JPH11269140A - Differentiation-inducing agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new sulfonamide benzamide derivative having a differentiating effect on a cell and useful as a therapeutic or improving agent as a medicine for malignant tumors, a autoimmune diseases, dermatological diseases and a parasitic infectious diseases. SOLUTION: This differentiation-inducing agent is a sulfonamide benzamide derivative expressed by formula I [X is a direct bond, CH2 , CH2 CH2 , CH=CH, OCH2 on the like.; (n) is 0, 1; A is an aromatic heterocyclic ring containing one or two nitrogen atoms or formula II; R1 is H, a 1-4C alkyl or benzyl; R2 to R6 are each H, a halogen, amino or the like). For example, a compound expressed by formula III. The compound of formula I is obtained e.g. by subjecting a compound expressed by the formula: A-X-SO2 Q (Q is hydroxyl or a halogen) and a compound expressed by formula IV (E is t-butoxycarbonyl, benzyloxycarbony or the like) to a condensation reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel sulfonamide benzamide derivative, and more particularly to the use of a novel sulfonamide benzamide derivative in cancer drugs and pharmaceuticals based on differentiation-inducing action.

[0002]

2. Description of the Related Art At present, cancer has overtaken death due to heart disease and cerebrovascular disease and has become the leading cause of death by disease. On the other hand, various treatments such as surgery, radiation therapy, hyperthermia, and chemotherapy have been studied to control cancer. Among them, chemotherapy is one of the major pillars of cancer treatment, and many drugs have been found so far, but unfortunately no satisfactory drug has been found to date, including side effects,
It is the present situation that a new drug is awaited. Many anticancer drugs found so far have targeted cancer cells themselves and have been chosen with the goal of killing all cells that have become cancerous. The mechanism is that DN in cancer cells
A acts directly on A and exerts a cancer-killing effect by expressing a cell-killing effect. However, these anticancer drugs have poor selectivity between cancer cells and normal cells, and as a result, the side effects expressed in normal cells often limit their therapeutic use.

On the other hand, among the anticancer agents, the differentiation inducer is not a direct cell killing effect but a property of cancer cells (infinite proliferation ability).
And promote differentiation of cancer cells.
Various check mechanisms act on the differentiated cells and lead to spontaneous death of the cells.
And it can happen until the cancer regresses. Due to the mechanism of differentiation-inducing action, in terms of cancer regression, it is not as effective as an anticancer drug having a cell killing effect, but on the other hand, selectivity to normal cells, low toxicity, etc. can be expected. Indeed, it is well known that the differentiation inducer retinoic acid is used for therapy and has a high effect on acute promyelocytic leukemia [Huang et al .;
Blood, vol. 72, 567-572 (198
8), Castaign et al .; Blood, vol. 7
6, 1704-1709 (1990) or Warr
ell et al; New Engl. J. Med. , Vol.
324, 1385-1393 (1991), etc.]. In addition, since vitamin D derivatives show differentiation-inducing effects, many applications to cancer drugs have been studied [Olsson et al .;
Cancer Res. , Vol. 43, 5862-5
867 (1983) et al.]. Based on these studies, a differentiation inducer, a vitamin D derivative (JP-A-6-17962)
No. 2), isoprene derivatives (JP-A-6-19207)
No. 3), tocopherol (JP-A-6-256181)
), Quinone derivatives (JP-A-6-305595), acyclic polyisoprenoids (JP-A-6-3165)
No. 20), benzoic acid derivatives (JP-A-7-20676)
No. 5), glycolipids (JP-A-7-258100)
Application of anticancer agents has been reported. However, none of these studies has reached a level sufficient for cancer treatment, and there is a strong demand for a drug that is effective and highly safe against various cancers.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a cell differentiation-inducing effect, which is useful as a drug for treating and / or improving malignant tumors, autoimmune diseases, skin diseases, and parasitic infections. To provide compounds. An object of the present invention is to provide a novel sulfonamide benzamide derivative or a pharmacologically acceptable salt thereof.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a novel sulfonamide benzamide derivative has a differentiation inducing action, and have completed the present invention. That is, the present invention relates to [1] Formula (1)

[0006]

Embedded image Wherein X is a direct bond, a —CH ₂ — group, —CH ₂ —CH ₂
- group, -CH = CH- group, -O-CH ₂ - group, -NR7-
CH ₂ — group, —CH ₂ —CH ₂ —CH ₂ — group, —O—CH ₂
-CH ₂ - group, -CH ₂ -O-CH ₂ - group, -NR7-CH
₂ -CH ₂ - group, -CH ₂ -NR7-CH ₂ - represents a radical, n
Represents 0 or 1, A represents an aromatic heterocyclic ring containing one or two optionally substituted nitrogen atoms, or a compound represented by the formula (2)
[Formula 8]

[0007]

Embedded image Wherein R 1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
R2 to R6 each independently represent a hydrogen atom, a halogen atom, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms,
4, an alkoxy group, an alkylamino group having 1 to 4 carbon atoms,
Represents a dialkylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, or CO ₂ R 1, wherein R 7 is a hydrogen atom,
To 4 alkyl groups, benzyl groups, COR1 groups, COPh
Represents a group. A sulfonamide benzamide derivative or a pharmacologically acceptable salt thereof,

[2] Formula (3) [Formula 9]

[0009]

Embedded image [Wherein, X, A and R1 to R7 have the same meanings as described above. A sulfonamide benzamide derivative according to [1] or a pharmacologically acceptable salt thereof;

[3] A pyridyl group in which A may be substituted
X is a direct bond, -CH _Two-Group, -CH_Two-C
H_Two-Group, -CH = CH- group, -O-CH_Two-Group, -NR
7-CH_Two-The sulfonamidoben according to [2],
Zudamide derivatives or pharmacologically acceptable salts thereof
And

[4] Formula (4) [Formula 10]

[0012]

Embedded image [Wherein, A, X and R1 to R3 are as defined above. ] The sulfonamide benzamide derivative according to [1] and a pharmacologically acceptable salt thereof,

[5] A pyridyl group in which A may be substituted
And X is -CH_Two-CH_Two-Group, -CH = CH-
Group, -O-CH_Two-Group, -NR7-CH_Two-Group, -CH_Two−
CH _Two-CH_Two-Group, -O-CH_Two-CH_Two-Group, -CH_Two
-O-CH_Two-Group, -NR7-CH_Two-CH_Two-Group, -CH
_Two-NR7-CH_TwoThe sulfone according to [4],
Midobenzamide derivatives or their pharmacologically acceptable
Is a salt that is

[6] Formula (5) [Formula 11]

[0015]

Embedded image [Wherein, A, X and R1 to R3 are as defined above. A sulfonamide benzamide derivative according to [1] or a pharmacologically acceptable salt thereof;

[7] Formula (6) [Formula 12]

[0017]

Embedded image [Wherein, R4 to R6 are as defined above. A sulfonamide benzamide derivative according to [1] or a pharmacologically acceptable salt thereof;

[8] A medicament comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient,

[9] An anticancer agent comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.

[0020]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The term "C1-4" as used herein refers to the number of carbon atoms per unit substituent. That is, in the case of dialkyl substitution, it means having 2 to 8 carbon atoms. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkyl group having 1 to 4 carbon atoms includes, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, a sec-butyl group and a t-butyl group. And the like.

The alkoxy group having 1 to 4 carbon atoms includes, for example, methoxy, ethoxy, n-propoxy, iso-
Propoxy group, allyloxy group, n-butoxy group, is
Examples thereof include an o-butoxy group, a sec-butoxy group, and a t-butoxy group. The alkylamino group having 1 to 4 carbon atoms includes, for example, N-methylamino group, N-ethylamino group, N-iso-propylamino group, Nn-propylamino group, Nn-butylamino group and the like. Can be mentioned.

The dialkylamino group having 1 to 4 carbon atoms is
The same or different alkyl groups are included, and for example, N, N-dimethylamino group, N, N-diethylamino group, N-ethyl-N-methylamino group, N-methyl-N
-N-propylamino group, N-ethyl-NNn-propylamino group and the like. An alkylthio group having 1 to 4 carbon atoms means a methylthio group, an ethylthio group, n
-Propylthio group, n-butylthio group and the like.

The aromatic heterocyclic ring containing one or two nitrogen atoms includes, for example, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, imidazolyl, thiazoyl, oxazoyl, quinolyl, isoquinolyl and the like. Can be.

The salts of pharmaceutically acceptable compounds include inorganic acids commonly used in this field such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as acetic acid, tartaric acid, fumaric acid, maleic acid and citric acid. And salts with organic acids such as benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, and methanesulfonic acid.

When the compound of the formula (1) has an acidic group such as a carboxyl group, an alkali metal such as lithium, sodium and potassium, an alkaline earth metal such as magnesium and calcium, methylamine, ethylamine, dimethylamine and trimethylamine , Triethylamine,
Salts with organic bases such as benzylamine and inorganic bases such as ammonia can also be mentioned as salts of the compounds.

