CA1280428C - Pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity and synthesis and use thereof - Google Patents
Pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity and synthesis and use thereofInfo
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- CA1280428C CA1280428C CA000523852A CA523852A CA1280428C CA 1280428 C CA1280428 C CA 1280428C CA 000523852 A CA000523852 A CA 000523852A CA 523852 A CA523852 A CA 523852A CA 1280428 C CA1280428 C CA 1280428C
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Abstract
NOVEL PYRROLIDINYLAMIDE ESTER DERIVATIVE HAVING
ANTI-PROLYL ENDOPEPTIDASE ACTIVITY AND
SYNTHESIS AND USE THEREOF
Abstract A novel pyrrolidinylamide ester derivative that exhibits inhibitory activity against prolyl endopeptidase, methods for synthesis thereof and its use as an inhibitor against said enzyme are disclosed. The pyrrolidinylamide ester of the invention has the following general formula:
ANTI-PROLYL ENDOPEPTIDASE ACTIVITY AND
SYNTHESIS AND USE THEREOF
Abstract A novel pyrrolidinylamide ester derivative that exhibits inhibitory activity against prolyl endopeptidase, methods for synthesis thereof and its use as an inhibitor against said enzyme are disclosed. The pyrrolidinylamide ester of the invention has the following general formula:
Description
2~ 8 \
NOVEL PYRROLIDINYLAMIDE ESTER DERIVATIVE HAVING
ANTI-PROLYL ENDOPEPTIDASE ACTIVITY AND
SYNT~ESIS AND USE l'HEREOF
Backqround of the Invention:
Field of the Invention _ The present invention relates to a novel compound that exhibits enzyme inhibitory activity against prolyl endopeptidase (EC. 3.4.21.26). The invention also relates to a method for chemical synthesis of such novel compounds, as well as a prolyl endopeptidase activity inhibitor that contains said compound as the active ingredient.
Prolyl endopeptidase is known to inactivate neuro-transmitters such as substance P, thyrotropin-releasing hormone (TRH) and neurotensin, or vasopressin speculatively associated with memory. Tsuru and Yoshimoto of the Depart-ment of Pharmaceutical Sciences, Nagasaki University, found that compounds capable of inhibiting prolyl endopeptidase activity were effective in preventing experimental amnesia caused in rats by scopolamine. Based on this discovery, they suggested the potential use of anti-prolyl endo-peptidase substances as anti-amnesic asents.
Motivated by the report of Tsuru and Yoshimoto, the present inventors have made various efforts to find novel compounds that exhibit strong inhibitory activity against prolyl endopeptidase as an anti-amnesic activity and which yet display satisfactorily low toxicity levels.
Prior Art US Patent Nos. 4,701,465, 4,743,616 and 4,772,587 and Canadian patent application No. 506,770, all of which have been assigned to the assignee of this invention, djsclose certain types of compounds which have inhibitory activity against propyl endopeptidase and are thus effective in treating amnesia.
Summary_of the Invention:
The inventors have now found novel compounds having the general formula (I) shown below which exhibit strong - inhibitory activit~ against prolyl endopeptidase while ~ i.
:"' ' ;~;`
~. . ~ - .. , . . . - . .. . . .
" ~280~
displaying low toxicity and they are thus expected to be effective against amnesia. The compounds of the invention are close to natural substances, being a combination of fatty acids, which enjoy a high safety level as natural compounds, and amino acids or peptide compounds.
Detailed Description of the Invention:
The pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity of the present invention is represented by the general formula (I)-o ~ ( CH 2 ) n ~ O~ N~ (I) wherein n is 0 or an integer of 1 to 7, preferably 3 to 5,~and R is hydrogen atom or a straight or branched alkyl having 1 to 8, preferably 3 to 5, carbon atoms.
The compounds of formula (I) differ greatly from the known anti-amnesic agents of piracetam derivatives in that the former contains a pyrrolidine amide of a hydroxy acid.
Because they are derivatives of hydroxy acids, the compounds of the formula (I) present extremely low toxicity levels in organisms.
The following compounds of the formula (I) are particularly preferred because of their high anti-prolyl endopeptidase activities (the following compounds may be sometimes referred to by the numbers given in parentheses hereinafter):
o ~ CH
.r (SUAM 1287) o CH3~H3 (SUAM 1288) ~28~8 ~CH2)3 ~ O J N ~
(SUAM 1332) The compounds of the present invention of the formula (I) may also be synthesized by known acylation methods.
