JP2002332278A - Heterocyclic derivative having edg receptor antagonizing activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a heterocyclic derivative having antagonizing activities against an Edg1 receptor and/or Edg3 receptor, and a treating and preventing agent of arteriosclerosis, etc., caused by stimulation to these receptors. SOLUTION: This heterocyclic derivative is expressed by the general formula (1) [wherein, A is an alkyl or an alkylphenyl; R<1> is H or a lower alkyl; and (n) is 1 or 2 integer] or its pharmaceutically permissible salt, and the medicine containing the above derivative as an active ingredient is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound having an antagonistic action on Edg receptor and a medicament containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Sphingosine-1-phosphate (hereinafter, referred to as S)
Abbreviated as PP. ) And lysophosphatidic acid (hereinafter, LP)
Abbreviated as A. ) Has been thought to be a metabolite of lipids, but recently G-protein coupled receptor Endothelia
l It has been clarified that it plays a role as an intercellular messenger via differentiation gene (hereinafter abbreviated as Edg). Edg has been Edg1-
8 subtypes have been cloned and SP
Various effects such as a cell proliferation activating effect, a cell adhesion molecule expression effect, and a cell migration activating effect via P receptor and LPA receptor have been reported.

[0003] SPP receptors include Gq, Gi, G12, and G1.
It triggers various biochemical responses via 3 and Rho (Ras homologue) dependent pathways. In addition, these receptors are expressed on various cells such as smooth muscle cells, nerve cells and immune cells, and are considered to play an important role in each cell. SPP is known to be a cell growth factor that promotes the activation of MAPK (Mitogen-activated protein kinase) via the Edg receptor,
In particular, because it is expected to play a major role in atherosclerosis, angiogenesis, cancer and inflammatory diseases, controlling SPP signaling can provide an effective treatment for these diseases. (Pharmacol. Ther., 288, 115, 2000).

Furthermore, it has been shown that hypoxic stress due to thrombosis promotes sphingolipid production in the heart. In rat cardiomyocytes, S
PP causes Ca ²⁺ overload via the Edg receptor. From these facts, it is considered that in acute myocardial infarction, SPP plays a negative cardiotoxic function via the Edg receptor on cardiomyocytes (Eur. J. Bioc.
hem., 267, 5679, 2000).

On the other hand, SPP is composed of Edg1 receptor and Edg1.
Activates Rho through 3 receptors to promote cell adhesion, cell migration and angiogenesis. In particular, accumulation of integrins via Rho is considered to be a factor governing endothelial cell migration (J. Biol. Chem., 88, 2, 2001).

[0006] From the above, the Edg receptor, in particular, the Edg1 receptor expressed on vascular endothelial cells and the Edg receptor
It has been suggested that a g3 receptor antagonist is effective as a therapeutic agent for arteriosclerosis or an inhibitor of intimal hyperplasia. Also,
Since the SPP receptor is expressed not only in the cardiovascular system but also in the mesangial cells of the kidney, and SPP is considered to be a precipitating factor of glomerulonephritis that promotes its proliferation, the Edg receptor antagonist Is thought to be useful for preventing the progression of progressive renal injury (29th Annual Meeting of the Eastern Nephrological Society of Japan, abstract p614).

[0007] Edg receptor antagonists reported to date include Edg antisense, but antisense has problems in large supply and its efficient introduction for use as pharmaceuticals is a problem. Becomes Also,
Although the synthetic compound suramin has been reported as a selective antagonist of the Edg3 receptor (J. Biol. Chem., 274, 18997,
1999), which has a molecular weight of more than 1200 and does not provide good oral absorption.

[0008]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a low molecular weight compound which has an antagonistic action on the Edg receptor and is useful as a drug, particularly as a therapeutic agent for arteriosclerosis.

[0009]

Means for Solving the Problems In view of such circumstances, the present inventors have searched for low molecular weight compounds having an antagonistic action on Edg receptor with the aim of developing Edg receptor antagonists as pharmaceuticals. We studied diligently. As a result, they have found that a thiazolidine or thiazinane derivative or a pharmaceutically acceptable salt thereof has excellent Edg receptor antagonistic activity and is useful as a medicament.

That is, the present invention provides a compound represented by the general formula (1):

[0011]

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[In the formula, A represents an alkyl group or an alkylphenyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and n represents an integer of 1 or 2. Or a pharmaceutically acceptable salt thereof. The present invention also provides a medicament and an Edg receptor antagonist containing the heterocyclic derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), examples of the lower alkyl group represented by R ¹ include a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group and a propyl group. , Isopropyl group, butyl group, isobutyl group, se
Examples thereof include a c-butyl group and a tert-butyl group. Among them, a methyl group, an ethyl group or a tert-butyl group is preferred.

