JPH01226880A - Thiazolidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (Ar is phenyl, naphthyl or pyridyl; Y is 1-4C saturated or unsaturated alkylene; n is 0 or 1; formula II is a 5-6-membered saturated heterocyclic ring which may contain a hetero- atom other than bonded N; R is H or alkoxycarbonyl). EXAMPLE:3-[(R)-(-)-3-(3-Phenylpropionyl)thiazolidine-4-carbonyl]thiazo lidine. USE:A medicine and remedy for amnesia having prolyl endopeptidase inhibitory activity with low toxicity. The dose thereof is 50-1,000mg/day/adult expressed in terms of an active ingredient in the case of oral administration and 1-500mg/ day/adult in the case of parenteral administration. PREPARATION:For example, a carboxylic acid expressed by formula III or a reactive functional derivative thereof is reacted with a cyclic amine expressed by formula IV in the presence of a condensing agent, such as N,N'- dicyclohexylcarbodiimide, in a solvent, such as dioxane, to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to thiazolidine derivatives useful as pharmaceuticals.

More specifically, the present invention relates to prolyl endopeptidase (Prolyl Endopeptidase).
PEP) has inhibitory activity and is useful as an amnesia treatment agent, with the general formula (in the formula, Ar is a phenyl group, naphthyl group, or pyridyl group, and Y is a saturated or unnatural atom having 1 to 4 carbon atoms). or an alkoxycarbonyl group).

[Conventional technology]

As the population ages, issues of geriatric medical care are becoming more important. Among these, senile dementia is a serious social problem, so there is a desire for the prompt development of effective therapeutic agents.

So far, as therapeutic agents for amnesia, dementia, etc., cerebral circulation improving agents with cerebral vasodilatory effects, and cerebral metabolism activators with increasing effects on brain cell oxygen consumption, etc. have been used. However, although these drugs are effective for dementia caused by cerebrovascular disorders, the drawback is that they are not certain to be effective against dementia caused by other causes.

PUP is known as an enzyme that acts on physiologically active peptides and synthetic substrates containing proline and specifically cleaves the carboxyl side of proline. This enzyme is vasopressin, which is thought to be related to memory.
and thyrotropin-releasing hormone (Thyrotro
Pin Releasing Hormone, TR
) I), etc., various studies have been conducted on the relationship between the inhibitory activity of this enzyme and the anti-amnestic effect, and the results suggest that PEP inhibitors can be used as therapeutic agents for dementia and amnesia. (Biochemistry, Vol. 55, No. 8, 831 pages, 1983).

Until now, compounds represented by the formula have been known as compounds that inhibit PEP, but these compounds have completely different structures from the compound of the present invention (as disclosed in Japanese Patent Publication No. 1983 -188317).

As the thiazolidine derivative of the present invention, a compound represented by the formula [Chemical Abstracts (Chem.
, 8 bstr, ) Volume 86, No. 17, 117082V
(1977)], the compound represented by 0OCH3 [Chemical Abstracts (Chm
e, Abstr,) Volume 105, No. 25, 22732
2s (1986)], the formula and the compound represented by the formula [Chemical Abstracts (Ch.
me, Abstr,) Volume 95, No. 19, 16917
3f (1981), vol. 96, no. 15, 1233
03r (1982)] are known.

The first of these compounds was synthesized for the purpose of studying fragments in mass spectra, and there is no description of its pharmacological action at all. Furthermore, the second compound is used as one of the intermediates for the production of a series of compounds that exhibit therapeutic activity for liver diseases, and nothing is described about its pharmacological activity. The third group of compounds exhibits a blood pressure lowering effect and was synthesized as part of a series of compounds useful as antihypertensive agents, but nothing has been described regarding PEP inhibitory activity as in the present invention. .

[Problem to be solved by the invention]

Since the cerebral circulation improving agents and cerebral metabolism activating agents conventionally used as therapeutic agents for amnesia and dementia are not very effective, it has been desired to develop an anti-amnestic therapeutic agent with a new action.

The present inventors investigated to find a therapeutic agent for amnesia that has an action different from that of conventional therapeutic agents, and found that certain thiazolidine derivatives exhibit strong PEP inhibitory activity and that the objective can be achieved.

The present invention is based on these findings.