But the compounds may advantageously be synthesized by the following methods of the invention which will be explained hereunder. The abbreviation "WSCD" as used herein means N-ethyl-N'IN'-dimethylaminopropylcarbodiimide.
The intermediate O-acyl hydroxy acid of the formula (II):
~ (CH2)n ~ o COOH (II) wherein n and R have the meanings given above, may be obtained by reacting an ~-phenylalkyl carbonyl halide of the formula (III):
~ (CH2)n ~ X (III) wherein n has the same meaning as given above and X repre-sents a halogen atom, with a hydroxycarboxylic acid of the formula (IV):
OH \ / COOH
T (IV) R
wherein R has the same meaning as given above, in the presence of a base. As bases which may be used in this reaction, trialkylamines and aromatic amines etc. can be mentioned. The reaction temperature is preferably below room temperature. The solvent may be selected from those which remain inert in the reaction, such as ether type solvent. Especially preferred is tetrahydrofurane.
The compound of the invention may be obtained from the compound of the formula (II) by condensation of the -4- ~8~ 8 latter with pyrrolidine under the presence of a condensation agent. Examples of suitable condensation agents are those which are commonly used in peptide synthesis such as N',N'-dicyclohexylcarbodiimide and WSCD, etc. However, the con-densation may be conducted by any conventional method suchas the acid chloride method.
Alternatively, the compound of the present invention may be obtained from a carbonyl imide of the formula (V):
HO~ N~
R
wherein R has the same meaning as given above, by reacting said compound with an ~-phenylal~yl carbonyl halide of the foregoing formula (III) in the presence of an organic base as mentioned above.
The present invention is hereinunder described in greater detail by way of Examples.
1~ Example 1 N-[~-L~-~henyl)butyryloxy-4-methylvaleryllpyrrolidine (SUAM 1287) 2-Hydroxy-4-methylvaleric acid (10 mmol) was dis-solved in anhydrous tetrahydrofurane (ca. 50 ml), to which triethylamine (10 mmol) was then added~ y-Phenylbutyryl chloride (10 mmol) and then triethylamine (10 mmol) were slowly added dropwise to the resulting solution under cool-ing with ice. The mixture was allowed to return to room temperature and then stirred throughout one whole day and night.
After the reaction, the hydrochloride salt of tri-ethylamine which had precipitated was removed by filtration.
The resultant solution in tetrahydrofurane was distilled off in vacuo to obtain the residue which was then dissolved in ethyl acetate and the solution was washed twice with 1 N
hydrochloric acid. The organic layer was dried over anhy-drous magnesium sulfate, the solvent was distilled off under vacuum and the resulting residue was purified by medium pressure column chromatography on silica gel. The resulting 2-(y-phenyl)butyryloxy-4-methylvaleric acid was dissolved in -5~ 4~
dry methylene chloride (100 ml) together with pyrrolidine (1 equivalent). WSCD (1 equivalent) was added thereto and the mixture was stirred throughout one whole day and night.
After the completion of the reaction, the mixture was washed successively with 1 N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate and again saturated brine, in that order, and was then dried over anhydrous magnesium sulfate. The dried mixture was concentrated by distillation under vacuum. The residue was subjected to medium pressure cclumn chromatography on silica gel whereby the titled compound was obtained.
Appearance: colorless oil IR spectrum (film, cm 1): 2950, 2860, 1720, 1650, 1440, 740, 6g5 NMR spectrum (CDC13, ~): 0.96(3H,d,J=3Hz), 1.00(3H,d, J=3Hz), 1.20-2.80(13H,m), 3.20-
NOVEL PYRROLIDINYLAMIDE ESTER DERIVATIVE HAVING
ANTI-PROLYL ENDOPEPTIDASE ACTIVITY AND
SYNT~ESIS AND USE l'HEREOF
Backqround of the Invention:
Field of the Invention _ The present invention relates to a novel compound that exhibits enzyme inhibitory activity against prolyl endopeptidase (EC. 3.4.21.26). The invention also relates to a method for chemical synthesis of such novel compounds, as well as a prolyl endopeptidase activity inhibitor that contains said compound as the active ingredient.