Examples of the alkyl group represented by A include straight-chain or branched-chain alkyl groups. Among them, an alkyl group having 6 to 15 carbon atoms is preferable, and an alkyl group having 8 to 13 carbon atoms is more preferable. ~ 12 straight-chain alkyl groups such as nonyl, decyl, undecyl or dodecyl are preferred. As the alkylphenyl group for A, 2-
Alkylphenyl group, 3-alkylphenyl group or 4-
Examples thereof include an alkylphenyl group, and a 3-alkylphenyl group or a 4-alkylphenyl group is preferable.
_{A 3-11} alkylphenyl group or a 4- _C3-11 alkylphenyl group is more preferred. Here, examples of the alkyl group on the phenyl group include a linear or branched alkyl group,
Among them, an alkyl group having 3 to 11 carbon atoms, and further having 4 carbon atoms
Preferred are alkyl groups having 10 to 10, especially linear alkyl groups having 5 to 9 carbon atoms, for example, pentyl, hexyl, heptyl, octyl or nonyl groups.

The following compounds are mentioned as specific examples of the compounds. (4R) -2-nonylthiazolidine-4-carboxylic acid, (4R) -2-decylthiazolidine-4-carboxylic acid, (4R) -2-undecylthiazolidine-4-carboxylic acid, (4R) -2-dodecyl Thiazolidine-4-carboxylic acid, (4S) -2-decylthiazolidine-4-carboxylic acid, (4R) -2- (3-pentylphenyl) thiazolidine-4-carboxylic acid, (4
R) -2- (4-Pentylphenyl) thiazolidine-4
-Carboxylic acid, (4R) -2- (3-heptylphenyl) thiazolidine-4-carboxylic acid, (4R) -2-
(4-heptylphenyl) thiazolidine-4-carboxylic acid, (4R) -2- (3-nonylphenyl) thiazolidine-4-carboxylic acid, (4R) -2- (4-nonylphenyl) thiazolidine-4-carboxylic acid , 2-nonyl-
1,3-thiazinane-4-carboxylic acid, 2-decyl-1,
3-thiazinane-4-carboxylic acid, 2-undecyl-
1,3-thiazinan-4-carboxylic acid, 2-dodecyl-
Ethyl 1,3-thiazinan-4-carboxylic acid, 2- (3-nonylphenyl) -1,3-thiazinan-4-carboxylic acid and (4R) -2-decylthiazolidine-4-carboxylic acid.

The present invention also includes a salt of the compound of the general formula (1) (hereinafter, the compound of the general formula (1) and a salt thereof may be collectively referred to as the compound (1) of the present invention). As a salt of the compound of the general formula (1), a pharmaceutically acceptable salt is preferable in consideration of use in medicine. Specific examples of such salts include hydrochloride, hydrobromide, hydroiodide,
Salts with inorganic acids such as sulfates, nitrates and phosphates; organic acids such as acetates, trifluoroacetates, oxalates, fumarates, maleates, tartrates, mesylates and tosylates And salts with alkali metals such as sodium salt and potassium salt; salts with alkaline earth metals such as calcium salt. These salts can be obtained according to a conventional method.

The compound (1) of the present invention has optical isomers based on asymmetric carbon atoms. The present invention includes isolated ones of these various isomers and a mixture of these isomers. The compound (1) of the present invention includes hydrates and various solvates. Furthermore, the compounds of the present invention include all their crystalline forms.

Next, the method for producing the compound (1) of the present invention will be described. The compound (1) of the present invention can be produced, for example, according to the following reaction formula.

[0019]

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[Wherein A, R ¹ and n are the same as those described above] That is, the compound (1) of the present invention comprises a compound represented by the general formula (2) and a compound represented by the general formula (3) , In an inert solvent.

The amount of the compound represented by the general formula (2) is 1 to the amount of the compound represented by the general formula (3).
10 to 10 equivalents, preferably 1 to 3 equivalents. As the solvent used in the reaction, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and the like,
Alternatively, these mixed solvents can be used as a solvent for the reaction, and among them, water, ethanol or a mixed solvent of water and ethanol is preferable. The reaction temperature is usually from -20 ° C to around the boiling point of the solvent used, preferably from room temperature to 50 ° C. The reaction time is usually 15 minutes to 24 hours, especially 3 to 24 hours.
12 hours is preferred. In this reaction, an inorganic base such as potassium carbonate, sodium carbonate, sodium acetate, and potassium acetate or an amine such as triethylamine and pyridine can be added as necessary.

The compound (1) of the present invention thus obtained can be isolated and purified by conventional means such as recrystallization and column chromatography.

As shown in the test examples described below, the compound (1) of the present invention has excellent Edg receptor antagonism, particularly Edg1 and / or Edg3 receptor antagonism. It is useful as a medicament for treating or preventing various diseases caused by stimulation of receptors, for example, arteriosclerosis, intimal hypertrophy, cardiac hypertrophy, thrombosis, acute myocardial infarction, arrhythmia, progressive renal disorder and the like. .

The compound (1) of the present invention can be administered orally or parenterally (for example, intravenously or intramuscularly).

Examples of preparations for oral administration include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions and suspensions. Can be This preparation for oral administration can be produced according to a known method by blending additives usually used in the field of preparation. Examples of such additives include excipients such as lactose, mannitol, anhydrous calcium hydrogen phosphate; binders such as hydroxypropylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrants such as starch and carboxymethylcellulose; magnesium stearate; A lubricant such as talc is used.