[Means to solve the problem]

The thiazolidine conductor of the present invention represented by the general formula (1) exhibits strong PEP inhibitory activity, has 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 -N is a 5- to 6-membered saturated heterocyclic ring such as pyrrolidine, thiazolidine, piperidine, morpholine, and the like.

An alkoxycarbonyl group is, for example, an alkoxycarbonyl group having 2 to 6 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the alkyl group in the alkoxy moiety may be linear or branched. But that's fine.

The compound of the general formula (1) of the present invention is a novel compound, and can be produced as follows.

For example, a carboxylic acid represented by the general formula (^rSY and n in the formula have the same meanings as above) or a reactive functional derivative thereof,
It can be produced by reacting with a cyclic amine represented by the general formula (2).

Alternatively, a carboxylic acid represented by the general formula % (wherein Ar, Y and n have the same meanings as above) or a reactive functional derivative thereof;
It can also be produced using a general formula.

In the production method of the present invention, the compounds of general formulas (n), (III), (rV) and (V) used as starting materials are generally known compounds and are available as commercial products or by methods described in literature. It can be easily manufactured by

In producing the compound of general formula (1) of the present invention, when using a carboxylic acid of general formula (II) or general formula (IV) and reacting it with a compound of general formula (I) or general formula (V), The reaction is carried out in the presence of a condensing agent, such as a condensing agent commonly used in peptide synthesis, such as N,N'-dicyclohexylcarbodiimide.

The reactive functional derivatives of the compound of general formula (II) or general formula (rV) used in the process for producing the compound of general formula (1) of the present invention include acid halides, acid anhydrides, and mixed acid anhydrides. , active esters, etc.

The compound of general formula (1) of the present invention has 1 to 2 asymmetric carbon atoms including the thiazolidine-4-carboxylic acid moiety, but in the present invention, the arrangement of substituents on each asymmetric carbon is RSS or a mixture thereof. Each optically active compound can be obtained by using an optically active compound as a starting material and condensing it in a steric retention manner.

The compound of general formula (1) of the present invention can be made into various pharmaceutical preparations according to conventional methods. That is, by adding pharmaceutical additives such as excipients, disintegrants, condensing agents, and lubricants as necessary, and preparing according to conventional methods, various preparations such as tablets, powders, granules, and capsules can be prepared. etc.

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

〔Effect of the invention〕

The compound of the general formula (1) of the present invention is a bovine brain-derived protein using N-carbobenzoxy-glycyl-prolyl β-naphthylamide (hereinafter referred to as Z-Gly-Pro-β~NA) as a substrate. In the inhibitory activity measurement test against lyluendopeptidase, approximately 5 Xl0-s to 8
It shows 50% inhibitory activity at X10-8 molar concentration.

For example, 1c5 of 3-C(R)-(-)-3-phenylacetylthiazolidine-4-carbonylcutiazolidine
o! , * is 6.3 Xl0-8 moles. As described above, the compound of the general formula (1) of the present invention exhibits strong PEP inhibitory activity and has low toxicity, so it is a safe and useful compound as an excellent amnesia therapeutic agent.

〔Example〕

In order to explain the present invention in more detail, reference examples and examples are given below. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference example 1 (R) -(-)-thiazolidine-4-carboxylic acid 2.
66 g of 3-phenylpropionyl chloride was dissolved in 10 d of an aqueous IJ solution, and while stirring under cooling with water, 5.5 g of 3-phenylpropionyl chloride and 1 d of a 2N aqueous sodium hydroxide solution were added.
5 mN was added dropwise at the same time. After the dropwise addition, the mixture was further stirred at room temperature for 2 hours, washed with diethyl ether, and made acidic by adding concentrated hydrochloric acid while cooling with water. After standing for 30 minutes, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure and recrystallized from ethyl acetate to give (R) -(-) -[:3-
4.06 g (76.5%) of (3-phenylpropionyl)thiazolidine]-4-carboxylic acid were obtained.

Melting point: 93-95°C IR (KBr): vco 1730. 1596
cm-'MS (1: C, 3H, 503NS
= 265.28m/z 265 (kP), 24
8.220.174° 160, 150.91 [α] −-99,9° (cm0.5. diethyl needle) Elemental analysis value:
(as C13HISO3NS)C% )1%
8% 8% Calculated value 58.86 5.70 5.28 12.0
6 Actual value 58.71 5.71 5.33 12.
05 Reference Example 2 Using the corresponding raw materials, a reaction was carried out in the same manner as in Reference Example 1 to synthesize the following compound.

