JP2000159665A - Preventive or therapeutic agent of rheumatism - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preventive or therapeutic agent of rheumatism, having excellent activities as the preventive or therapeutic agent of the rheumatism such as inflammatory rheumatism, and providing small toxicity by including a specific sulfonamide derivative (salt) as an active ingredient. SOLUTION: The objective preventive or therapeutic agent contains a sulfonamide derivative (salt) of the formula [R1 is H, a halogen, a lower alkyl, nitro, OH or the like; R2 and R3 are each H, a halogen, a lower alkyl or a lower alkoxy; A is =N-or =CH-; B is a (substituted) aromatic six-membered ring (including one to two Ns) in the ring or CO-R4 (R4 is H, a lower alkyl, 2-thienyl or the like)] as an active ingredient. The derivative is exemplified by N- 2-[(4- hydroxyphenyl)amino]-3-pyridyl}-4-methoxybenzenesulfonamide. The preventive or therapeutic agent is orally or parenterally (whole body administration, topical administration or the like) administered.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive or therapeutic agent for rheumatism such as inflammatory rheumatism containing a sulfonamide compound as an active ingredient. Further, the compound of the present invention can be used as a tubulin polymerization inhibitor.

[0002]

2. Description of the Related Art A sulfonamide compound used in the present invention is disclosed as an antitumor agent in JP-A-5-39256. It is not known that this compound has an antirheumatic effect.

Conventionally, for the treatment of rheumatoid arthritis (RA) among inflammatory rheumatism, steroids such as corticosteroids; non-steroidal anti-inflammatory agents such as piroxicam and indomethacin; gold, salazosulfapyridine and D -Antirheumatic drugs such as penicillamine; immunosuppressants such as cyclophosphamide, azathioprine, and bledinin have been used.

Recently, it has been reported that low-dose intermittent therapy with methotrexate has a high effective rate and a rapid onset of the effect. However, serious side effects such as interstitial pneumonia and the risk of lymphoma have been pointed out.

[0005] Rheumacon having an antirheumatic effect is
There is a report that lignan glycoside, which is an extract from nature, exhibits a tubulin polymerization inhibitory action.

[0006]

The above-mentioned drugs have problems such as serious or side effects that make continuous use difficult, non-sustained effects, or ineffectiveness in some patients. . Moreover, while there is a need for a drug that can change the natural history of RA, there is still no drug that satisfies it, and the emergence of a drug with a new mechanism of action, a more potent, and less toxic drug is expected. It is rare

[0007]

[Means for solving the problem] To solve this problem,
The present inventors have conducted a sincere study in search of a more effective and less toxic rheumatism preventive or therapeutic agent such as inflammatory rheumatism, and as a result, a sulfonamide compound represented by the following general formula (1) and a sulfonamide compound represented by the formula (1): The present inventors have found that a pharmacologically acceptable salt has an excellent action as a preventive or therapeutic agent for rheumatism such as inflammatory rheumatism and has low toxicity, and completed the present invention. That is, the present invention provides the following (1) to
(9). (1) The following general formula (1)

[0008]

Embedded image

[Wherein R1 is a hydrogen atom, a halogen atom,
Lower alkyl group, lower alkoxy group, nitro group, hydroxyl group, cyano group, acetyl group, phenoxy group, and optionally substituted amino group. R2 and R3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group. A =
It means N- or = CH-. B represents the same or different aromatic 6-membered ring group which may have 1 to 3 substituents G (which may contain 1 or 2 nitrogen atoms in the ring). G represents a halogen atom, a lower alkyl group, a lower alkoxy group, or an optionally protected hydroxyl group. B is -CO-R4 (wherein R4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, an amino group which may have a substituent, a 2-thienyl group, a 2-furyl group, or a compound represented by the formula

[0010]

Embedded image

(Wherein R5 and R6 are the same or different and each represent a hydrogen atom, a halogen atom, a nitro group, an optionally protected hydroxyl group, a lower alkyl group or a lower alkoxy group. D is represented by = N-. Or a pharmaceutically acceptable salt thereof as a prophylactic or therapeutic agent for rheumatism.

(2). 2. A prophylactic or therapeutic agent for rheumatism, comprising as an active ingredient the sulfonamide derivative or the pharmaceutically acceptable salt thereof according to the above 1, wherein R1 is a lower alkoxy group and R2 and R3 are hydrogen in the general formula (1).

(3). In the general formula (1), B is -C
O-R4 (wherein R4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, an amino group which may have a substituent,
2-thienyl group, 2-furyl group, or formula

[0014]

Embedded image

(Wherein R5 and R6 are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, an optionally protected hydroxyl group, a lower alkyl group or a lower alkoxy group. D is represented by = N-) 3. A preventive or therapeutic agent for rheumatism, comprising as an active ingredient a sulfonamide derivative or a pharmaceutically acceptable salt thereof according to the above item 2, which represents a group or ＝ CH—.