Prolyl endopeptidase is known to inactivate neuro-transmitters such as substance P, thyrotropin-releasing hormone (TRH) and neurotensin, or vasopressin speculatively associated with memory. Tsuru and Yoshimoto of the Depart-ment of Pharmaceutical Sciences, Nagasaki University, found that compounds capable of inhibiting prolyl endopeptidase activity were effective in preventing experimental amnesia caused in rats by scopolamine. Based on this discovery, they suggested the potential use of anti-prolyl endo-peptidase substances as anti-amnesic asents.
Motivated by the report of Tsuru and Yoshimoto, the present inventors have made various efforts to find novel compounds that exhibit strong inhibitory activity against prolyl endopeptidase as an anti-amnesic activity and which yet display satisfactorily low toxicity levels.
Prior Art US Patent Nos. 4,701,465, 4,743,616 and 4,772,587 and Canadian patent application No. 506,770, all of which have been assigned to the assignee of this invention, djsclose certain types of compounds which have inhibitory activity against propyl endopeptidase and are thus effective in treating amnesia.
Summary_of the Invention:
The inventors have now found novel compounds having the general formula (I) shown below which exhibit strong - inhibitory activit~ against prolyl endopeptidase while ~ i.
:"' ' ;~;`
~. . ~ - .. , . . . - . .. . . .
" ~280~
displaying low toxicity and they are thus expected to be effective against amnesia. The compounds of the invention are close to natural substances, being a combination of fatty acids, which enjoy a high safety level as natural compounds, and amino acids or peptide compounds.
Detailed Description of the Invention:
The pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity of the present invention is represented by the general formula (I)-o ~ ( CH 2 ) n ~ O~ N~ (I) wherein n is 0 or an integer of 1 to 7, preferably 3 to 5,~and R is hydrogen atom or a straight or branched alkyl having 1 to 8, preferably 3 to 5, carbon atoms.
The compounds of formula (I) differ greatly from the known anti-amnesic agents of piracetam derivatives in that the former contains a pyrrolidine amide of a hydroxy acid.
Because they are derivatives of hydroxy acids, the compounds of the formula (I) present extremely low toxicity levels in organisms.
The following compounds of the formula (I) are particularly preferred because of their high anti-prolyl endopeptidase activities (the following compounds may be sometimes referred to by the numbers given in parentheses hereinafter):
o ~ CH
.r (SUAM 1287) o CH3~H3 (SUAM 1288) ~28~8 ~CH2)3 ~ O J N ~
(SUAM 1332) The compounds of the present invention of the formula (I) may also be synthesized by known acylation methods.
But the compounds may advantageously be synthesized by the following methods of the invention which will be explained hereunder. The abbreviation "WSCD" as used herein means N-ethyl-N'IN'-dimethylaminopropylcarbodiimide.
The intermediate O-acyl hydroxy acid of the formula (II):
~ (CH2)n ~ o COOH (II) wherein n and R have the meanings given above, may be obtained by reacting an ~-phenylalkyl carbonyl halide of the formula (III):
~ (CH2)n ~ X (III) wherein n has the same meaning as given above and X repre-sents a halogen atom, with a hydroxycarboxylic acid of the formula (IV):
OH \ / COOH
T (IV) R
wherein R has the same meaning as given above, in the presence of a base. As bases which may be used in this reaction, trialkylamines and aromatic amines etc. can be mentioned. The reaction temperature is preferably below room temperature. The solvent may be selected from those which remain inert in the reaction, such as ether type solvent. Especially preferred is tetrahydrofurane.
The compound of the invention may be obtained from the compound of the formula (II) by condensation of the -4- ~8~ 8 latter with pyrrolidine under the presence of a condensation agent. Examples of suitable condensation agents are those which are commonly used in peptide synthesis such as N',N'-dicyclohexylcarbodiimide and WSCD, etc. However, the con-densation may be conducted by any conventional method suchas the acid chloride method.
Alternatively, the compound of the present invention may be obtained from a carbonyl imide of the formula (V):
HO~ N~
R
wherein R has the same meaning as given above, by reacting said compound with an ~-phenylal~yl carbonyl halide of the foregoing formula (III) in the presence of an organic base as mentioned above.
The present invention is hereinunder described in greater detail by way of Examples.