Melting point: 87-90°C (diethyl ether) IR (KBr): vca 1715.1610
cm-'MS (El)'C+<H+tOsNS
=279.30m/z 279 (M”), 2
35.188. 175゜133,91 [α) −-90,8゜(C・0.46.Ethyl acetate) Elemental analysis value: (C1l (+JdlS) C%
1% 8% 8% Calculated value 60°20 6,14 5.02 11.4
5 Actual value 59,99 6.13 4.97 11.
374-carboxylic acid Melting point: 136-138°C (ethyl acetate) IR (K
Br): L'CO1710,1590cm-'[α
] = -115,4° (C・1.0.methanol) Elemental analysis value = (as C1□H, 30, NS) 0%
8% N% 8% Calculated value 57.37 5.22 5.58 12.7
4 Actual measurement value 57.51 5.27 5.45 12.
68(3) (R) -(-)-3-cinnamoylthiazolidine-4-carboxylic acid Melting point = 184-186°C (Improper Tools) IR (KBr): vco 1740. 1650
cm-' [α] = -129.6° (cm1.0. Methanol) Elemental analysis value' (as CI381303NS) 0%
8% N% 3% calculated value 59
．． 31 4.98 5.32 12.16 Actual value 5
9.21 5.26 5.00 11.74 Melting point: 1
46-148℃ (Ethyl acetate) IR (Br):
l'co 1735. 1610 cm-'M
S (El): C16H1SO3NS”
301.30m/z 301 (M”),
229. 168. 141゜132, 88 [α) = -86,7゜ (cm0.75. Dimethyl sulfoxide) elemental analysis value' (as C1sH + 5OJS) 0% 8%
N% 8% Calculated value 63.78 5.02 4.65 10.6
2 Actual measurement value 63.89 5.28 4.65 10.
58 Example 1 Azolidine-4-carbonyl]thiazolidine (R) -
(-) 2.65 g of -3-(3-phenylpropionyl)thiazolidine-4-carboxylic acid and 1.15 g of N-hydroxysuccinimide were dissolved in 20-dioxane, and while stirring under cooling, N, N A solution of 2.06 g of '-dicyclohexanelupodiimide and dioxane 5- was added dropwise. After standing in a cool place overnight, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in 15-dimethoxyethane, and 0.89 g of thiazolidine was added dropwise while stirring under water cooling. After cooling the reactor for the night, the solvent was distilled off under reduced pressure, 5 d of water was added to the residue, the mixture was stirred for 30 minutes, and then extracted with ethyl acetate. Organic layer IN-
The mixture was washed successively with hydrochloric acid, a 5% aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/benzene = 6/4) to obtain colorless needle-like crystals of 3-C(R)-(-)-(3
-phenylpropionyl)thiazolidine-4-carbonyl]thiazolidine was obtained.

Melting point: 65-67°C IR (KBr): vco 1660.1640
cm'-'MS (El): Cl8H2002N
2S2 ” 336.38m/z 336 (M”
), 247.203.143゜105,88 [α) = -108,0゜(C・0.5.ethanol) Elemental analysis value' (as C+5HzoO2N2S2)
0% 8% N% 8% Calculated value 57.13 5.99 8.33 19.0
2 Actual measurement value 57.39 6.18 8.23 18.
56 Example 2 Using the corresponding raw materials, a reaction was carried out in the same manner as in Example 1 to synthesize the following compound.

Melting point: 82-83℃ (diethyl ether) IR (Br): C81680.1640
CT11-'MS (El): C,,)12□0°N, S・318.38m/z 318 (M”),
247.185.126°105,88 [α) = -109,6° (cm0.5.methylene chloride) Elemental analysis value: (as C+7Hz20□N,S)
0% 8% 1% 8% Calculated value 64.13 6.97 8.80 10.0
5 Actual value 64.19 6.97 8.54 9.
78 Melting point: 93-94°C (ethyl acetate-diethyl ether) IR (KBr): vco 1740.1660
cm-'MS (81): C,, H220, N,
S, = 394.39m/z 394 (M”
), 363. 308. 20i.

