JPH0670023B2 - Thiazolidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to a thiazolidine derivative useful as a medicine.

More specifically, the present invention has a prolyl endopeptidase (hereinafter referred to as PEP) inhibitory activity and is useful as a therapeutic agent for amnesia having the general formula: (In the formula Is a 5- to 6-membered saturated heterocyclic ring which may contain heteroatoms other than N, and R is a hydrogen atom or an alkoxycarbonyl group).

[Conventional technology]

With the aging of the population, the problem of medical care for the elderly has been emphasized. Among them, senile dementia is a serious social problem, and therefore, the immediate development of an effective therapeutic agent is desired.

Hitherto, as therapeutic agents for amnesia and dementia, there have been used cerebral circulation improving agents due to cerebral vasodilatory action, cerebral metabolism activating agents due to cerebral cell oxygen consumption enhancing action and the like. However, although these agents are effective for dementia due to cerebrovascular disorder, it has been considered difficult to be surely effective for dementia due to other causes.

PEP is known as an enzyme that acts on a physiologically active peptide containing proline and a synthetic substrate to specifically cleave the carboxyl side of proline. This enzyme is associated with memory vasopressin (Vasopressin) and thyrotropin releasing hormone (Thyrotropin Releasing Hormone, TR
H) and the like are decomposed, various studies have been conducted on the relationship between the inhibitory activity of this enzyme and the anti-amnestic effect.
It has been suggested that a PEP inhibitor may be a therapeutic agent for dementia and amnesia (Biochemistry, 55, No. 8, page 831, 1983.
Year).

So far, compounds that inhibit PEP have the formula: Compounds represented by the following are known, but these compounds have completely different constitutions from the compound of the present invention (Japanese Patent Laid-Open No. 60-188317).

The thiazolidine derivative as in the present invention has the formula: Compound represented by [Chem.Abs
tr.) 86, No. 17, 117082v (1977)], formula The compound represented by [Chemical Abstracts (Chem.A
bstr.) 105, No. 25, 227322s (1986)], formula formula And the expression The compound represented by [Chemical Abstracts (Chem.A
bstr.) Volume 95, Issue 19, 169173f (1981), Volume 96, 15
No. 123303r (1982)] and the like are known.

The first of these compounds was synthesized for the study of fragments in the mass spectrum and no description of its own pharmacological action. In addition, the second compound is used as one of the intermediates for the production of a series of compounds having a therapeutic effect on liver diseases, and nothing is described about the pharmacological effect of itself. The third group of compounds has a blood pressure effect and was synthesized as a part of a series of compounds useful as a drug for treating hypertension, but there is no description about the PEP inhibitory activity as in the present invention. .

[Problems to be solved by the invention]

Since a cerebral circulation improving agent and a cerebral metabolism activating agent which have been conventionally used as a therapeutic agent for amnesia and dementia are not so effective, development of an anti-amnestic therapeutic agent with a new action has been desired.

As a result of investigations to find out a therapeutic agent for amnesia which has an action different from that of conventional therapeutic agents, the present inventors have found that a certain thiazolidine derivative exhibits a strong PEP inhibitory activity and can achieve the object.

The present invention is based on these findings.

[Means for solving problems]

The thiazolidine derivative represented by the above general formula (I) of the present invention has a strong PEP inhibitory activity and low toxicity, and is useful as a therapeutic agent for amnesia.

In the general formula (I) of the present invention, The saturated heterocyclic ring of is a 5- to 6-membered saturated heterocyclic ring such as pyrrolidine, thiazolidine, pepidine and morpholine.

The alkoxycarbonyl group is, for example, an alkoxycarbonyl group having 2 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc., and the alkyl group of the alkoxy moiety is linear or branched. But it's okay.

The compound of the general formula (I) of the present invention is a novel compound and can be produced as follows.

For example, the expression A carboxylic acid or a reactive functional derivative thereof represented by the general formula (In the formula And R have the same meanings as described above).

