JP2864190B2 - Water-soluble methine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a methine compound which is useful as a photographic material, a medicine and the like.

[0002]

BACKGROUND OF THE INVENTION In the field of photographic science, the methine compounds of the present invention are described, for example, in U.S. Pat.
It belongs to a material used as a spectral sensitizing dye similarly to the compound described in No. 8. As described in JP-A-4-4259, when such a spectral sensitizing dye is added to a photographic light-sensitive material, its solubility is one of the important points. On the other hand, in the fields of medicine and pharmacy, the compounds of the present invention are effective as pharmaceuticals. Also in the art, the solubility of a drug is an important issue, and it is not allowed for the administered drug to precipitate or coagulate, especially in a medium with a high salt concentration such as blood in a living body. Thus, various attempts have been made to increase the solubility of compounds similar to the methine compound of the present invention, but at present there is no satisfactory solution in view of other properties. For example, a method in which a carboxylate ion is used as a counter ion, as described in Japanese Patent Application Laid-Open No. 4-4259, is certainly effective in increasing the solubility. However, it has been found that when applied to the methine compound represented by the general formula (I), the stability over time in a powder state is low, and the storage stability after production is problematic. As described above, it has been very difficult for a compound similar to the methine compound of the present invention to achieve both solubility and stability over time, although it has been known for a long time.

[0003]

Accordingly, an object of the present invention is to provide a methine compound having excellent solubility and stability over time.

[0004]

The object of the present invention has been attained by a methine compound represented by the general formula (I).

[0005]

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Wherein R ₁ , R ₂ and R ₃ are a methyl group, an ethyl group or a phenyl group, and R ₄ and R ₅ are a hydrogen atom, an alkyl group, an aryl group, a benzo-fused ring or a naphtho-fused ring. And X represents an inorganic anion.) The alkyl groups represented by R ₄ and R ₅ include methyl, ethyl, propyl,
Those having 5 or less carbon atoms such as isopropyl and butyl are preferred, and the most preferred is a methyl group. As the aryl group represented by R ₄ and R ₅ , those having 7 or less carbon atoms such as phenyl and tolyl are preferable, and the phenyl group is most preferable. As the inorganic anion represented by X, a halide ion such as fluorine, chlorine, bromine and iodine is preferable, and a chloride ion is most preferable.
The methine compound of the present invention can be used as a spectral sensitizing dye, an anticancer agent and the like. The methine compound of the present invention can be easily synthesized generally by the synthesis methods described in U.S. Pat. Nos. 2,388,963 and 2,504,468. Hereinafter, specific examples of the compound represented by formula (I) of the present invention are shown, but the present invention is not limited thereto.

[0007]

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[0008]

[Table 1] _{─────────────────────────────────── No. R 4 R 5 R 1} R 2 R ₃ X ^- ─────────────────────────────────── I-1 H 4-CH ₃ CH ₃ C _{2 ^{H 5 C 2 H 5 Cl -}} I-2 H 4,5- benzo ^{_{CH 3 CH 3 CH 3 Cl -}} I-3 H 4,5- benzo CH ₃ phenyl ^{_{CH 3 Cl - I-4 H}} 4,5- naphtho (1,2) CH ₃ CH ₃ CH ₃ Cl ^- ───────────────────────────────────

[0009]

The methine compound of the present invention has a very good solubility in water and stability over time as compared with a similar methine compound. A wide range of applications are expected. Next, the effectiveness of the methine compound represented by the general formula (I) of the present invention will be clarified by examples.

[0010]

EXAMPLES Example 1 (1) Synthesis of Compound I-1 3-Ethyl-5- (3-methylbenzothiazoline-
2-ylidene) thiazolin-4-one-2-thione
A 3-liter three-necked flask equipped with a formed reflux cooling tube 40
0 g of 2-methylthiobenzothiazole, 616 g of p
-Methyl toluenesulfonate and 560 ml of anisole were added. After heating this mixture at 120 ° C. for 4 hours, the reaction mixture was cooled to room temperature, 8 liters of acetonitrile was added, and the mixture was stirred at room temperature for 15 minutes. Thereafter, the mixture was transferred to a 10-liter three-necked flask, and 35
4 g of 3-ethylthiazolidine-4-one-2-thione was added and cooled to 5 ° C. 0.5 liter of triethylamine was added dropwise to this mixture at 10 ° C. over 30 minutes, and the obtained compound was stirred at 10 ° C. for 4 hours. The yellow precipitate was filtered off with suction and washed successively with 0.4 l of acetonitrile and 1.4 l of methanol to give 800
g of crude crystals were obtained. The above crude crystals, 2.1 liter of acetone, and 4.2 liter of methanol were weighed into a 10-liter three-necked flask equipped with a reflux condenser. The mixture was heated to reflux with stirring for 15 minutes, cooled to 25 ° C., the resulting mixture was filtered off with suction, washed with 1.4 liters of methanol and dried. 89.3% yield

