysuccinimide in the presence of 12.36 g of carbodiimide to obtain 15.5 g of 3-(4-tert-butylbenzoyl)propionic acid, N-hydroxysuccinimide, with a melting point of 135-138°C. The above compound was mixed with 8.05 g of L-proline in 400 ml of ethanol-water (1:1).
and 11.76 g of sodium bicarbonate.
The mixture was stirred overnight, filtered, and the liquid was concentrated in vacuo. Acidify this mixture with concentrated hydrochloric acid,
Extracted with dichloromethane. After removing the solvent, an amber colored rubber was obtained, which was used as a solvent for 2
Hexane containing % acetic acid-ethyl acetate (1:
1) on 150 g of silica gel. 12.4 g of glass was obtained from the column. In a solution of 9.8 g of the above glass in 150 ml of acetic acid,
4.8g of bromine was added. This mixture was stirred overnight and
Concentrated and poured onto ice and water. This mixture was extracted with dichloromethane, the extract was concentrated and
I got g. The above glass was mixed with 1.94 g of sodium methylate and 4.56 g of thiol acetic acid in 50 ml of ethanol.
g solution. After stirring for 2 hours, add 1 ml of acetic acid.
was added and the mixture was diluted with water. The mixture was extracted with dichloromethane, the extract was washed with water, dried (MgSO ₄ ) and the solvent was removed to give 12 g of product as a yellow glass. Ta. Example 41 1-[3-(5-benzoyl-2-pyrimidinylthio)-3-(4-chlorobenzoyl)propionyl]-L-proline Sodium methylate 0.54 in 50 ml methanol
2.16 g of 5-benzoyl-2-mercaptopyrimidine was added to the solution of g. Add 1-[3-
3.88 g of bromo-3-(4-chlorobenzoyl)propionyl]-L-proline was added, a yellow solid separated, saturated sodium bicarbonate was added (solid dissolved) and the mixture was stirred for 5 minutes. Acetic acid (1 ml) was added and the mixture was stirred overnight. The mixture was diluted with water and filtered. Dissolve the solid in dichloromethane, wash this solution with water,
And dried. Removal of the solvent gave 3.83 g of product as a yellow glass. Example 42 1-[3-acetylthio-3-(5-indanylcarbonyl)propionyl]-L-proline As in Example 40, 21.8 g of 3-(5-indanylcarbonyl)propionic acid was dissolved in dioxane. 11.5g of N-hydroxysuccinimide and N,N
-Reacted with 20.6 g of dicyclohexylcarbodiimide to obtain 27.6 g of N-hydroxysuccinimide ester as yellow crystals with a melting point of 112-117°C.
Add the above compound to 600 ml of ethanol-water (1:1).
12.25g of L-proline and sodium bicarbonate
Added to 17.8g of solution. The mixture was stirred overnight, filtered, concentrated and acidified to a pH of 4 with concentrated hydrochloric acid. This mixture was extracted with dichloromethane, and the extract was concentrated to obtain 24 g of oil. Crystals separated on standing and ethyl acetate-ether was added. By filtration, 15.5 g of 1-[3-(5-indanylcarbonyl)propionyl]-L-proline was obtained as white crystals with a melting point of 89-91°C. Bromine to a solution of 13.9 g of the above compound in 200 ml of acetic acid.
Added 7.06g. The mixture was stirred overnight and concentrated under vacuum to give an oil. This oil was chromatographed on a silica gel column using hexane-ethyl acetate (1:1) containing 2% acetic acid as solvent to give 14.9 g of a pale yellow oil. This oil was added to a solution of 2.55 g sodium methylate and 5.78 g thiol acetic acid in 75 ml methanol and the mixture was stirred overnight. Acidification, dilution with water and extraction with dichloromethane gave 13 g of product as a pale yellow glass. Example 43 1-[3-(4-chlorobenzoyl)-3-[5-
(2-Thenoyl)-2-pyrimidinylthio)propionyl]-L-proline To a solution of 2.52 g of sodium bicarbonate in ethanol-water was added 2.22 g of 5-(2-thenoyl)-2-mercaptopyrimidine. Add 1-[3-
3.88 g of bromo-3-(4-chlorobenzoyl)propionyl]-L-proline was added. After stirring for 15 minutes, 1 ml of acetic acid was added and the mixture was stirred overnight. The mixture was filtered, concentrated and extracted with chloroform. The chloroform extract was washed with water, dried (MgSO ₄ ), and concentrated to a glass. Chromatography on silica gel gave 3.9 g of product as a glass. Example 44 The acute toxicity of the compound obtained in Example 33 was as follows. Oral administration (mouse) 4.8g/Kg, intravenous injection (mouse) 1.2g/Kg, intravenous injection (rat) 1.2g/Kg.