(4). In the general formula (1), B has the same or different 1 to 3 substituents G (G means a halogen atom, a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group). 3. The sulfonamide derivative or pharmacologically acceptable salt thereof according to the above item 2, which is an aromatic six-membered ring group (which may contain one or two nitrogen atoms in the ring). Or a prophylactic or therapeutic agent for rheumatism.

(5). In the general formula (1), A is = C
4. A preventive or therapeutic agent for rheumatism, comprising the sulfonamide derivative according to the above-mentioned 3 which is H- or a pharmaceutically acceptable salt thereof as an active ingredient.

(6). In the general formula (1), A is:
5. A prophylactic or therapeutic agent for rheumatism, comprising as an active ingredient the sulfonamide derivative or a pharmaceutically acceptable salt thereof according to the above 4, which is N-.

(7). 2. A prophylactic or therapeutic agent for rheumatism, comprising as an active ingredient the sulfonamide derivative according to the above item 1 or a pharmacologically acceptable salt thereof, wherein the compound is selected from the sulfonamide derivatives listed below. (1) N- [2-[(4-hydroxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (2) N- [2-[(4-fluorophenyl) amino] -3-pyridyl ] -4-methoxybenzenesulfonamide (3) N- [2-[(4-methoxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (4) N- (2-anilino-3-pyridyl) ) -4-Methoxybenzenesulfonamide (5) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-methylnicotinamide (6) N- [2- (4-methoxybenzenesulfonamido) phenyl] 2-methylbenzamide (7) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-furancarboxamide (8 N- [2- (4-methoxybenzenesulfonamido) phenyl] acetamide (9) N- [2- (4-methoxybenzenesulfonamido) phenyl] nicotinamide (10) 2-chloro-N- [2- (4 -Methoxybenzenesulfonamido) phenyl] nicotinamide (11) 4-benzyloxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide (12) 4-hydroxy-N- [2- (4-methoxy) (13) 4-methoxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide

(8). 8. A preventive or therapeutic agent for inflammatory rheumatism, comprising the sulfonamide derivative according to any one of the above 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient. (9). 8. The sulfonamide derivative according to any one of the above 1 to 7 or a pharmacologically acceptable salt thereof (provided that R1 is a methoxy group, R2 and R3 are hydrogen atoms, A is = N-, A tubulin polymerization inhibitor comprising, as an active ingredient, a combination in which B is a 4-hydroxyphenyl group.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The details of the present invention will be described below. In the compound of the general formula (1), the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, amyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl Group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl Group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,
Examples thereof include a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. Of these, preferred groups are methyl group,
An ethyl group can be mentioned.

In the general formula (1), a lower alkoxy group means a methoxy group, an ethoxy group, an isopropoxy group, n
And lower alkoxy groups derived from lower alkyl groups such as -butoxy, isobutoxy and t-butoxy. Among these, preferred groups include a methoxy group and an ethoxy group. In the general formula (1), the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and the like.

In the general formula (1), the optionally substituted amino group includes an unsubstituted amino group and a lower acylamino group (for example, formylamino group, acetylamino group, propionylamino group, etc.) 1-4), benzyloxycarbonylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-
Examples include a dipropylamino group, an N, N-diisopropylamino group, an N, N-di-n-butylamino group.

The sulfonamide derivative represented by the general formula (1) may form a salt with an acid. The present invention also includes a salt of the compound of the general formula (1). As salts with acids,
For example, inorganic acid salts such as hydrochloride, hydrobromide and sulfate,
Examples thereof include salts with organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid. When hydrates of these compounds exist, all of them are included.

Some of the compounds represented by the general formula (1) are shown together with their compound numbers. (1) N- [2-[(4-hydroxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (2) N- [2-[(4-fluorophenyl) amino] -3-pyridyl ] -4-methoxybenzenesulfonamide (3) N- [2-[(4-methoxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (4) N- (2-anilino-3-pyridyl) ) -4-Methoxybenzenesulfonamide (5) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-methylnicotinamide (6) N- [2- (4-methoxybenzenesulfonamido) phenyl] 2-methylbenzamide (7) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-furancarboxamide (8 N- [2- (4-methoxybenzenesulfonamido) phenyl] acetamide (9) N- [2- (4-methoxybenzenesulfonamido) phenyl] nicotinamide (10) 2-chloro-N- [2- (4 -Methoxybenzenesulfonamido) phenyl] nicotinamide (11) 4-benzyloxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide (12) 4-hydroxy-N- [2- (4-methoxy) (13) 4-methoxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide

The compounds of the present invention are described, for example, in JP-A-5-39.
It can be manufactured in the same manner according to 256.

