JP2528343B2 - Novel proline derivative - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to prolyl endopeptidase.
A novel prolinal derivative represented by the following general formula having opeptidase) inhibitory activity (In the formula, the meanings of all symbols are as described below.)
Regarding

2. Description of the Related Art Recent studies have gradually elucidated the identity of neurotransmitters and substances that are deeply related to memory in the brain, but they are believed to be neuropeptides containing many of these prolines. .

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 prolyl endopeptidase (E).
It is believed that C, 3.4.21.26) is 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 Japan Society of Agricultural Chemistry 58 (11), 1147
(1984); J. Neurochem., 41 , 69 (1983); 42 , 237 (198).
See 4)).

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 [In the formula, A ^a is a protecting group for an amina group in amino acid chemistry,
X ^a represents an amino acid residue. ] A prolinal derivative represented by (see JP-A-60-188317), (ii) a general formula Wherein, nb represents a number of 1 to 4, R ^b is a lower alkyl ester group, -CH ₂ OH group or aldehyde group. ] N-acyl pyrrolidine derivative represented by
37764; by amendment compounds with n = 5 are also disclosed) and (iii) the general formula [In the formula, A ^c represents a methyl group or a benzyloxy group,
R ^c represents an isopropyl group or an isobutyl group provided that they have the same meaning in one formula, and nc represents 2 or 3. ] It is disclosed that the compound represented by the formula (see JP-A-61-183297) is useful for the above purpose.

More recently, five patent applications have been published for anti-amnestic agents having a prolinal skeleton.

(Iv) General formula (In the formula, R ^d is —CH ₃ , Or Represents the base of. ) (See JP-A-61-238775), (v) general formula [In the formula, R ^3e represents a lower alkyloxycarbonyl group, a hydroxymethyl group or a formyl group, R ^1e represents a hydrogen atom or a lower alkyl group, and R ^2e represents a phenyl group or a group of the following formulae. (Here, R ^4e represents a hydrogen atom, a halogen atom or a lower alkoxy group, R ^5e represents a hydrogen atom or a lower alkyl group, ne represents 0 or 1, and A ^e represents an oxygen atom, a methylene group or hydroxymethylene. Base,
Represents a phenylmethylene group or a carbonyl group) or R ^1e and R ^2e are ^arbitered to represent an aromatic ring-substituted or unsubstituted benzylidene group. ] An N-acyl pyrrolidine derivative represented by the formula (see JP-A-61-238776), (vi) a general formula (In the formula, nf represents a number of 0 to 2, R ^1f represents a saturated or unsaturated linear organic group having 5 to 25 carbon atoms, and the unsaturated carbon chain represents a plurality of double bonds. May be included, Or a —CH ₃ group, and R ^3f represents a lower alkyl ester group, a —CH ₂ OH group, or an aldehyde group. ) (See JP-A-61-238799).

(Vii) General formula (In the formula, ng represents an integer of 1 or more, R _1g represents a saturated or unsaturated linear hydrocarbon group having 5 to 25 carbon atoms, and the unsaturated carbon chain is a plurality of double bonds. R _3g represents a lower alkyl ester group, a hydroxymethyl group, or a formyl group of the following formula —COOR _4g (wherein R _4g represents a lower alkyl group), and R _2g represents a methyl group. Represents a phenyl group, a hydroxyphenyl group, an indolyl group, an imidazolyl group, a carboxyl group, a formyl group, an amino group, a hydroxy group, a hydroxyalkyl group, a thiol group, a methylthio group, or a guanidino group,
Each of these groups may be substituted, and when R _5g represents a hydrogen atom, or when ng represents a number of 3, R _2g and R _2g
5g can also be taken together to represent a single bond between carbon and nitrogen. Compound represented by the formula (JP-A-62-8405).
See No. 8).

(Viii) General formula (In the formula, mh represents an integer of 1 to 8, nh represents an integer of 1 to 6, R ^1h represents a hydrogen atom, R ^2h represents a hydrogen atom, a branched alkyl group having 3 to 5 carbon atoms, and a phenyl group. , A hydroxyphenyl group, an indolyl group, an imidazolyl group or a methylthio group, or R ^1h and R ^2h are taken together to represent a carbon-nitrogen bond, and R ^3h is a lower alkyl ester group, a hydroxymethyl group or a formyl group. Represents.)
A dipeptide derivative having (see JP-A-62-148467).

Further, the present inventors have filed an application for a prolinal derivative having an antiamnestic effect prior to the present application. That is, (ix) general formula [In the formula, A ^j represents an alkylene or alkenyl group having 1 to 8 carbon atoms, or a saturated hydrocarbon ring having 3 to 7 carbon atoms, and R ^j is a hydrogen atom, a phenyl group, a benzyl group, or a carbon number 1 to 1
8 represents an alkyl group having 8 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, B ^j 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 ^j represents halogen. Atom, alkyl or alkoxy group having 1 to 4 carbon atoms, nitro group or trifluoromethyl group 1
1 to 3 represents a carbocycle or heterocycle which is substituted or unsubstituted. ] A prolinal derivative represented by
See No. 57).

