JPH07118231A - Sulfamoylbenzoic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new stable sulfamoylbenzoic acid derivative, capable being readily taken in a biomembrane, having low toxicity and high protecting effects on cytotoxicity and useful as a protecting agent against the cytotoxicity with active oxygen species. CONSTITUTION:This sulfamoylbenzoic acid derivative is expressed by formula I (R<1> is H or a l-5C alkyl; R<2> is a 5-22C saturated or unsaturated alkyl), e.g. 4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)-3-(cis-9-octadecenylam inosulfonyl) benzamide. The compound expressed by formula I is obtained by reacting and alkylating 4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)-3-sulfamoylbenzamide expressed by formula II or a derivative thereof with an alkylating agent. This protecting agent against cytotoxicity is effective against diseases such as ischemic cardiopathies, ischemic cerebropathies, circulatory diseases, diseases in digestive organs, dermatopathies, cancers, nephritides or pulmonary diseases.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel and useful sulfamoylbenzoic acid derivative, and a drug for preventing and treating diseases caused by cytotoxicity caused by reactive oxygen species.

[0002]

2. Description of the Related Art There are many active oxygen scavenging systems in the living body, which protect the living body from oxidative stress. It has been clarified that the active oxygen generated from the disturbance of the defense system is involved in the development of various diseases. Particularly in recent years, it has been noted that the damage of vascular endothelial cells due to active oxygen is deeply involved in the pathogenesis of arteriosclerosis.

Cellular damage caused by reactive oxygen species causes inflammation and
It is considered to be a part of various diseases that occur in the heart, circulatory system, digestive system, and so on, and until now, studies have been conducted on drugs that eliminate these reactive oxygen species in the living body. For example, antioxidant compounds having actions such as elimination of active oxygen and decomposition of lipid peroxide have been developed as active oxygen scavengers by various approaches (radical scavenger, Mebio,
5 , 90-94, 1988).

However, the enzymes such as superoxide dismutase which have been studied up to now have a large molecular weight and have a negative tissue migration property, and there is a problem in stability. Further, vitamin E and vitamin C have drawbacks such as insufficient stability and active oxygen scavenging effect in an experiment using a living body.

By the way, as a compound having a structure of a sulfamoylbenzoic acid derivative, 4-chloro-N- (2,
3-Dihydro-2-methyl-1H-indol-1-yl) -3-sulfamoylbenzamide is known as the diuretic antihypertensive agent indapamide (USP No. 3565).
911). Also, 4-chloro-N- (2,3-dihydro-
2-Methyl-1H-indol-1-yl) -3-sulfamoylbenzamide has been reported to have an antioxidant effect (Chem. Pharm. Bull., 38 , 255 (1990), etc.). However, no cytotoxic protective action has been reported, and as a result of our research, as shown later in Comparative Example 1,
4-chloro-N- (2,3-dihydro-2-methyl-1
H-indol-1-yl) -3-sulfamoylbenzamide had no cytotoxic protective action.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel and useful sulfamoylbenzoic acid derivative which is easily incorporated into a biological membrane, is stable and has low toxicity, and has a high cytotoxicity-protecting effect, and an active ingredient thereof. To provide a cytotoxic agent.

[0007]

[Means for Solving the Problems] In general, cells in vivo,
For example, as substances that damage vascular endothelial cells, lipid peroxides and superoxide, hydroxyl radicals,
Reactive oxygen species such as singlet oxygen and hydrogen peroxide are known. The present inventors created an experimental system in which cultured vascular endothelial cells labeled with ⁵¹ Cr were injured by activated leukocytes, and the cytotoxicity was quantified by the amount of released ⁵¹ Cr, to suppress the vascular endothelial cell injury inhibition of various compounds. As a result of examining various effects,
The present invention has been completed by finding that the sulfamoylbenzoic acid derivative represented by the formula [1] described later has a strong inhibitory effect.

That is, the present invention provides the following sulfamoylbenzoic acid derivative and a cytotoxic agent containing the same as an active ingredient. (1) A sulfamoylbenzoic acid derivative represented by the following general formula [1].

