JPH0255426B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to N-(4-phenyl-2-thiazolyl)amide derivatives, processes for their production, and pharmaceutical compositions containing them. More specifically, the present invention has immunomodulatory ability,
Therefore, N-(4-phenyl-2-thiazolyl) is effective against immune diseases such as rheumatoid arthritis, useful for viral diseases or anti-cancer immunotherapy, and has a weak toxic effect, making it extremely desirable as a medicine. ) An amide derivative, a method for producing the same, and a pharmaceutical composition containing the same. Traditionally, for autoimmune diseases such as rheumatoid arthritis,
Steroidal and non-steroidal anti-inflammatory drugs
It is also widely used clinically. However, many of these drugs are still not fully satisfactory in terms of their original effects, side effects, toxicity, etc. The compounds of the invention have specific effects on cells involved in the immune response and have the ability to alter the immune response of the host. General formula (1) (In the formula, R is α-halogenoethyl group or α-
N-, which represents a halogenopropyl group)
(4-phenyl-2-thiazolyl)amide derivatives specifically include the following. However, although these compounds can exhibit amine type and imine type tautomerism, general formula (1) includes all tautomers. 2-(α-chloropropionylamino)-4-phenylthiazole. 2-(α-bromopropionylamino)-4-phenylthiazole. 2-(α-
Chloro-n-butyrylamino)-4-phenylthiazole. 2-(α-bromo-n-butyrylamino)-4-phenylthiazole. 2-(α-chloro-α-methylpropionylamino)-4-phenylthiazole. 2-(α-bromo-α-methylpropionylamino)-4-phenylthiazole. These compounds represented by the general formula (1) are 2-amino-4-phenylthiazole and the general formula (2) It can be obtained by a method of reacting with carboxylic acid halides represented by (representing a halogen atom). The reaction is carried out by dissolving or suspending 2-amino-4-phenylthiazole (which may exist in the form of a suitable acid addition salt) in a solvent, and adding the compound of general formula (2) dropwise. It is best to add this method. Examples of solvents include benzene, toluene, xylene,
Acetone, ethyl methyl ketone, dioxane,
1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide and the like are suitable. Furthermore, it is also useful to use organic bases such as pyridine and triethylamine or inorganic bases such as sodium carbonate, potassium carbonate, and sodium bicarbonate for the purpose of removing the acid produced by the reaction. Although this reaction proceeds even at temperatures below room temperature, it is also possible to heat the solvent to the boiling point in order to accelerate the reaction. The compound represented by the general formula (1) of the present invention is:
Possesses pharmacological activity. It has been particularly surprisingly found by the inventors that the compounds of the invention have immunomodulatory properties. The compounds of the present invention have low toxicity and are extremely useful as medicines. Next, this will be explained using a test example. Many experimental systems are commonly used to test immunomodulatory ability using animals, but the results of the most representative test, the delayed-type hypersensitivity reaction enhancement test, are illustrated below as a test example. do. Delayed hypersensitivity induced in mice by applying picryl chloride (2-chloro-1,3,5-trinitrobenzene) to the skin is known as a typical cell-mediated immune phenomenon, and as an experimental system. It is one of the systems widely used worldwide (Asherson. GLand Ptak, W.: Contact and
delayed hypersensitivity in the mouse I.
Active sensitization and passive transfer.
Immunology, 15 , 405-416 (1968)). This experimental system was used in a delayed hypersensitivity enhancement test. Test Example 1 Delayed hypersensitivity reaction enhancement test Test method: ICR male mice weighing approximately 30 g were used in a group of 8 mice. Sensitization was performed by dissolving 3% picryl chloride in a 4:1 mixture of olive oil and acetone and applying it to the shaved abdomen of the mouse. Simultaneously with sensitization, the compound of the present invention dissolved or suspended in 0.2% carboxymethylcellulose physiological saline was orally administered at a rate of 50 mg per kg of mouse body weight. For the control group, 0.2% carboxymethylcellulose physiological saline was administered in the same manner. To induce delayed-type hypersensitivity (challenge), 7 days after sensitization, a felt wrapped in a felt soaked in olive oil containing 1% picry chloride was applied to the ears of the mouse. I did it.
The thickness of the mouse ears was measured before the challenge and 24 hours after the challenge, and the rate of increase in thickness (average value of both ears of 8 mice) is shown in Table 1. For comparison, the results of a similar test using levamisole hydrochloride are also shown. An F-t test was conducted on the test results, and those with a significant risk ratio of P<0.05 compared to the control group were marked with *. Results: When the compound of the present invention was administered simultaneously with sensitization, the delayed hypersensitivity reaction induced by challenge was enhanced. The compound of the present invention was found to have an activity equal to or greater than that of levamisole used for comparison. That is, the compound of the present invention is considered to have an effect of regulating the cellular immune response of mice (immunomodulating ability).