Pharmaceuticals include cancer drugs or autoimmune diseases,
Drugs for treating and / or improving skin diseases, parasitic infections and the like can be mentioned. To contain as an active ingredient,
The preparation contains one or more compounds represented by the formula (1). When the compound of the formula (1) has an asymmetric carbon, these include the racemic form and all of the respective optically active forms. Hereinafter, representative compounds represented by the formula (1) of the present invention are specifically exemplified in Table 1 [Tables 1 to 30]. Note that the present invention is not limited to these examples.

[0028]

[Table 1]

[0029]

[Table 2] Table 1 Continued 1

[0030]

[Table 3] Table 1 Continuation 2

[0031]

[Table 4] Table 1 Continuation 3

[0032]

[Table 5] Table 1 continued 4

[0033]

[Table 6] Table 1 Continuation 5

[0034]

[Table 7] Table 1 continued 6

[0035]

[Table 8] Table-1 7

[0036]

[Table 9] Table 1 8 continued

[0037]

[Table 10] Table 1 Continuation 9

[0038]

[Table 11] Table 1 Continuation of 10

[0039]

[Table 12] Table 1 Continuation of 11

[0040]

[Table 13] Table 1 Continuation of 12

[0041]

[Table 14] Table-1 continued 13

[0042]

[Table 15] Table-1 Continued 14

[0043]

[Table 16] Table-1 Continuation 15

[0044]

[Table 17] Table-1 continued 16

[0045]

[Table 18] Table-1 17

[0046]

[Table 19] Table-1 continued 18

[0047]

[Table 20] Table 1 Continuation 19

[0048]

[Table 21] Table-1 Continuation 20

[0049]

[Table 22] Table-1 continued 21

[0050]

[Table 23] Table-1 continued 22

[0051]

[Table 24] Table-1 continued 23

[0052]

[Table 25] Table 1 24 continued

[0053]

[Table 26] Table-1 Continuation 25

[0054]

[Table 27] Table 1 continued 26

[0055]

[Table 28] Table-1 continued 27

[0056]

[Table 29] Table-1 continued 28

[0057]

[Table 30] Table-1 Continued 29 The compound of the present invention can be produced, for example, by the following method. (A) Formula (7)

[0058]

Embedded image Wherein A and X are as defined above. Q represents a hydroxyl group or a halogen group. And a compound represented by the formula (8):
[Formula 14]

[0059]

Embedded image [Wherein R1, R2, R3, and n are as defined above. E represents an amino group or a nitro group bonded to a protecting group such as a t-butoxycarbonyl group and a benzyloxycarbonyl group used in a usual peptide formation reaction. Or a compound represented by the formula (9):

[0060]

Embedded image [Wherein, A, X, R1, R2, n, and Q are as defined above. And a compound represented by the formula (10):

[0061]

Embedded image [Wherein, R3 and E are as defined above. Formula (11) obtained by subjecting a compound represented by the formula

[0062]

Embedded image [Wherein, A, X, R1, R2, R3, n, and E are as defined above. And the reduction of the nitro group.

The compound represented by the formula (7) is commercially available, is a known compound, and can be easily synthesized. In the case of a novel compound, it is applied by applying a known method for synthesizing a known compound. It is possible to manufacture. For example, a novel sulfonyl chloride is Chemish Berichte (Che
m. Ber. ), Vol. 90, 841 (195
7), Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 6,307
(1963), Chemistry Letters (Chem.
Lett. ) 1992, 1483, Journal of
American Chemical Society (J. Am.
Chem. Soc. ), Vol. 59, 1837
(1937), vol. 78, 2171 (1956),
It can be produced by a method applying a synthesis method described in, for example.

The compound represented by the formula (8) is a known compound and can be easily synthesized, or the compound represented by the formula (12)

[0065]

Embedded image [In the formula, Z represents an amino group or an aminomethyl group protected by a nitro group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, a trifluoroacetyl group, an acetyl group, or the like. R2 and Q are as defined above. ] And the compound represented by the formula (10) are obtained by condensing the compound represented by the formula (10).

[0066]

Embedded image [Wherein, Z, E, R2 and R3 are as defined above. Can be obtained by reduction of the nitro group in Z of the compound represented by the formula or by deprotection of the protecting group.

The compound represented by the formula (9) is a known compound and can be easily synthesized, or a compound represented by the formula (7) and a compound represented by the formula (14)

[0068]

Embedded image [Wherein, R1, R2, and n are as defined above. Y has 1 to 4 carbon atoms
Represents an alkoxy group, a benzyloxy group, or a hydroxy group. Formula (15) obtained by condensing a compound represented by the formula:

[0069]

Embedded image [Wherein, A, X, R1, R2, and Y are as defined above. And the alkoxy group in Y of the compound represented by the formula: The compound represented by the formula (10) is commercially available, is a known compound, is easily synthesized, or can be synthesized by a method described in Examples described later.

The condensation reaction (a) can be carried out by a usual sulfonamide bond forming reaction, for example, an acid chloride method. For example, in the case where X is a hydroxyl group in the formula (7), the compound is reacted with a halogenating agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl chloride, etc., and converted into an acid chloride. And a compound represented by the formula (8). The reaction is usually performed in the range of -20 ° C to + 50 ° C for 0.5 to 100 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and ethyl ether, halogenated hydrocarbons such as dichloromethane and chloroform, N, N-dimethylformamide, pyridine, A basic solvent such as lutidine can be used. The reaction rate can also be increased by adding an organic base such as triethylamine or pyridine, 4- (N, N-dimethylamino) pyridine and the like.

The condensation reaction (b) can be carried out by an ordinary amide bond forming reaction in a peptide, for example, a method of active ester or mixed acid anhydride or acid chloride. For example, a compound represented by the formula (9),
A phenol such as 4,5-trichlorophenol, pentachlorophenol or 4-nitrophenol or an N-hydroxy compound such as N-hydroxysuccinimide or N-hydroxybenztriazole is condensed in the presence of dicyclohexylcarbodiimide to form an active ester. It is obtained by reacting with a compound represented by the formula (10) after converting into a body.

Further, the compound represented by the formula (9) is reacted with oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosgene, etc. to be converted into an acid chloride, and then condensed with the compound represented by the formula (10) This can be done by causing A mixed acid anhydride was obtained by reacting the compound represented by the formula (9) with methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate, isobutyl chlorocarbonate or methanesulfonyl chloride, trifluoroacetic anhydride, or the like. Thereafter, it can also be obtained by condensing with the compound represented by the formula (10).

Further, the condensation reaction is carried out using a peptide condensation reagent such as dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, diphenylphosphoric acid azide, diethyl cyanophosphate, 2-chloro-N, N'-dimethylimidazolidinium chloride. Can be performed alone or in the presence of a base.

The reaction is usually carried out at a temperature in the range of -20 ° C to + 50 ° C for 0.5 to 100 hours. Examples of the solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, dioxane and ethyl ether, halogenated hydrocarbons such as dichloromethane and chloroform, N, N-dimethylformamide, methanol, Examples include alcohols such as ethanol, organic bases such as pyridine and lutidine, and mixtures thereof. The reaction rate can also be increased by adding an organic base such as triethylamine or pyridine, 4- (N, N-dimethylamino) pyridine and the like.

The compound represented by the formula (1) can easily form a salt with a pharmacologically acceptable acid. The acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid commonly used in this field, acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p- Organic acids such as toluenesulfonic acid and methanesulfonic acid can be mentioned. These salts can also be used as the active ingredient compound of the present invention in the same manner as the molecular compound of the formula (1). The compound represented by the formula (1) can be isolated and purified from the reaction mixture by a usual separation means such as an extraction method, a recrystallization method, and a column chromatography.

The novel sulfonamide benzamide derivative of the present invention has a differentiation-inducing effect, and is useful as a therapeutic and / or ameliorating agent for malignant tumors, autoimmune diseases, skin diseases, parasitic infections and the like. Here, malignant tumor refers to hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, and macroglobulinemia, as well as colorectal cancer, brain tumor, head and neck cancer, breast cancer, lung cancer, esophageal cancer, and gastric cancer. , Liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, pancreatic islet cell cancer, renal cell carcinoma, adrenal cortex cancer, bladder cancer, prostate cancer, testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer Solid tumors such as malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, and retinoblastoma.

Autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, ulcerative colitis and the like.

Skin diseases include psoriasis, acne, eczema, atopic dermatitis and the like. Parasitic infection refers to a disease caused by parasitic infection, such as malaria infection. The target disease of the present invention is not limited to these.

The active ingredient compounds of the present invention are useful as pharmaceuticals, and they are used in the form of general medical preparations. The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as humectants, disintegrants, surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspensions). And suppositories.

In molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, glucose, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose and silicic acid, water, ethanol,
Binders such as propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, polyvinylpyrrolidone, disintegrators such as dried starch, sodium alginate, agar powder, carmellose calcium, starch, lactose, etc. Disintegration inhibitors such as sucrose, cocoa butter, hydrogenated oils, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. And a lubricant such as talc, stearate and polyethylene glycol. Furthermore, tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multilayer tablets.

In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples include crystalline cellulose, lactose, starch,
Excipients such as hardened vegetable oil, kaolin, talc, etc., binders such as gum arabic powder, tragacanth powder, gelatin and the like, disintegrants such as carmellose calcium, agar and the like can be mentioned. Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above in accordance with a conventional method, and hard gelatin capsules,
It is prepared by filling in a soft capsule or the like.

When prepared as an injection, the liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, they are commonly used as diluents in this field. Things, such as water,
Ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, an amount of salt, glucose or glycerin necessary for preparing an isotonic solution may be contained in the pharmaceutical preparation,
Further, ordinary solubilizers, buffers, soothing agents and the like may be added.

In molding into a suppository, a wide variety of conventionally known carriers can be used. Examples thereof include semi-synthetic glycerides, cocoa butter, higher alcohols, esters of higher alcohols, polyethylene glycol and the like. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent or the like and other pharmaceuticals can be contained in the pharmaceutical preparation. The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably about 5 to 5% by weight in the preparation composition. The content is preferably set to 50% by weight.

The method of administering these pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, the age, sex, degree of disease and other conditions of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, and injections are
It is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acids, and if necessary, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dose of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, age, sex, degree of disease and other conditions of the patient. Usually, the amount of the active ingredient compound is one per kg of body weight. It is preferable to use about 0.0001 to 100 mg per day. It is desirable that the active ingredient compound be contained in a dosage unit form in a range of about 0.001 to 1,000 mg. The compound of the present invention represented by the formula (1) and a salt thereof do not show toxicity at a pharmacologically effective dose.

[0086]

EXAMPLES The present invention will be described below in detail with reference to Examples and Pharmacological Test Examples, but the present invention is not limited thereto. The numbers in parentheses in the title are the numbers of the compounds exemplified in the detailed description.

Example 1 N- (2-amino) phenyl-
Synthesis of 4-benzenesulfonylaminobenzamide (Table 1, Compound No. 1) (1-1) 54.0 g of o-phenylenediamine (50
0 mmol) in a dioxane (1000 ml) solution and 22 g (550 mmol) of sodium hydroxide in water (500 m2).
l) The solution was added, and 109.1 g (550 mmol) of ditert-butyl dicarbonate in dioxane (5
00 ml) solution was added. After stirring at room temperature for 6 hours, the mixture was left at room temperature overnight. After concentrating the solvent to 1/2 volume, it was extracted with ethyl acetate. The organic layer is washed with saturated saline, dried,
The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform), and the obtained solid was washed with ethyl ether to give 34.2 g of N-tert-butoxycarbonyl-o-phenylenediamine.
(33% yield) as a white solid. ¹ H NMR (270 MHz, CDCl ₃ ) δppm: 1.51 (9H, s), 3.75 (2H,
s), 6.26 (1H, s), 6.77 (1H, d, J = 8.1Hz), 6.79 (1H, dd, J =
7.3,8.1Hz), 7.00 (1H, dd, J = 7.3,8.1Hz), 7.27 (1H, d, J =
8.1Hz).

(1-2) 20.8 g (100 mmol) of the compound obtained in the step (1-1) was added to dichloromethane (30
0ml) solution in triethylamine (21ml, 150m
mol), and a solution of 20.0 g (108 mmol) of 4-nitrobenzoyl chloride in dichloromethane (100 ml) was gradually added under ice-cooling, followed by stirring for 7 hours. After adding saturated aqueous sodium hydrogen carbonate, the mixture was extracted with chloroform. The organic layer was washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried and the solvent was distilled off. By washing the obtained residue with diisopropyl ether, N-
35.1 g of [2- (N-tert-butoxycarbonyl) aminophenyl] -4-nitrobenzamide (yield 9
8%) as a pale yellow solid. _{^{1 H NMR (270MHz, CDCl 3}} ) δppm: 1.53 (9H, s), 7.17-7.29
(4H, m), 7.85 (1H, br d, J = 7.3Hz), 8.17 (2H, d, J = 8.8Hz),
8.32 (2H, d, J = 8.8Hz), 9.88 (1H, br s).

(1-3) 10.0 g (28.0 mmol) of the compound obtained in the step (1-2) was added to THF (200 m
l) A solution of 10% palladium on carbon (50% wet., 2.5
g) was added and the mixture was stirred under a hydrogen stream for 1.5 hours. After the absorption of hydrogen was stopped, diisopropyl ether and ethyl acetate were added to the residue obtained by filtering off the solvent and distilling off the solvent, and the obtained solid was collected by filtration and dried to give N-.
7.9 g of [2- (tert-butoxycarbonyl) aminophenyl] -4-aminobenzamide (86% yield)
Was obtained as a white solid. ¹ H NMR (270 MHz, DMSO-d6) δ ppm: 1.46 (9H.s), 5.84 (2H,
s), 6.61 (2H, d, J = 8.8Hz), 7.10-7.18 (2H, m), 7.46-7.55
(2H, m), 7.68 (2H, d, J = 8.8Hz), 8.67 (1H, s), 9.49 (1H,
s).

(1-4) 0.60 g (1.83 mmol) of the compound obtained in the step (1-3) in pyridine (7 ml)
The solution was added with benzenesulfonyl chloride 0.25 under ice cooling.
ml (2.2 mmol) was gradually added dropwise, followed by stirring for 4 hours under ice cooling. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution, and then dried over sodium sulfate. After filtering the drying agent, diisopropyl ether was added to the residue obtained by evaporating the solvent, and the precipitated solid was collected by filtration and dried to give N 2
0.82 g (yield 95.7%) of-[2- (N-tert-butoxycarbonyl) aminophenyl] -4-benzenesulfonylaminobenzamide was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δppm: 1.42 (9H, s), 7.08-7.24
(5H, m), 7.44-7.66 (4H, m), 7.80-7.85 (4H, m), 8.62 (1H,
br s), 9.68 (1H, br s), 10.78 (1H, br s).

(1-5) To 0.30 g (0.64 mmol) of the compound obtained in the step (1-4) was added 4N hydrochloric acid-dioxane (4 ml) at room temperature, and the mixture was suspended and stirred. After a few minutes, it became a pale brown solution and after about 10 minutes a milky suspension. After further stirring for 1 hour, water was added to dissolve, and a saturated aqueous sodium hydrogen carbonate solution was added. After extraction with ethyl acetate-methyl ethyl ketone, the organic layer was washed with saturated saline and dried over sodium sulfate. After filtration, the solvent was distilled off, and methanol and diisopropyl ether were added to the residue. The resulting precipitate was collected by filtration and dried to give N- (2-aminophenyl) -4-benzenesulfonylaminobenzamide 0.1.
18 g (76.5% yield) was obtained as a white solid. ^{. mp 216-8 ℃ 1 H-NMR} (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 6.55 (1H, d
d, J = 7.3,8.1Hz), 6.95 (1H, dd, J = 7.3,7.3Hz), 7.10 (1H,
d, J = 7.3Hz), 7.21 (2H, d, J = 8.1Hz), 7.55-7.64 (3H, m),
7.83-7.86 (4H, m), 9.51 (1H, s), 10.73 (1H, br s) .IR (KBr, cm ^-1 ): 3307 (br), 1634,1609,1508,1456,1329,13
10,1290,1161,1092,931,851. The compounds of Examples 2 to 14 were synthesized in the same manner as in Example 1. The melting point (mp.), NMR, and IR of the compound are shown below.
The data of is shown.

Example 2 N- (2-aminophenyl)-
4- [N- (2-fluorobenzene) sulfonylamino] benzamide (Table 1, Compound No. 6) mp. 216-8 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.85 (2H, br s), 6.56 (1
H, dd, J = 7.3,8.1Hz), 6.74 (1H, d, J = 6.6Hz), 6.95 (1H, dd
d, J = 1.5,7.3,8.1Hz), 7.10 (1H, d, J = 7.3Hz), 7.20 (2H, d,
J = 8.8Hz), 7.35-7.47 (2H, m), 7.66-7.75 (1H, m), 7.85 (2
H, d, J = 8.1Hz), 7.93 (1H, ddd, J = 1.5,7.3,7.3Hz), 9.50 (1
H, br s), 11.0 (1H, br s) .IR (KBr) cm ^-1 : 3380.3319,1636,1609,1509,1477,1455,11
67,938,852,757,745.