[Chemical 2] (In the formula, R ¹ is H or an alkyl group having 1 to 5 carbon atoms, R ²
Is a saturated or unsaturated alkyl group having 5 to 22 carbon atoms, R
³ represents H or a saturated or unsaturated alkyl group having 5 to 22 carbon atoms. (2) A cytotoxic agent comprising the sulfamoylbenzoic acid derivative according to (1) above as an active ingredient.

In the present invention, R ^{1 of the} general formula [1] is
Examples of the alkyl group having 1 to 5 carbon atoms represented by are methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group and the like. When R ¹ is a methyl group or a hydrogen atom, the cytotoxicity-protecting effect is particularly high.

The saturated or unsaturated alkyl group having 5 to 22 carbon atoms represented by R ² or R ³ in the above general formula [1] is a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group or a decyl group. , Undecyl group, dodecyl group,
Linear saturated alkyl groups such as tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group; branched chain saturated alkyl groups such as isopentyl group, neopentyl group, tert-pentyl group, isohexyl group; cis -9-tetradecenyl group, trans-3-hexadecenyl group, cis-9-
Hexadecenyl group, cis-6-octadecenyl group, c
is-9-octadecenyl group, trans-9-octadecenyl group, cis-11-octadecenyl group, cis
-9-eicosenyl group, cis-13-docosenyl group,
2,4-hexadienyl group, cis-9, cis-1
2-octadecadienyl group, cis-6, cis-9-
Octadecadienyl group, cis-9, cis-12, c
is-15-octadecatrienyl group, cis-6, c
is-9, cis-12-octadecatrienyl group, c
is-9, trans-11, trans-13-octadecatrienyl group, cis-5, cis-8, cis
-11, cis-14-eicosatetraenyl group, ci
s-5, cis-8, cis-11, cis-14, c
is-17-eicosapentaenyl group, cis-4, c
is-7, cis-10, cis-13, cis-16
-Docosapentaenyl group, cis-4, cis-7, c
is-10, cis-13, cis-16, cis-1
Examples thereof include alkyl groups having 1 to 6 unsaturated bonds such as 9-docosahexaenyl group.

R ¹ and R ² may be the same alkyl group or different alkyl groups. In addition, R
^When the combination of ² and R ³ is a cis-9-octadecenyl group and a hydrogen atom, or a cis-9, cis-12-octadecadienyl group and a hydrogen atom, the cytotoxicity-protecting effect is particularly high.

Specific examples of the sulfamoylbenzoic acid derivative of the present invention represented by the above general formula [1] include:
4-chloro-N- (2,3-dihydro-2-methyl-1
H-indol-1-yl) -3- (cis-9-octadecenylaminosulfonyl) benzamide, 4-chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3- (cis-9, cis-1
2-Octadecadienylaminosulfonyl) benzamide, 4-chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3-pentylaminosulfonylbenzamide, 4-chloro-3- Decylaminosulfonyl-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) benzamide, 4,
-Chloro-N- (2,3-dihydro-2-methyl-1H
-Indol-1-yl) -3-octadecylaminosulfonylbenzamide, 4-chloro-N- (2,3-
Dihydro-2-methyl-1H-indol-1-yl)
-3-dipentylamino sulfonyl benzamide etc. are mentioned.

The sulfamoylbenzoic acid derivative of the present invention has the general formula [2]

[Chemical 3] (In the formula, R ¹ has the same meaning as in the general formula [1].)
4-chloro-N- (2,3-dihydro-2 represented by
It can be produced by reacting -methyl-1H-indol-1-yl) -3-sulfamoylbenzamide or a derivative thereof with a known alkylating agent by a conventional method for alkylation.

Examples of the alkylating agent include alkyl halides and alkyl sulfonates. The desired sulfamoylbenzoic acid derivative can be produced by appropriately selecting the reaction temperature, the reaction time, the type and amount of the halogenating agent used, and the like.

The sulfamoylbenzoic acid derivative thus obtained can be isolated and purified by conventionally known methods such as extraction, recrystallization and chromatography. The compound represented by the general formula [2] can be obtained, for example, from USP No. 3565911, EP54892A
It can be produced by the known method described in 1).