Examples of preparations for parenteral administration include injections. Such injections are produced by known methods, for example, by dissolving the compound of the present invention or a salt thereof in water for injection in Japan Pharmacopoeia. If necessary, an isotonic agent such as sodium chloride; a buffering agent such as sodium hydrogen phosphate and sodium monohydrogen phosphate may be added.

The daily dose of the compound (1) of the present invention per adult can vary depending on the patient's condition, body weight, age, compound type, administration route and the like. 1 to 1,000 mg is appropriate, about 10 to 5
00 mg is more preferred. In the case of parenteral administration, the dose may be 1/10 to 1/2 that of oral administration. These dosages can be appropriately increased or decreased depending on the condition, weight, age, etc. of the patient.

[0028]

Next, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited to these.

Reference Example 1 3-heptylbenzaldehyde
Under de argon atmosphere, 3-iodo-benzoic acid ethyl (3.25
g) in acetonitrile (25 mL) was added to 1-heptin (1.9%).
mL), diisopropylamine (2.5 mL) and bistriphenylphosphine palladium dichloride (83 mg) were added, followed by copper iodide (45 mg). After stirring at room temperature for 12 hours, a 5% aqueous solution of potassium bisulfate (150 mL) was added at 0 ° C., extracted with diethyl ether, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: diethyl ether = 50: 1) to obtain ethyl 3-heptynylbenzoate as a mixture with ethyl benzoate. Then, under an argon atmosphere, lithium aluminum hydride (471 mg) was added to a solution of this mixture in diethyl ether (100 mL) at 0 ° C.
Stirred for hours. After the reaction, methanol (5m
L) slowly and add saturated Rochelle salt aqueous solution (50m
After L) was added, the mixture was stirred at room temperature for 1 hour. After extraction with diethyl ether, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue. Next, manganese (IV) oxide (chemical treatment (Wako Pure Chemical Industries)) was added to a methylene chloride (50 mL) solution of this residue (5.
90 g) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: diethyl ether = 100: 1) to obtain the title compound (973 mg) as a colorless liquid.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.24 Hz, 3
H), 1.28-1.42 (m, 8H), 1.59-1.67 (m, 2H), 2.66 (t, J =
7.34Hz, 2H), 7.43-7.45 (m, 2H), 7.70-7.71 (m, 2H), 1
0.01 (s, 1H) .IR (neat) ν _max : 2927, 2856, 1700, 1456, 1278, 1142,
781, 692cm ^-1 .

Reference Example 2 4-heptylbenzaldehyde
The title compound (636 mg) was obtained as a colorless liquid from ethyl do4-iodobenzoate (5.00 g) and 1-heptin (2.9 mL) in the same manner as in Reference Example 1. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.79 Hz, 3H), 1.21-1.32
(m, 8H), 1.59-1.66 (m, 2H), 2.66-2.71 (t-like, 2H),
7.33 (d, J = 7.89Hz, 2H), 7.79 (d, J = 7.89Hz, 2H), 9.97
(s, 1H) .IR (neat) ν _max : 2927, 2856, 1699, 1606, 1540, 1606,
1507, 1456, 1167, 823cm ^-1 .

Reference Example 3 Ethyl 3 -nonylbenzaldehyde 3-iodobenzoate (2.48 g) and 1-nonine (1.8
mL) in the same manner as in Reference Example 1 to give the title compound (1.31 g) as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.79 Hz, 3H), 1.24-1.28
(m, 12H), 1.58-1.64 (m, 2H), 2.68 (t, J = 7.42Hz, 2H),
7.68-7.69 (m, 2H), 7.83-7.84 (m, 2H), 10.00 (s, 1H) .IR (neat) ν _max : 2925, 2854, 1701, 1540, 1240, 114
1, 692cm ^-1 .

Reference Example 4 Ethyl 4 -nonylbenzaldehyde 4-iodobenzoate (5.00 g) and 1-nonine (3.6 g)
mL) in the same manner as in Reference Example 1 to give the title compound (573 mg) as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.97 Hz, 3H), 1.26-1.30
(m, 12H), 1.56-1.64 (m, 2H), 2.68 (t, J = 7.52Hz, 2H),
7.33 (d, J = 7.89Hz, 2H), 7.79 (d, J = 7.89Hz, 2H), 9.97
(s, 1H) .IR (neat) ν _max : 2926, 2855, 2729, 1698, 1606, 157
5, 1305, 1213, 1167, 825cm ^-1 .

Reference Example 5 3-pentylbenzaldehyde
The title compound (886 mg) was obtained as a colorless liquid from ethyl 3-iodobenzoate (5.29 g) and 1-pentyne (2.3 mL) in the same manner as in Reference Example 1. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 6.79 Hz, 3H), 1.31-1.40
(m, 8H), 1.62-1.70 (m, 2H), 2.68 (t, J = 7.52Hz, 2H),
7.43-7.45 (m, 2H), 7.68-7.70 (m, 2H), 10.00 (s, 1H) .IR (neat) ν _max : 2929, 2857, 2725, 1701, 1456, 1242,
1142, 780, 692cm ^-1 .