OBJECT OF THE INVENTION The present inventors have conducted extensive studies to find a novel compound useful as an anti-amnestic agent, and as a result, found that the prolinal derivative represented by the general formula (I) achieves the object and completed the present invention. did.

Comparison with the Prior Art The compounds of the present invention represented by the general formula (I) are shown in the compounds represented by the general formulas (A) to (J) described above and in the literature (J. Neurochem., 41 ). The compound is a prolyl endopeptidase inhibitor having a prolinal (pyrrolidin-2-al) skeleton similar to the above compounds.

However, the compound of the present invention is a novel compound structurally different from these compounds.

That is, a modification for introducing an oxo group into an alkylene chain between a benzene ring and prolinal is known (see (v) of the prior art; see JP-A-61-238776), in which the oxo group is It is directly bonded to the benzene ring.

The compound of the present invention has the general formula (E) described in the prior art.
It is a compound in which an alkylene chain is further introduced between the benzene ring and the oxo group of the compound represented by, and the present inventors have found that these compounds have prolyl endopeptidase inhibitory activity.

Furthermore, in some compounds, conversion of the alkylene portion of A into a saturated hydrocarbon ring, introduction of a substituent into the benzene ring, conversion of the benzene ring into a naphthalene ring was attempted, and these modified compounds were used. It was also found that both have prolyl endopeptidase inhibitory activity.

In addition, the present inventors have made some modifications to the group represented by D in the previous application (the compound represented by the general formula (J)), and as a result, changed the benzene ring to another aromatic ring ( Also includes heterocycles and saturated rings; eg naphthalene,
It has been confirmed that the prolyl endopeptidase inhibitory activity is maintained even in the compound substituted with fluorene or furan ring).

Of the compounds of the present invention, which are compounds of the general formula (J) in which a portion other than D is modified, if a compound having a benzene ring as D has sufficient activity, D is replaced with another ring. It is not unexpected that the activity of some compounds will be maintained.

DISCLOSURE OF THE INVENTION The present invention has the general formula [In the Formula, A is C 1-4 alkylene or C 3
To 7 saturated hydrocarbon ring, n represents 2, 3 or 4 and D is a monocyclic, bicyclic or tricyclic aromatic ring having 15 or less carbon atoms which may be partially or entirely saturated. , Or a monocyclic, bicyclic or tricyclic carbon which may be partially or wholly saturated, and plural rings having 15 or less heterocyclic atoms, and D
The aromatic ring and heterocyclic ring represented by are halogen atoms,
It may be substituted with 1 to 3 alkyl or alkoxy groups having 1 to 4 carbon atoms, trifluoromethyl group or nitro group. ] It is related with the novel prolinal derivative shown by these.

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

In the general formula (I), the saturated hydrocarbon ring having 3 to 7 carbon atoms represented by A means a cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane ring.

In the general formula (I), the halogen atom in D is fluorine,
Refers to chlorine, bromine and iodine atoms. Also, carbon number of 1 to 4
The alkyl group of is a methyl, ethyl, propyl and butyl group and isomers thereof, and the alkoxy group having 1 to 4 carbon atoms is a methoxy, ethoxy, propoxy and butoxy group and isomers thereof.

In the general formula (I), a mono-, bi- or tricyclic aromatic ring having 15 or less carbon atoms, which may be partially or entirely saturated, represented by D includes, for example, benzene, naphthalene, indene and azulene. , Fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene rings and rings in which some or all of them are saturated.

In the general formula (I), one or more of the monocyclic, bicyclic or tricyclic carbon atoms which may be partially or fully represented by D and plural rings having 15 or less heteroatoms have one hetero atom or Two is preferable.

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, xanthine, phenazine, phenothiazine ring and some or all of them Included are saturated rings.

Particularly preferred rings as D in the general formula (I) are benzene, naphthalene and a ring in which a part thereof is saturated.

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

In the present specification including the claims, stereoisomers caused by the configuration (asymmetric carbon, etc.) and structural isomers caused by branching of the carbon chain are all 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 branched chain as well as a straight chain.

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

The compound of the present invention represented by the general formula (I) is and [In each formula, Represents a saturated hydrocarbon ring having 3 to 7 carbon atoms, AlK represents an alkylene group having 1 to 4 carbon atoms, and other symbols have the same meanings as described above. ] It can be divided into two types of compound groups represented by.

According to the present invention, the compound of the present invention represented by the general formula (I) has the general formula Or [In the formula, all symbols have the same meanings as described above. ] It can manufacture by oxidizing the prolinol derivative shown by these on mild conditions.