The cytotoxic agent of the present invention contains the sulfamoylbenzoic acid derivative represented by the general formula [1] as an active ingredient. The cytotoxic agent of the present invention protects cell injury caused by reactive oxygen species, and ischemic heart disease, ischemic brain disease, cardiovascular disease (such as arteriosclerosis), digestive organ disease (such as gastrointestinal tract, It is effective against diseases such as liver and pancreas), skin diseases, cancer, nephritis and lung diseases.

When the sulfamoylbenzoic acid derivative of the present invention is used as a cytotoxic agent, the sulfamoylbenzoic acid derivative is a per se known pharmacologically acceptable carrier, excipient, disintegrating agent, corrective agent, bulking agent, Formulated in the form of tablets, capsules, granules, powders, powders, pills, liquids, drinks, injections, drops, suppositories, etc. according to a known method by mixing with a diluent, a solubilizing agent, etc. Can be converted. Such a formulation can be administered orally or parenterally.

Although the dose varies depending on the administration subject, administration route, symptom, etc., when administered orally, the sulfamoylbenzoic acid derivative is usually about 0.01 as a single dose.
mg-100 mg / kg body weight, preferably about 0.01 m
g-10 mg / kg body weight is administered about once to three times a day.
When administered parenterally, for example, in a suppository, the sulfamoylbenzoic acid derivative is about 0.05 mg to
20 mg / kg body weight is administered 1-2 times a day. In the case of an oil-based injection, it is preferable to administer about 0.001 to 5 mg / kg body weight of the sulfamoylbenzoic acid derivative once or twice a day.

[0019]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, a novel and useful sulfamoylbenzoic acid derivative and a cytotoxic agent which are easily incorporated into a biological membrane, are stable and have low toxicity, and have a high cytotoxic effect. Is obtained. Since this cytotoxicity-preventing agent has an excellent effect of eliminating active oxygen species in vivo, it exerts an excellent effect in the prevention and treatment of diseases based on cell injury caused by active oxygen species.

[0020]

EXAMPLES Next, examples of the present invention will be described. Example 1 [4-chloro-N- (2,3-dihydro-2-methyl-
Synthesis of 1H-indol-1-yl) -3- (cis-9-octadecenylaminosulfonyl) benzamide] N-N-dimethylformamide (hereinafter abbreviated as DMF) 4 ml of 4-chloro-N- (2 , 3-dihydro-2
-Methyl-1H-indol-1-yl) -3-sulfamoylbenzamide (459 mg) was dissolved and the mixture was cooled to 6 under ice-cooling.
50 mg of 0% sodium hydride was added in small portions. 0 ° C
After stirring for 30 minutes, a solution of 300 mg of 1-chloro-cis-9-octadecene dissolved in 2 ml of DMF was added dropwise little by little and stirred for 30 minutes. After removing the ice bath and returning to room temperature, the reaction solution was heated and stirred in an oil bath at 150 ° C. for 2 hours.

After standing to cool, the reaction solution was poured into water and extracted with 20 ml of diethyl ether, the aqueous layer was further extracted twice with 20 ml of diethyl ether, the diethyl ether layers were combined, washed with an aqueous sodium chloride solution three times, and dried. It was dried over magnesium sulfate. After the solvent was distilled off, the obtained yellow viscous oily substance (707 mg) was purified by silica gel column chromatography (eluent: hexane → 20% (V / V) ethyl acetate / hexane) to obtain the desired 4-chloro-N-
(2,3-dihydro-2-methyl-1H-indole-
1-yl) -3- (cis-9-octadecenylaminosulfonyl) benzamide (in the general formula [1], R ¹ is a methyl group, R ² is a cis-9-octadecenyl group, and R ³ is a hydrogen atom. Compound (3.) was obtained as a pale yellow amorphous solid (yield 53.3%).

