JPH0825995B2 - Heterocyclic compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to prolylendopeptidase (prolylendo).
The present invention relates to a novel compound having peptidase) inhibitory activity.

More specifically, the present invention relates to a novel heterocyclic compound represented by the following general formula, which has prolyl endopeptidase inhibitory activity. (In the formula, all symbols are as described below.)

2. Description of the Related Art Recent studies have gradually elucidated the identity of neurotransmitters and substances closely related to memory in the brain, but most of these are believed to be proline-containing neuropeptides. .

It has been reported that administration of these proline-containing neuropeptides to experimental amnestic rats restores memory (see Science 211 , 601 (1981)).

On the other hand, these neuropeptide hormones are presumed to be metabolized by endogenous peptidases in the brain, and especially prolylen endopeptidase (E).
C, 3.4.21.26) is believed to be deeply involved in metabolism (see J. Biochem 94 , 1179 (1983)).

From these facts, research guidelines have been directed toward the possibility that inhibition of prolyl endopeptidase could suppress the metabolism of neurotransmitters and prevent or treat amnesia (protein・ Nucleic acid / enzyme 25 (6) ,
513 (1980); Journal of Japanese Society of Agricultural Chemistry 58 (11) , 1147 (1984);
J. Neurochem., 41 , 69 (1983); 42 , 237 (1984)).

There are some compounds synthesized for these purposes, but N-benzyloxycarbonyl-glycyl-L-
Prolyl-chloromethane and N-benzyloxycarbonyl-L-prolyl-prolinal have been shown to potently inhibit prolyl endopeptidase (see J. Neurochem., 41 , 69 (1983)).

Recently, (i) general formula And R ² represents a lower alkyl group, an unsubstituted or substituted phenyl group or —CH ₂ —R ²² .

However, R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, an unsubstituted or substituted phenyl group, -CH ₂ R ⁹ , -X-R ¹⁰ , -NH _2, -NHR ¹⁴ or Represents {However, R ⁹ represents an unsubstituted or substituted phenyl group. X represents an oxygen atom or a sulfur atom, and R
¹⁰ represents a lower alkyl group, an unsubstituted or substituted phenyl group or -CH ₂ R ¹¹ (wherein R ¹¹ represents an unsubstituted or substituted phenyl group). R ¹² is a lower alkyl group, an unsubstituted or substituted phenyl group or —CH ₂ R ¹³ (provided that R 12
¹³ represents an unsubstituted or substituted phenyl group. ) Is represented. R ¹⁴ is a lower alkyl group, a 5- or 6-membered cycloalkyl group, an unsubstituted or substituted phenyl group, -CH
₂ R ¹⁵ (wherein R ¹⁵ represents an unsubstituted or substituted phenyl group), or (Wherein R ¹⁶ represents a lower alkyl group or an unsubstituted or substituted phenyl group). R ¹⁷ and R ¹⁸ each independently represent a lower alkyl group or —CH ₂ R ¹⁹ (wherein R ¹⁹ represents an unsubstituted or substituted phenyl group). } R ⁶ represents a hydrogen atom or a lower alkyl group. R ⁷
Is a hydrogen atom, a lower alkyl group, a benzyl group, Or - it represents a (CH _{2) n} -R ^20. {However, n represents an integer of 0 to 4, R ²⁰ is -OH, -SH, -NH ₂ , -SCH ₃ , -CONH ₂ , —CO ₂ R ²¹ (wherein R ²¹ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a heterocyclic group. ｝
R ⁸ represents a hydrogen atom, or represents a 5-membered heterocyclic group together with a nitrogen atom and a carbon atom which are bonded to R ⁷ and are adjacent to each other. R ²² represents an unsubstituted or substituted phenyl group. ] A pyrrolidine derivative represented by (see JP-A-62-221666), (ii) general formula However, R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, an unsubstituted or substituted phenyl group, —CH ₂ R ⁹ , —X—R ¹⁰ , -NH _2, -NHR ¹⁴ or Represents {However, R ⁹ represents an unsubstituted or substituted phenyl group. X represents an oxygen atom or a sulfur atom, and R
¹⁰ represents a lower alkyl group, an unsubstituted or substituted phenyl group or -CH ₂ R ¹¹ (wherein R ¹¹ represents an unsubstituted or substituted phenyl group). R ¹² is a lower alkyl group, an unsubstituted or substituted phenyl group or —CH ₂ R ¹³ (provided that R 12
¹³ represents an unsubstituted or substituted phenyl group. ) Is represented. R ¹⁴ is a lower alkyl group, a 5- or 6-membered cycloalkyl group, an unsubstituted or substituted phenyl group, -CH
₂ R ¹⁵ (wherein R ¹⁵ represents an unsubstituted or substituted phenyl group) or (Wherein R ¹⁶ represents a lower alkyl group or an unsubstituted or substituted phenyl group). R ¹⁷ and R ¹⁸ each independently represent a lower alkyl group or —CH ₂ R ¹⁹ (wherein R ¹⁹ represents an unsubstituted or substituted phenyl group). } R ⁶ represents a hydrogen atom or a lower alkyl group.

R ⁷ is a hydrogen atom, a lower alkyl group, a benzyl group, Or - it represents a (CH _{2) n} -R ^20. {However, n represents an integer of 0 to 4, R ²⁰ represents -OH, -SH, -NH ₂ , -SCH ₃ , -CONH ₂ , —CO ₂ R ²¹ (wherein R ²¹ represents a hydrogen atom, a lower alkyl group or a benzyl group) or a heterocyclic group. } R ⁸ represents a hydrogen atom or a 5-membered heterocycle together with a nitrogen atom and a carbon atom which are bonded to R ⁷ and are adjacent to each other.

R ²² represents a hydrogen atom, a lower alkyl group, an unsubstituted or substituted phenyl group or —CH ₂ R ²⁴ (wherein R ²⁴ represents an unsubstituted or substituted phenyl group).

R ²³ represents a lower alkyl group or a lower alkylene group bonded to each other. ] It was disclosed that the pyrrolidine derivative represented by the formula (see JP-A-62-221667) is useful for the above purpose.

Further, the present inventors have filed an application for a prolinal derivative having an antiamnestic effect prior to the present application. That is, (iii) the general formula [In the formula, A represents an alkylene or alkenylene group having 1 to 8 carbon atoms, or a saturated hydrocarbon ring having 3 to 7 carbon atoms, and R represents a hydrogen atom, a phenyl group, a benzyl group, or 1 to 8 carbon atoms.
Represents an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, B represents an alkylene group having 1 to 8 carbon atoms which may be substituted with a phenyl group or a benzyl group, or a single bond, and D represents a halogen atom or a carbon atom. It represents a carbocycle or heterocycle substituted or unsubstituted by 1 to 3 alkyl or alkoxy groups of the formulas 1 to 4, nitro group or trifluoromethyl group. ] It is a prolinal derivative represented by (JP-A-1-56957)
No.).

Comparison with Prior Art The compounds of the present invention represented by the general formula (I) are a novel group of compounds having chemical modifications that have not been known so far.