3-ethyl-5- (3-methylbenzothiazoline-
2-ylidene) -2-methylthio-4-oxo-2-thio
Synthesis of azolium p-toluenesulfonate In a 10-liter three-necked flask equipped with a reflux condenser, 750 g of 3-ethyl-5- (3-methylbenzothiazoline-2-
Ylidene) thiazolidine-4-one-2-thione, 13
60 g of methyl p-toluenesulfonate and 0.75
One liter of dimethylformamide was weighed. This mixture was heated and stirred at 130 ° C. for 2.5 hours, the obtained mixture was cooled to 95 ° C., and 6.5 liters of acetone was added. After cooling to 25 ° C., the precipitate was filtered off with suction and washed with 2 l of acetone. The crude product and 5.2 liters of acetone were weighed into a 10 liter three-necked flask equipped with a reflux condenser. The mixture was heated to reflux with stirring for 15 minutes, cooled to 25 ° C., the precipitate was filtered off with suction, washed with 2 l of acetone and dried. Yield 92.3% 3-ethyl-4-methyl-2-{[3-ethyl-5
-(3-methylbenzothiazoline-2-ylidene)]-
4-oxothiazolidine-2-ylidenemethyldithiazo
Synthesis of Lithium Iodide In a 500 mL three-necked flask, 2.5 g of 3-ethyl-5- (3-methylbenzothiazoline-2-ylidene) -2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate was added. 1.4 g of ethyl-2,4-dimethylthiazolium iodide was weighed and suspended in 50 ml of acetonitrile. 7.5 ml of triethylamine was added dropwise to this suspension at room temperature with stirring, followed by stirring for 2 hours. The precipitate formed from the reaction solution was filtered off with suction and washed with 20 mL of acetonitrile. The residue was recrystallized from methanol-chloroform to give the title compound. Yield 1.2 g (44%) λ _max (MeOH) 480 nm (7.28 × 10 ⁴ )

3-ethyl-4-methyl-2-{[3-ethyl-5
-(3-methylbenzothiazoline-2-ylidene)]-
4-oxothiazolidine-2-ylidenemethyldithiazo
Synthesis of lithium chloride (I-1) strong basic anion exchange resin (Diaion P manufactured by Mitsubishi Kasei )
A318) was immersed in 240 ml of methanol. After 5 hours, 90 ml of methanol were decanted. 90 ml of fresh methanol was added and left for another 30 hours. The resin (PA318) soaked in methanol was transferred to an ion exchange column and washed with 300 ml of methanol. 4.0
g of 3-ethyl-4-methyl-2-{[3-ethyl-5
-(3-methylbenzothiazoline-2-ylidene)]-
4-oxothiazolidine-2-ylidenemethyldithiazolium iodide was dissolved in 100 ml of a 2: 1 (v / v) methanol / dichloromethane solution. This dye solution was passed through a resin column. The eluate was collected and filtered through a microfilter (0.2 μm), and the filtrate was concentrated under reduced pressure. Yield 93% mp 295-296 [deg.] C. 1-2 to 1-4 were synthesized by the same synthesis process. Physical properties data are shown in the table below.