The results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 615 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δ ppm 0.88 (t, J = 6.6 Hz, 3 H) 1.13-1.42 (m, 24 H) 1.39 ( d, J = 5.9 Hz, 3H) 1.42-1.57 (m, 2H) 1.94-2.11 (m, 4H) 2.62 (dd, J = 11.1 Hz, 15.1 Hz, 1
H) 3.00 (q, J = 6.9 Hz, 2H) 3.19 (dd, J = 8.3 Hz, 15.1 Hz, 1
H) 4.02-4.20 (m, 1H) 5.27-5.41 (m, 2H) 6.60 (d, J = 7.9 Hz, 1H) 6.71-6.84 (m, 2H) 7.03 (t, J = 7.9 Hz, 1H) 7.08 (d, J = 7.3 Hz, 1H) 7.78 (d, J = 8.3 Hz, 1H) 8.20 (dd, J = 2.3 Hz, 8.3 Hz, 1H) 8.60 (d, J = 2.3 Hz, 1H) 9.73 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 14.36, 19.08, 23.31, 27.17, 2
7.78, 28.98-30.69, 32.60, 3
6.64, 43.81, 64.04, 109.74, 1
20.93, 125.23, 127.85, 128.0
2,130.51,130.65,132.85,13
3.22, 133.74, 135.34, 139.7
3,152.49,164.81

IR (neat, cm ^-1 ): 3265 (NH, expansion / contraction) 3050, 3000 (CH, expansion / contraction) 1665 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ bending angle) 1335 (-SO _2- ) , Expansion / contraction) 1165 (-SO _2- , expansion / contraction) 750 (CH, bending angle)

Example 2 [4-chloro-N- (2,3-dihydro-2-methyl-
1H-indol-1-yl) -3- (cis-9, c
is-12-octadecadienylaminosulfonyl)
Synthesis of benzamide] 4-chloro-to 1.5 ml of DMF
N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3-sulfamoylbenzamide 20
Dissolve 0 mg, and under ice cooling, 60% sodium hydride 26
mg was added in small portions. After stirring at 0 ° C for 30 minutes, cis
A solution of 230 mg of DMF (1.5 ml) of −9, cis-12-octadecadiel = p-toluenesulfonate was added dropwise little by little, and the mixture was stirred for 30 minutes. After returning to room temperature and stirring for 8 hours, the reaction solution is poured into water and diethyl ether 20m
It was extracted with 1. The aqueous layer was further extracted twice with diethyl ether, the diethyl ether layers were combined, washed with an aqueous sodium chloride solution three times, and dried over anhydrous magnesium sulfate.

After evaporation of the solvent, a yellow viscous oil 31 was obtained.
7 mg was purified by silica gel column chromatography (eluent; hexane → 20% (V / V) ethyl acetate / hexane) to obtain the desired 4-chloro-N- (2,3).
-Dihydro-2-methyl-1H-indol-1-yl) -3- (cis-9, cis-12-octadecadienylaminosulfonyl) benzamide (in the general formula [1], R ¹ is a methyl group, R ² is cis-9, c
97 mg of a compound in which is-12-octadecadienyl group and R ³ is a hydrogen atom) was obtained as a white lard solid (yield 28.9%).

The results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 613 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δppm 0.88 (t, J = 6.6 Hz, 3H) 1.07-1.65 (m, 21H) 1.98- 2.14 (m, 4H) 2.62 (dd, J = 11.2 Hz, 15.5 Hz, 1
H) 2.79 (t, J = 5.6 Hz, 2H) 3.00 (q, J = 6.9 Hz, 2H) 3.19 (dd, J = 8.2 Hz, 15.2 Hz, 1
H) 4.01-4.21 (m, 1H) 5.24-5.43 (m, 2H) 6.60 (d, J = 7.9 Hz, 1H) 6.75 (t, J = 7. 3Hz, 1H) 6.80 (t, J = 5.9Hz, 1H) 7.03 (t, J = 7.6Hz, 1H) 7.08 (d, J = 7.3Hz, 1H) 7.78 ( d, J = 8.3 Hz, 1H) 8.20 (dd, J = 2.3 Hz, 8.3 Hz, 1H) 8.60 (d, J = 2.0 Hz, 1H) 9.75 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 14.34, 19.04, 23.22, 26.22, 2
7.19, 27.80, 28.98 to 30.69, 3
2.22, 36.66, 43.85, 63.99, 10
9.74, 120.93, 125.25, 127.8
9, 128.12, 128.79, 130.67, 13
2.88, 133.24, 133.82, 135.3
6,139.76,152.54,164.80

IR (neat, cm ^-1 ): 3280 (NH, expansion / contraction) 2930, 2860 (CH, expansion / contraction) 1660 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ deflection) 1335 (-SO _2- ) , Expansion / contraction) 1170 (-SO _2- , expansion / contraction) 750 (CH, bending angle)

Example 3 [4-chloro-N- (2,3-dihydro-2-methyl-
Synthesis of 1H-indol-1-yl) -3-pentylaminosulphonylbenzamide] 4-chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3-sulfa was added to 3 ml of DMF. 200 mg of moylbenzamide was dissolved, and 26 mg of 60% sodium hydride was added little by little under ice cooling. After stirring for 30 minutes at 0 ° C,
91 mg of 1-bromopentane was added little by little and stirred for 30 minutes. After removing the ice bath and returning to room temperature, the reaction solution was
The mixture was heated and stirred in an oil bath at ℃ for 3 hours.

After cooling, the reaction solution was poured into water and extracted with 20 ml of diethyl ether, the aqueous layer was further extracted twice with 20 ml of diethyl ether, the diethyl ether layers were combined, washed with an aqueous sodium chloride solution three times, and dried. It was dried over magnesium sulfate. After distilling off the solvent, 224 mg of the obtained yellow viscous oily substance was purified by silica gel column chromatography (eluent; hexane → 20% (V / V) ethyl acetate / hexane) to obtain the desired 4-chloro-N-
(2,3-dihydro-2-methyl-1H-indole-
1-yl) -3-pentylaminosulfonylbenzamide (in the general formula [1], R ¹ is a methyl group, R ²
Is a pentyl group and R ³ is a hydrogen atom) 107 m
g was obtained as a pale yellow amorphous solid (yield 44.9%).

The measurement results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 435 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δ ppm 0.88 (t, J = 6.6 Hz, 3 H) 1.10-1.60 (m, 6 H) 1.38 ( d, J = 6.3 Hz, 3H) 2.61 (dd, J = 11.2 Hz, 15.3 Hz, 1
H) 2.99 (q, J = 6.9 Hz, 2H) 3.18 (dd, J = 8.2 Hz, 15.4 Hz, 1
H) 4.02-4.20 (m, 1H) 6.59 (d, J = 7.9 Hz, 1H) 6.75 (t, J = 7.3 Hz, 1H) 6.72-6.82 ( m, 1H) 7.02 (t, J = 7.6Hz, 1H) 7.08 (d, J = 7.3Hz, 1H) 7.76 (d, J = 8.3Hz, 1H) 8.19 ( dd, J = 2.3 Hz, 8.3 Hz, 1H) 8.60 (d, J = 2.0 Hz, 1H) 9.73 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 14.14, 19.07, 22.79, 28.97 to 3
0.67, 36.66, 43.81, 64.02, 10
9.74, 120.93, 125.23, 127.8
7, 128.12, 130.65, 132.86, 13
3.22, 133.80, 135.34, 139.7
5,152.50,164.83

IR (neat, cm ^-1 ): 3290 (NH, expansion / contraction) 2960, 2930, 2870 (CH, expansion / contraction) 1660 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ bending angle) 1330 (-SO) ₂₋ , expansion / contraction) 1165 (−SO ₂ −, expansion / contraction) 750 (CH, bending angle)

Example 4 [4-chloro-3-decylaminosulfonyl-N-
(2,3-dihydro-2-methyl-1H-indole-
Synthesis of 1-yl) benzamide], except that 1-bromodecane was used in place of 1-bromopentane of Example 3,
In the same manner as in Example 3, the desired 4-chloro-3-decylaminosulfonyl-N- (2,3-dihydro-2-
143 mg of methyl-1H-indol-1-yl) benzamide (a compound of the general formula [1] in which R ¹ is a methyl group, R ² is a decyl group, and R ³ is a hydrogen atom) is obtained as a pale yellow amorphous solid. (Yield 51.7%).