More specifically, the general formula (Ic) shown below will be described.
The group corresponding to R in the general formula (I) of each of the compounds represented by (If) is a conventionally unknown substituent,
It was first discovered by the present inventors that these compounds have prolyl endopeptidase inhibitory activity.

The compounds represented by the general formulas (Ia) and (Ib) are a completely new group of compounds.

As described above, the present inventors have made some modifications to the group represented by D in the previous application (the compound represented by the general formula (C)). It has been confirmed that the compounds substituted with rings (including heterocycles and saturated rings; for example, naphthalene, fluorene, and furan rings) maintain prolyl endopeptidase inhibitory activity.

Since the symbol D of the compound represented by the general formula (C) corresponds to G in the compound of the present invention represented by the general formula (I),
From these facts, it is not difficult to predict that if a compound in which G is a benzene ring has sufficient activity, the compound in which G is replaced by another ring will maintain the activity.

DISCLOSURE OF THE INVENTION The present invention includes: 1) General formula [In the formula, Z represents a methylene group or a sulfur atom, R represents a general formula G-E-D-B-A- (in the formula, A is a single bond, alkylene having 1 to 6 carbons, and 2 to 6 carbons). Alkenylene, or general formula Represents a group represented by, a saturated hydrocarbon ring having 4 to 7 carbon atoms, or a monocyclic heterocycle, Y represents alkylene having 1 to 4 carbons or alkenylene having 2 to 4 carbons, and B represents a single bond or Represents an alkylene having 1 to 6 carbon atoms, D is a single bond, an oxygen atom, a carbonyl group or a general formula R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, and E represents a single bond, an alkylene group having 1 to 8 carbon atoms, or a phenyl group or a benzyl group. Represents an alkylene having 1 to 8 carbon atoms, G is an unsubstituted or 1 to 3 alkyl having 1 to 6 carbon atoms, an alkoxy having 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group or a nitro group. Represents a substituted carbocycle or heterocycle, L is a general formula —CO—COR ² , -CO-R ⁴ , -CO-CH ₂ -COR ² , -CO-CF ^₂ -COR _2, Or (In the formula, R ² is a hydrogen atom, a hydroxyl group, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, phenyl, alkyl having 1 to 6 carbons substituted with phenyl, or carbon substituted with phenyl. Represents an alkoxy having 1 to 6 carbon atoms, R ³ represents an alkyl having 1 to 6 carbon atoms, phenyl or an alkyl group having 1 to 6 carbon atoms substituted with phenyl, and R ⁴ represents alkyl having 1 to 6 carbon atoms, phenyl Represents a C 1-6 alkyl group substituted with phenyl or a trifluoromethyl group, and R ⁵ and R ⁶ are independently substituted with a hydrogen atom, C 1-6 alkyl, phenyl, or phenyl. Represents an alkyl group having 1 to 6 carbon atoms).

However, the following compounds are excluded: (i) A compound in which A is a single bond and B is also a single bond, (ii) Z is a methylene group, and L is a general formula. -CO-CF ₃ or -CO-CF ^₂ -COR ₂ (in each formula, all symbols have. As defined above) is a group represented by and R is (1) G-E-CONR 1 -B-A-, (2) G -CO-B-A-, (3) G-O-AlK-, (4) G-CHQ- (CH 2) m -, Or (8) phenylene (in each formula, AlK represents a single bond or an alkylene group having 1 to 3 carbon atoms, Q represents a hydrogen atom, a lower alkyl group or a phenyl group, and m represents 0 or an integer of 1 to 5, p represents an integer of 1 to 5, and the other symbols have the same meanings as described above). ] The heterocyclic (pyrrolidine derivative or thiazolidine derivative) compound shown by these, its nontoxic salt, and a hydrate.

The present invention more specifically includes the following compound groups.
That is, the general formula and (In each formula, L ¹ is a general formula —CO—R ⁴ , —CO—CH ₂ —COR ² , -CO-CF ^₂ -COR _2, (In each formula, all symbols have the same meanings as described above.), L ² is a general formula —CO—COR ² , (Wherein all symbols have the same meanings as described above), A'is a single bond, alkylene having 1 to 6 carbons, or 2 to 2 carbons.
Alkenylene of 6 or general formula Represents a group represented by, a saturated hydrocarbon ring having 4 to 7 carbon atoms or a monocyclic heterocycle containing 2 heteroatoms, Y represents alkylene having 1 to 4 carbons or alkenylene having 2 to 4 carbons, E'represents alkylene having 1 to 8 carbon atoms or alkylene having 1 to 8 carbon atoms substituted with phenyl or benzyl, and AlK 'represents alkylene having 4 to 20 carbon atoms. ] It is a compound shown by these.

In the general formulas (I) and (Id), "alkylene having 1 to 6 carbon atoms" represented by A, A'and B means methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene and isomers thereof. Say.

In the general formulas (I), (Id) and (Ie), E and E '
The "alkylene having 1 to 8 carbon atoms" represented by means the above-mentioned group to which heptamethylene, octamethylene and isomers thereof are added.

In the general formula (I), the “alkylene having 1 to 4 carbon atoms” represented by Y means methylene, ethylene, trimethylene and tetramethylene and isomers thereof.

In the general formula (I), the “alkenylene having 2 to 4 carbon atoms” represented by Y means vinylene, propenylene, butenylene, butadienylene and isomers thereof.

In formulas (I) and (Id), "alkenylene having 2 to 6 carbon atoms" represented by A and A'means pentenylene, pentanedienylene, hexenylene, hexadienylene, hexatrienylene and their isomers based on the above groups. It is the one with the body added.

In the general formulas (I) and (Id), the “saturated hydrocarbon ring having 4 to 7 carbon atoms” represented by A and A ′ means cyclobutane, cyclopentane, cyclohexane and cycloheptane.

In the general formula (I), the monocyclic heterocycle represented by A means an aromatic 3-7 membered ring containing one or two heteroatoms which may be partially or entirely saturated.

Examples of these rings include furan, thiophenyl,
Examples thereof include pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine rings, and rings in which some or all of these rings are saturated.

In formula (I), the particularly preferred heterocycle as A is a piperidine, pyrrolidine or thiazolidine ring.

In the general formula (Id), the monocyclic heterocycle represented by A ′ and containing two heteroatoms means an aromatic 3 to 7-membered ring which may be partially or entirely saturated.

Examples of these rings include oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyridazine, pyrimidine,
Examples include a pyrazine ring and a ring in which some or all of these rings are saturated.

A particularly preferred heterocycle as A'is a thiazolidine ring.

In the general formula (If), "alkylene having 4 to 20 carbon atoms" represented by AlK 'means tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tris. Decamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, heptadecamethylene, octadecamethylene, nonadecamethylene, eicosamethylene and isomers thereof.

The "alkylene having 1 to 3 carbon atoms" represented by AlK in the general formula (I) means methylene, ethylene, trimethylene and isomers thereof.

In the general formula (I), “alkyl having 1 to 6 carbon atoms” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ means methyl, ethyl, propyl, butyl, pentyl and hexyl and Refers to these isomers.