[0013]

Table 2 Compound melting point λ _mxa (MeOH) NMR chemical shift No. [° C] [nm] (ε) DMSO-d ₆ TMS standard ───────────────────────────────── ── I-1 295-296 480 (6.35 × 10 ⁴ ) δ7.95 (1H, d, 8.0 Hz), 7.68 (1H, d, 8.0 Hz), 7.57 (1H, s), 7.53 (1H, d, 8.0Hz), 7.36 (1H, t, 8.0Hz), 7.55 (1H, s), 4.42 (2H, q, 6.7Hz), 4.20 (2H, q, 6.7Hz), 4.11 (3H, s), 1.35 (3H, t, 6.7Hz), 1.24 (3H, t, 6.7Hz) I-2 285-287 498 (6.61 × 10 ⁴ ) δ8.22 (1H, d, 8.0Hz), 7.93 (1H, d, 6.7 Hz), 7.90 (1H, d, 6.7Hz) 7.68 (1H, d, 6.7Hz), 7.66 (1H, d, 6.7Hz), 7.50 (1H, t, 8.0Hz) 7.43 (1H, t, 8.0Hz) , 7.28 (1H, t, 8.0Hz), 6.56 (1H, s), 4.18 (3H, s), 4.02 (3H, s), 3.52 (3H, s) I-3 250-252 500 (6.79 × 10 ⁴ ) δ8.26 (1H, d, 8.0Hz) 、 7.91 (1H, t, 8.0Hz) 、 7.5 ~ 7.8 (9H, m) 7.43 (1H, t, 8.0Hz) 、 7.26 (1H, t, 8.0Hz) , 5.90 (1H, s), 4.30 (3H, s), 3 .63 (3H, s) I-4> 300 508 (7.97 × 10 ⁴ ) δ8.70 (1H, d, 8.0Hz), 8.20-7.40 (7H, m), 7.33 (1H, t, 8.0 Hz), 7.35 (1H, t, 8.0Hz), 6.60 (1H, s), 4.40 (3H, s), 4.08 (3H, s), 3.02 (3H, s) ───────────── ──────────────────────

Example 2 A compound of the present invention synthesized according to the synthesis method described in Example 1 was tested for solubility and stability over time. The results are shown below. Solubility Experimental conditions Weigh 10 mg of compound into a test tube, and add 0.1 ml of ion-exchanged water.
, And shaken at room temperature for 3 minutes to visually check the solubility. Stability test conditions over time Weigh 100mg compound and Petri dish, 100% RH,
The sample is left at room temperature and its weight change is measured. Comparative compound

[0015]

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[0016]

[Table 3] 化合物 Compound No. Solubility in water Room temperature, 100% RH, 3 days later 10 mg / 0.1 ml of water 増 加 S -1 (comparative example) Dissolution + 42% (liquefaction) S-2 (〃) Insoluble + 15% (crystal form unchanged) I-1 (present invention) Dissolution + 11% (（) I-2 (〃) 〃 + 20% ( ）) I-3 (〃) 〃 + 19% (〃) I-4 (〃) ＋ + 21% (〃) ──────────────────────── ───────────

The time-lapse sample of S-1 used in the comparative example is liquefied and difficult to weigh. S-2 has low solubility in water and is not usable. The compound I-1 of the present invention has high solubility and absorbs moisture slightly after lapse of time, but the moisture absorption is constant even after lapse of 3 days or more, and does not hinder handling such as weighing operation. As is clear from the above results, the methine compound of the present invention is excellent in solubility and stability over time.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Noriaki Tatsuta 210 Nakanakanuma, Minamiashigara-shi, Kanagawa Fujisha Shin Film Co., Ltd. (56) References JP-A-6-80892 (JP, A) JP-A-5-95 286953 (JP, A) JP-A-6-82948 (JP, A) JP-A-6-172330 (JP, A) US Patent 3576639 (US, A) (58) Fields investigated (Int. Cl. ⁶ , DB Name) C09B 23/00 CA (STN)

Claims (2)

(57) [Claims] 1. A methine compound represented by the general formula (I). Embedded image (Wherein R ₁ , R ₂ and R ₃ represent a methyl group, an ethyl group or a phenyl group, and R ₄ and R ₅ represent a hydrogen atom, an alkyl group, an aryl group, a benzo-fused ring or a naphtho-fused ring) X represents a nonmetallic atom group required for the above.) 2. In the formula (I), R ₄ and R ₅ are a hydrogen atom, a methyl group, a phenyl group, or a group of nonmetal atoms necessary for forming a benzo-fused ring, and X is a chloride ion. The methine compound according to claim 1.