In the production method of the present invention, the compounds of formula (II) and general formula (III) used as starting materials are known compounds and can be obtained as commercial products, or can be easily produced by the methods described in the literature. .

When the compound of the general formula (I) of the present invention is produced by using the carboxylic acid of the general formula (II) and the compound of the general formula (III), the reaction is carried out in the presence of a condensing agent. As the condensing agent, a condensing agent generally used in peptide synthesis, such as N, N'-dicyclohexylcarbodiimide, is used.

Examples of the reactive functional derivative of the compound of the general formula (II) used in the method for producing the compound of the general formula (I) of the present invention include acid halides, acid anhydrides, mixed acid anhydrides and active esters. be able to.

The compound of the general formula (I) of the present invention has 1 to 2 asymmetric carbons including the thiazolidine-4-carboxylic acid moiety, but in the present invention, the configuration of the substituent on each asymmetric carbon is R. , S, or a mixture thereof. Each optically active compound can be obtained by using an optically active compound as a starting material and condensing sterically.

The compound of the general formula (I) of the present invention can be made into various pharmaceutical preparations according to a conventional method. That is, if necessary, pharmaceutical additives such as an excipient, a disintegrant, a condensing agent, a lubricant, etc. are added, and various preparations are prepared according to a conventional method, for example, tablets, powders, granules, capsules, etc. Can be

When the compound of the general formula (I) of the present invention is used as a therapeutic agent for amnesia, its dosage is appropriately determined according to the age, weight, sex, degree of symptoms of the patient, etc.
It is used within the range of 50 to 1000 mg for oral administration and 1 to 500 mg for parenteral administration per day.

〔The invention's effect〕

The compound of the general formula (I) of the present invention is a bovine brain-derived prodrug using N-carbobenzoxy-L-glycyl-L-prolyl β-naphthylamide (hereinafter referred to as Z-Gly-Pro-β-NA) as a substrate. In a test for measuring the inhibitory activity against rill endopeptidase, it shows 50% inhibitory activity at a molar concentration of 7 × 10 ^{−5 to} 3 × 10 ⁻¹⁰ .

Especially 3-((R)-(-)-3-carbobenzoxythiazolidine-4
The IC ₅₀ value of -carbonyl) thiazolidine is 2.6 × 10 ^-10 mol. As described above, the compound of the general formula (I) of the present invention has a strong PEP inhibitory activity and low toxicity, and is therefore a safe and excellent compound useful as a therapeutic agent for amnesia.

〔Example〕

Reference examples and examples will be given below to describe the present invention in more detail. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference example (R)-(-)-3-carbobenzoxythiazolidine-4-carboxylic acid (R)-(-)-thiazolidine-4-carboxylic acid 2.66 g was dissolved in 2N-sodium hydroxide aqueous solution 10 ml and iced. While stirring under cooling, 4.1 g of carbobenzoxy chloride and 15 ml of 2N-sodium hydroxide aqueous solution were simultaneously added dropwise. 2 more at room temperature after dropping
After stirring for an hour, the mixture was washed with diethyl ether and acidified by adding concentrated hydrochloric acid under ice cooling. After standing for 30 minutes, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, (R)-(-)-
3-carbobenzoxy thiazolidine-4-carboxylic acid 4.14
Obtained g (77.5%). This colorless transparent viscous liquid was left to cool and solidify, and recrystallized from diethyl ether-petroleum ether to give colorless needle crystals.