Claims (1)

[Claims] 1 formula where n is 0 or 1; R ₁ is hydrogen or alkyl having up to 3 carbon atoms;
R ₂ is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R ₃ is mercapto, formylthio, benzoylthio, alkanoylthio having 2 to 4 carbon atoms or the formula -S-CO ₂ R ₅ or -S- _CH2CO2R5 ; _R4 is hydrogen, phenyl or alkyl having 1 _to 4 carbon atoms; _R5 is hydrogen or alkyl having _up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methoxy -1-naphthyl, 5-acenaphthyl, 4-biphenylyl, 5-indanyl, 4-
indanyl and formula selected from the group consisting of, where R ₆ is hydrogen,
Fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, 4 carbon atoms alkylamino having up to
selected from the group consisting of alkanoylamino having 2 to 4 carbon atoms and alkoxycarbonyl having 2 to 4 carbon atoms, R ₇ being chloro, fluoro, bromo, alkyl having up to 4 carbon atoms and 4 carbon atoms and m is 0, 1 or 2, and a pharmaceutically acceptable cationic salt thereof when R ₅ is hydrogen. 2 The compound according to claim 1 of the formula (), wherein R ₃ is acetylthio, ARYL is 1-naphthyl, and R ₁ , R ₂ and R ₅ are all hydrogen, i.e. 1-[2 -acetylthio-3-(1
-naphthoyl)propionyl]-L-proline. 3 R ₃ is benzoylthio and ARYL is 2-
The compound according to claim 1 of the formula (), wherein R ₁ , R ₂ and R ₅ are all hydrogen, i.e. 1-[2-benzoylthio-3
-(2-naphthoyl)propionyl]-L-proline. 4. A compound according to claim 1 of the formula (), wherein R ₃ is mercapto, ARYL is phenyl, and R ₁ , R ₂ and R ₅ are all hydrogen;
That is, 1-[2-mercapto-3-(benzoyl)propionyl]-L-proline. 5 A compound according to claim 1 of formula (), wherein n is 0, ARYL is 4-biphenylyl, R ₃ is acetylthio, and both R ₄ and R ₅ are hydrogen, i.e. 1-[3-acetylthio-3-(4-biphenylylcarbonyl)
propionyl]-L-proline. 6 R ₃ is acetylthio, ARYL is 4-chlorophenyl, R ₁ is hydrogen, and
A compound according to claim 1 of the formula () in which R ₂ is methyl, i.e. [S(R ^* ,S ^* )]-1
-[3-acetylthio-4-(4-chlorobenzoyl)-2-methylbutyryl]-L-proline. 7 n is 0, R ₃ is acetylthio,
Compounds according to claim 1 of the formula () in which ARYL is 4-chlorophenyl, R ₄ is methyl and R ₅ is hydrogen, i.e. 1-
[3-acetylthio-3-(4-chlorobenzoyl)-2-methylpropionyl]L-proline. 8 n is 0, R ₃ is acetylthio,
Compounds according to claim 1 of formula (), wherein ARYL is 3-fluorophenyl, R ₄ is methyl and R ₅ is hydrogen, i.e. 1
-[3-acetylthio-3-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline. 9 n is 0 and ARYL is 4-chloro-1-
A compound according to claim 1 of the formula (), which is naphthyl, R ₃ is acetylthio, and both R ₄ and R ₅ are hydrogen, i.e. 1-
[3-Acetylthio-3-(4-chloro-1-naphthoyl)propionyl]-L-proline. 10 n is 0, m is 0, R ₆ is 4-
(4-chlorophenoxy), R ₃ is acetylthio, and both R ₄ and R ₅ are hydrogen, i.e. 1-{3- Acetylthio-3-[4-
(4-chlorophenoxy)benzoyl]propionyl}-L-proline. 11 n is 0, m is 1, R ₆ and R ₇
are chloro, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen,
That is, 1-[3-acetylthio-3-(3,4-
dichlorobenzoyl)-2-methylpropionyl]
-L-proline. 12 n is 0, m is 1, and R ₆ is 4-
methoxy, R ₇ is 3-fluoro, R ₃
is benzoylthio and both R ₄ and R ₅ are hydrogen, i.e. 1-[3-benzoylthio-3-(3-fluoro-4 -methoxybenzoyl)propionyl]-L-proline. 13 of formula () where n is 0, m is 2, R ₆ is methoxy, R ₇ is methoxy, R ₃ is acetylthio, and both R ₄ and R ₅ are hydrogen The compound according to claim 1, namely 1-[3-acetylthio-3-(3,
4,5-Trimethoxybenzoyl)propionyl]-L-proline. 14 n is 0, R ₃ is acetylthio,