Example 3 N- (2-aminophenyl)-
4- [N- (2-chlorobenzenesulfonyl) amino]
Benzamide (Table 1, Compound No. 7) mp.213-5 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.84 (2H, brs), 4.56 (1
H, dd, J = 8.1,8.1Hz), 6.74 (1H, dd, J = 1.5,8.1Hz), 6.94 (1
H, ddd, J = 1.5,7.3,8.1Hz), 7.09 (1H, d, J = 6.6Hz), 7.18 (2
(H, d, J = 8.8Hz), 7.50-7.61 (1H, m), 7.83 (2H, d, J = 8.1Hz),
8.13 (1H, d, J = 7.3Hz), 9.47 (1H, br s), 11.0 (1H, br s) .IR (KBr) cm ^-1 : 3358,1652,1500,1453,1339,1168,916, 75
1.

Example 4 N- (2-aminophenyl)-
4- [N- (2-bromobenzene) sulfonylamino]
Benzamide (Table 1, compound No. 8) mp. 170 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 7.06-7.27 (5H, m), 7.38-
7.44 (1H, m), 7.48-7.72 (2H, m), 7.83 (1H, dd, J = 1.5,8.1H
z), 7.93 (2H, d, J = 8.8Hz), 8.18 (1H, dd, J = 1.5,8.1Hz), 1
0.21 (1H, br s), 11.15 (1H, br s) .IR (KBr) cm ^-1 : 3178,2833,2567,1639,1609,1541,1509,13
26,1237,1156,1030,943.

Example 5 N- (2-aminophenyl)-
4- [N- (2-cyanobenzene) sulfonylamino]
Benzamide (Table 1, Compound No. 14) mp. 205-8 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.85 (2H, brs), 6.57 (1
H, dd, J = 8.1,8.1Hz), 6.75 (1H, d, J = 8.1Hz), 6.95 (1H, dd,
J = 7.3,8.1Hz), 7.10 (1H, d, J = 6.6Hz), 7.20 (2H, d, J = 8.8H
z), 7.80-7.95 (4H, m), 8.11 (2H, d, J = 8.8Hz), 9.52 (1H,
s), 11.3 (1H, br s) .IR (KBr) cm ^-1 : 3374,3325 (br), 2237,1635,1610,1509,145
5,1353,1169,940,853,760.

Example 6 N- (2-aminophenyl)-
4- [N- (2-trifluoromethylbenzene) sulfonylamino] benzamide (Table 1, compound No. 10) mp. 153-8 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.85 ( 2H, s), 6.57 (1H, d
d), 6.75 (1H, d) 6.95 (1H, ddd), 7.11 (1H, d), 7.18 (2H,
d), 7.80-7.90 (4H, m), 8.01 (1H, dd), 8.14 (1H, d), 9.49
(1H, br s), 11.06 (1H, br s) .IR (KBr) cm ^-1 : 3330 (br), 1635,1508,1164,936,854,764,7
47.

Example 7 N- (2-aminophenyl)-
4- [N- (3-chlorobenzene) sulfonylamino]
Benzamide (Table 1, Compound No. 22) mp. 214-6 ° C. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.86 (2H, brs), 6.56 (1
H, ddd, J = 1.5,6.6,7.3Hz), 6.75 (1H, dd, J = 1.5,8.1Hz),
6.95 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.11 (1H, d, J = 6.6Hz),
7.21 (2H, d, J = 8.1Hz), 7.62 (1H, dd, J = 8.1,8.1Hz), 7.71-
7.79 (2H, m), 7.82-7.89 (2H, m), 9.52 (1H, br s), 10.7 (1
H, br s) .IR (KBr) cm ^-1 : 3375,3307,1635,1608,1509,1455,1166,93
4,853,676.

Example 8 N- (2-aminophenyl)-
4- “N- (2,5-dichlorobenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound No. 34) mp. 182-4 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6 ) δppm: 7.15-7.3 (5H, m), 7.39-
7.42 (1H, m), 7.70 (1H, d, J = 8.1Hz), 7.76 (1H, dd, J = 2.1,
8.1Hz), 7.96 (2H, d, J = 8.1Hz), 8.10 (1H, d, J = 2.8Hz), 1
0.23 (1H, br s), 11.30 (1H, br s) .IR (KBr) cm ^-1 : 3209,2822,1652,1607,1559,1507,1449,12
35,1167,935,837,750.

Example 9 N- (2-aminophenyl)-
4- [N- (2-nitro-4-methoxybenzene) sulfonylamino] benzamide (Table 1, compound No. 41) mp. 171-5 ° C. (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 3.87 (3H, s), 4.86 (2H, b
rs), 6.57 (1H, dd, J = 7.3,7.3Hz), 6.75 (1H, d, J = 7.3Hz),
6.95 (1H, dd, J = 7.3,7.3Hz), 7.11 (1H, d, J = 7.3Hz), 7.20
(2H, d, J = 7.3Hz), 7.32 (1H, dd, J = 2.1,8.1Hz), 7.59 (1H,
d, J = 8.8Hz), 7.88 (2H, d, J = 8.8Hz), 7.94 (1H, d, J = 2.1H
z), 9.52 (1H, br s), 10.97 (1H, br s) .IR (KBr) cm ^-1 : 3327,1636,1607,1542,1507,1457,1168,10
49.

Example 10 N- (2-aminophenyl)
-4- [N- (2,4,6-trimethylbenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound No. 42) amorphous solid ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 2.23 ( 3H, s), 2.61 (6H,
s), 7.03 (2H, s), 7.09 (2H, d), 7.25-7.51 (4H, m), 7.94
(4H, s), 10.27 (1H, br s), 10.71 (1H, br s) .IR (KBr) cm ^-1 : 2853 (br), 1608,1508,1456,1309,1152,91
4,758,654.

Example 11 N- (2-aminophenyl)
-4- (N-benzylsulfonylamino) benzamide hydrochloride (Table 1, hydrochloride of compound No. 49) mp. 158-163 ° C. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.59 (2H, s), 7.24-7.38
(10H, m), 7.49-7.52 (1H, m), 8.08 (2H, d, J = 8.8Hz), 10.3
2 (1H, br s), 10.37 (1H, br s) .IR (KBr) cm ^-1 : 2844 (br), 1634,1608,1502,1152,929,904,
757,699.

Example 12 N- (2-aminophenyl)
-4- [N- (2-phenylethyl) sulfonylamino] benzamide (Table 1, compound No. 50) mp. 227-9 ° C ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 2.95-3.07 (2H, m ), 3.4-
3.50 (2H, m), 4.88 (2H, brs), 6.59 (1H, dd, J = 6.6,8.1Hz),
6.77 (1H, d, J = 8.1Hz), 6.96 (1H, ddd, J = 1.5,7.3,8.1Hz),
7.12-7.31 (6H, m), 7.33 (2H, d, J = 8.8Hz), 7.96 (2H, d, J =
8.8Hz), 9.57 (1H, br s), 10.27 (1H, br s) .IR (KBr) cm ^-1 : 3314,1635,1510,1455,1329,1144,934.

Example 13 N- (2-aminophenyl)
-4- [N- (pyridin-3-yl) sulfonylamino] benzamide (Table 1, compound 47) mp. 235-8 ° C (dec.) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.86 (2H , br s), 6.57 (1
H, ddd, J = 1.3,7.6,7.6Hz), 6.75 (1H, dd, J = 1.3,7.9Hz),
6.95 (1H, ddd, J = 1.3,7.3,7.9Hz), 7.10 (1H, d, J = 7.9Hz),
7.22 (2H, d, J = 8.6Hz), 7.60-7.66 (1H, m), 7.87 (2H, d, J =
8.9Hz), 8.17-8.21 (1H, m), 8.80 (1H, d, J = 1.6,4.9Hz),
8.96 (1H, d, J = 1.6Hz), 9.53 (1H, s), 11 (1H, brs).

Example 14 N- (2-aminophenyl)
-4- [N- (pyridin-2-yl) sulfonylamino] benzamide (Table 1, compound 46) mp. 203-6 ° C ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.85 (2H, brs) , 6.56 (1
H, dd, J = 7.3,7.3Hz), 6.74 (1H, dd, J = 1.5,8.1Hz), 6.94 (1
H, ddd, J = 1.5,7.3,8.1Hz), 7.10 (1H, d, J = 6.6Hz), 7.24 (2
(H, d, J = 8.8Hz), 7.63-7.69 (1H, m), 7.83 (2H, d, J = 8.8Hz),
8.03-8.12 (2H, m), 8.71 (1H, d, J = 4.4Hz), 9,49 (1H, br
s), 11.0 (1H, br s) .IR (KBr) cm ^-1 : 3354,3263 (br), 1637,1609,1508,1458,134
8,1175,1122,928.

Example 15 N- (2-aminophenyl)
-4- [N- (2-phenoxyethane) sulfonylamino] benzamide (Table 1, compound 54) ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 3.67 (2H, t, J = 5.3 Hz),
4.32 (2H, t, J = 5.3Hz), 4.88 (2H, br s), 6.60 (1H, ddd, J =
1.5,7.3,7.6Hz), 6.76-6.89 (3H, m), 6.92-7.01 (4H, m),
7.15 (1H, d, J = 7.9Hz), 7.25-7.35 (4H, m), 7.97 (2H, d, J =
8.9Hz), 9.59 (1H, s), 10.35 (1H, br s).

Example 16 N- (2-aminophenyl)
Synthesis of 4- [N- (2-nitrobenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound No. 3) (16-1) Compound 1 obtained in step (1-3) of Example 1 0.06 g (3.24 mmol) of pyridine (16 m
l) After adding 0.93 g (4.21 mmol) of 2-nitrobenzenesulfonyl chloride to the solution under ice cooling, the mixture was stirred for 7 hours while gradually warming to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform / ethyl acetate = 1: 1), and further crystallized from methanol-diisopropyl ether. Gives N- [2- (N-
tert-butoxycarbonyl) aminophenyl-4
1.28 g (77.1% yield) of-[N- (2-nitrobenzene) sulfonylamino] benzamide was obtained as a white solid. ¹ H-NMR (270 MHz, DMSO-d6) δppm: 1.42 (9H, s), 7.11-7.23
(2H, m), 7.25 (2H, d, J = 8.8Hz), 7.45-7.54 (2H, m), 7.80-
7.88 (4H, m), 7.99-8.07 (2H, m), 8.61 (1H, br s), 9.71 (1
H, br s), 11.19 (1H, br s).

(16-2) 0.20 g (0.39 mmol) of the compound obtained in the step (16-1) was treated with methanol (1
ml) suspension was added with 4N hydrochloric acid-dioxane (5 ml) and stirred at room temperature for 6 hours. Diisopropyl ether was added to the residue from which the solvent was distilled off, and the resulting residue was collected by filtration and dried to give N- (2-aminophenyl) -4- [N
-(2-Nitrobenzene) sulfonylamino] benzamide hydrochloride (0.15 g, yield 86%) was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 7.15-7.29 (5H, m), 7.38
(1H, d, J = 8.1Hz), 7.82-8.09 (7H, m), 10.19 (1H, brs), 1
1.26 (1H, br s) .IR (KBr) cm-1: 2854 (br), 1652,1608,1541,1506,1354,130
7,1164,934.

Example 17 N- (2-aminophenyl)
Synthesis of -4- [N- (3-nitrobenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound 18) (17-1) Compound 1 obtained in step (1-3) of Example 1. 00 g (3.05 mmol) of pyridine (15 m
l) 0.88 g (3.97 mmol) of 3-nitrobenzenesulfonyl chloride was added to the solution under ice cooling, and the mixture was stirred for 7 hours while gradually rising to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was washed with diisopropyl ether to give N- [2- (N-te
rt-butoxycarbonyl) aminophenyl] -4-
1.37 g (87.6% yield) of [N- (3-nitrobenzene) sulfonylamino] benzamide was obtained as a pale pink solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 1.41 (9H, s), 7.09-7.18
(2H, m), 7.25 (2H, d, J = 8.8Hz), 7.45 (1H, d, J = 7.3Hz), 7.5
1 (1H, d, J = 7.3Hz), 7.85 (2H, d, J = 8.8Hz), 7.90 (1H, d, J =
7.3Hz), 8.23 (1H, d, J = 8.1Hz), 8.48 (1H, dd, J = 2.1,8.1H
z), 8.56 (1H, d, J = 2.1Hz), 8.62 (1H, s), 9.71 (1H, s), 1
1.0 (1H, br s).

(17-2) 0.20 g (0.39 mmol) of the compound obtained in the step (17-1) was treated with methanol (1
ml) 4N hydrochloric acid-dioxane (5 ml) was added to the suspension, and the mixture was stirred at room temperature for 4 hours. Diisopropyl ether was added to the residue obtained by evaporating the solvent, and the resulting residue was collected by filtration and dried to give N- (2-aminophenyl) -4- [N-
(3-Nitrobenzene) sulfonylamino] benzamide hydrochloride (0.15 g, yield 86%) was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 7.05-7.34 (6H, m), 7.89
(1H, dd, J = 8.1,8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.23 (1H,
d, J = 8.1Hz), 8.47 (1H, dd, J = 2.1,7.3Hz), 8.57 (1H, d, J =
1.5Hz), 10.11 (1H, br s), 11.08 (1H, br s) .IR (KBr) cm ^-1 : 3386 (br), 3084 (br), 1608,1532,1507,135
1,1168,1126,930.

Example 18 N- (2-aminophenyl)
Synthesis of -4- [N- (4-nitrobenzene) sulfonylamino] benzamide (Table 1, Compound No. 26) (18-1) 1.00 g of the compound obtained in step (1-3) of Example 1 (3. 05 mmol) of pyridine (15 m
l) Under ice cooling, 0.88 g (3.97 mmol) of 4-nitrobenzenesulfonyl chloride was added to the solution, followed by stirring for 4 hours while gradually raising the temperature to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Diisopropyl ether was added to the obtained residue, and the obtained solid was collected by filtration and dried to give N- [2- (N-tert). -Butoxycarbonyl) aminophenyl] -4- [N- (4-nitrobenzene) sulfonylamino] benzamide (1.44 g, yield 92%) was obtained as a pale yellow solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 1.41 (9H, s), 7.12-7.23
(2H, m), 7.25 (2H, d), 7.46 (2H, d), 7.51 (2H, d), 7.83 (2
H, d), 8.07 (2H, d), 8.40 (2H, d), 8.63 (1H, br s), 9.71 (1
H, br s), 11.08 (1H, br s).

(18-2) 0.26 g (0.51 mmol) of the compound obtained in the step (18-1) in dioxane (5
ml) suspension, 4N hydrochloric acid-dioxane (5 ml) was added at room temperature, and the mixture was stirred for 3 hours. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate-THF (3: 1). The organic layer was washed with a saturated saline solution, dried, and the residue obtained by evaporating the solvent was dried to obtain N- (2-aminophenyl).
0.20 g of 4- [N- (4-nitrobenzene) sulfonylamino] benzamide (96% yield) was obtained as a light brown solid. ^{. mp 239-41 ℃ 1 H-NMR} (270MHz, DMSO-d6) δppm: 4.85 (2H, s), 6.57 (1H, d
d, J = 7.3,7.3Hz), 6.75 (2H, d, J = 7.3Hz), 6.95 (1H, dd, J =
7.3,7.3Hz), 7.10 (1H, dd, J = 7.3,7.3Hz), 7.22 (2H, d, J =
8.8Hz), 7.87 (2H, d, J = 8.1Hz), 8.07 (2H, d, J = 8.8Hz), 8.
40 (2H, d, J = 8.8Hz), 9,54 (1H, br s), 11.03 (1H, br s) .IR (KBr) cm ^-1 : 3371,3310,1632,1608,1529,1508, 1456,13
49,1164,1089,855,609.

Example 19 N- (2-aminophenyl)
Synthesis of 4- [N- (2-aminobenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound No. 2) (19-1) Compound obtained in step (16-1) of Example 16 1.00 g (1.95 mmol) of THF (30 m
l) -Methanol (30 ml) solution under a nitrogen stream
% Palladium on carbon (50% wet, 0.25 g) was added, and the mixture was stirred under a hydrogen stream for 1 hour. After removing the catalyst, diisopropyl ether was added to the residue obtained by evaporating the solvent, and the resulting precipitate was collected by filtration and dried to give N- [2
0.89 g (yield 95%) of-(N-tert-butoxycarbonyl) aminophenyl] -4- [N- (2-aminobenzene) sulfonylamino] benzamide was obtained as a white solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 1.42 (9H, s), 6.05 (2H,
s), 6.58 (1H, dd, J = 7.3,7.3Hz), 6.76 (1H, d, J = 8.1Hz),
7.11-7.23 (4H, m), 7.47 (1H, d, J = 8.1Hz), 7.52 (1H, d, J =
8.8Hz), 7.59 (1H, d, J = 8.1Hz), 7.80 (2H, d, J = 8.8Hz), 8.
61 (1H, s), 9.66 (1H, s), 10.72 (1H, br s).

(19-2) 0.20 g (0.41 mmol) of the compound obtained in step (19-1) in methanol (1
ml) 4N hydrochloric acid-dioxane (5 ml) was added to the suspension and stirred for 1 hour. The residue obtained after distilling off the solvent was washed with diisopropyl ether and dried to give N-
(2-aminophenyl) -4- [N- (2-aminobenzene) sulfonylamino] benzamide hydrochloride 0.1
6 g (85% yield) was obtained. mp.210-215 ° C ¹ H-NMR (270 MHz, DMSO-d6) δppm: 6.58 (1H, dd, J = 7.3,7.3H
z), 6.77 (1H, d, J = 8.1Hz), 7.19 (2H, d, J = 8.8Hz), 7.20-
7.53 (5H, m), 7.60 (1H, d, J = 8.1Hz), 7.97 (2H, d, J = 8.8H
z), 10.40 (1H, br s), 10.80 (1H, br s) .IR (KBr) cm ^-1 : 2835 (br), 1607,1503,1476,1351,1308,116
9,1140,922,770,760.