Example 1 (4R) -2-nonylthiazo
To an aqueous solution (25 mL) of lysine-4-carboxylic acid L-cysteine hydrochloride (1.08 g),
Sodium acetate (0.61 g) was added, followed by a solution of decylaldehyde (1.15 g) in ethanol (25 mL) with vigorous stirring. After stirring at room temperature for 3 hours, the precipitate was collected by filtration, washed with water and diethyl ether, and recrystallized from isopropanol to give the title compound (1.
09g).

Melting point: 153 to 154 ° C. (isopropanol) ¹ H-NMR (DMSO-d6) δ: 0.86 (t, J = 6.42 Hz, 3H), 1.25-1.5
4 (m, 14H), 1.67-1.91 (m, 2H), 2.72 (dd, J = 9.36, 19.0
9Hz, 0.5H) and 2.91 (dd, J = 5.14, 10.09Hz, 0.5H), 3.
07 (dd, J = 6.97, 9.91Hz, 0.5H) and 3.18 (dd, J = 6.97,
9.91Hz, 0.5H), 3.68 (t, J = 7.34Hz, 0.5H) and 4.40 (t,
J = 6.97Hz, 0.5H), 4.05 (t, J = 6.61Hz, 0.5H) and 4.53
(t, J = 6.97Hz, 0.5H). IR (KBr) ν _max : 2922, 2846, 1617, 1508, 1375, 1301,
1237, 1134, 1069, 874 cm ^-1 .MS (ESI: m / z): 260 (M + H) ⁺ .

Example 2 (4R) -2-decylthiazo
The title compound (1.01 g) was obtained as a colorless powder from lysine-4-carboxylic acid L-cysteine hydrochloride (1.08 g) and undecylaldehyde (1.26 g) in the same manner as in Example 1. Melting point: 153-154 ° C (isopropanol) ¹ H-NMR (DMSO-d6) δ: 0.86 (t, J = 6.79 Hz, 3H), 1.24-1.5
4 (m, 16H), 1.70-1.89 (m, 2H), 2.74 (t, J = 9.52Hz, 0.5
H) and 2.91 (dd, J = 5.14, 10.28Hz, 0.5H), 3.07 (dd, J
= 6.97, 10.28Hz, 0.5H) and 3.20 (dd, J = 6.97, 16.80H
z, 0.5H), 3.69 (t, J = 6.81Hz, 0.5H) and 4.40 (t, J = 6.6
1Hz, 0.5H), 4.05 (t, J = 6.23Hz, 0.5H) and 4.53 (t, J =
6.79Hz, 0.5H) .IR (KBr) ν _max : 2922, 2852, 1602, 1466, 1381, 1211,
1140, 1069, 1013, 846 cm ^-1 .MS (ESI: m / z): 274 (M + H) ⁺ .

Example 3 (4R) -2-undecylch
The title compound (941 mg) was obtained as a colorless powder from azolidine-4-carboxylic acid L-cysteine hydrochloride (1.08 g) and dodecylaldehyde (1.36 g) in the same manner as in Example 1. Melting point: 151-152 ° C (isopropanol) ¹ H-NMR (DMSO-d6) δ: 0.85 (t, J = 6.79 Hz, 3H), 1.24-1.5
4 (m, 18H), 1.70-1.88 (m, 2H), 2.74 (t, J = 9.35Hz, 0.5
H) and 2.92 (dd, J = 4.86, 10.28Hz, 0.5H), 3.08 (dd, J
= 6.97, 17.07Hz, 0.5H) and 3.19 (dd, J = 6.97, 16.88H
z, 0.5H), 3.69 (t, J = 7.34Hz, 0.5H) and 4.39 (t, J = 6.9
7Hz, 0.5H), 4.05 (t, J = 6.42Hz, 0.5H) and 4.52 (t, J =
6.42Hz, 0.5H) .IR (KBr) ν _max : 2921, 2852, 1599, 1467, 1382, 1305,
1210, 1140, 1006, 905,844 cm ^-1 .MS (ESI: m / z): 288 (M + H) ⁺ .

Example 4 (4R) -2-dodecylthia
To an aqueous solution (25 mL) of Zolidine-4-carboxylic acid L-cysteine hydrochloride (1.08 g),
Sodium acetate (0.61 g) was added, and then a solution of tridecylaldehyde (1.46 g) in ethanol (25 mL) was added with vigorous stirring. After stirring at room temperature for 3 hours, the precipitate was collected by filtration, washed with water and diethyl ether, and recrystallized from isopropanol to give the title compound (1.34 g) as a colorless powder. Melting point: 150-151 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 6.79 Hz, 3H), 1.30-1.32
(m, 20H), 1.76-1.84 (m, 1H), 2.00-2.07 (m, 1H), 3.17
(dd, J = 8.08, 11.19Hz, 0.5H) and 3.29-3.36 (m, 0.5H),
3.37-3.42 (m, 1H), 4.10 (t, J = 7.52Hz, 0.5H) and 4.3
0 (t, J = 6.97Hz, 0.5H), 4.60 (dd, J = 5.01, 8.26Hz, 0.5
H) and 4.74 (dd, J = 5.08, 8.99Hz, 0.5H) .IR (KBr) ν _max : 3347, 2923, 2854, 1685, 1523, 1461,
1369, 1249, 1172, 1060, 844cm ^-1 . MS (ESI: m / z): 302 (M + H) ⁺ .

Example 5 (4S) -2-decylthiazo
The title compound (1.01 g) was obtained as a colorless powder from lysine-4-carboxylic acid D-cysteine hydrochloride (1.08 g) and undecylaldehyde (1.26 g) in the same manner as in Example 1. Melting point: 151-152 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 6.79 Hz, 3H), 1.27-1.31
(m, 16H), 1.76-1.84 (m, 1H), 2.00-2.06 (m, 1H), 3.16
(dd, J = 8.26, 11.10Hz, 0.5H) and 3.29-3.36 (m, 0.5H),
3.37-3.42 (m, 1H), 4.09 (t, J = 7.52Hz, 0.5H) and 4.3
0 (t, J = 7.16Hz, 0.5H), 4.60 (dd, J = 5.69, 8.26Hz, 0.5
H) and 4.74 (dd, J = 5.14, 8.81Hz, 0.5H) .IR (KBr) ν _max : 3286, 2919, 2854, 1743, 1712, 1469,
1411, 1249, 1199, 1095, 1064, 987, 717 cm ^-1 .MS (ESI: m / z): 274 (M + H) ⁺ .

Example 6 (4R) -2- (3-Pliers)
From the (phenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (325 mg) and 3-pentylbenzaldehyde (359 mg), the title compound (206 mg) was obtained as a colorless powder in the same manner as in Example 1. Melting point: 153-154 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 7.16 Hz, 3H), 1.34-1.36
(m, 4H), 1.63-1.66 (m, 2H), 2.63 (t, J = 7.34Hz, 2H),
3.39 (dd, J = 4.93, 15.78Hz, 1H), 3.51 (dd, J = 7.52, 1
0.46Hz, 1H), 4.08 (t, J = 7.52Hz, 0.5H) and 4.39-4.41
(m, 0.5H), 5.55 (s, 0.5H) and 5.73 (s, 0.5H), 7.28-
7.38 (m, 4H) .IR (KBr) ν _max : 2927, 2855, 2728, 1572, 1309, 1244,
1136, 1016, 864, 830,799, 701, 637 cm ^-1 .MS (ESI: m / z): 280 (M + H) ⁺ .

Example 7 (4R) -2- (4-Pliers)
From the (phenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (190 mg) and 4 -pentylbenzaldehyde (182 mg), the title compound (182 mg) was obtained as a colorless powder in the same manner as in Example 1.

Melting point: 159 to 160 ° C. (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 7.16 Hz, 3H), 1.31-1.34
(m, 4H), 1.62-1.64 (m, 2H), 2.62 (t, J = 8.81Hz, 2H),
3.40 (dd, J = 4.96, 11.02Hz, 1H), 3.48-3.54 (m, 1H),
4.07 (t, J = 7.34Hz, 0.5H) and 4.40 (dd, J = 4.96, 12.84
Hz, 0.5H), 5.55 (s, 0.5H) and 5.73 (s, 0.5H), 7.21
(dd, J = 3.30, 8.07Hz, 2H), 7.46 (dd, J = 3.30, 8.07Hz,
2H) .IR (KBr) ν _max : 2928, 1576, 1435, 1380, 1138, 1016,
921, 860, 833, 815, 693, 644, 613 cm ^-1 .MS (ESI: m / z): 280 (M + H) ⁺ .

Example 8 (4R) -2- (3-hepti)
From the (phenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (56 mg) and 3 -heptylbenzaldehyde (71 mg), the title compound ( 49 mg) was obtained as a colorless powder in the same manner as in Example 1. Melting point: 142-144 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 6.42 Hz, 3H), 1.30-1.33
(m, 8H), 1.62-1.64 (m, 2H), 2.63 (t, J = 8.08Hz, 2H),
3.40 (dd, J = 4.77, 11.01Hz, 1H) and 3.51 (dd, J = 7.1
6, 10.64Hz, 1H), 4.08 (t, J = 7.16Hz, 0.5H) and 4.40
(dd, J = 4.77, 7.16Hz, 0.5H), 5.55 (s, 0.5H) and 5.7
3 (s, 0.5H), 7.28-7.37 (m, 4H) .IR (KBr) ν _max : 2925, 2853, 2727, 1571, 1437, 1382,
1309, 1242, 1136, 1016, 865, 831, 789 cm ^-1 . MS (ESI: m / z): 308 (M + H) ⁺ .

Example 9 (4R) -2- (4-hepti)
From the (phenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (117 mg) and 4-heptylbenzaldehyde (150 mg), the title compound (158 mg) was obtained as a colorless powder in the same manner as in Example 1. Melting point: 154-156 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 6.97 Hz, 3H), 1.29-1.32
(m, 8H), 1.61-1.63 (m, 2H), 2.61 (t, J = 7.16Hz, 2H),
3.45 (dd, J = 4.77, 16.88Hz, 1H) and 3.50-3.55 (m, 1
H), 4.09 (t, J = 7.34Hz, 0.5H) and 4.40 (dd, J = 4.77,
7.34Hz, 0.5H), 5.56 (s, 0.5H) and 5.73 (s, 0.5H), 7.
21 (dd, J = 3.30, 8.07Hz, 2H), 7.47 (dd, J = 3.30, 8.07H
z (2H) .IR (KBr) ν _max : 2924, 2854, 1577, 1509, 1458, 1437,
1380, 670 cm ^-1 .MS (ESI: m / z): 308 (M + H) ⁺ .

Example 10 (4R) -2- (3-noni
Ruphenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (300 mg) and 3-nonylbenzaldehyde (437 mg) in the same manner as in Example 1.
The title compound (356 mg) was obtained as a colorless powder. Melting point: 130-131 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 6.97 Hz, 3H), 1.29-1.33
(m, 12H), 1.60-1.63 (m, 2H), 2.63 (t, J = 7.89Hz, 2H),
3.40 (dd, J = 4.77, 10.83Hz, 1H) and 3.50 (dd, J = 7.52,
10.54Hz, 1H), 4.10 (t, J = 7.52Hz, 0.5H) and 4.42 (d
d, J = 4.77, 7.16Hz, 0.5H), 5.56 (s, 0.5H) and 5.73
(s, 0.5H), 7.16-7.37 (m, 4H) .IR (KBr) ν _max : 2916, 2851, 1572, 1465, 1437, 1383,
1310, 1243, 1136, 865,799, 701, 640 cm ^-1 .MS (ESI: m / z): 336 (M + H) ⁺ .

Example 11 (4R) -2- (4-noni)
Ruphenyl) thiazolidine-4-carboxylic acid L-cysteine hydrochloride (158 mg) and 4-nonylbenzaldehyde (230 mg) in the same manner as in Example 1.
The title compound (135 mg) was obtained as a colorless powder. Melting point: 130-131 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 6.42 Hz, 3H), 1.28-1.31
(m, 12H), 1.61-1.63 (m, 2H), 2.62 (t, J = 6.61Hz, 2H),
3.45 (dd, J = 4.95, 16.88Hz, 1H) and 3.50-3.55 (m, 1
H), 4.10 (t, J = 7.34Hz, 0.5H) and 4.41 (dd, J = 4.95,
7.34Hz, 0.5H), 5.57 (s, 0.5H) and 5.74 (s, 0.5H),
7.20 (dd, J = 3.30, 8.02Hz, 2H), 7.46 (dd, J = 3.30, 8.0
IR (KBr) ν _max : 2922, 2852, 2750, 1576, 1466, 1435,
1380, 1310, 1236, 1138, 1015, 919, 857 cm ^-1 .MS (ESI: m / z): 336 (M + H) ⁺ .

Example 12 2-Nonyl-1,3-thia
D, L-Homocysteine dinan-4-carboxylate (500 mg) was suspended in water (50 mL) and ethanol (25 mL), and then, while stirring vigorously, a solution of decylaldehyde (693 mg) in ethanol (5 mL) was added.
0 mL) was added. After stirring at 50 ° C. for 12 hours, the precipitate was collected by filtration, washed with water and diethyl ether, and recrystallized from isopropanol to give the title compound (61) as a colorless powder.
1 mg). Melting point: 140-141 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 6.97 Hz, 3H), 1.28-1.35
(m, 14H), 1.74-1.97 (m, 2H), 2.63 (dd, J = 3.10, 17.80H
z, 1H), 2.80-2.86 (m, 2H), 3.04 (t-like, 1H), 3.51 (d
d, J = 2.75, 12.66Hz, 0.6H) and 3.90 (t, J = 4.59Hz, 0.
4H), 4.30 (dd, J = 4.04, 10.09Hz, 0.6H) and 4.67 (dd,
J = 4.96, 8.81Hz, 0.4H) .IR (KBr) ν _max : 2923, 2853, 1611, 1439, 1324, 1280,
. 1099, 969, 771, 670cm - 1 MS (ESI: m / z): 274 (M + H) +.

Example 13 2-decyl-1,3-thia
From the dinan-4-carboxylic acid D, L-homocysteine (500 mg) and undecylaldehyde (755 mg), the title compound (560 mg) was obtained as a colorless powder in the same manner as in Example 12. Melting point: 148-149 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 6.97 Hz, 3H), 1.30-1.33
(m, 16H), 1.74-1.93 (m, 2H), 2.59 (dd, J = 3.12, 11.58H
z, 1H), 2.73-2.87 (m, 2H), 3.04 (t-like, 1H), 3.49 (d
d, J = 2.75, 12.66Hz, 0.6H) and 3.90 (t-like, 0.4H),
4.31 (dd, J = 3.85,9.91Hz, 0.6H) and 4.66 (dd, J = 4.96,
13.76Hz, 0.4H) .IR (KBr) ν _max : 2921, 2854, 1610, 1438, 1325, 1280,
1197, 1149, 1089, 1010, 960, 898, 792 cm ^-1 .MS (ESI: m / z): 288 (M + H) ⁺ .

Example 14 2-Undecyl-1,3-
The title compound (792 mg) was obtained as a colorless powder from D, L-homocysteine thiazinan-4-carboxylate (500 mg) and dodecylaldehyde (818 mg) in the same manner as in Example 12. Melting point: 150-151 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 6.97 Hz, 3H), 1.29-1.33
(m, 18H), 1.77-1.93 (m, 2H), 2.60 (d-like, 1H), 2.73-
2.86 (m, 2H), 3.04 (t-like, 1H), 3.49 (dd, J = 2.75, 1
2.66Hz, 0.6H) and 3.90 (t, J = 4.77Hz, 0.4H), 4.31 (d
d, J = 4.04, 9.91Hz, 0.6H) and 4.68 (dd, J = 4.95, 8.63H
z (0.4H) .IR (KBr) ν _max : 2921, 2852, 2751, 1611, 1441, 1409,
1325, 1281, 1101, 969, 771, 728, 670 cm ^-1 .MS (ESI: m / z): 302 (M + H) ⁺ .

Example 15 2-Dodecyl-1,3-h
The title compound (831 mg) was obtained as a colorless powder from D, L-homocysteine azinan-4-carboxylate (500 mg) and tridecylaldehyde (880 mg) in the same manner as in Example 12. Melting point: 146-147 ° C. (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.90 (t, J = 7.16 Hz, 3H), 1.29-1.35
(m, 20H), 1.74-1.93 (m, 2H), 2.63 (dd, J = 3.12, 14.68H
z, 1H), 2.81-3.00 (m, 2H), 3.04 (t-like, 1H), 3.50 (d
d, J = 2.75, 12.66Hz, 0.6H) and 3.90 (t, J = 4.77Hz, 0.
4H), 4.31 (dd, J = 4.04, 9.91Hz, 0.6H) and 4.67 (dd, J
= 5.51, 8.49Hz, 0.4H) .IR (KBr) ν _max : 2919, 2854, 2781, 1685, 1608, 1474,
1437, 1281, 1089, 973,772, 712, 663 cm ^-1 .MS (ESI: m / z): 316 (M + H) ⁺ .

Example 16 2- (3-nonylphenyi)
L ) 1,3-Thiadinane-4-carboxylic acid D, L-homocysteine (234 mg) and 3-nonylbenzaldehyde (482 mg) in the same manner as in Example 12 to give the title compound (177 mg) as a colorless powder. I got Melting point: 132-133 ° C (isopropanol) ¹ H-NMR (CD ₃ OD) δ: 0.89 (t, J = 10.29 Hz, 3H), 1.29-1.33
(m, 12H), 1.59-1.64 (m, 2H), 2.64 (t, J = 6.06Hz, 2H),
2.90-2.94 (m, 2H), 3.21-3.27 (m, 2H), 3.65 (dd, J = 2.9
4, 12.48Hz, 0.6H) and 3.90-4.01 (m, 0.4H), 5.40 (s,
0.6 (H) and 5.86 (s, 0.4H), 7.31-7.43 (m, 4H) .IR (KBr) ν _max : 2917, 2850, 1625, 1569, 1427, 1382,
1329, 1281, 1197, 1148, 792, 719 cm ^-1 .MS (ESI: m / z): 350 (M + H) ⁺ .

Example 17 (4R) -2-decylthia
Ethyl Zolidine-4-carboxylate L-cysteine hydrochloride (5.03 g) in ethanol solution (25 m
To L), sodium acetate (2.67 g) was added, and an ethanol solution (25 mL) of undecylaldehyde (5.99 g) was added. After stirring at room temperature for 24 hours, 5% aqueous sodium hydrogen carbonate (150 mL) was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5:
Purify the title compound as a colorless oily substance (2.79)
g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.97 Hz, 3
H), 1.25-1.41 (m, 19H), 1.98-2.06 (m, 1H), 2.44-2.48
(m, 1H), 3.37 (dd, J = 4.22, 11.75Hz, 0.5H) and 3.59
(dd, J = 6.61, 11.74Hz, 0.5H), 3.47 (d, J = 5.14Hz, 1
H), 4.38-4.37 (m, 2H), 4.80 (t, J = 4.32Hz, 1H), 4.85-
4.97 (m, 1H) .IR (neat) ν _max : 2924, 2853, 1742, 1507, 1456, 1375,
1246, 1165, 1023, 806, 716 cm ^-1 .MS (ESI: m / z): 316 (M + H) ⁺ .