【table】

[Table] Next, adjuvant arthritis in rats, which is caused by injection of Mycobacterium tuberculosis adjuvant, is frequently used as an experimental model for human rheumatoid arthritis. Although the onset mechanism of this disease is not fully understood, it is known that cell-mediated immunity plays an important role. Using this known adjuvant arthritis test, the immunomodulatory potential of the compounds of the invention was investigated. Test Example 2 Adjuvant Arthritis Test (Table 2) Test method: Using 8-week-old SD male rats, 0.4 mg of dried dead Mycobacterium tuberculosis cells was suspended in 0.1 ml of liquid paraffin. It was injected intracutaneously into the pad of the hind leg. The compound of the present invention was administered subcutaneously a total of 9 times before and after injection of the adjuvant.
The compound was dissolved or suspended in 0.2% carboxymethylcellulose physiological saline at a concentration of 5% per kg body weight.
Administered at the rate of mg. The volume of edema in the left hind paw was measured from the day of adjuvant injection until the end of the test, and the swelling rate was calculated. For comparison, the results of a test using levamisole hydrochloride are also shown. The test results were subjected to an Ft test, and those with a significance ratio of P<0.05 were marked with * compared to the control group in which only 0.2% carboxymethylcellulose physiological saline was administered. Results: The compound of the present invention strongly suppressed secondary inflammation in adjuvant arthritis, and the effect was statistically significant compared to the control group. The compound of the present invention was found to have an activity equal to or greater than that of levamisole used for comparison. That is, the compounds of the present invention are considered to have immunomodulatory ability and anti-arthritic activity.