The measurement results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 505 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δ ppm 0.87 (t, J = 6.6 Hz, 3 H) 1.09-1.58 (m, 16 H) 1.38 ( d, J = 5.9 Hz, 3H) 2.62 (dd, J = 11.2 Hz, 15.2 Hz, 1
H) 3.00 (q, J = 6.9 Hz, 2H) 3.19 (dd, J = 8.3 Hz, 15.2 Hz, 1
H) 4.03-4.21 (m, 1H) 6.60 (d, J = 7.6 Hz, 1H) 6.75 (t, J = 7.3 Hz, 1H) 6.80 (t, J = 5.9 Hz, 1 H) 7.03 (t, J = 7.6 Hz, 1 H) 7.08 (d, J = 7.3 Hz, 1 H) 7.78 (d, J = 8.6 Hz, 1 H) 7. 20 (dd, J = 2.0 Hz, 8.3 Hz, 1H) 8.60 (d, J = 2.3 Hz, 1H) 9.75 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 13.71, 18.45, 22.68, 26.56, 2
8.36-30.06, 31.97, 36.05, 4
3.22, 63.36, 109.11, 120.30,
124.62, 127.26, 127.51, 130,
04, 132.27, 132.61, 133.21, 1
34.73, 139.15, 151.91, 164.1
8

IR (neat, cm ^-1 ): 3280 (NH, expansion / contraction) 2930, 2860 (CH, expansion / contraction) 1665 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ deflection) 1330 (-SO _2- ) , Expansion / contraction) 1170 (-SO _2- , expansion / contraction) 750 (CH, bending angle)

Example 5 [4-chloro-N- (2,3-dihydro-2-methyl-
Synthesis of 1H-indol-1-yl) -3-octadecylaminosulfonylbenzamide] In the same manner as in Example 3 except that 1-bromooctadecane was used instead of 1-bromopentane in Example 3, the objective 4 was obtained. -Chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3-octadecylaminosulfonylbenzamide (in the above formula [1], R ¹ is a methyl group and R ² is octadecyl. 106 mg (a compound in which R ³ is a hydrogen atom) was obtained as a pale yellow amorphous solid (yield 31.4%).

The results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 617 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δ ppm 0.88 (t, J = 6.6 Hz, 3 H) 1.03-1.72 (m, 32 H) 1.39 ( d, J = 5.9 Hz, 3H) 2.61 (dd, J = 10.9 Hz, 15.2 Hz, 1
H) 3.00 (q, J = 6.9 Hz, 2H) 3.19 (dd, J = 8.3 Hz, 15.5 Hz, 2
H) 4.01-4.21 (m, 1H) 6.59 (d, J = 7.9 Hz, 1H) 6.75 (t, J = 7.6 Hz, 1H) 6.80 (t, J = 6.6 Hz, 1 H) 7.02 (t, J = 7.6 Hz, 1 H) 7.08 (d, J = 6.9 Hz, 1 H) 7.77 (d, J = 8.3 Hz, 1 H) 7. 19 (dd, J = 2.3 Hz, 8.3 Hz, 1H) 8.60 (d, J = 2.0 Hz, 1H) 9.73 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 14.36, 19.08, 23.31, 27.19, 2
8.94-30.56, 32.61, 36.66, 4
3.85, 64.04, 109.74, 120.93
125.25, 127.87, 128.12, 130.
65, 132.88, 133.22, 133.78, 1
35.36, 139.76, 152.50, 164.8
5

IR (neat, cm ^-1 ): 3280 (NH, expansion / contraction) 2925, 2855 (CH, expansion / contraction) 1665 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ deflection) 1330 (-SO _2- ) , Expansion / contraction) 1165 (-SO _2- , expansion / contraction) 750 (CH, bending angle)