Melting point: 58 to 63 ° C ▲ [α] ²² _D ▼ = -97.5 ° (c = 1, ethyl acetate) MS = m / z = 267 (M ⁺ ) IR (KBr): νco 1742, 1664 cm ^-1 NMR ( CDCl ₃ ) δ: 3.30 (d, 2H), 4.58 (AB-q, 2H), 4.90 (br-s, 1H),
5.18 (s, 2H), 7.34 (s, 5H), 8.50 (s, 1H) Elemental analysis value: (as C ₁₂ H ₁₃ ND ₄ S) C% H% N% Calculated value 53.93 4.90 5.24 Measured value 53.86 4.87 5.19 Example 1 3-((R)-(-)-3-Carbobenzoxythiazolidine-4-carbonyl) thiazolidine (Compound A) (R)-(-)-3-Carbobenzoxythiazolidine-4-carboxylic acid 2.67 g of N-hydroxysuccinimide 1.15 g was dissolved in 20 ml of dioxane, and N, N'- was added while stirring under cooling.
A solution of 2.06 g of dicyclohexylcarbodiimide and 5 ml of dioxane was added dropwise. After standing overnight in a cold place, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residual oily substance was dissolved in 15 ml of dimethoxyethane, and 0.89 g of thiazolidine was added dropwise while stirring under ice cooling. After leaving it overnight, the solvent was distilled off under reduced pressure, 5 ml of water was added to the residue, and the mixture was stirred for 30 minutes and then extracted with ethyl acetate. The organic layer was 1N-hydrochloric acid,
55 The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / benzene = 6/4) to give colorless needle crystals of 3-((R)-(-)-3-carbobenzoxythiazolidine-
4-Carbonyl) thiazolidine was obtained.

Melting point: 73 to 75 ° C ▲ [α] ²⁰ _D ▼ = -83.0 ° (c = 1, ethyl acetate) MS = m / z = 338 (M ⁺ ) IR (KBr): νco 1701,1640 cm ^-1 NMR ( CDCl ₃ ) δ: 2.8 to 3.2 (br-m, 2H), 3.25 (m, 2H), 3.4 to 4.0 (br
-M, 2H), 4.5 to 5.0 (m, 5H), 5.13 (s, 2H), 7.34 (s, 5
H) Elemental analysis value: (as C ₁₅ H ₁₈ N ₂ O ₃ S ₂ ) C% H% N% Calculated value 53.25 5.36 8.28 Measured value 53.61 5.55 8.01 Example 2 Same as Example 1 using corresponding raw materials Reaction was performed to synthesize the following compound.

Example 3 PEP Inhibitory Activity Measurement Experiment Using Z-Gly-Pro-β-NA as a substrate, the inhibitory activity against bovine brain-derived PEP was measured.

(Measurement method) 20 mM containing 10 mM EDTA and 10 mM 2-mercaptoethanol
Tris-HCl buffer (20 mM-Tris HCl Buffer, pH = 7.0)
100 μl of PEP (about 0.14 u / ml) in 0.7 ml and each concentration (0, 1
100 μl of a solution of the test compound adjusted to 0 ⁻⁹ to 10 ⁻⁴ M) was added, and preincubation (Preincubation) was performed at 37 ° C. for 5 minutes.
ation). Then, the substrate of each concentration (5.0, 2.5, 1.25, 0.625, 0.3125 mM) dissolved in 100 μl of 40% dioxane was added thereto, and incubation was carried out again at 37 ° C. for 15 minutes to allow the enzymatic reaction to proceed. Stop the reaction with 25% trichloroacetic acid, centrifuge at 3000 rpm for 10 minutes, and remove the supernatant.
0.5 ml was taken out, 0.5 ml of 0.1% nitrous acid was added thereto, and 0.05% N- (1-naphthyl) ethylenediamine dihydrochloride ethanol solution was further added for 3 minutes. The mixture
After leaving at 37 ° C. for 25 minutes, the absorbance at 570 nm was measured, the enzyme activity at each concentration was calculated by the following formula, and the 50% inhibitory concentration (IC ₅₀ value) was determined from the activity value of the inhibitory activity.

Enzyme activity unit (μmol / min / ml) = Δ0D × 0.42 × dilution rate (Result) Compound IC ₅₀ value Compound A 260 pM Compound B 72 μM Compound C 160 nM Compound F 0.23 mM Compound G 0.21 μM

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Claims (2)

[Claims] 1. A general formula (In the formula Is a 5- to 6-membered saturated heterocyclic ring which may contain a heteroatom other than N, and R is a hydrogen atom or an alkoxycarbonyl group). 2. A formula The thiazolidine derivative according to claim 1, which is represented by: