JPH07188209A - 3-phenylthiochromone compound and aldose reductase inhibitor - Google Patents

Abstract

PURPOSE:To obtain a new 3-phenylthiochromone compound useful as an aldose reductase inhibitor as a preventive and a therapeutic agents for various kinds of diabetic complications. CONSTITUTION:This 3-phenylthiochromone compound is expressed by formula I (R1 is H, an alkyl or a halogen; R2 is H, an alkyl, an alkoxy, nitro or a halogen). The compound of formula I, for example, is obtained by reacting a 2,3- epoxychromone compound of formula II-(2) with a thiophenol compound of formula II-(3) in the presence of a base such as diazabicycloundecene in a proper organic solvent. The various kinds of diabetic complications include, for example, diabetic cataract, diabetic neurosis, diabetic nephritis, diabetic retinopathy or diabetic keratopathy.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 3-phenylthiochromone compound and an aldose reductase inhibitor containing the 3-phenylthiochromone compound as an active ingredient. The aldose reductase inhibitor according to the present invention is effective as a preventive and therapeutic drug for various diabetic complications, for example, diabetic cataract, diabetic neuropathy, diabetic renal disease, diabetic retinopathy or diabetic keratopathy. .

[0002]

2. Description of the Related Art Most of the glucose in the living body is normally converted into glucose-6-phosphate by the action of hexokinase and metabolized in the glycolytic system, and is an important energy source. However, in a hyperglycemic state such as diabetes, abnormal accumulation of sorbitol is promoted by enhancing the polyol metabolism system in which glucose is metabolized to fructose via sorbitol. It is considered that this sorbitol is highly polar, so that it does not migrate to the outside of the cell, accumulates in the cell, increases the osmotic pressure in the cell, and causes tissue damage. Therefore, it is possible to prevent and treat diabetic complications by inhibiting aldose reductase (aldose reductase), which is an enzyme that converts glucose into sorbitol in the polyol metabolism system. Conventionally,
As aldose reductase inhibitors, many compounds such as hydantoin derivatives (see JP-A-53-53653) and thiazoline derivatives (see JP-A-57-28073) are known. Further, as an existing drug prepared by total synthesis, a thioxoazolidine acetic acid derivative (Kinedac Tablets: Ono Pharmaceutical Co., Ltd.) is commercially available.

[0003]

As described above, there have been many aldose reductase inhibitors conventionally, but
Their inhibitory effect was not always sufficient, and the effect was not always satisfactory as a therapeutic / preventive drug for diabetic complications. Therefore, development of an aldose reductase inhibitor having high activity and high safety has been desired. As a result of repeated studies to solve such problems, the present inventor has found that the novel 3-phenylthiochromone compound has an aldose reductase inhibitory activity. The present invention is based on these findings.

[0004]

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

[Chemical 2] And a 3-phenylthiochromone compound represented by
Furthermore, the present invention relates to an aldose reductase inhibitor characterized by containing a 3-phenylthiochromone compound represented by the above general formula (1).

In the present specification, the halogen atom is, for example, a chlorine atom, a bromine atom, an iodine atom or a fluorine atom, preferably a chlorine atom or a fluorine atom. The alkyl group R ₁ is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, n- or i-propyl group, n-, i-, s. -Or t-butyl group, preferably methyl group or ethyl group. The alkyl group R ₂ is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably a linear or branched alkyl group having 1 to 4 carbon atoms, for example, , Methyl group, ethyl group, n- or i-propyl group, n-, i- or t-butyl group. The alkoxy group R ₂ preferably has 1 carbon atom.
To 4 alkoxy groups such as methoxy group, ethoxy group, n- or i-propoxy group, n-, i- or t-butoxy group, more preferably methoxy group or ethoxy group. The position of the substituent R ₂ is o
Any of position, m position or p position may be used.

The 3-phenylthiochromone compound represented by the general formula (1) according to the present invention can be prepared, for example, by the route shown in the following reaction formula (I).

[Chemical 3]

That is, the 2,3-epoxychromone compound (2) and the thiophenol compound (3) are added in the presence of a base [eg diazabicycloundecene] to a suitable organic solvent (eg acetonitrile, dichloromethane, chloroform). , Toluene or benzene) at 0-50 ° C
The reaction is carried out at (preferably 0 to 20 ° C.) for 5 minutes to 2 hours (preferably 5 to 10 minutes). Here, it is preferable to use 0.5 to 10 mol of the thiophenol compound (3) with respect to 1 mol of the 2,3-epoxychromone compound (2). Water is added to the reaction solution, followed by extraction with an organic solvent (for example, dichloromethane, chloroform, toluene or benzene). After drying the extract with a desiccant such as sodium sulfate,
The solvent is evaporated under reduced pressure, the residue is purified by, for example, chromatography (eg silica gel column chromatography, thin layer preparative chromatography or flash chromatography), recrystallized from benzene-hexane to give 3-
Crystals of the phenylthiochromone compound (1) can be obtained.

The 3-phenylthiochromone compound represented by the general formula (1) according to the present invention has an action of inhibiting aldose reductase activity. Therefore, the 3-phenylthiochromone compound represented by the general formula (1) can be used as an aldose reductase inhibitor for the treatment / prevention of diabetic complications. The aldose reductase inhibitor of the present invention containing the 3-phenylthiochromone compound represented by the general formula (1) as an active ingredient can be administered orally or parenterally. Oral administration includes sublingual administration, parenteral administration includes
Subcutaneous, intravenous, intramuscular, rectal or pulmonary administration is included.

The aldose reductase inhibitor of the present invention comprises tablets, powders, granules, capsules, syrups,
It can be used in various dosage forms such as a dispersant, an injection, a sublingual tablet, a fine granule, an external preparation, an ointment, a suppository or a tape.
Each of these preparations is, if necessary, a known carrier (eg, binder, excipient, lubricant, disintegrant, wetting agent,
It can be prepared by a conventional method using a colorant, a diluent, an emulsifier, a suspending agent or a filler. As the carrier, for example, corn starch for granules, crystalline cellulose for tablets, silicic acid anhydride for capsules, or glucose solution for injection can be used. The aldose reductase inhibitor according to the present invention contains the compound (1) of the present invention as an active ingredient in an amount of 5 to 100% by weight, preferably 25 to 100% by weight. The dose varies depending on the administration subject, administration route, and / or symptoms, etc., but is usually 0.1 to 200 mg / kg / day, and this can be administered 1 to 5 times a day in divided doses.

[0010]

The present invention will be described in detail below with reference to examples, but these do not limit the scope of the present invention. Example 1: Preparation of 3-phenylthiochromone Thiophenol (440 mg) and diazabicycloundecene (456 mg) were dissolved in acetonitrile (20 ml), and the mixture was stirred at room temperature for 1 hr, and then the solution was cooled to 0 ° C. 2,3-epoxychromone (162 m
A solution of g) in acetonitrile (5 ml) was added dropwise and the mixture was stirred for 5 minutes. Ice water was added to the reaction solution, the mixture was extracted with dichloromethane, dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography [ethyl acetate-hexane (1: 8)] to give 3 of the following structural formula (11).
-Phenylthiochromone was obtained in a yield of 92%.

[0011]

[Chemical 4]

[0012] mp: 97 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1656cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 7.18
-7.33 (3H, m), 7.39 (2H, d, J =
7.9 Hz), 7.42-7.50 (2H, m), 7.
70 (1H, t, J = 7.8Hz), 8.16 (1H,
s), 8.26 (1H, dd, J = 7.9, 2.0H)
z) UV (methyl alcohol) λmax: 245 nm (lo
g ε = 4.16), 300 nm (log ε = 3.5)
6) MS m / z 254 (M ⁺ ), C ₁₅ H ₁₀ O ₂ S

Example 2: 3- (4-methylphenythio)
Preparation of chromone 3- (4-methylphenylthio) chromone was converted to 9 by the same method as described in Example 1 except that paramethylthiophenol and 2,3-epoxychromone were reacted.
Obtained in a yield of 1%. Mp: 106 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1650cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 2.31
(3H, s), 7.11 (2H, d, J = 8.9H
z), 7.35 (2H, d, J = 8.9 Hz), 7.4
2 (1H, t, J = 7.5Hz), 7.45 (1H,
d, J = 7.9 Hz), 7.68 (1H, t, J = 7.
8 Hz), 8.05 (1H, s), 8.25 (1H, d
d, J = 7.9, 2.0 Hz) UV (methyl alcohol) λmax: 243 nm (lo
g ε = 4.18), 300 nm (log ε = 3.5)
6) MS m / z 268 (M ⁺ ), C ₁₆ H ₁₂ O ₂ S

Example 3: 3- (4-t-butylphenyl)
Preparation of thio) chromone 3- (4-t-butylphenylthio ) chromone was prepared in the same manner as in Example 1 except that para-t-butylthiophenol and 2,3-epoxychromone were reacted. Was obtained in a yield of 83%. Melting point: 106 ° C. (benzene-hexane recrystallization) MS m / z 310 (M ⁺ ), C ₁₉ H ₁₈ O ₂ S

Example 4: 3- (4-methoxyphenylthio)
E) Preparation of chromone 3- (4-methoxyphenylthio) chromone was obtained at a yield of 79% in the same manner as in Example 1 except that paramethoxythiophenol and 2,3-epoxychromone were reacted. Got at a rate. Mp: 108 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1650cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 3.79
(3H, s), 6.98 (2H, d, J = 8.9H
z), 7.36-7.46 (2H, m), 7.48 (1
H, d, J = 8.9 Hz), 7.68 (1H, t, J =
7.9 Hz), 7.91 (1 H, s), 8.24 (1
H, dd, J = 7.9, 1.5 Hz) UV (methyl alcohol) λmax: 242 nm (lo
g ε = 4.22) MS m / z 284 (M ⁺ ), C ₁₆ H ₁₂ O ₃ S

Example 5: 3- (4-chlorophenylthio)
E) Preparation of chromone 8- (3-chlorophenylthio) chromone was prepared in the same manner as in Example 1 except that parachlorothiophenol and 2,3-epoxychromone were reacted.
Obtained in a yield of 4%. Mp: 159 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1650cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 7.24
(2H, d, J = 8.9 Hz), 7.32 (2H, d,
J = 8.9 Hz), 7.45 (1H, t, J = 7.5H)
z), 7.49 (1H, d, J = 7.9 Hz), 7.7
1 (1H, t, J = 7.8Hz), 8.24 (1H,
s), 8.24 (1H, dd, J = 7.9, 1.5H)
z) UV (methyl alcohol) λmax: 247 nm (lo
g ε = 4.39) MS m / z 288 (M ⁺ ), C ₁₅ H ₉ ClO ₂ S

Example 6: 3- (4-fluorophenylthio)
E) Preparation of chromone 3- (4-fluorophenylthio) chromone was obtained in a yield of 84% in the same manner as in Example 1 except that parafluorothiophenol and 2,3-epoxychromone were reacted. Got at a rate. Mp: 135 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1640cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 7.00
(2H, d, J = 8.9 Hz), 7.42-7.47
(4H, m), 7.68 (1H, t, J = 6.9H
z), 8.14 (1H, s), 8.23 (1H, dd,
J = 7.9, 1.4 Hz) UV (methyl alcohol) λmax: 240 nm (lo
g ε = 4.39), 297 nm (log ε = 3.7)
6) MS m / z 272 (M ⁺ ), C ₁₅ H ₉ FO ₂ S

Example 7: 3- (4-nitrophenylthio)
E) Preparation of chromone 3- (4-nitrophenylthio ) chromone was prepared in the same manner as in Example 1 except that para-nitrothiophenol and 2,3-epoxychromone were reacted.
Obtained in a yield of 6%. Mp: 272 ° C. (benzene - hexane ^{recrystallization) IR (KBr): 1638cm -1} 1 H-NMR: (CDCl 3) δ (ppm): 7.41
(1H, t, J = 7.5 Hz), 7.53 (1H, d,
J = 8.4 Hz), 7.69 (1H, t, J = 7.8H)
z), 8.10 (2H, d, J = 8.8Hz), 8.1
0 (2H, d, J = 8.8Hz), 8.33 (1H, d
d, J = 7.8, 1.9 Hz), 8.85 (1 H, s) UV (methyl alcohol) λmax: 220 nm (lo
g ε = 4.20), 315 nm (log ε = 4.0)
1) MS m / z 299 (M ⁺ ), C ₁₅ H ₉ NO ₄ S

Example 8: 3- (3-methylphenylthio)
E) Preparation of chromone 3- (3-methylphenylthio) chromone was prepared in the same manner as in Example 1 except that metamethylthiophenol and 2,3-epoxychromone were reacted.
Obtained in a yield of 5%. Melting point: 117 ° C. (benzene-hexane recrystallization) MS m / z 268 (M ⁺ ), C ₁₆ H ₁₂ O ₂ S

Example 9: 3- (3-methoxyphenylthio)
E) Preparation of chromone 3- (3-methoxyphenylthio) chromone was obtained at a yield of 75% in the same manner as in Example 1 except that metamethoxythiophenol and 2,3-epoxychromone were reacted. Got at a rate. Melting point: 123-124 ° C (benzene-hexane recrystallization) MS m / z 284 (M ⁺ ), C ₁₆ H ₁₂ O ₃ S

Example 10: 3- (2-methoxyphenyl)
Preparation of thio) chromone 3- (2-methoxyphenylthio) chromone was obtained in a yield of 83% in the same manner as in Example 1 except that orthomethoxythiophenol and 2,3-epoxychromone were reacted. Got at a rate. Mp: 114-115 ° C. (benzene - hexane recrystallization) MS m / z 284 (M +), C 16 H 12 O 3 S

Example 11: 3- (3-chlorophenylthio)
E) Preparation of chromone 8- (3-chlorophenylthio) chromone was prepared in the same manner as in Example 1 except that metachlorothiophenol and 2,3-epoxychromone were reacted.
Obtained in a yield of 3%. Melting point: 145-146 ° C (benzene-hexane recrystallization) MS m / z 288 (M ⁺ ), C ₁₅ H ₉ ClO ₂ S

Example 12: 3-Phenylthio-6-methyi
Preparation of luchromone 3-phenylthio-6- methylchromone was prepared in the same manner as in Example 1 except that thiophenol was reacted with 2,3-epoxy-6-methylchromone.
Obtained in a yield of 0%. Melting point: 102-103 ° C (benzene-hexane recrystallization) MS m / z 268 (M ⁺ ), C ₁₆ H ₁₂ O ₂ S.

Example 13: 6-Chloro-3-phenylthio
Preparation of Ocromon 6-Chloro-3-phenylthiochromone was prepared in the same manner as in Example 1 except that thiophenol was reacted with 6-chloro-2,3- epoxychromone.
Obtained in a yield of 3%. Melting point: 133-134 ° C. (benzene-hexane recrystallization) MS m / z 288 (M ⁺ ), C ₁₅ H ₉ ClO ₂ S

Pharmacological test example 1 (1) Preparation of aldose reductase Six-week-old Wistar rats were killed under anesthesia with ether, and the lens was immediately removed to remove the lens at -20 ° C.
It was saved at. The lens was homogenized with 0.1 M phosphate buffer (pH 7.0) containing 0.01 mM phenylmethylsulfonyl fluoride and 5 mM dithiothreitol, and centrifuged at 40,000 rpm for 30 minutes.
20% polyethylene glycol 6000 was added to the supernatant, stirred for 30 minutes, and then centrifuged at 15,000 rpm for 30 minutes. The obtained supernatant was used as a crude enzyme solution of aldose reductase. In addition, all the above operations are performed at 4 ° C,
The crude enzyme solution was stored at -20 ° C.

(2) Measurement of aldose reductase inhibitory activity Kador was measured for aldose reductase inhibitory activity.
Et al. [Biophys. Chem. 8 , 81-85
(1978)]. That is, the above (1)
The crude enzyme solution obtained in Example 1 was added to the above Examples 1 to 4, 8, 10, 11
An ethanol solution of each compound obtained in 13 and 13, 0.2 mM NADPH (nicotinamide adeninucleotide phosphate reduced form) as a coenzyme, and 50 mM phosphate buffer (pH 7.0) were added. Furthermore, 1 as a substrate
The reaction was initiated by the addition of 00 μM methylglyoxal. The reaction was carried out at 37 ° C. for 5 minutes, and the decrease in NADPH concentration was followed by the decrease in absorbance at 340 nm. The tan θ value at that time was calculated, and the aldose reductase inhibition rate was calculated by the following formula. Inhibition rate (%) = [(B−A) / B] × 100 where A is the tan θ value when the 3-phenylthiochromone compound is added, and B is the case where the 3-phenylthiochromone compound is not added. Tan θ value. The results are shown in Table 1 below.

[0027]

[Table 1]

Formulation Preparation Example 10 parts by weight of the 3-phenylthiochromone of the present invention obtained in Example 1 above, 421.0 parts by weight of lactose and 50 parts by weight of potato starch were mixed well, and this was mixed with a fluid bed granulator. And put in hydroxypropyl cellulose (binder) 18.7
5 parts by weight was made into a 5% aqueous solution and sprayed to obtain granules. Next, carboxymethyl cellulose calcium (disintegrant)
20 parts by weight and magnesium stearate (lubricant) 15
And parts by weight were added and mixed. The obtained mixture was pressure-molded so that the weight of one tablet was 125 mg to obtain tablets. An enteric coated tablet was obtained by spraying a coating liquid having the following formulation on the tablet. Cellulose acetate phthalate 5.0 parts by weight 95% ethanol 47.5 parts by weight Ethyl acetate 47.5 parts by weight

[0029]

INDUSTRIAL APPLICABILITY The novel 3-phenylthiochromone compound according to the present invention has a high aldose reductase inhibitory activity and is useful as a preventive or therapeutic agent for diabetic complications.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location A61K 31/35 AED (72) Inventor Mitsuru Nakayama 23 Ono-shiba, Sakai-shi, Osaka Prefecture Ohnoshiba Housing Company 4 − 105

Claims (2)

[Claims] 1. General formula (1): A 3-phenylthiochromone compound represented by: 2. An aldose reductase inhibitor comprising the 3-phenylthiochromone compound represented by the general formula (1) according to claim 1.