Example 6 [4-chloro-N- (2,3-dihydro-2-methyl-
Synthesis of 1H-indol-1-yl) -3-dipentylaminosulfonylbenzamide] 3 mL of DMF 4-
Chloro-N- (2,3-dihydro-2-methyl-1H-
200 mg of indole-1-yl) -3-sulfamoylbenzamide was dissolved, and 44 mg of 60% sodium hydride was added little by little under ice cooling. After stirring at 0 ° C. for 30 minutes, 248 mg of 1-bromopentane was added little by little to 3
Stir for 0 minutes. After removing the ice bath and returning to room temperature, the reaction solution was heated and stirred in an oil bath at 80 ° C. for 3 hours. After allowing to cool, the reaction solution was poured into water and extracted with 20 ml of diethyl ether, the aqueous layer was further extracted twice with 20 ml of diethyl ether, and the diethyl ether layers were combined and combined with an aqueous sodium chloride solution to 3 times.
It was washed twice and dried over anhydrous magnesium sulfate.

After distilling off the solvent, the obtained yellow viscous oily substance 31
1 mg was purified by silica gel column chromatography (eluent: hexane → 20% (V / V) ethyl acetate / hexane) to obtain the desired 4-chloro-N- (2,3).
-Dihydro-2-methyl-1H-indol-1-yl) -3-dipentylaminosulfonylbenzamide (a compound in which R ¹ is a methyl group and R ² and R ³ are pentyl groups in the general formula [1]) 83 mg Was obtained as a pale yellow amorphous solid (yield 30.0%).

The measurement results of mass spectrometry, NMR spectrum and infrared absorption spectrum of the obtained target substance are as follows. Mass spectrometry: FAB (pos) Matrix: m-nitrobenzyl alcohol m / z; 505 [M ⁺ ] 147,132

¹ H-NMR (270 MHz, TMS standard, Acetone-d ₆ ): δppm 0.84 (t, J = 6.6 Hz, 3H) 1.05-1.63 (m, 12H) 1.38 ( d, J = 6.3 Hz, 3H) 2.61 (dd, J = 11.2 Hz, 15.5 Hz, 1
H) 3.19 (dd, J = 8.3 Hz, 15.5 Hz, 1
H) 3.36 (t, J = 7.6Hz, 2H) 4.02-4.20 (m, 1H) 6.58 (d, J = 7.9Hz, 1H) 6.75 (t, J = 7.3 Hz, 1 H) 7.02 (t, J = 7.6 Hz, 1 H) 7.08 (d, J = 6.9 Hz, 1 H) 7.78 (d, J = 8.3 Hz, 1 H) 8. 19 (dd, J = 2.3 Hz, 8.3 Hz, 1H) 8.62 (d, J = 2.3 Hz, 1H) 9.73 (br.S, 1H)

¹³ C-NMR (67.8 Hz, Acetone-d
₆ ): δppm 14.21, 19.07, 22.86, 28.37-3
0.69, 36.66, 47.60, 63.97, 10
9.72, 120.95, 125.26, 127.8
9, 128.14, 131.35, 133.22, 13
3.26, 133.76, 135.74, 139.9
4,152.52,164.72

IR (neat, cm ^-1 ): 3245 (NH, expansion / contraction) 2960, 2930, 2870 (CH, expansion / contraction) 1660 (-CO-, expansion / contraction) 1460 (CH ₃ , CH ₂ bending angle) 1335 (-SO) ₂₋ , expansion / contraction) 1150 (−SO ₂ −, expansion / contraction) 750 (CH, bending angle)

Example 7 A pharmacological test of the sulfamoylbenzoic acid derivatives obtained in Examples 1 to 6 was conducted as follows. 1) Bovine Vascular Endothelial Cell Culture Method After removing 5 to 10 cm of bovine carotid artery blood vessel, P added with antibiotics (penicillin, streptomycin, etc.)
Lightly washed with BS (phosphate buffer solution) and similar antibiotic-containing MEM (minimum essential medium)
It was soaked in the medium, ice-cooled and brought back to the culture room. Blood vessels were further washed several times with MEM medium containing antibiotics. Then, the fat adhering to the blood vessel was removed cleanly, the bifurcation was cut with scissors, and the blood vessel was cut open vertically so as to pass through the bifurcation. The blood vessels were pinned in a stretched fashion with the intimal side facing up on a flat fixation surface. Using a # 11 scalpel, the endothelial cells were peeled off by lightly touching the intimal surface. At that time, the female was pre-moistened with MEM medium containing 20% FBS (fetal bovine serum) (containing antibiotics) to make the female's movement smoother and prevent smooth muscle cell contamination.