The prophylactic or therapeutic agent for rheumatism such as inflammatory rheumatism of the present invention may be orally or parenterally (systemically administered,
It is safely administered (eg, local administration). The dosage depends on the route of administration, the age of the patient and the actual condition to be prevented or treated. For example, when given orally to adults,
It is about 0.01 mg to 2000 mg per day as an active ingredient. It can be administered once or several times a day. The administration is not limited to continuous administration, but when continuous administration is required, it is desirable to reduce the amount used per day.

Oral preparations, injection preparations and the like can be prepared by mixing the compound of the formula (1) with a solid carrier, a liquid carrier and, if necessary, pharmaceutically acceptable additives such as diluents, suspensions and solubilizers. Suspended and dissolved powders, granules, tablets, capsules,
It is formulated into injections and the like.

[0029]

EXAMPLES Next, as examples of the present invention, pharmacological actions will be described by test examples and further formulation examples.

Test Example 1 Tubulin Polymerization Inhibition Test Using Pig Brain-Derived Microtubule Protein Shelansky Method (Protein Experiment Method, Seizure Chemistry Experiment Course, Vol. 6, Structure and Function of Cytoskeleton (Top) Tokyo Chemical Dojin) The microtubule protein was further purified, and the microtubule protein was polymerized by turbidity measurement. The microtubule protein previously depolymerized on ice was added to a polymerization buffer containing GTP (100 mM MES, 0.5 mM
Heating in magnesium chloride, 1 mM EGTA pH 6.8) reconstitutes microtubules and increases turbidity. Measure the change in turbidity with an absorptiometer. The compound of the present invention was dissolved in dimethyl sulfoxide. 5 μl of the compound of the present invention was added to and dissolved in 245 μl of a polymerization buffer containing microtubule protein (2 mg / ml final concentration) and GTP (1 mM final concentration), followed by heating at 37 ° C. for 30 minutes. 34 with a spectrophotometer
The absorbance at 0 nm was measured, the inhibition rate was calculated from the following equation, and the concentration of the test compound that inhibited by 50% was determined. The absorbance at 340 nm of the test compound was measured in advance.

[0031]

## EQU1 ## Suppression rate (%) = (1- (T-Cmin) / (C
max-Cmin)) x100 T: Absorbance of a sample to which a test compound was added and heated. Cma
x: Absorbance of a sample heated without adding a test compound. Cm
in: Absorbance of the sample that was not heated without adding the test compound. result

The 50% inhibitory concentration (IC5
0) is shown in Table 1. The compound of the present invention showed a strong tubulin polymerization inhibitory action.

[0033]

[Table 1]

Test Example 2 Effect on Mouse Collagen-Induced Arthritis Test Compound Compound No. 5 Compound Tuberculosis H37RA Freu
2m to nt incomplete adjuvant
g / ml, mixed with the same amount of 0.3% type 2 collagen (derived from bovine joint, collagen technology workshop) and emulsified. This 0.1 ml was sensitized by injecting it into the skin of the ridge of male DBA / 1J mouse (10 or 11 weeks old, Charles River Japan). 0.3% after 21 days
Dilute type 2 collagen 6 times with physiological saline, 0.2ml
Was injected intraperitoneally for secondary sensitization. Mice that developed arthritis due to primary sensitization alone were excluded. The compound of the present invention may be used in an amount of 0.
5% sodium carboxymethylcellulose (CMC
-Na) (25 mg / kg) and orally administered once a day for 32 days from the second sensitization day. A group to which only 0.5% CMC-Na was orally administered without the compound of the present invention was set as a control group. Each group consists of 7 animals. Observe the symptoms of the extremities over time, according to the following criteria,
Scored (0-4, and therefore up to 16). On the last day, blood tests were performed on all cases.

Criteria for scoring of extremity symptoms: 0; no symptoms 1: only one finger (or toe) swelling and redness 2; two or more fingers (or toes) swelling redness or hand (or foot) Slight swelling and redness 3; overall swelling and redness including hand (or foot) joints 4; tonic changes in hand (or foot) joints and finger (or toe) joints

The compound No. 1 was tested according to the method described above. Provided that the compound of the present invention is
% Carboxymethylcellulose sodium (CMC-
Na) (50 mg / kg) and orally administered three times a week for 5 weeks from the second sensitization day.

The results of the blood test for the compound No. 5 are shown in Table 2. Low toxicity of the compounds of the present invention
No deaths were observed even after continuous administration for 5 days, and the blood test values were bone marrow toxicity (leukocyte) and liver toxicity (ALP)
And no renal toxicity (BUN).