In the general formula (I), "alkyl having 1 to 6 carbon atoms" in G.
The same is true for Further, "alkoxy having 1 to 6 carbon atoms" in R ² and G means methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy and isomers thereof.

In the general formula (I), the “halogen atom” in G means a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.

In the general formula (I), the carbocycle represented by G means a monocyclic, bicyclic or tricyclic aromatic ring having 15 or less carbon atoms which may be partially or entirely saturated.

Examples of these rings include benzene, naphthalene, indene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene rings, and rings in which some or all of them are saturated.

In the general formula (I), the heterocyclic ring represented by G means a monocyclic, bicyclic or tricyclic carbon which may be partially or wholly saturated, and a heterocyclic ring having 15 or less hetero atoms.

Of these rings, those having one or two heteroatoms are preferred.

Examples of these rings include furan, thiophene,
Pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran,
Benzothiophene, indolizine, chromene, quinoline, isoquinoline, quinolidine, purine, indazole, quinazoline, cinnoline, quinoxaline, phthalazine, pteridine, carbazole, acridine, phenanthridine, xanthene, phenazine, phenothiazine ring and some or all of them Included are saturated rings.

Particularly preferred rings as G in the general formula (I) are benzene, naphthalene, fluorene, pyridine, furan, isoquinoline and acridine rings, and rings in which a part thereof is saturated.

Among these rings, a substituted benzene ring is preferable as the ring further substituted with a substituent.

The heteroatom in the heterocycle in the present invention means a nitrogen atom, an oxygen atom or a sulfur atom.

In the present specification including the claims, all stereoisomers caused by the configuration (asymmetric carbon, double bond, etc.) and structural isomers caused by branching of the carbon chain are included in the present invention.

For example, it is easily understood by those skilled in the art that the alkylene and alkenylene groups referred to in the present invention include those having a molecular chain as well as a straight chain.

The ring represented by A and the ring in G may be bonded to adjacent groups at any positions.

Non-Toxic Salt Among the compounds of the present invention represented by the general formula (I), the compound containing a carboxyl group in L is converted into a salt by a known method.

 The salt is preferably non-toxic and water-soluble.

Suitable salts include salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.) and the like. The salt here includes a hydrate.

Method for producing the compound of the present invention (1) Among the compounds of the present invention represented by the general formula (I), the general formula [In the formula, L ²¹ is a general formula -CO-COR ² , (In the formula, all symbols have the same meanings as described above.), And the other symbols have the same meanings as described above. ] The compound represented by the following can be produced according to the following reaction process formula [A].

The symbol in each formula has the same meaning as described above or the following meaning.

R ²¹ : an alkoxy group having 1 to 6 carbon atoms The reactions in the reaction process formula [A] are all known, but will be briefly described.

The step <a> is an N-acylation reaction, and is performed, for example, using an aqueous solution of an alkali (sodium hydrogen carbonate or the like) and benzoyl chloride in an organic solvent (acetone or the like) which can be mixed with water.

The step <b> is an oxidation reaction, and is performed by using, for example, a Swan oxidation method or a Jones oxidation method.

Step <c> is a hydrocyanation reaction, and is carried out using potassium cyanide in the presence of an acid (hydrochloric acid etc.) in an organic solvent (THF etc.) miscible with water.

Step <d> is a hydrolysis reaction, and is carried out by refluxing in the presence of an acid (hydrochloric acid or the like).

Step <e> is an esterification reaction, and is performed, for example, by using thionyl chloride or hydrogen chloride gas in a corresponding alcohol (methanol, ethanol, etc.).

Step <f> is an amidation reaction, for example, a compound represented by the general formula (VI
The carboxylic acid represented by II) is converted to the corresponding acid halide using an acid halogenating reagent (thionyl chloride, oxalyl chloride, etc.), and this is converted to a tertiary amine (triethylamine) in an inert organic solvent (methylene chloride, etc.). Etc.) in the presence of an amine represented by the general formula (VII) or a carboxylic acid represented by the general formula (VIII) in an inert organic solvent (THF, etc.) in a mixed acid anhydride ( Isobutyl chloroformate, ethyl chloroformate, pivaloyl chloride, etc.) is used as an active ester, which is reacted with an amine represented by the general formula (VII) in the presence or absence of a tertiary amine (same as above). It is carried out by

The step <g> is an oxidation reaction, and is performed by using, for example, a Swan oxidation or a Johns oxidation technique.

Step <h> is a hydrolysis reaction, and is performed using an aqueous solution of alkali (potassium carbonate, sodium hydroxide, etc.) in an organic solvent (methanol, etc.) mixed with water, for example.

Step <i> is an amidation reaction, for example, a tertiary amine (triethylamine, etc.) in an inert organic solvent (THF, etc.)
In the presence of a chloroformate (such as isobutyl chloroformate) and the corresponding amine.

Step <j> is an esterification reaction. For example, using a halide (benzyl bromide, alkyl bromide, etc.) in the presence of a base (potassium carbonate, triethylamine, etc.) in an inert organic solvent (DMSO, DMF, acetone, etc.) Will be performed.

The step <k> is a hydrolysis reaction and is performed in the same manner as the suburb <h>.

Step <l> is an esterification reaction and is performed in the same manner as step <j>.

The step <m> is an oxidation reaction and is performed in the same manner as the step <g>.

Method for producing compound of the present invention (2) Of the compounds represented by the general formula (I), general formula [Wherein L ²² is a general formula ^{-CO-R 4, -CO-CH} 2 -COR 2, -CO-CF ^₂ -COR _2, And all other symbols have the same meanings as described above. ] The compound represented by the following reaction formula [B] or [C]
Can be manufactured according to.

The symbol in each formula has the same meaning as described above or the following meaning.

R ⁴¹ : alkyl having 1 to 6 carbons, phenyl or an alkyl group having 1 to 6 carbons substituted with phenyl The reactions in the reaction steps [B] and [C] are known, but will be briefly described.

Step <n> is a Reformatsky reaction, and is carried out, for example, by refluxing with a corresponding alkyl bromoacetate in the presence of zinc powder and iodine in an inert organic solvent (THF, benzene, etc.).

Step <o> is a hydrolysis reaction, and the above step <h>
The same is done as.

The step <p> is a mild oxidation reaction, and is performed using a Dess-Martin reagent in an inert organic solvent (methylene chloride, etc.), for example.

Step <q> is a hydrolysis reaction, and the above step <h>
The same is done as.

Step <r> is an amidation reaction, and the above step <i>
The same is done as.

Step <s> is a Reformatsky reaction, and is carried out in the same manner as in step <n> using the corresponding alkyl bromodifluoroacetate instead of alkyl bromoacetate.

Step <t> is a hydrolysis reaction, and the above step <h>
The same is done as.

The step <u> is a mild oxidation reaction and is performed in the same manner as the step <p> described above.

Step <v> is a hydrolysis reaction, and the above step <h>
The same is done as.

The step <w> is an acetalization reaction, and is performed, for example, by using an acid catalyst (camphorsulfonic acid, p-toluenesulfonic acid, etc.) in alcohol (methanol, ethanol, etc.).

Step <x> is an acetalization reaction, and is carried out, for example, by refluxing with ethylene glycol in the presence of an acid catalyst (p-toluenesulfonic acid etc.) in an inert organic catalyst (benzene etc.).

The step <y> is a Grignard reaction, and is carried out, for example, in ether (THF or the like) using a corresponding Grignard reagent (alkylmagnesium chloride or the like).

The step <z> is an oxidation reaction and is performed in the same manner as the step <g>.

Step <aa> is a fluoroalkylation reaction, and is performed, for example, using trifluoromethyl iodide under ultrasonic irradiation.

The step <bb> is an oxidation reaction and is performed in the same manner as the step <u>.

Starting materials and respective reagents in the present invention are known,
For example, compounds represented by the general formulas (VIII) and (IX) are disclosed in JP-A-1-156957, JP-A-63-162672, JP-A-63-264454, JP-A-64-69 or 64-6263. It is described together with its manufacturing method.

The reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, etc. can do. Purification may be carried out for each reaction, or may be carried out after the completion of some reactions.

Pharmacological activity of the compound of the present invention The compound of the present invention represented by the general formula (I) has a prolyl endopeptidase inhibitory activity as described above. For example, in a laboratory experiment, the following results were obtained. .

Prolyl endopeptidase inhibitory activity in in vitro system The compounds of the present invention showed the activity shown in the following Table I in the experimental system described later.

The prolyl endopeptidase inhibitory activity in the in vitro system was determined by the following experimental system.

20 mM Tris-HCl buffer (pH 7.5; 10 mM EDTA and 10 mM
Contains mercaptoethanol. ) 935 μl, 10 μl of a DMSO solution of the compound of the present invention, and a tris-hydrochloric acid buffer solution of prolyl endopeptidase purified from bovine brain (0.13 unit
/ ml; J. Biochem., 94 , 1179 (1983). )
15 μl of the mixture was pre-incubated for 15 minutes at 37 ° C. To this, 40 μl of 5 mM N-benzyloxycarbonyl-glycyl-prolyl-p-nitroanilide (40% dioxane aqueous solution) was added, and the mixture was incubated at the same temperature for 1 minute, and then the absorbance (a ₁ ) at 405 nm was measured. Incubate the reaction at 37 ° C for 30 minutes and
The absorbance (a ₂ ) at 5 nm was measured.

At the same time, an experiment was conducted in which the solution of the present invention was replaced with DMSO in the above system, and the absorbances b ₁ and b ₂ were measured in the same manner.

The inhibition formula is The concentration required for 50% inhibition (IC ₅₀ ) was calculated (see Protein / Nucleic Acid / Enzyme 25 (6) , 513 (1980)).

Toxicity On the other hand, the toxicity of the compound of the present invention is very low, and it can be judged that it is sufficiently safe for use as a medicine.

Application to pharmaceuticals Inhibiting prolyl endopeptidase in animals including humans, especially humans, is a substance considered to be involved in neurotransmitters and memory in the brain as described above (both It is useful for the prevention and / or treatment of amnesia because it prevents the metabolism of (peptide).

Since the compound of the present invention has a prolyl endopeptidase inhibitory activity, as is clear from the experimental results in an in vitro system, it is expected to be useful for the prevention and / or treatment of amnesia.

When the compound of the present invention is used for the above purpose, it is usually administered systemically or locally, orally or parenterally.

Dosage depends on age, body weight, symptoms, therapeutic effect, administration method,
Depending on the treatment time, etc., it is usually administered in the range of 1 mg to 500 mg once per adult orally once to several times a day, or in the range of 1 mg to 100 mg once per adult. Parenteral administration (preferably intravenous administration) is performed once to several times a day.

Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be required in some cases.

When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like.

Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.

In such solid compositions, the one or more active substances are at least one inert diluent (lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate). It is used as a mixture with magnesium).

These compositions are prepared according to a conventional method by using additives other than inert diluents such as lubricants (magnesium stearate, etc.), disintegrants (calcium fibrin gluconate, etc.), solubilizing agents (glutamic acid, aspartic acid, etc.). ) Or a stabilizer (lactose etc.) may be contained.

If necessary, tablets or pills may be gastric or enteric coated substances (sucrose, gelatin, hydroxypropylcellulose,
Hydroxypropyl methylcellulose phthalate etc.).

Capsules include hard capsules and soft capsules.

Liquid compositions for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Such a liquid composition contains a generally used inert diluent (purified water, ethanol, etc.).

These compositions include a wetting agent, in addition to an inert diluent,
An auxiliary agent such as a suspension agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative may be contained.

Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated by conventional methods. Spray agents include stabilizers (sodium sulfite, etc.) and buffer agents (sodium chloride, sodium citrate,
Citric acid etc.) may be contained. The method described in US Pat. Nos. 2,868,691 and 3,095,355 can be used for producing the spray agent, for example.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.

In such an injection, at least one inactive aqueous diluent (distilled water for injection, physiological saline, etc.) or an inactive nonaqueous diluent (propylene glycol) is used as one or more active substances. , Polyethylene glycol, olive oil, ethanol, polysorbate 80 (registered trademark), etc.).

These injections further include preservatives, wetting agents, emulsifiers,
An auxiliary agent such as a dispersant, a stabilizer (lactose, etc.), a solubilizing agent (glutamic acid, aspartic acid, etc.) may be contained.

These are usually sterilized by excess (bacterial retention filter, etc.), blending of a bactericide or irradiation, or after these treatments, a solid composition is prepared by a method such as freeze-drying, and sterile water is added immediately before use. , Or by adding a sterile injectable diluent.

Other compositions for parenteral administration include external preparations containing one or more active substances and prepared by a conventional method, external preparations such as coating agents, suppositories for rectal administration, vagina. Includes pessaries for internal administration.

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

The solvent in parentheses described in the column of separation by chromatography indicates the elution solvent or the developing solvent used, and the ratio indicates the volume ratio. Unless otherwise specified, IR is measured by the liquid film method.

Reference Example 1 Synthesis of (2S) -1-benzoylpyrrolidine-2-methanol (S) -2-pyrrolidinemethanol (12.0 g) was dissolved in a mixed solvent of acetone (70 ml) -water (14 ml), and a solution of benzoyl chloride (18.5 ml) and sodium carbonate (17.0 g) in water (50 ml) was added. Dropped. After the dropping, the mixture was stirred at room temperature for 30 minutes and filtered. Water was added to the filtrate, and the mixture was extracted with methylene chloride. The extract was washed, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (24.1 g) having the following physical data.

TCL: Rf 0.19 (EtOAc).

Reference Example 2 Synthesis of (2S) -1-benzoylpyrrolidin-2-al A solution of oxalyl chloride (16.4 ml) in methylene chloride (300 ml) was cooled to −70 ° C., a solution of DMSO (27.9 ml) in methylene chloride (50 ml) was added dropwise, and the mixture was stirred for 30 minutes. To this, a solution of (2S) -1-benzoylpyrrolidine-2-methanol (24.1 g) in methylene chloride (120 ml) was added to -70.
The mixture was added dropwise at 0 ° C and stirred for 30 minutes. Triethylamine (89.5 ml) was added dropwise to the reaction solution at -70 ° C, the mixture was stirred at the same temperature for 50 minutes, and the temperature was gradually raised to 0 ° C. Water was added and the mixture was extracted with methylene chloride. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (23.7 g) having the following physical data.

TLC: Rf 0.38 (EtOAc).

Reference Example 3 (2RS) -2-[(2S) -1-benzoylpyrrolidine]
Synthesis of 2-hydroxyacetonitrile (2S) -1-benzoylpyrrolidin-2-al (2
3.7 g) was dissolved in a mixed solvent of THF (200 ml) -water (135 ml), potassium cyanide (8.36 g) was added thereto, ice-cooled, and concentrated hydrochloric acid (10 ml) was added dropwise. The reaction solution was stirred at the same temperature for 1 hour and then at room temperature for 20 minutes. Water was added to the reaction solution, which was extracted with methylene chloride. The extract was washed, dried and concentrated under reduced pressure to give the title compound having the following physical data.

TLC: Rf 0.44 and 0.51 (EtOAc).

Reference Example 4 (2RS) -2-[(2S) -pyrrolidin-2-yl] -2
-Hydroxyacetic acid synthesis Concentrated hydrochloric acid (210 ml) was added to (2RS) -2-[(2S) -1-benzoylpyrrolidine] -2-hydroxyacetonitrile (21 mg), and the mixture was refluxed for 1 hour. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and washed with ether. The aqueous layer was adsorbed on an Amberlite column and eluted with aqueous ammonia. The eluate was concentrated under reduced pressure, dissolved in water, activated carbon was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure,
By cooling to 10 ° C and collecting the precipitated crystals by filtration,
The title compound (5.84 g) having the following physical data was obtained.

TLC: Rf 0.16 (EtOAc: AcOH : H 2 O = 3: 1: 1).

Reference Example 5 Synthesis of (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidine-2-methanol A solution of 3- (N-benzyl-N-methylcarbamoyl) propionic acid (2.5g) in THF (30ml) was cooled to -20 ° C, triethylamine (4.0ml) and isobutyl chloroformate (1.86ml) were added dropwise. Stirred at temperature for 30 minutes. THF of (S) -2-pyrrolidinemethanol (1.45g)
Triethyleneamine (4 ml) was added to the (30 ml) solution, and -2
After cooling to 5 ° C, the above solution was added dropwise and stirred at the same temperature for 1 hour. After the reaction, water was added and the mixture was extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ —CH ₃ OH) to give the title compound (2.59 g) having the following physical data.

TLC: Rf 0.24 (EtOAc: CH 3 OH = 9: 1).

Reference Example 6 Synthesis of (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al Using (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidine-2-methanol (2.59 g) and by the same operation as in Reference Example 2, the title compound having the following physical properties ( 2.37 g) was obtained.

TLC: Rf 0.40 (EtOAc: CH 3 OH = 9: 1).

Example 1 (2RS) -2-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
Synthesis of 2-yl] hydroxyacetic acid ethyl ester 3- (N-Methyl-N-benzylcarbamoyl) propionic acid (1.33 g) was dissolved in THF (16 ml), to which triethylamine (3.5 ml) and isobutyl chloroformate (9
80 μl) was added, and the mixture was stirred at −15 ° C. for 15 minutes (this solution is designated as). (2RS) -2-[(2S) -pyrrolidin-2-yl]-
2-Hydroxyacetic acid (1.0 g) was dissolved in ethanol (25 ml), the reaction solution was cooled to -20 ° C, thionyl chloride (10 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to -20 ° C again and triethylamine (5 ml) was added.
Was added dropwise and the mixture was returned to room temperature and then concentrated under reduced pressure. To the residue
THF (26 ml) and triethylamine (1.15 ml) were added, and -1
Cooled to 0 ° C. The above solution was added dropwise to this, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOA).
Purified in c), the title compound having the following physical data (1.67 g)
I got

TLC: Rf 0.41 (CH ₂ Cl ₂ : CH ₃ OH = 9: 1); IR (CHCl ₃ solution): ν 3470 to 3350, 3000, 1730, 1630,
1440, 1250-1210, 1120 cm ^-1 .

Example 1 (a) -1 (n) By the same operation as in Example 1, the title compound having the physical properties shown in Table II below was obtained.

Example 2 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of 2-oxoacetic acid ethyl ester Oxalyl chloride (260 μl) in methylene chloride (1
The solution (0 ml) was cooled to −78 ° C., DMSO (443 μl) was added dropwise thereto, and the mixture was stirred at the same temperature for 15 minutes. In this solution,
(2RS) -2-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl] propanoyl] pyrrolidine-
2-yl] -2-hydroxyacetic acid ethyl ester (700 m
A solution of g) in methylene chloride (6 ml) was added dropwise at the same temperature and stirred for 20 minutes, then triethylamine (1.42 ml) was added dropwise, the mixture was stirred for 10 minutes at the same temperature and further for 30 minutes at 0 ° C. Water was added to the reaction solution and extracted with EtOAc.
The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (627 mg) having the following physical data.

TLC: Rf 0.18 (EtOAc); IR (CHCl ₃ solution): ν 3000, 1725, 1630, 1440, 1205,
1050 cm ^-1 .

Example 2 (a) -2 (s) By the same operation as in Example 2, the title compound having the physical properties shown in Table III below was obtained.

Example 3 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of 2-oxoacetic acid monohydrate 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid ethyl ester (626 mg), potassium carbonate (277 mg), methanol (7 ml ) And water (4m
The mixture of l) was stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure to give the title compound (458 mg) having the following physical data.

TLC: Rf 0.42 (EtOAc: AcOH: H ₂ O = 3: 1: 1); IR (CHCl ₃ solution): ν 3000, 1725, 1625, 1445 cm ⁻¹ .

Example 3 (a) -3 (r) By the same operation as in Example 3, the title compound having the physical properties shown in Table IV below was obtained.

Example 4 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]-
Synthesis of 2-oxo-N-ethylacetamide A solution of 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid (98 mg) in THF (3 ml) was added to -20.
The mixture was cooled to ° C, triethylamine (188 µl) and isobutyl chloroformate (77 µl) were added dropwise, and the mixture was stirred at the same temperature for 20 minutes. Add ethylamine solution (70
%; 200 μl) was added dropwise, the temperature was gradually raised to room temperature, and the mixture was stirred for 1 hour. Water was added to the reaction solution and extracted with EtOAc.
The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ —CH ₃ OH) to give the title compound (62 mg) having the following physical data.

TLC: Rf 0.34 (EtOAc: AcOH: H ₂ O = 3: 1: 1); IR: ν 3300, 2980, 2940, 2875, 1730, 1630, 1520, 14
35, 1375, 1355, 1240, 1145, 1120, 1040 cm ^-1 .

Example 4 (a) -4 (b) By the same operation as in Example 4, the title compound having the physical properties shown in Table V below was obtained.

Example 5 (2RS) -2-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
Synthesis of 2-yl] -2-hydroxyacetic acid monohydrate (2RS) -2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid ethyl ester (67
The title compound (517 mg) having the following physical data was obtained by the same procedure as in Example 3 using 0 mg).

TLC: Rf 0.42 (EtOAc: AcOH: H ₂ O = 3: 1: 1); IR (CHCl ₃ solution): ν 3000, 1725, 1625, 1440 cm ⁻¹ .

Example 6 (2RS) -2-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
Synthesis of 2-yl] -2-hydroxyacetic acid benzyl ester (2RS) -2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid (134 mg), potassium carbonate (64 mg), benzyl Bromide (51 μl) and
A mixture of DMSO (1 ml) was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with a mixed solvent of hexane-EtOAc (1: 1). The extract was washed, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-
The title compound (141
mg) was obtained.

TLC: Rf 0.46 (CH ₂ Cl ₂ : CH ₃ OH = 10: 1); IR (KBr tablets): ν 3400 to 3340, 2950 to 2920, 1735, 162
5, 1440-1410, 1240, 1185, 1120 cm ^-1 .

Example 6 (a) By the same operation as in Example 6, the title compound having the physical properties shown in Table VI below was obtained.

Example 7 Synthesis of 2-[(2S) -1- [3- (N-benzyl-N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid benzyl ester Example using (2RS) -2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid benzyl ester (129 mg). The same operation as in 2 gave the title compound (109 mg) having the following physical data.

TLC: Rf 0.56 (CH ₂ Cl ₂ : CH ₃ OH = 10: 1); IR: ν 2950 to 2910, 1720, 1630, 1435, 1260, 1120, 10
50 cm ^-1 .

Example 8 (1RS) -1-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
2-yl] -2,2,2-trifluoroethanol Trifluoroiodomethane (2.3 g) was trapped at -78 ° C, and DMF (7 ml), (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidine-2-al ( 710 mg) and zinc (1.0 g) were added and sonicated at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with EtOAc. Wash the extract, dry,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (217 mg) having the following physical data.

TLC: Rf 0.24 and 0.33 (EtOAc); IR: ν 3300-3250, 2920, 1735, 1690, 1640-1610, 14
40-1400, 1375, 1265, 1160, 1120 cm ^-1 .

Example 9 1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of -2,2,2-trifluoroethan-1-one (1RS) -1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2,2,2-trifluoroethanol (103m
A mixture of g), Dess-Martin reagent (435 mg) and methylene chloride (1.5 ml) was stirred at room temperature for 3 hours. After the reaction, the reaction solution was diluted with ether and saturated sodium hydrogen carbonate aqueous solution (30 g) in which sodium thiosulfate (3.0 g) was dissolved (30
ml) and stirred at room temperature for 10 minutes. This is EtOA
Extract with c, wash the extract, dry and concentrate under reduced pressure.
The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (5
2 mg) was obtained.

TLC: Rf 0.32 (EtOAc): IR: ν 3270-3150, 2920, 1730, 1630-1600, 1445-14
05, 1260 to 1240, 1160 cm ^-1 .

Example 10 (3RS) -3-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
Synthesis of 2-yl] -3-hydroxy-propionic acid ethyl ester Ethyl bromoacetate (0.70 ml) was dissolved in THF (6 ml), zinc dust (482 mg) and a small amount of iodine were added thereto, and the mixture was refluxed for 30 minutes. This solution was added to (2S) -1- [3-
(N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (1.21 g) benzene (10 m
l) The solution was added dropwise and refluxed for 30 minutes. After the reaction, 1N hydrochloric acid was added, and the mixture was extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (1.21 g) having the following physical data.

TLC: Rf 0.38 (CH ₂ Cl ₂ : CH ₃ OH = 10: 1); IR: ν3450-3350, 2980, 1730, 1630, 1440-1410, 137
5, 1270-1240, 1180-1150, 1110, 1030 cm ^-1 .

Example 11 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of 3-oxopropionic acid ethyl ester (3RS) -3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -3-hydroxypropionic acid ethyl ester (230 mg) in acetone (1 ml) The solution was cooled to -30 ° C, excess Jones reagent was added dropwise, and at the same temperature for 1 hour,
The mixture was stirred at -20 ° C for 1 hour and then at -10 ° C for 1 hour.
After adding isopropyl alcohol to the reaction mixture, water was added and the mixture was extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (98 mg) having the following physical data.

TLC: Rf 0.50 (CH ₂ Cl ₂ : CH ₃ OH = 10: 1); IR; ν2980 to 2920, 1710, 1630, 1430 to 1400, 1360, 130
5, 1255, 1020 cm ^-1 .

Example 12 (3RS) -3-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
Synthesis of 2-yl] -3-hydroxy-2,2-difluoro-propionic acid ethyl ester Zinc dust (520 mg) was added to THF (8 ml) and refluxed, and ethyl bromodifluoroacetate (815 μl) was added to THF.
(6 ml) solution was added dropwise. After refluxing for 2 minutes, (2S)
-1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (800 mg)
THF solution (8 ml) was added dropwise and the mixture was refluxed for 10 minutes. After cooling down,
A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOA).
Purification in c) gave the title compound (754 mg).

TLC: Rf 0.21 (EtOAc); IR: ν 3270-3200, 3000-2925, 1780-1760, 1635-16
05, 1440-1425, 1375, 1310 cm ^-1 .

Example 13 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of -3-oxo-2,2-difluoro-propionic acid ethyl ester To a suspension of Dess-Martin reagent (448 mg) in methylene chloride (6 ml), (3RS) -3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidine-2- A solution of ethyl] -3-hydroxy-2,2-difluoro-propionic acid ethyl ester (250 mg) in methylene chloride (1.5 ml) was added dropwise and the mixture was stirred for 3 hours. The reaction mixture was diluted with ether, a saturated aqueous sodium hydrogen carbonate solution (30 ml) in which sodium thiosulfate (2.26 g) was dissolved was added thereto, and the mixture was stirred for 10 minutes and extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOA).
Purified in (c), the title compound (238m
g) was obtained.

TLC: Rf 0.25 (EtOAc), IR: ν 3000 to 2930, 1765, 1630, 1435, 1370, 1305, 12
00, 1125, 1085, 1015 cm ^-1 .

Example 14 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of -3-oxo-2,2-difluoro-propionic acid hydrate 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -3-oxo-2,2-difluoro-propionic acid ethyl ester By the same operation as in Example 3, the title compound having the following physical data was obtained.

TLC: Rf 0.40 (EtOAc: AcOH: H ₂ O = 3: 1: 1); IR (CHCl ₃ solution): ν2990, 2920, 1755, 1625, 1440, 1
120 cm ^-1 .

Example 15 (1RS) -1-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
2-yl] propan-1-ol (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (70
A solution of 0 mg) in THF (5 ml) was cooled to -25 ° C, and a solution of ethylmagnesium chloride in THF (2M, 1.5 ml) was added dropwise thereto,
The mixture was stirred at the same temperature for 30 minutes, 0 ° C. for 30 minutes, and room temperature for 1 hour. After the reaction, saturated aqueous ammonium chloride solution was added to separate the layers. The organic layer was washed, dried and concentrated under reduced pressure. Silica gel column chromatography (EtOA
Purification by c-CH ₃ OH), to give the title compound having the following physical data (270 mg).