Oxidation reactions under mild conditions are known, for example,
Inert organic solvent (DMSO, methylene chloride, chloroform,
Benzene or the like) with or without a tertiary amine (triethylamine, pyridine, etc.), an oxidizing agent (sulfur trioxide-pyridine complex, chromium trioxide-pyridine complex, t-
Butyl chloroformate, oxalyl chloride, etc.) at a temperature of 0 ° C to 50 ° C.

Method for Producing Intermediate The prolinol derivative represented by the general formula (II) or (III) can be produced according to a series of reactions in the reaction scheme [A] shown below.

In the reaction scheme [A], each symbol has the following meaning or the same meaning as described above.

 B-alkenyl or alkynyl group having 2 to 4 carbon atoms, m-1, 2, 3 or 4.

Each reaction in the reaction scheme [A] is carried out by a known method, and all the starting materials and reagents used in the reaction are known per se or can be produced by a known method.

The reaction product may be purified by a conventional purification means such as 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 or recrystallization. You can 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 μm, DMSO solution 10 μm of the compound of the present invention, and a solution of prolyl endopeptidase purified from bovine brain in tris-hydrochloric acid buffer solution (0.13 unit / ml; J. Biochem., 94 , 1179 (1983)). ) 15μ of the mixture was preincubated for 15 minutes at 37 ° C. To this, 40 μm 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. Further, the reaction solution was incubated at 37 ° C. for 30 minutes, and the absorbance (a ₂ ) at 405 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 rate is The concentration required for 50% inhibition (IC ₅₀ ) was calculated (see Protein / Nucleic Acid / Enzyme 25 (6) , 513, 1980).

On the other hand, the toxicity of the compound of the present invention is extremely low,
It can be judged to be sufficiently safe for use as a medicine.

Indications to pharmaceuticals Inhibiting prolyl endopeptidase in animals including humans, especially humans, is a substance thought 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 a solid composition, a liquid composition and other compositions for oral administration, an injection for parenteral administration, an external preparation, a suppository and the like.

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

In such a solid composition, the one or more active substances may comprise at least one inert diluent (lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, alumina metasilicate) Magnesium, etc.).

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.). Etc.) and a stabilizer (lactose etc.) may be contained.

If necessary, tablets or pills may be gastric or enteric coated substances (sucrose, gelatin, hydroxypropylcellulose,
It may be coated with a film of hydroxypropylmethyl cellulose phthalate or the like).

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 commonly 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 U.S. Pat. Nos. 2868691 and 3095355 can be used for producing the spray agent.

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.

“TLC”, “NMR” and “IR” in Reference Examples and Examples respectively represent “thin layer chromatography”, “nuclear magnetic resonance spectrum” and “infrared absorption spectrum”. The solvent in parentheses described in the column of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Unless otherwise specified, IR is measured by the liquid film method, and NMR is measured by deuterated chloroform (CDCl ₃ ).

Reference Example 1 Synthesis of 7-phenyl-4-oxoheptanoic acid Jones reagent (3.4 ml; 2.6N) was added to a solution of 7-phenylheptane-1,4-diol (630 mg) in acetone (6 ml), and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl ether, washed successively with water and saturated brine, dried and concentrated to give the title compound (580 mg; partially containing lactone) having the following physical data.

TLC: Rf 0.14 and 0.43 (hexane: EtOAc = 1: 1).

Reference Example 2 Synthesis of N- (7-phenyl-4-oxoheptanoyl-L-prolinol Diisopropylcarbodiimide (0.5 ml) was added to a solution of the carboxylic acid (580 mg) synthesized in Reference Example 1 in methylene chloride (6 ml) in an argon atmosphere, and the mixture was stirred for 30 minutes. L-Prolinal (0.31 ml) was added to the reaction solution, and the mixture was stirred for 1 hour and left at -5 ° C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (219 mg) having the following physical data.

TLC: Rf 0.20 (EtOAc); NMR: δ 7.1-7.35 (5H, m), 4.05-4.25 (1H, m), 3,4
0-3.75 (4H, m), 2.40-2.80 (8H, m), 1.8-2.2 (6H, m)
m).

Reference Example 3 Synthesis of 2- [3- (2-nitrophenyl) propyl] tetrahydrofuran-5-one 2- (3-phenylpropyl) tetrahydrofuran-
5-one (230 mg) was dissolved in acetic anhydride (1 ml), ice-cooled, and concentrated nitric acid (70 μ) was added dropwise thereto. After standing for 20 minutes, the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution,
The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and purified by silica gel column chromatography (EtOAc: hexane = 1: 1) to give the title compound (255 mg) having the following physical data. .

TLC: Rf 0.21 and 0.24 (EtOAc: hexane = 1: 1).