Endothelial cells attached to the scalpel were dispersed in 10 ml of the above MEM medium and centrifuged at 800 rpm for 5 minutes. Then, the above-mentioned MEM medium was added to the precipitate, dispersed with a pipette until the rice ears were formed by collecting dozens of endothelial cells, and seeded and cultured on a plastic petri dish.

2) Reactive oxygen protection experiment using vascular endothelial cells Bovine carotid artery endothelial cells isolated and cultured by the above method were seeded in a 96-well microplate at 2 × 10 ⁴ cells per well, and 2 The cells were cultured for one day to be confluent. Various test drugs shown in Table 1 were added thereto so that the final target concentration was reached, and the test drug was incorporated into endothelial cells by culturing for 24 hours. After that, ⁵¹ Cr-sodium chromate was added at 0.5 μCi per well, and the cells were further cultured for 18 hours to incorporate ⁵¹ Cr-sodium chromate into the cells.

Then, Hanks balanced salt solution (GIBCO
BRL) and washed 3 times, 4 × 10 ⁵ cells / w
ell white blood cells (Ficoll (trade name,
(Pharmacia) neutrophils) was added, and 12-
O-Tetradecanoyl-phorbol-13-acetate was added for stimulation at 10 ng / ml. This compound acts on the leukocyte membrane, stimulates the NADPH-dependent pentasaccharide phosphate cycle to promote the production of active oxygen, and damages endothelial cells. At this time, radioactivity is released from cells damaged by active oxygen.

The radioactivity released into the culture medium after 5 hours was measured with a γ-scintillation counter and used as the amount released in the test drug uptake state. The total amount of ⁵¹ Cr incorporated into endothelial cells was 0.1% Triton X-100.
Was added to dissolve the cell membrane, and the radioactivity released into the culture solution was measured and defined as the amount released when Triton X-100 was added. Moreover, the amount of radioactivity obtained when white blood cells and 12-O-tetradecanoyl-phorbol-13-acetate were not added was defined as the amount released without stimulation.

The injury rate of endothelial cells is calculated by the following formula [1], the release rate of ⁵¹ Cr (specific release).
se of ⁵¹ Cr; SL).

[Equation 1]

Next, the rate of inhibition of endothelial cell damage was calculated by the following formula [2]. The results are shown in Table 1.

[Equation 2]

Comparative Example 1 4-chloro-N- (2,3-dihydro-2) as a test drug
The inhibition rate of endothelial cell damage was determined in the same manner as in Example 7, except that -methyl-1H-indol-1-yl) -3-sulfamoylbenzamide was used. The results are shown in Table 1.

[0062]

[Table 1] **: P <0.01 *: P <0.05 vs control 1) 4-chloro-N- (2,3-dihydro-2-methyl-1H-indol-1-yl) -3-sulfamoyl Benzamide

Example 8 (Acute toxicity test) The compound of Example 1 was applied to male ICR (CD-1) mice in duplicate.
Oral administration of 000 mg / kg and observation for 7 days. No deaths were observed and no behavioral or physiological abnormalities were observed.

As is clear from the above test results, the sulfamoylbenzoic acid derivative of the present invention was rapidly taken up by the biological membrane, suppressed endothelial cell damage due to reactive oxygen species, and had low toxicity.

Claims (2)

[Claims] 1. A sulfamoylbenzoic acid derivative represented by the following general formula [1]. [Chemical 1] (In the formula, R ¹ is H or an alkyl group having 1 to 5 carbon atoms, R ²
Is a saturated or unsaturated alkyl group having 5 to 22 carbon atoms, R
³ represents H or a saturated or unsaturated alkyl group having 5 to 22 carbon atoms. ) 2. A cytotoxic protective agent comprising the sulfamoylbenzoic acid derivative according to claim 1 as an active ingredient.