[Table] As shown in Test Example 1 and Test Example 2, the compound of the present invention has strong activity as an immunomodulator, and is therefore useful for diseases known to be accompanied by decreased or abnormal immune function, e.g. It is effective in treating autoimmune diseases such as rheumatoid arthritis. Next, Test Example 3 shows a toxicity test for the active ingredient of the medicine of the present invention. Test Example 3 Acute toxicity test by oral administration Test method: A drug dissolved or suspended in physiological saline was orally administered to male DDY mice (5 mice per group). Observe the progress for 7 days after administration, and estimate the estimated LD ₅₀
I found the value. Results: The estimated LD ₅₀ value of the active ingredient of the medicament of the present invention was 1000 mg/Kg or more. This value is much larger than the estimated LD ₅₀ =200-300 mg/Kg of levamisole hydrochloride, and the toxicity of the active ingredient of the present invention is considered to be weak. When using the compound of the present invention as a medicine, it is possible to use it as a free base as a raw material for pharmaceutical preparations. When the drug is required to be water-soluble, it is preferable to use it as a pharmaceutically acceptable salt, such as hydrochloride, citrate, or phosphate, in the drug raw material. The medicament of the present invention can be used in the same dosage form and administration method as conventional immunomodulators or anticancer agents. For example, as oral preparations, capsules, granules, pills, fine granules, tablets, syrups, etc. can be used. Suppositories are suitable for intrarectal administration, and subcutaneous, intramuscular, or intravenous injections can be used for injections. Diseases to which the immunomodulator of the present invention can be applied include diseases known to be accompanied by abnormalities in immune function, such as autoimmune diseases such as rheumatoid arthritis and polymyositis, various infectious diseases, and various cancers. It can be expected to normalize the immune function of patients with the disease. It is desirable that the administration method and dosage form of the medicament of the present invention be appropriately selected depending on the type of disease, patient's condition, etc. The dose is 1 body weight for oral administration.
The appropriate daily dose per kg is 0.5 mg to 100 mg, preferably 1 mg to 30 mg, 1 mg to 100 mg for rectal administration, 1 mg to 10 mg for intravenous administration, subcutaneous or intramuscular administration. In these cases, 1mg to 30mg is appropriate, but
It is desirable to select appropriate doses for these doses depending on the type of disease, patient's condition, etc. Furthermore, depending on the type of disease and the condition of the patient, the therapeutic effect of the active ingredient of the present invention can be increased by using other drugs in combination as necessary. For example, cancer chemotherapy drugs such as alkylating agents and antimetabolites have side effects that reduce the patient's immune system.
By using the active ingredients of the present invention when administering such drugs, it is expected that the side effects of these drugs will be prevented and the therapeutic effects will be synergistically enhanced. Examples of the present invention will be described below. Example 1 12.5 g of 2-amino-4-phenylthiazole and 7.0 g of triethylamine were added to 50 ml of acetone and cooled to -10 to -20°C. α-
11.7 g of chloropropionyl chloride was gradually added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 3 hours, the reaction mixture was poured into 500 ml of water, and the resulting oil was extracted with ethyl acetate. was removed, and the residue was recrystallized from a mixed solvent of ether and n-hexane to give 2-(α-chloropropionylamino).
13.2 g of -4-phenylthiazole was obtained. Melting point: 98-99℃ Elemental analysis value: C ₁₂ H ₁₁ ClN ₂ As OS C H Cl N S Theoretical value % 54.03 4.16 13.29 10.50 12.02 Experimental value % 53.95 4.09 13.36 9.99 11.98 IR (υ ^KBr _nax , cm ^-1 ): 3150, 2900, 1705, 1610,
1570, 1550, 1490, 1450, 1340, 1280,
1180, 1080, 1000, 910, 740, 700 NMR (δ ^CDCl3 _TMS , ppm): 1.70 (3H, d, J=
8.0Hz), 4.40 (1H, q, J = 8.0Hz), 7.16
(1H, s), 7.3-7.9 (5H, m), 10.45 (1H,
bs: disappears with D ₂ O) Example 2 3.5 g of 2-amino-4-phenylthiazole and 2.0 g of triethylamine were added to 50 ml of tetrahydrofuran and cooled to 0 to -5°C. 4.3 g of α-bromopropionyl bromide was added dropwise to this mixed solution. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the residue was taken out in chloroform and washed with water. The crude product obtained by removing chloroform was subjected to silica gel column chromatography, eluted with a mixed solvent of chloroform-methyl alcohol (40:1), and further recrystallized with a mixed solvent of ether and cyclohexane. 2-(α-bromopropionylamino)-
4.2 g of 4-phenylthiazole was obtained. Melting point: 113.5-115℃ Elemental analysis value: C ₁₂ H ₁₁ BrN ₂ As OS C H Br N S Theoretical value % 46.31 3.56 25.68 9.00 10.30 Experimental value % 46.45 3.49 25.71 8.97 10.32 NMR (δ ^CDCl3 _TMS , ppm): 1 .72 ( 3H, d, J=
7.0Hz), 4.24 (1H, q, J = 7.0Hz), 7.18
(1H, s), 7.4-7.9 (5H, m), 12.1 (1H,
bs: Disappeared with D ₂ O) Compounds of the following examples were produced in the same manner as in Examples 1 and 2 above. Example 3 2-(α-bromo-n-butyrylamino)-4-
Phenylthiazole. Melting point: 85-86.5 ° C. element analysis values: C ₁₃ H ₁₃ Brn ₂ OS C H BR N S theoretical value 48.01 48.01 24.57 8.61 9.86 Experimental value 48.18 4.13 24.61 8.51 9.78 NMR (Δ ^CDCL3 _TMS , PPM): 0.64 (0.64) 3H, t, J=
7.0Hz), 1.84 (2H, m), 3.72 (1H, t, J
=7.0Hz), 7.13 (1H, s), 7.3~7.84 (5H,
m) Example 4 2-(α-bromo-α-methylpropionylamino)-4-phenylthiazole. Melting point: 93.5-94.5℃ Elemental analysis value: C ₁₃ H ₁₃ BrN ₂ As OS C H Br N S Theoretical value % 48.01 4.03 24.57 8.61 9.86 Experimental value % 47.99 3.96 24.67 8.59 9.87 NMR (δ ^CDCl3 _TMS , ppm): 2.0 0( 6H, s), 7.20 (1H,
s), 7.4-7.9 (5H, m), 9.92 (1H, bs:
Disappeared in _D2O )

Claims (1)

[Claims] 1 General formula (1) (In the formula, R is α-halogenoethyl group or α-
N-, which represents a halogenopropyl group)
(4-phenyl-2-thiazolyl)amide derivative. 2 General formula (1) (In the formula, R is α-halogenoethyl group or α-
N-, which represents a halogenopropyl group)
In the production of (4-phenyl-2-thiazolyl)amide derivatives, general formula (2) RCOX (2) (wherein, R is α-halogenoethyl group or α-
(represents a halogenopropyl group, X represents a halogen atom);
A method of reacting with amino-4-phenylthiazole. 3 General formula (1) (In the formula, R is α-halogenoethyl group or α-
N-, which represents a halogenopropyl group)
A pharmaceutical composition for immunomodulation, characterized in that it contains a (4-phenyl-2-thiazolyl)amide derivative as an active ingredient. 4. The immunomodulating pharmaceutical composition according to claim 3, which is combined with a pharmaceutically acceptable diluent or carrier. 5. The pharmaceutical composition for immunomodulation according to claim 3, which is used for the treatment of rheumatoid arthritis. 6. The immunomodulating pharmaceutical composition according to claim 3, which is used in cancer immunotherapy.