Reference Example 4 Synthesis of N- [4-hydroxy-7- (2-nitrophenyl) heptanoyl] -L-prolinol The lactone (250 mg) synthesized in Reference Example 3 was added to THF (5 ml).
, L-prolinol (163 μ) was added, and the mixture was ice-cooled. Sodium hydride (45 mg) was added to the reaction solution, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was adjusted to be acidic with 1N hydrochloric acid, and ethyl acetate was added. The organic layer was dried and concentrated under reduced pressure to give the title compound having the following physical data.

TLC: Rf 0.14 (EtOAc: CH 3 OH = 95: 5).

Example 1 N- (7-phenyl-4-oxoheptanoyl) -L-
Prolinal synthesis Prolineol (105 mg) synthesized in Reference Example 2 was dried with DMS.
Dissolve in O (1 ml) and add triethylamine (0.32
ml) was added. A solution of sulfur trioxide-pyridine complex (185 mg) in DMSO (1 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into ice water and stirred, and then ethyl acetate was added. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EtOAc: hexane = 8:
The title compound (69.4mg) having the following physical properties after purified in 2)
I got

TLC: Rf 0.31 (EtOAc: hexane = 8: 2); IR: (nu) 2900,1705,1700,1630,1420,735,680 cm < ^-1 >.

Examples 1 (a) -1 (m) By the same operations as in Reference Examples 1 and 2 and Example 1, compounds having the physical properties shown in the following Table II were obtained. For Example 1 (j), the compound of Reference Example 4 was used as the starting material.

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

N- (7-phenyl-4-oxoheptanoyl) -L
-Prolinal: 5 g Fibrin calcium gluconate (disintegrant): 0.2 g Magnesium stearate (lubricant): 0.1 g Microcrystalline cellulose: 4.7 g

Claims (11)

(57) [Claims] 1. A general formula [In the formula, A represents an alkylene group having 1 to 4 carbon atoms or a saturated hydrocarbon ring having 3 to 7 carbon atoms, n represents 2, 3 or 4, and D is partially or completely saturated. A good monocyclic, bicyclic or tricyclic aromatic ring having 15 or less carbon atoms, or a monocyclic, bicyclic or tricyclic carbon which may be partially or fully saturated, and having 15 or less heterocyclic atoms The aromatic ring and the heterocycle represented by D, which represent a plurality of rings, may be substituted with 1 to 3 halogen atoms, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group or a nitro group. . ] The prolinal derivative shown by these. 2. A phenyl or naphthyl group which is substituted with 1 to 3 halogen atoms, an alkyl or alkoxy group having 1 to 4 carbon atoms, a trifluoromethyl group or a nitro group or is unsubstituted. The compound according to item 1 in the range. 3. The compound has the general formula [In the formula, Represents a saturated hydrocarbon ring having 3 to 7 carbon atoms, and other symbols have the same meanings as described above. ] The compound of Claim 1 which is a prolinal derivative shown by these. 4. The compound is N- [trans-2- (3-phenylpropanoyl) cyclopentanecarbonyl] -L-prolinal or N- [trans-2- (3-phenylpropanoyl) cyclohexanecarbonyl] -L-. The compound according to claim 1 or 3, which is prolinal. 5. The compound has the general formula [In the formula, AlK represents an alkylene group having 1 to 4 carbon atoms,
Other symbols have the same meanings as described above. ] The compound of Claim 1 which is a prolinal derivative shown by these. 6. The compound according to claim 5, wherein D is an unsubstituted naphthyl group. 7. The compound is N- [6- (1-naphthyl) -4.
-Oxohexanoyl] -L-prolinal or N-
[6- (2-naphthyl) -4-oxohexanoyl]-
The compound according to claim 1 or 6, which is L-prolinal. 8. The compound according to claim 5, wherein D is an unsubstituted phenyl group. 9. The compound is N- (6-phenyl-4-oxohexanoyl) -L-
Prolinal, N- (7-phenyl-4-oxoheptanoyl) -L-
Prolinal, N- (8-phenyl-4-oxooctanoyl) -L-
The compound according to claim 1 or 8, which is prolinal or N- (2RS-isopropyl-3-oxo-7-phenylheptanoyl) -L-prolinal. 10. The compound according to claim 5, wherein D is a phenyl group substituted with a substituent. 11. The compound is N- [6- (4-methylphenyl) -4-oxohexanoyl] -L-prolinal, N- [6- (4-methoxyphenyl) -4-oxohexanoyl]-. L-prolinal, N- [6- (4-chlorophenyl) -4-oxohexanoyl] -L-prolinal, N- [6- (3-chlorophenyl) -4-oxohexanoyl] -L-prolinal, N- [7- (2-nitrophenyl) -4-oxoheptanoyl] -L-prolinal or N- [4-oxo-6- (p-trifluoromethylphenyl) hexanoyl] -L-prolinal A compound according to the range 1 or 10.