[Test Examples] With respect to the representative compounds of the present invention, the following test examples show that the Edg1 receptor and Edg3
The antagonism of the receptor was tested. By using HeLa cells stably expressing the Edg1 receptor or Edg3 receptor, the increase in [Ca ²⁺ ] _i induced by SPP stimulation was measured. HeLa-Edg1 or Edg
3 cells were added to Dulbecco supplemented with 10% FBS.
co) The cells were suspended in MEM, seeded on a 96-well plate (10 ⁵ cells / well), and cultured for 24 hours. After removing the culture solution and washing with MEM containing no FBS, the cells were further cultured in the same medium for 24 hours. After removing the culture solution and washing twice with Dulbecco's PBS (+), the fluorescent Ca ²⁺ indicator Calcium Green1 (Molecular Probes) was 5 × 10 ^−6.
The buffer was replaced with the same buffer prepared to be M, and left at 37 ° C. for 60 minutes. Dulbecco P except Calcium Green1 solution
After washing twice with BS (+), the plate was further left at 37 ° C. for 25 minutes using the same buffer. The solution was removed, and the mixture was incubated for 5 minutes using the same buffer prepared so that the test compound concentration was 10 ⁻⁵ M. After measuring the baseline using a fluorimeter (Fluoroscan Ascent FL, Labsystems), [C] induced by SPP (1 nM) stimulation
a ²⁺ ] _i was measured for 30 seconds at 3 second intervals (485n
m excitation, 535 nm detection). The test compound was dissolved in 10 ⁻² M using dimethyl sulfoxide (DMSO), and then diluted to 10 ⁻⁵ M using Dulbecco's PBS before use. Dulbecco's PBS (+) solution containing 0.1% DMSO was used as a control. By the following formula,
The inhibition rate of the increase in [Ca ²⁺ ] _i due to the antagonistic effect of the test compound on Edg1 cells or Edg3 cells was calculated.

Inhibition rate (%) = 100 − [((maximum RFU upon SPP stimulation after test compound incubation) − (baseline)] / [maximum RFU upon (SPP) stimulation) −
(Base line)] x 100

Where RFU is the relative fluorescence intensity (Relati
ve Fluorescence Unit). Table 1 shows the antagonism of the representative compounds against the Edg1 receptor and the Edg3 receptor, and shows the inhibitory rate of [Ca ²⁺ ] _i increase against SPP stimulation.

[0058]

[Table 1]

[0059]

The compound (1) of the present invention has an antagonistic effect on the Edg1 receptor and / or the Edg3 receptor. Therefore, various diseases caused by stimulation of these receptors, for example, arteriosclerosis, intravascular disease, etc. It is useful as a medicament for treating or preventing membrane hypertrophy, cardiac hypertrophy, thrombosis, acute myocardial infarction, arrhythmia, progressive renal disorder and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/06 A61P 9/06 9/10 9/10 103 103 13/12 13/12 C07D 277/12 C07D 277/12 279/06 279/06 (72) Inventor Takeshi Hasegawa 1-Tanaka, Yuno, Iinosaka-cho, Fukushima City, Fukushima Prefecture F-term in the Fukushima Research Laboratory of TOA-AIYO Co., Ltd. 4C033 AB05 AB17 AC10 AC17 4C036 AA09 AA17 AA20 4C086 AA01 AA02 BC82 BC87 MA01 MA04 MA09 NA14 ZA36 ZA45 ZA54 ZA81

Claims (7)

[Claims] 1. A compound of the general formula (1) [Wherein, A represents an alkyl group or an alkylphenyl group, R ¹ represents a hydrogen atom or a lower alkyl group, and n represents 1
Or an integer of 2. Or a pharmaceutically acceptable salt thereof. 2. A is an alkyl group having 6 to 15 carbon atoms,
The heterocyclic derivative according to claim 1, which is an alkylphenyl group or a 4-alkylphenyl group, or a pharmaceutically acceptable salt thereof. 3. (4R) -2-nonylthiazolidine-4
-Carboxylic acid, (4R) -2-decylthiazolidine-4
-Carboxylic acid, (4R) -2-undecylthiazolidine-4-carboxylic acid, (4R) -2-dodecylthiazolidine-4-carboxylic acid, (4S) -2-decylthiazolidine-4-carboxylic acid, (4R) -2- (3-pentylphenyl) thiazolidine-4-carboxylic acid, (4R) -2
-(4-pentylphenyl) thiazolidine-4-carboxylic acid, (4R) -2- (3-heptylphenyl) thiazolidine-4-carboxylic acid, (4R) -2- (4-heptylphenyl) thiazolidine-4-carboxylic acid Acid, (4R)
-2- (3-nonylphenyl) thiazolidine-4-carboxylic acid, (4R) -2- (4-nonylphenyl) thiazolidine-4-carboxylic acid, 2-nonyl-1,3-thiazinan-4-carboxylic acid, 2-decyl-1,3-thiazinan-4-carboxylic acid, 2-undecyl-1,3-thiazinan-4-carboxylic acid, 2-dodecyl-1,3-thiazinan-4-carboxylic acid, 2- (3- Nonylphenyl)-
1,3-thiazinan-4-carboxylic acid and (4R) -2
-A heterocyclic derivative selected from ethyl decylthiazolidine-4-carboxylate or a pharmaceutically acceptable salt thereof. 4. A medicament comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. An arteriosclerosis, intimal hyperplasia, cardiac hypertrophy, thrombosis, acute use comprising the heterocyclic derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic or prophylactic agent for myocardial infarction, arrhythmia or progressive renal injury. 6. An Edg receptor antagonist comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. An Edg1 receptor and / or an Edg3 receptor antagonist comprising the heterocyclic derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.