146, 115. 88 [α) = -185,6° (C・0.5.
Ethyl acetate) Elemental analysis value (as C1B+42□0.!12S2) 0% 8% 1% 8% Calculated value 54.82 5.62 7.10 16.2
3 Actual measurement value 54.98 5.64 7.03 16.
10 Melting point: 84-86°C (ethyl acetate-diethyl ether) IR (KBr): L' co 1640 C
m-'MS (El): Cl7H2202N2S2
・350.40m/z 350 (!, L”), 2
61.234.203゜174, 157.147.91 Elemental analysis value' (as C=J2□02N2S) 0
% 8% 1% 8% calculated value 5
8.27 6.33 8.00 18.27 Actual value
58.36 6J0 8.04 18.14 Melting point
: 63-64°C (diethyl ether) IR (KBr): vco 1660.1638
Cm-'has (81): C, IIH2402
N2S = 332.41m/z 332 (M”)
, 207.185.147゜126, 91.70 Elemental analysis value' (as CI882402N2S)
0% 8% 1% 8% Calculated value 65.04 7.28 8.43 9.6
3 Actual measurement value 65.17 7.24 8.44 9.
Methyl 44dine-4-carboxylate (compound F)
Point: 84-85°C (Ethyl acetate-diethyl ether) IR (KBr)' Wco 1735.1660.
1650 c++r') As (El);' Paste 5
)IznO+N25z・408.40m/z 408
(M”), 377, 361.201°147, 11
5.91 Elemental analysis value: (as CI9H240-N2S2)
0% 8% 1% 8% Calculated value 55.87 5.92 6.86 15.6
7 Actual measurement value 56.27 6.00 6.98 15.
42 Melting point: 127-129℃ (ethyl acetate) IR
(KBr): vco 1660. 1650
c+++-'MS (El)' Cl5ff1802
N2S2 = 322.31m/z 322 (M”
), 239. 179 [α] = -113.5° (cm1.0. Methanol) Elemental analysis value' (as CISH1802N2S2)
0% 8% 8% 8% calculated value
55.89 5.63 8.69 18.85 Actual value
55.91 5.63 8.72 19.80 fusion
Point: 122-124 °C (diethyl ether) IR (KBr): l'c0 1650 cm-'
~Is (Cl)' Cl6H2002N2S =
304.32m/z 304 (M”), 206
Elemental analysis value' (as C16H2002N2S)
0% 8% 8% 8% Calculated value 63.14 6.62 9.21 10.5
2 Actual measurement value 62,80 6.55 9.12 10.
27 Melting point; 170℃ (methanol) IR (KB
r): vco 1652. 1640 cm
-'MS (El): C+aLaO□N252
= 334.32m/z 334 (M”),
203. 131. 103 [α] --10
1,9' (C=1.0. Methanol) Elemental analysis value' (C16H1802N2S2 (!:
shite) 0% 8% 8% 8% Calculated value 58.61 5.79 8.04 18.4
0 Actual value 5g, 56 5.77 7.89 18.
41 Melting point: 154-155°C (ethyl acetate) I
R (KBr): “Co 1650. 1640
cm-'MS (El): C,, H2O0,N,
S = 316°35m/z 317 (M”+1
), 227.255 elemental analysis value' (ClJz.O
□N, S) 0% 8% 8% 8% Calculated value 64.54 6.37 8.86 10.1
2 Actual measurement value 64.61 6.56 8.87 9.7
4-concave 4- ((R)-(-)-3-cinnamoylthiazolidine-Melting point: 144-146°C (Ethyl acetate) IR (KBr): l'co 1650 cm
−'MS(εI)' C+7L. 02N2.32 =
348.35m/z 348 (M”), 245
．． 217. 131゜[α'] --119,1
6゜(C=1.0.methanol) Elemental analysis value' (as C+7H2゜02N2S2)
0% 8% 8% 8% Calculated value 58.61 5.79 8.04 18.4
0 Actual value 58°56 5.77 7.97 18.
41 compound) IR (neat): vco 1740.1660
c+yr'MS (1: C2OH, 20, N,
S = 354.40m/z 354 (M”),
283.168.141゜126, 115.88 [α) = -84,6゜ (C = 0.52. Ethyl acetate) Elemental analysis value: (C2゜H2□0□N2S i/3!1
20) 0% 8% 8% 8% calculated value 66.65 6.19 7.77 8.88
Actual value 66.62 6.43 7.42 8.4
8IR (neat): vc, 1553 cm
-'MS (Mirror: C,, H2O02N2S
2 = 372.39m/z 372 (M”),
283,256,224°168, 141. 115
．． 88 [α) = -82.8° (cm0.5. Ethyl acetate) Elemental analysis value' (C1!1) As 12002N2s2) 0% 1% N% 8% Calculated value 61.28 5.41 7.52 17 .19 Actual value 60.74 5°? 1 7.15 15.82 Example 3 3-[:(R)-(-
)-3-benzyloxycarbonylthiazolidine-4-
After adding 1.55 g of carbonylphthiazolidine and stirring for 2 hours while cooling, the solvent was distilled off under reduced pressure.