Example 20 N- (2-aminophenyl)
Synthesis of -4- [N- (3-aminobenzene) sulfonylamino] benzamide (Table 1, Compound No. 17) (20-1) 1.00 g of the compound obtained in Step (17-1) of Example 17 (1 .95 mmol) in THF (30 m
l) -Methanol (30 ml) solution under a nitrogen stream
% Palladium on carbon (50% wet, 0.30 g) was added, and the mixture was stirred under a hydrogen stream for 1.5 hours. After removing the catalyst, diisopropyl ether was added to the residue obtained by distilling off the solvent, and the resulting precipitate was collected by filtration and dried to give N-
0.89 g (yield 95%) of [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (3-aminobenzene) sulfonylamino] benzamide was obtained as a white solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 1.42 (9H, s), 5.63 (2H,
s), 6.73 (1H, dd, J = 1.5,8.1Hz), 6.91 (1H, d, J = 8.8Hz),
7.03 (1H, d, J = 7.3Hz), 7.11-7.23 (5H, m), 7.45-7.54 (2H,
m), 7.82 (2H, d, J = 8.8Hz), 8.60 (1H, br s), 9.68 (1H, br
s), 10.66 (1H, br s).

(20-2) 0.21 g (0.43 mmol) of the compound obtained in the step (20-1) in methanol (2
4N hydrochloric acid-dioxane (5 m
l) was added and stirred for 3 hours. The residue obtained by distilling off the solvent was washed with diisopropyl ether and dried to give N- (2-aminophenyl) -4- [N- (3-
0.16 g (yield 81%) of [aminobenzene) sulfonylamino] benzamide hydrochloride was obtained as a light brown solid. mp.> 250 ° C ¹ H-NMR (270 MHz, DMSO-d6) δppm: 6.90-7.51 (10H, m), 7.9
9 (2H, d), 10.40 (1H, brs), 10.78 (1H, brs) .IR (KBr) cm ^-1 : 3420 (br), 2850 (br), 1608,1507,1308,115
8,918.

Example 21 N- (2-aminophenyl)
Synthesis of -4- [N- (4-aminobenzene) sulfonylamino] benzamide (Table 1, Compound No. 25) (21-1) 2.20 g of the compound obtained in Step (18-1) of Example 18 (4 .3 mmol) in THF (50 m
l) -Methanol (50 ml) solution in a nitrogen stream at 10%
Palladium carbon (50% wet, 0.50 g) was added, and the mixture was stirred at room temperature under a hydrogen stream for 1 hour. Diisopropyl ether was added to the residue obtained by filtering the catalyst, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (chloroform / methanol / ethyl acetate = 60: 3: 10) to obtain a solid. N- [2-
0.62 g (30% yield) of (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (4-aminobenzene) sulfonylamino] benzamide was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 1.42 (9H, s), 6.04 (2H,
s), 6.55 (2H, d, J = 8.1Hz), 7.08-7.20 (4H, m), 7.44-7.53
(4H, m), 7.80 (2H, d, J = 8.1Hz), 8.62 (1H, br s), 9.66 (1
H, br s), 10.36 (1H, br s).

(21-2) 0.40 g (0.83 mmol) of the compound obtained in the step (21-1) was treated with dioxane (1
0 ml) solution was added 4N hydrochloric acid-dioxane (10 ml) and stirred at room temperature for 5 hours. After adding saturated aqueous sodium bicarbonate,
Extracted with ethyl acetate-THF (3: 1). The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform / chloroform).
Purification with methanol / ethyl acetate = 30: 3: 10 → chloroform / methanol / water = 6: 4: 1)
0.05 g (16% yield) of (2-aminophenyl) -4- [N- (4-aminobenzene) sulfonylamino] benzamide was obtained as a light brown amorphous solid. mp.amorphous solid ¹ H-NMR (270MHz, DMSO-d6) δppm: 4.85 (2H, br s), 6.02 (2
H, br s), 6.53-6.65 (3H, m), 6.74 (1H, d), 6.87 (1H, s),
6.95 (1H, dd), 7.09-7.17 (3H, m), 7.45 (2H, d), 7.82 (2H,
d), 9.48 (1H, br s), 10.30 (1H, br s).

Example 22 N- (2-aminophenyl)
-4- [N- (2-methoxycarbonylbenzene) sulfonylamino] benzamide (Table 1, compound No. 13)
(22-1) 1.00 g (3.05 mmol) of the compound obtained in step (1-3) of Example 1 in pyridine (10 m
l)-In a dichloromethane (20 ml) solution,
0.83 g of methyl chlorosulfonylbenzoate
(6.66 mmol) was added, and the mixture was stirred for 5 hours while being heated to room temperature, and then left overnight. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was washed with an aqueous hydrochloric acid solution, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried, and the solvent was distilled off. Diisopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried to give N- [2 − (N-tert
-Butoxycarbonyl) aminophenyl] -4- [N-
(2-methoxycarbonylbenzene) sulfonylamino] benzamide (1.04 g, yield 66%) was obtained. ¹ H-NMR (270 MHz, DMSO-d6) δppm: 1.41 (9H, s), 3.89 (3H,
s), 7.08-7.23 (4H, m), 7.46 (1H, d, J = 7.3Hz), 7.46 (1H, d, J
= 8.1Hz), 7.64-7.75 (3H, m), 7.83 (2H, d, J = 8.8Hz), 7.90-
7.96 (1H, m), 8.61 (1H, br s), 9.68 (1H, br s), 10.77 (1H,
br s).

(22-2) 0.30 g (0.57 mmol) of the compound obtained in step (22-1) in dioxane (3
ml) -methanol (1 ml) suspension, 4N hydrochloric acid-dioxane (5 ml) was added, and the mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Diisopropyl ether-methanol was added to the resulting residue, and the resulting precipitate was collected by filtration and dried to give N-.
0.13 g (yield 54%) of (2-aminophenyl) -4- [N- (2-methoxycarbonylbenzene) sulfonylamino] benzamide was obtained. ^{mp.189-92 ℃ 1 H-NMR (270MHz} , DMSO-d6) δppm (dec.): 3.88 (3H, s), 4.85 (2H, b
rs), 6.56 (1H, dd), 6.75 (1H, d), 6.94 (1H, dd), 7.10 (1
H, d), 7.18 (2H, d), 7.64-7.74 (3H, m), 7.85 (2H, d), 7.9
1 (1H, dd), 9.50 (1H, br s), 10.7 (1H, br s) .IR (KBr) cm ^-1 : 3274,1729,1660,1506,1279,1165,1119,76
2.

Example 23 N- (2-aminophenyl)
Synthesis of 4- [N- (2-carboxylbenzene) sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound No. 12) (23-1) Compound obtained in step (22-1) of Example 22 0.64 g (1.22 mmol) of methanol (5
ml) -water (7 ml) suspension, and 0.30 g (7.4 mmol) of lithium hydroxide monohydrate was added, followed by stirring at 50 ° C for 5 hours. After allowing to cool, the precipitate formed by acidification with a 10% aqueous hydrochloric acid solution was collected by filtration and dried to give N- [2- (Nt
tert-butoxycarbonyl) aminophenyl] -4-
0.56 g (yield 90%) of [N- (2-carboxylbenzene) sulfonylamino] benzamide was obtained as a light brown solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 1.41 (9H, s), 7.1-7.25
(2H, m), 7.24 (2H, d, J = 8.8Hz), 7.46 (1H, d, J = 8.1Hz), 7.
52 (1H, d, J = 7.3Hz), 7.60-7.70 (3H, m), 7.80-7.90 (3H, m),
8.60 (1H, br s), 9.69 (1H, br s), 10.53 (1H, br s).

(23-2) 0.49 g (0.96 mmol) of the compound obtained in the step (23-1) was treated with methanol (4
ml) solution, 4N hydrochloric acid-dioxane (4 ml) was added, and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent, diisopropyl ether was added to the obtained residue, and the resulting precipitate was collected by filtration and dried to give N- (2-aminophenyl) -4- [N- (2-carboxylbenzene) sulfonyl. Amino] benzamide hydrochloride 0.24 g (yield 56
%). mp.> 240 ° C ¹ H-NMR (270 MHz, DMSO-d6) δppm: 7.2-7.35 (4H, m), 7.35-
7.40 (1H, m), 7.45-7.50 (1H, m), 7.60-7.72 (3H, m), 7.90
(1H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 10.32 (1H, br
s), 10.60 (1H, br s) .IR (KBr) cm ^-1 : 3500 (br), 3000-2500 (br), 1698,1609,150
6,1389,1169,1124,756.