TLC: Rf 0.47 (EtOAc: CH ₃ OH = 9: 1); IR: ν 3350, 1600, 1400, 1220, 1090, 720, 680 cm ⁻¹ .

Example 15 (a) The title compound having the physical properties shown in Table VII below was obtained by the same procedure as in Example 15.

Example 16 1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Propan-1-one Example 2 using (1RS) -1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] propan-1-ol
The title compound having the following physical data was obtained in the same manner as described above.

TLC: Rf 0.49 (CH ₂ Cl ₂ : CH ₃ OH = 19: 1); IR: ν1700, 1620, 1400, 1100, 720, 670 cm ⁻¹ .

Example 17 (1RS) -1-phenyl-1-[(2S) -1- [3-
Synthesis of (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] methanol (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (20
A solution of 0 mg) in THF (5 ml) was cooled to -25 ° C, and a solution of phenylmagnesium bromide in THF (2M, 0.49 ml) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 30 min and at 0 ° C. for 30 min, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with EtOAc. The extract was washed, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc-CH ₃
The title compound (45mg) with the following physical data
I got

TLC: Rf 0.34 (EtOAc: CH ₃ OH = 19: 1); IR: ν 3350, 1610, 1420, 1180, 1040, 670 cm ⁻¹ .

Examples 17 (a) -17 (c) By the same procedure as in Example 17, the title compounds having the physical properties shown in Table VIII below were obtained.

Example 18 Synthesis of [(2S) -1 [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] dimethoxymethane (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (16
To a solution of 0 mg) in methanol (2 ml) was added α-camphorsulfonic acid (11.6 mg), and the mixture was stirred at room temperature for 3 hours. After the reaction, extraction was performed with EtOAc, the extract was washed, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography _{(EtOAc-CH 2 Cl 2 -CH} 3 OH), to give the title compound having the following physical data (156 mg).

TLC: Rf 0.42 (EtOAc: CH ₂ Cl ₂ : CH ₃ OH = 9: 5: 1) IR: ν 2900, 1620, 1400, 1180, 1110, 1050, 960, 73
0,690 cm ^-1 .

Examples 18 (a) -18 (b) By the same procedure as in Example 18, the title compounds having the physical properties shown in Table IX below were obtained.

Example 19 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of -1,3-dioxolane (2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-al (16
4 mg) in benzene solution (3 ml) with ethylene glycol (0.
3 ml), and p-toluenesulfonic acid (1 mg),
Refluxed for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with benzene. Wash the extract,
It was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol -EtOAc-CH ₂ Cl _2), to give the title compound having the following physical data (79 g).

TLC: Rf 0.35 (CH ₃ OH: EtOAc: CH ₂ Cl ₂ = 1: 9: 5); IR: ν 2900, 2850, 1720, 1620, 1400, 1110, 1050, 72
0,680 cm ^-1 .

Example 20 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Synthesis of 3-oxopropionic acid monohydrate By using the compound synthesized in Example 11 and following the same procedure as in Example 3, the title compound having the following physical data was obtained.

TLC: Rf 0.62 (EtOAc: AcOH: H ₂ O = 3: 1: 1); IR (CHCl ₃ solution): ν3000, 1725, 1630, 1440, 1410, 1
250-1210 cm ^-1 .

Formulation Example The following components were mixed by a conventional method and compressed to give 100 tablets each having 50 mg of active ingredient.

-(2RS) -2-[(2S) -N- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid ethyl ester ... 5 g-Fibrin calcium glycolate (Disintegrant)… 0.2g ・ Magnesium stearate (lubricant)… 0.1g ・ Microcrystalline cellulose… 4.7g

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 405/04 207 417/06 211

Claims (14)