A compound according to claim 1 of formula (), wherein ARYL is 3-trifluoromethylphenyl, R ₄ is methyl, and R ₅ is hydrogen;
That is, 1-[3-acetylthio-3-(3-trifluoromethylbenzoyl)-2-methylpropionyl]-L-proline. 15 n is 0, ARYL is phenyl,
R ₃ is acetylthio, R ₄ is methyl,
and a compound according to claim 1 of the formula () in which R ₅ is hydrogen, that is, [S-(R ^* ,
S ^* )]-1-[3-(acetylthio)-3-(benzoyl)-2-methylpropionyl]-L-proline. 16 Formula () where n is 0, ARYL is 3-fluorophenyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen
The compound according to claim 1, that is, [S-(R ^* ,S ^* )]-1-[3-acetylthio-3-
(3-fluorobenzoyl)-2-methylpropionyl]-L-proline. 17 The compound according to claim 1 of formula (), wherein n is 0, ARYL is 4-bromophenyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen , that is, [S-(R ^* ,S ^* )]-1-[3-acetylthio-3-
(4-bromobenzoyl)-2-methylpropionyl]-L-proline. 18 The compound according to claim 1 of the formula (), wherein n is 0, ARYL is 4-bromophenyl, R ₃ is acetyl, R ₄ is methyl, and R ₅ is hydrogen , that is, [S
(R ^* ,R ^* )]-1-[3-acetylthio-3-(4
-bromobenzoyl)-2-methylpropionyl]
-L-proline. 19 The compound according to claim 1 of the formula (), wherein n is 0, ARYL is 4-chlorophenyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen , that is, [S-(R ^* ,S ^* )]-1-[3-acetylthio-3-
(4-chlorobenzoyl)-2-methylpropionyl]-L-proline. 20 The compound according to claim 1 of the formula (), wherein n is 0, ARYL is 4-chlorophenyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen , that is, [S-(R ^* ,R ^* )]-1-[3-acetylthio-3
-(4-chlorobenzoyl)-2-methylpropionyl]-L-proline. 21 The compound according to claim 1 of the formula (), wherein n is 0, ARYL is 2-naphthyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen , that is, [S-
(R ^* ,S ^* )]-1-[3-acetylthio-3-(2-
naphthoyl)-2-methylpropionyl]-L-proline. 22 n is 0, ARYL is phenyl,
R ₃ is acetylthio, R ₄ is methyl,
and a compound according to claim 1 of the formula () in which R ₅ is hydrogen, that is, [S-(R ^* ,
R ^* )]-1-[3-acetylthio-3-(benzoyl)-2-methylpropionyl]-L-proline. 23 Formula () where n is 0, ARYL is 3-fluorophenyl, R ₃ is acetylthio, R ₄ is methyl, and R ₅ is hydrogen
The compound according to claim 1, that is, [S-(R ^* ,R ^* )]-1-[3-acetylthio-3
-(3-fluorobenzoyl)-2-methylpropionyl]-L-proline. 24 The compound according to claim 1 of the formula (), wherein ARYL is phenyl, R ₁ is hydrogen, R ₂ is methyl, R ₃ is acetylthio, and R ₅ is hydrogen, That is, [S-
(R ^* ,S ^* )]-1-[3-acetylthio-4-(benzoyl)-2-methylbutyryl]-L-proline. 25 ARYL is 3-fluorophenyl,
Formula () where R ₁ is hydrogen, R ₂ is methyl, R ₃ is acetylthio, and R ₅ is hydrogen
The compound according to claim 1, that is, [S-(R ^* ,S ^* )]-1-[3-acetylthio-4-
(3-fluorobenzoyl)-2-methylbutyryl]-L-proline. 26 ARYL is 2-naphthyl, R ₁ is hydrogen, R ₂ is methyl, R ₃ is acetylthio, and R ₅ is hydrogen according to claim 1 of the formula () compound, i.e. [S-
(R ^* ,S ^* )]-1-[3-acetylthio-4-(2-
naphthoyl)-2-methylbutyryl]-L-proline. 27 formula where n is 0 or 1; R ₃ is mercapto, formylthio, benzoylthio, carbon atom 2
alkanoylthio having ~4 or a group of the formula -S-CO ₂ R ₅ or -S-CH ₂ CO ₂ R ₅ ; R ₄ is hydrogen, phenyl or alkyl having up to 4 carbon atoms; Yes; R ₅ is hydrogen or alkyl having up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 5-acenaphthyl, 4-methoxy-1-naphthyl, 4 -biphenylyl, 5-indanyl, 4-
indanyl, 5,6,7,8-tetrahydro-1
-naphthyl, 5,6,7,8-tetrahydro-2