1~ Example 1 N-[~-L~-~henyl)butyryloxy-4-methylvaleryllpyrrolidine (SUAM 1287) 2-Hydroxy-4-methylvaleric acid (10 mmol) was dis-solved in anhydrous tetrahydrofurane (ca. 50 ml), to which triethylamine (10 mmol) was then added~ y-Phenylbutyryl chloride (10 mmol) and then triethylamine (10 mmol) were slowly added dropwise to the resulting solution under cool-ing with ice. The mixture was allowed to return to room temperature and then stirred throughout one whole day and night.
After the reaction, the hydrochloride salt of tri-ethylamine which had precipitated was removed by filtration.
The resultant solution in tetrahydrofurane was distilled off in vacuo to obtain the residue which was then dissolved in ethyl acetate and the solution was washed twice with 1 N
hydrochloric acid. The organic layer was dried over anhy-drous magnesium sulfate, the solvent was distilled off under vacuum and the resulting residue was purified by medium pressure column chromatography on silica gel. The resulting 2-(y-phenyl)butyryloxy-4-methylvaleric acid was dissolved in -5~ 4~
dry methylene chloride (100 ml) together with pyrrolidine (1 equivalent). WSCD (1 equivalent) was added thereto and the mixture was stirred throughout one whole day and night.
After the completion of the reaction, the mixture was washed successively with 1 N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate and again saturated brine, in that order, and was then dried over anhydrous magnesium sulfate. The dried mixture was concentrated by distillation under vacuum. The residue was subjected to medium pressure cclumn chromatography on silica gel whereby the titled compound was obtained.
Appearance: colorless oil IR spectrum (film, cm 1): 2950, 2860, 1720, 1650, 1440, 740, 6g5 NMR spectrum (CDC13, ~): 0.96(3H,d,J=3Hz), 1.00(3H,d, J=3Hz), 1.20-2.80(13H,m), 3.20-
3.90(4H,m), 5.16(1H,dd,J=4,J=9Hz), 7.20-7.40(5H,m) Example 2 20 N-~2-(Y-phenvl)butyryloxy-3-methylbutyryllpyrrolidine (SUAM 1288) The titled compound was obtained by repeating the process of Example 1 but using 2-hydroxy-3-methylbutyric acid in place of 2-hydroxy-4-methylvaleric acid.
~5 IR spectrum (film, cm 1): 2960, 2870, 1720, 1650, 1440, 740, 695 NMR spectrum (CDC13, ~): 0~98(3H,d,J=6Hz), 1.06(3H,d, J=6Hz), 1.80-2.80(llH,m), 3.30-
~5 IR spectrum (film, cm 1): 2960, 2870, 1720, 1650, 1440, 740, 695 NMR spectrum (CDC13, ~): 0~98(3H,d,J=6Hz), 1.06(3H,d, J=6Hz), 1.80-2.80(llH,m), 3.30-
4.00(4H,m) 7 4.80(lH,d,J=8Hz), 7.10-7.A0(5H,m) ExamPle 3 N-~2-(~-phenvl)butvrvloxY-n-caprvloyllpyrrolidine (SUAM 1332) The titled compound was obtained by repeating the process of Example 1 but using 2-hydroxy-n-caprylic acid in place of 2-hydroxy-4-methylvaleric acid.
IR spectrum (film cm 1): 2940, 2870, 1730, 1640, 1440, 740, 700 NMR spectrum (CDC13, ~) 0 98(3~,m), 1.30(8~,m), 1.60-2.80(12~,m), 3.20-3.80(4H,m),
IR spectrum (film cm 1): 2940, 2870, 1730, 1640, 1440, 740, 700 NMR spectrum (CDC13, ~) 0 98(3~,m), 1.30(8~,m), 1.60-2.80(12~,m), 3.20-3.80(4H,m),
5.06(1~,dd,J=5,J=8Hz), 7.10-7.40(5H,m) ExamPle 4 Measurement of anti-ProlYl endoPeptidase activitv The method of Yoshimoto and Tsuru [T. Yoshimoto and D. Tsuru, Agric.Biol. Chem., 42, 2417 (1978)] was used to measure the anti-prolyl endopeptidase activities of several compounds of the present invention. A mixture of 0.0025 M
Z-glycyl-proline~-naphthylamide (0.25 ml), 0.1 M phosphate buffer (pH, 7.0; 0.99 ml) and a solution of a particular anti-prolyl endopeptidase compound (0.01 ml) was incubated in a test tube at 37 C for 3 minutes. Thereafter, 0.1 ml of a solution of prolyl endopeptidase (0.2 U/ml) was added and the mixture was incubated at 35 C for 10 minutes. After the reaction, 2.0 ml of TRITON X-100 in 1 M acetate buffer (pH, 4.0) was added to the reaction mixture so that the final concentration of the surfactant was 10%. The mixture was left at room temperature for 15 minutes and the absorbance (a) at 410 nm was measured.