[Claims] 1. A general formula [In the formula, Z represents a methylene group or a sulfur atom, R represents a general formula G-E-D-B-A- (in the formula, A is a single bond, alkylene having 1 to 6 carbons, and 2 to 6 carbons). Alkenylene, or general formula Represents a group represented by, a saturated hydrocarbon ring having 4 to 7 carbon atoms, or a monocyclic heterocycle, Y represents alkylene having 1 to 4 carbons or alkenylene having 2 to 4 carbons, and B represents a single bond or Represents an alkylene having 1 to 6 carbon atoms, D is a single bond, an oxygen atom, a carbonyl group or a general formula R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, and E represents a single bond, an alkylene group having 1 to 8 carbon atoms, or a phenyl group or a benzyl group. Represents an alkylene having 1 to 8 carbon atoms, G is an unsubstituted or 1 to 3 alkyl having 1 to 6 carbon atoms, an alkoxy having 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group or a nitro group. Represents a substituted carbocycle or heterocycle, L is a general formula (In the formula, R ² is a hydrogen atom, a hydroxyl group, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, phenyl, alkyl having 1 to 6 carbons substituted with phenyl, or carbon substituted with phenyl. Represents an alkoxy having 1 to 6 carbon atoms, R ³ represents an alkyl having 1 to 6 carbon atoms, phenyl or an alkyl group having 1 to 6 carbon atoms substituted with phenyl, and R ⁴ represents alkyl having 1 to 6 carbon atoms, phenyl Represents a C 1-6 alkyl group substituted with phenyl or a trifluoromethyl group, wherein R ⁵ and R ⁶ are independently a hydrogen atom, C 1-6 alkyl, phenyl or a phenyl-substituted carbon group. Number 1-6
Represents an alkyl group. ) Represents a group represented by. However, the following compounds are excluded: (i) A compound in which A is a single bond and B is also a single bond, (ii) Z is a methylene group, and L is a general formula. -CO-CF ₃ or -CO-CF ^₂ -COR ₂ (in each formula, all symbols have. As defined above) is a group represented by and R is (1) G-E-CONR 1 -B-A-, (2) G -CO-B-A-, (3) G-O-AlK-, (4) G-CHQ- (CH 2) m -, Or (8) A is phenylene (in each formula, AlK represents a single bond or an alkylene group having 1 to 3 carbon atoms, Q represents a hydrogen atom, a lower alkyl group or a phenyl group, m represents 0 or an integer of 1 to 5, p represents an integer of 1 to 5, and other symbols have the same meanings as described above). ] The pyrrolidine derivative or thiazolidine derivative shown by these, or its nontoxic salt or hydrate. 2. The compound according to claim 1, wherein G is a substituted or unsubstituted phenyl, naphthyl or fluorenyl group. 3. General formula [Wherein L ¹ is a general formula (In each formula, all symbols have the same meanings as in claim 1), and the other symbols have the same meanings as in claim 1. ]
The compound according to claim 1, which is represented by: 4. (1RS) -1-[(2S) -1- [3- (N
-Benzyl-N-methylcarbamoyl) propanoyl]
Pyrrolidin-2-yl] -2,2,2-trifluoroethanol, 1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
-2,2,2-trifluoroethan-1-one, 1-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
Propan-1-one, 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
-3-Oxopropionic acid or its ethyl ester, (3RS) -3-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
2-yl] -3-hydroxypropionic acid or its ethyl ester, 3-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
-3-Oxo-2,2-difluoropropionic acid or its ethyl ester, (3RS) -3-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
2-yl] -3-hydroxy-2,2-difluoropropionic acid or its ethyl ester, 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl ]
2-oxo-N-ethylacetamide, 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
2-oxoacetamide or 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
The compound according to claim 1 or 3, which is 2-oxo-N-methyl-N-benzylacetamide. 5. A general formula (Wherein all symbols have the same meanings as in claim 1) and the compound according to claim 1. 6. [(4R) -3- [3- (N-benzyl-N
-Methylcarbamoyl) propanoyl] thiazolidine-
4-yl] dimethoxymethane, (1RS) -1-phenyl-1-[(4R) -3- [3-
(N-benzyl-N-methylcarbamoyl) propanoyl] thiazolidin-4-yl] methanol, (1RS) -1-phenyl-1-[(4R) -3-[(4R)
-3- (4-phenylbutanoyl) thiazolidine-4-
Iylcarbonyl] thiazolidin-4-yl] methanol, (1RS) -1-[(4R) -3- [1- (3-phenylpropanoyl) piperidin-2-ylcarbonyl] thiazolidin-4-yl] propane-1 -Ol, [(4R) -3- (10-phenyldecanoyl) thiazolidin-4-yl] dimethoxymethane or (1RS) -1-phenyl-1-[(4R) -3-[(2RS)
2- (4-Phenylbutanoylamino) -3-methylbutanoyl] thiazolidin-4-yl] methanol as claimed in claim 1 or claim 5. 7. General formula [Wherein L ² is a general formula (Wherein all symbols have the same meanings as in claim 1), and the other symbols have the same meanings as in claim 1. ]
The compound according to claim 1, which is represented by: 8. 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) carbamoyl] propanoyl] pyrrolidine-2
-Yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (9-fluorenyl))
Carbamoyl] propanoyl] pyrrolidin-2-yl]
2-oxoacetic acid, 2-[(2S) -1- [3- [N- (4-trifluoromethylphenylmethyl) -N-phenylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- (N-benzyl-Nt-butylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- (N-benzyl-N-phenylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (1-naphthyl) methyl-N-methylcarbamoyl] ) Propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (2,4-dichlorophenylmethyl) carbamoyl] propanoyl] pyrrolidin-2-yl] -2 -Oxo Acid, 2-[(2S) -1- [3- [N- (2-naphthyl) methyl-N-methylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S)- 1-[(1RS, 2R) -2- (N-benzylcarbamoyl) cyclopentanecarbonyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (4 -Methylphenylmethyl) carbamoyl] propanoyl] pyrrolidine-2
-Yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) -N-phenylcarbamoyl] propanoyl]
Pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) -N-methylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2- Oxoacetic acid, 2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) carbamoyl] propanoyl] pyrrolidine-2
-Yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (9-fluorenyl))
Carbamoyl] propanoyl] pyrrolidin-2-yl]
2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (4-trifluoromethylphenylmethyl) -N-phenylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- (N-benzyl-Nt-butylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- (N-benzyl-N-phenylcarbamoyl) propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (1-naphthyl) methyl-N-methylcarbamoyl] ] Propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1-[(1RS, 2R) -2- (N-benzylcarbamoyl) cyclopentanecarbonyl] pyrrolidine-2 2-[(2S) -1- [3- [N- (2,4-dichlorophenylmethyl) carbamoyl] propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2- [ (2S) -1- [3- [N- (2-naphthyl) methyl-N-methylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (4-methylphenylmethyl) carbamoyl] propanoyl] pyrrolidine-2
-Yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) -N-phenylcarbamoyl] propanoyl]
Pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [3- [N- (4-chlorophenylmethyl) -N-methylcarbamoyl] propanoyl] pyrrolidin-2-yl] -2- Hydroxyacetic acid, or their ethyl ester, benzyl ester or isobutyl ester or [2-[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] dimethoxymethane, 2 -[(2S) -1- [3- (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl]
-1,3-dioxolane, (1RS) -1-[(2S) -1- [3- (N-benzyl-
N-methylcarbamoyl) propanoyl] pyrrolidine-
2-yl] propan-1-ol or (1RS) -1-phenyl-1-[(2S) -1- [3-
The compound according to claim 1 or 7, which is (N-benzyl-N-methylcarbamoyl) propanoyl] pyrrolidin-2-yl] methanol. 9. General formula [In formula, A'is a single bond, C1-C6 alkylene, C2-C6 alkenylene, or general formula. Represents a group represented by, a saturated hydrocarbon ring having 4 to 7 carbon atoms or a monocyclic heterocycle containing 2 heteroatoms, Y represents alkylene having 1 to 4 carbons or alkenylene having 2 to 4 carbons, E'represents alkylene having 1 to 8 carbons or alkylene having 1 to 8 carbons substituted with phenyl or benzyl, and other symbols have the same meanings as described in claim 1 or 7. Represent. ] The compound of Claim 1 shown by these. 10. 2-[(2S) -1- (1RS, 2R) -2-
(3-Phenylpropanoyl) cyclopentanecarbonyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- (4-oxo-7-phenylheptanoyl) pyrrolidin-2-yl]- 2-oxoacetic acid, 2-[(2S) -1- [6- (2-naphthyl) methyl-4
-Oxohexanoyl] pyrrolidin-2-yl] -2-
Oxoacetic acid, 2-[(2S) -1- (1RS, 2R) -2- (3-phenylpropanoyl) cyclopentanecarbonyl] pyrrolidine-
Patents which are 2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- (4-oxo-7-phenylheptanoyl) pyrrolidin-2-yl] -2-hydroxyacetic acid, or their ethyl ester The compound according to claim 1 or 9. 11. General formula [In the formula, all symbols have the same meanings as in the first, fourth or ninth claims. ] The compound of Claim 1 shown by these. 12. A 2-[(2S) -1- [3- [4- (4-
Phenylbutoxy) phenyl] propenoyl] pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- [3- [4- (4-phenylbutoxy) phenyl] propenoyl] pyrrolidin-2-yl]
The compound according to claim 1 or 11, which is 2-hydroxyacetic acid or an ethyl ester thereof. 13. General formula [In the formula, AlK 'represents an alkylene having 4 to 20 carbon atoms,
Other symbols have the same meanings as described in claim 1 or claim 7. ] The compound of Claim 1 shown by these. 14. 2-[(2S) -1- (10-phenyldecanoyl) pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1-[(2RS) -2-isopuyl ] Pyrrolidin-2-yl] -2-oxoacetic acid, 2-[(2S) -1- (10-phenyldecanoyl) pyrrolidin-2-yl] -2-hydroxyacetic acid, 2-[(2S) -1- [(2RS) -2-Isopropyl-7
-Phenylheptanoyl] pyrrolidin-2-yl] -2
-Hydroxyacetic acid, or 2-[(2S) -1-[(2R
The compound according to claim 1 or 13, which is S) -2-isopropyl-6- (4-methoxyphenyl) hexanoyl] pyrrolidin-2-yl] -2-hydroxyacetic acid, or an ethyl ester thereof. .