- naphthyl or formula where R ₆ is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, Alkoxy with up to 4 carbon atoms, 4 carbon atoms
alkylamino having up to 2 to 4 carbon atoms
alkanoylamino or carbon atoms having 2
is an alkoxycarbonyl having ~4;
R ₇ is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is 0, 1 or 2; or when R ₅ is hydrogen; A method for producing a cationic salt thereof, the method comprising: where R ₄ and ARYL are as defined above; X is chloro, bromo, iodo, -SR or -
SO ₂ R, where R is alkyl having up to 4 carbon atoms, phenyl, p-tolyl, benzyl or p-methoxybenzyl; and Y is of the formula wherein R ₅ has the same definition as above, is a group of , is condensed with the anion of a thiolating agent of formula H-R ₃ , where R ₃ is as defined above. A method characterized by: 28 formula where n is 0 or 1, and when n is 0, A is [formula]; and when n is 1, A is [formula]; R ₁ is hydrogen or 3 carbon atoms is an alkyl having up to;
R ₂ is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R ₃ is mercapto, formylthio, benzoylthio, alkanoylthio having 2 to 4 carbon atoms or the formula -S-CO ₂ R ₅ or -S-CH ₂ CO ₂ R ₅ ; R ₅ is hydrogen or alkyl having up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4
-chloro-1-naphthyl, 4-methoxy-1-naphthyl, 5-acenaphthyl, 4-biphenylyl,
5-indanyl, 4-indanyl, 5,6,7,
8-tetrahydro-1-naphthyl, 5,6,7,
8-tetrahydro-2-naphthyl or formula where R ₆ is hydrogen, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, Alkoxy with up to 4 carbon atoms, 4 carbon atoms
alkylamino having up to 2 to 4 carbon atoms
alkanoylamino and carbon atoms having 2 to
is alkoxycarbonyl having 4; R ₇
is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms or alkoxy having up to 4 carbon atoms; and m is 0, 1 or 2, or its cation when R ₅ is hydrogen A method for producing a salt having the formula H-R ₃ (wherein
R ₃ is as defined above) the thiolating agent with the formula where A is a group of [formula] [formula] or [formula], R ₁ , R ₂ and ARYL are as defined above, and Y
is the expression A method characterized in that R ₅ is defined as above, and is a group of , and is reacted with a compound of . 29 formula where n is 0 or 1; R ₁ is hydrogen or alkyl having up to 3 carbon atoms;
R ₂ is hydrogen, phenyl or alkyl having up to 3 carbon atoms; R ₃ is mercapto, formylthio, benzoylthio, alkanoylthio having 2 to 4 carbon atoms or the formula -S-CO ₂ R ₅ or -S- _CH2CO2R5 ; _R4 is hydrogen, phenyl or alkyl having 1 _to 4 carbon atoms; _R5 is hydrogen or alkyl having _up to 4 carbon atoms; and ARYL is 1-naphthyl, 2-naphthyl, 4-chloro-1-naphthyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 4-methoxy -1-naphthyl, 5-acenaphthyl, 4-biphenylyl, 5-indanyl, 4-
indanyl and formula selected from the group consisting of the groups, where R ₆ is hydrogen,
Fluoro, chloro, bromo, trifluoromethyl, cyano, amino, phenoxy, halophenoxy, phenylthio, halophenylthio, p-cyclohexylphenoxy, alkyl having up to 4 carbon atoms, alkoxy having up to 4 carbon atoms, 4 carbon atoms alkylamino having up to
selected from the group consisting of alkanoylamino having 2 to 4 carbon atoms and alkoxycarbonyl having 2 to 4 carbon atoms; R ₇ is chloro, fluoro, bromo, alkyl having up to 4 carbon atoms and 4 carbon atoms; and m is 0, 1 or 2, and a pharmaceutically acceptable cationic salt thereof when R ₅ is hydrogen. Preparation for lowering blood pressure, characterized in that it contains together with physiologically acceptable excipients.