A sample of a blind test was prepared by using the buffer instead of the anti-prolyl endopeptidase compound and its absorbance (b) was also measured. The percent inhibi-tion of prolyl endopeptidase was calculated by the formula:
~ (b - a)/b] x 100 and the amount of a specific compound needed to achieve 50%
inhibition (IC50) was determined. The results are shown in Table 1.
Table 1 Compound IC50 (Example No.) (~g/test tube) 1 0.70 _ 2 0.90 3 _4.0 .
* Trade mark.
.-, ~; . .
~8~
The compounds of the invention are useful for their anti prolyl endopeptidase activity in treating patients suffering from amnesia. Therefore, the present invention also relates to a pharmaceutical composition comprising at least one compound of the formula (I) together with a pharmaceutically acceptable carrier.
The formulation of the agent of the invention includes either solid formulations such as capsules, tablets and powders, or liquid formulations such as elixirs, syrups and suspensions for oral administration. Alternatively, the active compounds (I) may be formulated as injections or suppositories.
The carrier included in the agent of the invention may be selected from pulverulent solid carriers such as lactose, saccharose, dextrose, mannitol, sorbitol, cellu-lose, and glycine etc.
The agent of the invention may further contain a lubricant, a binder or a disintegrator. Examples of suit-able lubricants are silicon dioxide, talc, magnesium stea-rate and polyethylene glycol. Examples of suitable bindersare starch, gelatin, tragacanth, methyl cellulose and poly-vinyl pyrrolidone. Examples of suitable disintegrators are starch and agar etc.
The active ingredient (I) of the agent of the inven-tion is orally administered to an adult patient in a doseof 10 to 4000 mg, preferably 100 to 1000 mg/day, or admin-istered parenterally in a dose of 1 to 2000 mg, preferably 50 to 500 mg/day. The dose may be varied depending on the disease, age, weight, or condition of the patient and the formulation of the drugs.
Formulation 1 Ingredient Part Compound of the formula (I)45 Starch 15 Lactose 40 The ingredients are mixed thoroughly, and tablets or capsules are formulated from the mixture.
Formulation 2 Ingredient Part Compound of the formula (I)10 Lactose 75 Magnesium oxide (MgO > 96~)15 The above ingredients are mixed thoroughly, and powders or fine granules are formed from the mixture.
Formulation 3 Ingredient Part Compound of the formula (I) Surface active agent S
Physiological saline 94 The above ingredien~s are mixed under warming, and dispensed under sterile conditions into ampoules for use as injections.
Z-glycyl-proline~-naphthylamide (0.25 ml), 0.1 M phosphate buffer (pH, 7.0; 0.99 ml) and a solution of a particular anti-prolyl endopeptidase compound (0.01 ml) was incubated in a test tube at 37 C for 3 minutes. Thereafter, 0.1 ml of a solution of prolyl endopeptidase (0.2 U/ml) was added and the mixture was incubated at 35 C for 10 minutes. After the reaction, 2.0 ml of TRITON X-100 in 1 M acetate buffer (pH, 4.0) was added to the reaction mixture so that the final concentration of the surfactant was 10%. The mixture was left at room temperature for 15 minutes and the absorbance (a) at 410 nm was measured.
A sample of a blind test was prepared by using the buffer instead of the anti-prolyl endopeptidase compound and its absorbance (b) was also measured. The percent inhibi-tion of prolyl endopeptidase was calculated by the formula:
~ (b - a)/b] x 100 and the amount of a specific compound needed to achieve 50%
inhibition (IC50) was determined. The results are shown in Table 1.
Table 1 Compound IC50 (Example No.) (~g/test tube) 1 0.70 _ 2 0.90 3 _4.0 .
* Trade mark.
.-, ~; . .
~8~
The compounds of the invention are useful for their anti prolyl endopeptidase activity in treating patients suffering from amnesia. Therefore, the present invention also relates to a pharmaceutical composition comprising at least one compound of the formula (I) together with a pharmaceutically acceptable carrier.