[0038]

[Table 2]

Table 3 shows the arthritis incidence rate and average limb symptom score on the last day of the evaluation for Compound Nos. 5 and 1. However, mice with a score of 3 or more in one of the limbs were defined as affected mice. The compound of the present invention was confirmed to have an excellent antirheumatic effect in a collagen-induced arthritis model which is an animal model of human rheumatoid arthritis.

[0040]

[Table 3]

Formulation Example A tablet is prepared according to the following formulation. Compound of Compound No. 1 or 5 100 g Lactose 3000 g Starch paste Appropriate amount Magnesium stearate 5 g After sufficiently mixing the above components, tablets are manufactured by a tableting machine.

[0042]

The compound of the present invention has been confirmed to have an excellent antirheumatic effect in a collagen-induced arthritis model which is an animal model of human rheumatoid arthritis. Therefore, the compound of the present invention has low toxicity and is useful as an agent for preventing or treating rheumatism such as inflammatory rheumatism.

Claims (9)

[Claims] [Claim 1] The following general formula (1) [Wherein, R1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxyl group, a cyano group,
An acetyl group, a phenoxy group, and an amino group which may have a substituent. R2 and R3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group. A is = N-, or
= CH-. B is the same or different from 1 to 3
Means an aromatic six-membered ring group optionally having one or more substituents G (which may contain one or two nitrogen atoms in the ring). G represents a halogen atom, a lower alkyl group, a lower alkoxy group, or an optionally protected hydroxyl group. B is -CO-R4 (where R4 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, an amino group which may have a substituent, a 2-thienyl group, a 2-furyl group, or a compound represented by the formula: ] (Wherein R5 and R6 are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, an optionally protected hydroxyl group, a lower alkyl group, or a lower alkoxy group.
It means a group represented by N- or ＣＨCH-. ))) A prophylactic or therapeutic agent for rheumatism comprising a sulfonamide derivative represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The prevention of rheumatism comprising a sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is a lower alkoxy group and R2 and R3 are hydrogen in the general formula (1). Or a therapeutic agent. 3. In the general formula (1), B is -CO-R4
(Wherein, R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, an amino group which may have a substituent, a 2-thienyl group, a 2-furyl group, or a compound represented by the formula: (Wherein R5 and R6 are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, an optionally protected hydroxyl group, a lower alkyl group, or a lower alkoxy group.
It means a group represented by N- or ＣＨCH-. A preventive or therapeutic agent for rheumatism comprising the sulfonamide derivative according to claim 2 or a pharmacologically acceptable salt thereof as an active ingredient. 4. In the general formula (1), B is the same or different and has 1 to 3 substituents G (G represents a halogen atom, a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group). 6-membered aromatic ring group (which may contain one or two nitrogen atoms in the ring)
3. A prophylactic or therapeutic agent for rheumatism comprising the sulfonamide derivative according to claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The preventive or therapeutic agent for rheumatism comprising a sulfonamide derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein A is ＣＨCH— in the general formula (1). 6. The preventive or therapeutic agent for rheumatism comprising a sulfonamide derivative or a pharmacologically acceptable salt thereof according to claim 4, wherein A in the general formula (1) is = N-. 7. A prophylactic or therapeutic agent for rheumatism comprising the sulfonamide derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient, wherein the compound is selected from the sulfonamide derivatives listed below. (1) N- [2-[(4-hydroxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (2) N- [2-[(4-fluorophenyl) amino] -3-pyridyl ] -4-methoxybenzenesulfonamide (3) N- [2-[(4-methoxyphenyl) amino] -3-pyridyl] -4-methoxybenzenesulfonamide (4) N- (2-anilino-3-pyridyl) ) -4-Methoxybenzenesulfonamide (5) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-methylnicotinamide (6) N- [2- (4-methoxybenzenesulfonamido) phenyl] 2-methylbenzamide (7) N- [2- (4-methoxybenzenesulfonamido) phenyl] -2-furancarboxamide (8 N- [2- (4-methoxybenzenesulfonamido) phenyl] acetamide (9) N- [2- (4-methoxybenzenesulfonamido) phenyl] nicotinamide (10) 2-chloro-N- [2- (4 -Methoxybenzenesulfonamido) phenyl] nicotinamide (11) 4-benzyloxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide (12) 4-hydroxy-N- [2- (4-methoxy) (13) 4-methoxy-N- [2- (4-methoxybenzenesulfonamido) phenyl] benzamide 8. A prophylactic or therapeutic agent for inflammatory rheumatism comprising the sulfonamide derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 9. The sulfonamide derivative according to claim 1 or a pharmacologically acceptable salt thereof (provided that R1 is a methoxy group, R2 and R2 in the general formula (1)).
3 is a hydrogen atom, A is = N-, and B is a 4-hydroxyphenyl group).