The residue was dissolved in 5 d of water, washed with an appropriate amount of diethyl ether, neutralized with 4N aqueous sodium hydroxide solution, and extracted with methylene chloride. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the residue was dissolved in 2% hydrochloric acid-methanol solution 2.
Dissolved in 0-. It was concentrated to dryness under reduced pressure, and the remaining crystals were recrystallized from ethyl acetate-methanol to give 3-[(R)-(-
) Thiazolidine-4-carbonylphthiazolidine
0.68 g (61.4%) of hydrochloride was obtained.

Melting point: 174-180°C IR (KBr): L'co 1660 Cm-
'[α) = -164,3゜(C・1.0.methanol) Elemental analysis value: (as C,,H13ON2CIS)
0% 1% N% 8% Calculated value 34.91 5.44 11.64 26.
63 actual value 34.95 5.28 11.44 2
6.513-[(R)-(-)thiazolidine-4
-0.48 g of carbonylphthiazolidine hydrochloride and 0.36 g of isonicotinic acid chloride hydrochloride were dissolved in 10-methylene chloride, and 1.6-g of triethylamine was added dropwise to the solution while stirring under water cooling. The reaction mixture was stirred at room temperature for 24 hours, washed with an appropriate amount of water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/acetonitrile = 1/1) to obtain 3-
((R) -(-)-3-ynenicotinoylthiazolidine-4-carbonylphthiazolidine 0.46g (42
%) was obtained.

Melting point °120-123°C (Ethyl acetate) IR (Br): L'CO1640cm-'MS (El
): C13HISO2N3S2 = 309
．． 40m/z 310 (M"+1) Elemental analysis value' (as C138ISO2N3S2)
0% 1% N% 8% Calculated value 50.46 4.89 13.58 20.
73 actual value 50.30 4.89 H, 3020
, 29 Example 4 PEP inhibitory activity measurement experiment 2 - Using Gly-Pr leaf β-N8 as a substrate, the inhibitory activity against bovine brain-derived PEP was measured.

(Measurement method) 20mM-Tris HCI Buffer containing 10mM IEDTA and lQmM 2-mercaptoethanol, pH
=7.0) 0.7ml! , to PEP (approximately 0.14
u/n+1) 100 Jil and each concentration (0,10-
Solution 1 of test compound adjusted to 9-10-' M)
00 copies were added and preincubated at 37°C for 5 minutes.

This was then added with 100 d of each of (7) 1 & (5,0,2,5,1,25,0,62 dissolved in 40% dioxane).
Add 5,0,3125mM) of substrate and incubate again at 37°C for 1
Incubation was performed for 5 minutes to allow the enzymatic reaction to proceed. The reaction was stopped with 25% trichloroacetic acid and
Centrifuge for 10 min at R, P, M, supernatant 0.5
d was collected, 0.5aj of 0.1% nitrous acid was added thereto, and after 3 minutes, 0.05% of N-(1-naphthyl) was added.
Ethylenediamine dihydrochloride ethanol solution was added. After the mixture was left at 37°C for 25 minutes, 570 n
Measure the absorbance at m, calculate the oxygen activity at each concentration using the following formula, and calculate the 50% inhibitory concentration (I
Cs. value) was calculated.

Enzyme activity unit (μmol/min/mN) -ΔO
D

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Ar in the formula is a phenyl group, naphthyl group or pyridyl group, Y is a saturated or unsaturated alkylene group having 1 to 4 carbon atoms, n is 0 or 1, ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ is a 5- to 6-membered saturated heterocyclic ring that may contain heteroatoms other than bonded nitrogen atoms, and R is a hydrogen atom or an alkoxy Thiazolidine derivatives represented by carbonyl group).