The formulation of the agent of the invention includes either solid formulations such as capsules, tablets and powders, or liquid formulations such as elixirs, syrups and suspensions for oral administration. Alternatively, the active compounds (I) may be formulated as injections or suppositories.
The carrier included in the agent of the invention may be selected from pulverulent solid carriers such as lactose, saccharose, dextrose, mannitol, sorbitol, cellu-lose, and glycine etc.
The agent of the invention may further contain a lubricant, a binder or a disintegrator. Examples of suit-able lubricants are silicon dioxide, talc, magnesium stea-rate and polyethylene glycol. Examples of suitable bindersare starch, gelatin, tragacanth, methyl cellulose and poly-vinyl pyrrolidone. Examples of suitable disintegrators are starch and agar etc.
The active ingredient (I) of the agent of the inven-tion is orally administered to an adult patient in a doseof 10 to 4000 mg, preferably 100 to 1000 mg/day, or admin-istered parenterally in a dose of 1 to 2000 mg, preferably 50 to 500 mg/day. The dose may be varied depending on the disease, age, weight, or condition of the patient and the formulation of the drugs.
Formulation 1 Ingredient Part Compound of the formula (I)45 Starch 15 Lactose 40 The ingredients are mixed thoroughly, and tablets or capsules are formulated from the mixture.
Formulation 2 Ingredient Part Compound of the formula (I)10 Lactose 75 Magnesium oxide (MgO > 96~)15 The above ingredients are mixed thoroughly, and powders or fine granules are formed from the mixture.
Formulation 3 Ingredient Part Compound of the formula (I) Surface active agent S
Physiological saline 94 The above ingredien~s are mixed under warming, and dispensed under sterile conditions into ampoules for use as injections.
Claims (9)
1. A pyrrolidinylamide ester derivative of the formula:
wherein n is O or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms.
wherein n is O or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms.
2. A compound according to Claim 1 wherein n is an integer of 3 to 5.
A compound according to Claim 1 wherein n is an integer of 3.
4. A compound according to Claim 1 wherein R is hydrogen atom.
5. A compound according to Claim 1 wherein R is a straight or branched alkyl having 3 to 5 carbon atoms.
6. A compound according to Claim 1 which is expressed by the following formula:
or
or
7. A process for producing a compound of the formula:
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, which comprises reacting an O-acyl hydroxy acid of the formula:
wherein n and R have the meanings given above, with pyrroli-dine in the presence of a condensation agent.
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, which comprises reacting an O-acyl hydroxy acid of the formula:
wherein n and R have the meanings given above, with pyrroli-dine in the presence of a condensation agent.
8. A process for producing a compound of the formula:
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, which comprises reacting an .omega.-phenylalkylcarbonyl halide of the formula:
wherein n has the meaning as given above and X represents a halogen atom, with a hydroxy acid of the formula:
wherein R has the meaning given above, in the presence of a base and the resulting product is thereafter condensed with pyrrolidine.
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, which comprises reacting an .omega.-phenylalkylcarbonyl halide of the formula:
wherein n has the meaning as given above and X represents a halogen atom, with a hydroxy acid of the formula:
wherein R has the meaning given above, in the presence of a base and the resulting product is thereafter condensed with pyrrolidine.
9. A pharmaceutical composition comprising a prolyl endopeptidase inhibiting amount of a compound of the formula:
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, together with a pharmaceutically acceptable carrier.
wherein n is 0 or an integer of 1 to 7 and R is hydrogen atom or a straight or branched alkyl having 1 to 8 carbon atoms, together with a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000523852A CA1280428C (en) | 1985-11-29 | 1986-11-26 | Pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity and synthesis and use thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP268994/1985 | 1985-11-29 | ||
| CA000523852A CA1280428C (en) | 1985-11-29 | 1986-11-26 | Pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity and synthesis and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1280428C true CA1280428C (en) | 1991-02-19 |
Family
ID=4134435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000523852A Expired - Lifetime CA1280428C (en) | 1985-11-29 | 1986-11-26 | Pyrrolidinylamide ester derivative having anti-prolyl endopeptidase activity and synthesis and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1280428C (en) |
-
1986
- 1986-11-26 CA CA000523852A patent/CA1280428C/en not_active Expired - Lifetime
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