Example 24 N- (2-aminophenyl)
-4- [N- (5-bromo-2-methoxybenzene) sulfonylamino] benzamide hydrochloride (Table 1, compound 3
Hydrochloride of 7) (24-1) 0.66 g (2.0 mmol) of the compound obtained in step (1-3) of Example 1 in pyridine (8 ml)-
To a dichloromethane (10 ml) solution was added 5-bromo-2-methoxybenzenesulfonyl chloride 0.64 under ice cooling.
After adding g (2.24 mmol), the mixture was stirred for 10 hours while gradually raising the temperature to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was washed with diisopropyl ether to give N- [2- (N-ter
t-butoxycarbonyl) aminophenyl] -4- [N
-(5-Bromo-2-methoxybenzene) sulfonylamino] benzamide (0.72 g, yield 62%) was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δppm: 1.41 (9H, s), 3.88 (3H,
s), 7.09-7.23 (5H, m), 7.45-7.52 (2H, m), 7.76-7.83 (3
H, m), 7.89 (1H, d), 8.63 (1H, br s), 9.66 (1H, br s), 1
0.66 (1H, br s).

(24-2) 0.19 g (0.33 mmol) of the compound obtained in the step (24-1) was treated with dioxane (3
4N hydrochloric acid-dioxane (5 ml) was added to the suspension, and methanol (2 ml) was further added thereto, followed by stirring at room temperature for 3 hours. Diisopropyl ether was added to the residue from which the solvent was distilled off, and the resulting residue was collected by filtration and dried to give N-
(2-aminophenyl) -4- [N- (5-bromo-2
-Methoxybenzene) sulfonylamino] benzamide hydrochloride (0.15 g, yield 95%) was obtained as a light brown solid. ^{. mp 181 ℃ 1 H-NMR} (270MHz, DMSO-d6) δppm (dec.): 3.77 (3H, s), 7.16-7.36
(6H, m), 7.42-7.46 (1H, m), 7.78 (1H, dd), 7.90 (1H, d),
7.96 (2H, d), 10.28 (1H, br s), 10.69 (1H, br s) .IR (KBr)
cm-1: 3525,3140 (br), 1613,1491,1331,1277,1155,1016,
923,813,768.

Example 25 N- (2-aminophenyl)
Synthesis of -4- [N- (2-methoxybenzene) sulfonylamino] benzamide (Table 1, Compound No. 5) (24-1) 0.20 g of the compound obtained in step (24-1) of Example 24 (0 .35 mmol) in THF (20 m
l) -Methanol (10 ml) solution in a nitrogen stream at 10%
Palladium carbon (50% wet, 0.24 g) was added, and the mixture was stirred for 6 hours under a hydrogen stream. After filtering off the catalyst, the filtrate was concentrated and dissolved in dioxane (1 ml), and 4N hydrochloric acid was added.
Dioxane (2 ml) was added and the mixture was stirred for 2 hours. Methanol (2 ml) was further added and the mixture was stirred for 2 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate-methyl ethyl ketone (2: 1). After washing the organic layer with saturated saline,
Diisopropyl ether was added to the residue obtained by drying and distilling off the solvent, and the precipitated solid was collected by filtration and dried to give N
0.10 g of-(2-aminophenyl) -4- [N- (2-methoxybenzene) sulfonylamino] benzamide
(72% yield). ^{. mp 213-5 ℃ 1 H-NMR} (270MHz, DMSO-d6) δppm (dec.): 3.88 (3H, s), 4.84 (2H, b
rs), 6.56 (1H, dd), 6.74 (1H, d), 6.94 (1H, dd), 7.07 (2
H, dd) 7.18 (2 + 1H, d), 7.58 (1H, dd), 7.81 (2H, d), 7.84 (1
H, d), 9.48 (1H, br s), 10.44 (1H, br s) .IR (KBr) cm-1: 3340,3198,1647,1605,1506,1482,1320,12
84,1155,930,760.

Example 26 N- (2-aminophenyl)
Synthesis of -4- [N- (2-nitrobenzene) sulfonylaminomethyl] benzamide (Table 1, Compound No. 129) (26-1) Methyl 4-aminomethylbenzoate hydrochloride 2.02 g (10.0 mmol) of pyridine ( 2
0 ml) -THF (20 ml) suspension and 2.44 g of 2-nitrobenzenesulfonyl chloride (11.
0 mmol) in THF (20 ml) was added dropwise over 30 minutes, and then 0.3 g (2.45 mmol) of 4- (N, N-dimethylamino) pyridine and 5.0 ml (35.6 mmol) of triethylamine were added. The mixture was stirred for 6 hours while the temperature was gradually increased. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (chloroform / methanol = 2).
0: 1) to give methyl 4- [N- (2
-Nitrobenzene) sulfonylaminomethyl] benzoate (1.90 g, yield 54%) was obtained as a brown solid. ¹ H-NMR (270 MHz, CDCl ₃ ) δ ppm: 3.89 (3H, s), 4.34 (2H, s),
7.35 (2H, d), 7.50-7.95 (7H, m).

(26-2) 1.35 g (3.85 mmol) of the compound obtained in the step (26-1) was treated with methanol (2
0 ml) -water (17 ml) suspension was added with 0.36 g (8.48 mmol) of lithium hydroxide monohydrate and stirred at room temperature for 8 hours. After the remaining precipitate was collected by filtration, the filtrate was acidified by adding a 1N aqueous hydrochloric acid solution, and the obtained precipitate was collected by filtration, washed with water, and dried to give 4- [N- (2-nitrobenzene). Sulfonylaminomethyl] benzoic acid 1.2
0 g (93% yield) was obtained as a white solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.25 (2H, d), 7.37 (2H,
d), 7.74-7.84 (4H, m), 7.94 (2H, d), 8.75 (1H, t), 12.9
(1H, br s).

(26-3) 0.65 g (2.0 mmol) of the compound obtained in the step (26-2) in toluene (15 m
l) 0.5 ml of thionyl chloride (6.9 m
mol), and the mixture was stirred at 85 ° C for 3 hours. After the solvent was distilled off, excess thionyl chloride was azeotroped with toluene. The obtained residue was suspended in dichloromethane (10 ml). To this solution was added 0.32 g (1.5 mol) of the compound obtained in the step (1-1) of Example 1 in pyridine (10 m
l) -Dichloromethane (5 ml) solution was added dropwise under ice cooling. The mixture was stirred for 5 hours while gradually warming to room temperature, and then left overnight. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was washed with an aqueous hydrochloric acid solution and saturated saline, dried, and the solvent was distilled off. The residue obtained was azeotropically distilled with toluene, and the obtained residue was washed with diisopropyl ether and dried to obtain N- 0.49 g (yield 65%) of [2- (N-tert-butoxycarbonylamino) phenyl] -4- [N- (2-nitrobenzene) sulfonylaminomethyl] benzamide was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 1.45 (9H, s), 4.26 (2H,
d), 7.14-7.22 (2H, m), 7.41 (2H, d), 7.51-7.56 (2H, m),
7.78-7.86 (4H, m), 7.93-7.99 (2H, m), 8.68 (1H, br s),
8.76 (1H, t), 9.78 (1H, s).

(26-4) 0.20 g (0.40 ml) of the compound obtained in the step (26-3) was treated with methanol (2 m
l) Add 4N hydrochloric acid-dioxane (4 ml) to the suspension at room temperature.
Was added and stirred at room temperature for 3 hours. After evaporating the solvent, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the obtained residue, and the mixture was further extracted with ethyl acetate. The residue obtained by drying the organic layer and distilling off the solvent was solidified with methanol-diisopropyl ether to give N- (2-aminophenyl) -4- [N- (2
[Nitrobenzene) sulfonylaminomethyl] benzamide (0.14 g, yield 82%) was obtained as a brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 4.25 (2H, d), 4.89 (2H, b
rs), 6.60 (1H, dd), 6.78 (1H, d), 6.97 (1H, dd), 7.16 (1
H, d), 7.38 (2H, d), 7.78-7.99 (6H, m), 8.75 (1H, d), 9.6
2 (1H, br s) .IR (KBr) cm ^-1 : 3363,1653,1540,1507,1362,1339,1164,85
Four.

Example 27 N- (2-aminophenyl)
-4- [2- (pyridin-3-yl) ethanesulfonylaminomethyl] benzamide (Table 1, Compound No. 14
Synthesis of 7) (27-1) 4-aminomethylbenzoic acid 21.16 g
To a suspension of (140 mmol) in dichloromethane (450 ml) was added 42 ml (300 mmol) of triethylamine.
Was added. Under ice cooling, a solution of 60.4 g (287 mmol) of trifluoroacetic anhydride in dichloromethane (50 ml) was added dropwise while maintaining the internal temperature at 3 to 8 ° C., and the mixture was stirred for 3 hours. After the reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, the solution was further acidified with a 10% aqueous hydrochloric acid solution. The precipitated gel precipitate was collected by filtration and dried to give 30.4 g of 4- (N-trifluoroacetylaminomethyl) benzoic acid (yield 87.8).
%) As an opalescent solid. ^{1 H NMR (270MHz, DMSO-} d6) δppm: 4.47 (2H, d, J = 5.8Hz),
7.39 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 10.08 (1H,
t, J = 5.8Hz), 12.95 (1H, br s).

(27-2) A suspension of 30.0 g (121 mmol) of the compound obtained in the step (27-1) in dichloromethane (200 ml) was added while cooling on ice (with an internal temperature of 10 to 10).
15 ° C) 21 g of oxalyl chloride (165 mmo)
l) was slowly added dropwise. Occasionally (about 2m
0.1 ml per 1 drop) DMF was added. After dropping the whole amount, the mixture was stirred until foaming stopped, and then stirred at 40 ° C. for 1 hour. After the solvent was distilled off, excess oxalyl chloride was azeotropically distilled with toluene, and dichloromethane (100 m
l). Compound 2 obtained in step (1-1)
2.88 g (110 mmol) of dichloromethane (10
0 ml) -pyridine (200 ml) solution was added dropwise with the previously prepared acid chloride solution under ice cooling (internal temperature 7 to 9 ° C).

After the completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was left overnight. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture, the mixture was extracted with chloroform, washed with saturated saline, dried, and the solvent was distilled off. Methanol-diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give N- [2- (N-tert-butoxycarbonyl).
[Aminophenyl] -4- (N-trifluoroacetylaminomethyl) benzamide (28.1 g, yield 58%) was obtained as a pale yellow solid. ^{1 H NMR (270MHz, DMSO-} d6) δpp
m: 1.44 (9H, s), 4.48 (2H, d, J = 5.9Hz), 7.12-7.23 (2H,
m), 7.44 (2H, d, J = 8.1Hz), 7.54 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz)
H, d, J = 8.1Hz), 8.68 (1H, br s), 9.83 (1H, s), 10.10 (1H,
br.t, J = 5.9Hz).

(27-3) 13.12 g (30 mmol) of the compound of step (27-2) in methanol (120 m
l) To a suspension of water (180 ml) was added potassium carbonate 4.70.
g (34.0 mmol) was added, and the mixture was heated and stirred at 70 ° C. for 4 hours. After extraction with chloroform, the organic layer was washed with saturated saline, dried, and the solvent was distilled off.
-Aminomethyl-N- [2- (N-tert-butoxycarbonyl) aminophenyl] benzamide 10.3 g
(Quantitative) was obtained as a pale yellow amorphous solid. ^{1 H NMR (270MHz, DMSO-} d6) δppm: 3.80 (2H, s), 7.13-7.2
3 (2H, m), 7.48-7.58 (4H, m), 7.90 (2H, d, J = 8.1Hz), 8.69
(1H, br s), 9.77 (1H, br s).

(27-4) 2.29 g (13.2 mmol) of 3-pyridineacetic acid hydrochloride in methanol (65 m
l) 1.6 ml of thionyl chloride (22 mm
ol) and heated to reflux for 3 hours. After cooling, the solvent was distilled off, and to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate. Further, the organic layer extracted and extracted with ethyl acetate is washed with a saturated saline solution, dried, and the residue obtained by evaporating the solvent is dried to obtain 1.85 g of methyl 3-pyridineacetic acid (yield 92. 4%) as a pale brown oil. ¹ H-NMR (90 MHz, CDCl ₃ ) δ ppm: 3.64 (2 H, s), 3.72 (3 H, s),
7.26 (1H, dd), 7.64 (1H, ddd), 8.50-8.55 (2H, m).

(27-5) 1.85 g (12.2 mmol) of the compound obtained in the step (27-4) was treated with methanol (2
Sodium borohydride 1.15 under ice-cooling
g (30 mmol) and stirred at room temperature for 2 hours.
The mixture was heated under reflux for 4 hours. After allowing to cool, water was added to the residue obtained by evaporating the solvent, and the mixture was further extracted with ethyl acetate. The organic layer was washed with brine, dried, and the residue obtained by evaporating the solvent was dried to give 1.39 g (yield 92.5%) of 2- (pyridin-3-yl) ethanol as pale yellow. Obtained as an oil. ¹ H-NMR (90 MHz, CDCl ₃ ) δ ppm: 2.86 (2H, t), 3.88 (2H, t),
7.21 (1H, dd), 7.57 (1H, ddd), 8.32-8.47 (2H, m).

(27-6) 1.14 ml of thionyl chloride was added to a solution of 0.88 g (7.1 mmol) of the compound obtained in the step (27-5) in 16 ml of dichloromethane.
(15.6 mmol) and the mixture was stirred at room temperature overnight. After the solvent was distilled off, excess thionyl chloride was azeotroped with toluene, diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give 2- (pyridin-3-yl) ethyl chloride hydrochloride. 1.18 g (93% yield) of the salt was obtained as a light brown solid. ^{1 H-NMR (90MHz, DMSO} -d6) δppm: 3.30 (2H, t, J = 6.6Hz), 4.
00 (2H, t, J = 6.6Hz), 8.03 (1H, dd, J = 5.7,8.1Hz), 8.55 (1
H, ddd, J = 1.5,1.5,8.1Hz), 8.84 (1H, dd, J = 1.5,5.7Hz),
8.93 (1H, d, J = 1.5Hz).

(27-7) 0.93 g (7.4 mmol) of sodium sulfite was added to a solution of 0.66 g (3.7 mmol) of the compound obtained in the step (27-6) in water (5 ml). Heated to reflux for an hour. After allowing to cool, the residue obtained by evaporating the solvent is subjected to reverse phase silica gel chromatography, the fraction eluted with water is concentrated, and the solid obtained by azeotroping with ethanol is dried to obtain a residue. −
0.91 g of sodium (pyridin-3-yl) ethanesulfonate was obtained as a pale yellow solid. ^{1 H-NMR (90MHz, DMSO} -d6) δppm: 2.64-3.00 (4H, m), 7.28
(1H, dd, J = 4.4,7.9Hz), 7.60-7.69 (1H, m), 8.34-8.42 (2
H, m).

(27-8) To 0.28 g of the compound obtained in the step (27-7), 1 ml of thionyl chloride was added, and a drop of DMF was further added, followed by heating and stirring at 70 ° C. for 7 hours. After cooling, the solvent was distilled off, and excess thionyl chloride was azeotropically distilled with toluene, and then suspended in dichloromethane (5 ml). 0.5 g of the compound obtained in (26-3) under ice-cooling
(1.46 mmol) of triethylamine (0.5 m
l) -Dichloromethane (5 ml) solution was added and left overnight. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform.
The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (ethyl acetate / methanol 10: 1) to give a residue.
N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [2- (pyridin-3-yl) ethanesulfonylaminomethyl] benzamide 0.05 g
(7% yield) as a light brown solid. ¹ H-NMR (90 MHz, CDCl ₃ ) δ ppm: 1.47 (9H, s), 3.0-3.1 (4H,
m), 4.3 (2H, d-like), 5.97 (1H, t), 7.1-7.5 (8H, m), 7.6
-7.95 (3H, m), 8.25 (1H, s-like), 8.42 (1H, d-like), 9.3
7 (1H, br s).

(27-9) Dioxane (2 ml) and methanol (1 ml) were added to 0.05 g of the compound obtained in the step (27-8), and 4N hydrochloric acid-dioxane (2 ml) was further added at room temperature. Stir for 2 hours. After adding saturated aqueous sodium hydrogen carbonate, ethyl acetate-methyl ethyl ketone (2:
Extracted in 1). The organic layer was washed with saturated saline, dried,
Diisopropyl ether was added to the residue obtained by evaporating the solvent, and the precipitated solid was collected by filtration and dried to give N- (2
-Aminophenyl) -4- [2- (pyridin-3-yl) ethanesulfonylaminomethyl] benzamide 21
mg (50% yield) as a light brown solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 2.93-2.99 (2H, m), 3.1
6-3.33 (2H, m), 4.28 (2H, d, J = 6.3Hz), 4.90 (2H, s), 6.60
(1H, dd, J = 6.9,7.3Hz), 6.79 (1H, d, J = 6.9Hz), 6.98 (1H, d
d, J = 6.9,7.3Hz), 7.17 (1H, d, J = 7.6Hz), 7.30 (1H, dd, J =
4.6,7.6Hz), 7.50 (2H, d, J = 8.3Hz), 7.62 (1H, d, J = 6.9H
z), 7.87-7.92 (1H, m), 7.98 (2H, d, J = 8.3Hz), 8.42 (2H,
s), 9.67 (1H, s).

Example 28 N- (2-aminophenyl)
Synthesis of -4-[(pyridin-3-yl) sulfonylaminomethyl] benzamide (Table 1, Compound No. 145) (28-1) Pyridine-3-sulfonic acid 0.80 g
(5.0 mmol) of thionyl chloride (5.5 m
l) The suspension of -DMF (0.5 ml) was stirred for 4 hours while gently heating to reflux. After standing to cool, thionyl chloride was distilled off, azeotroped with toluene, and suspended in dichloromethane (20 ml). Step (27-) under ice-cooling
1.36 g (4.0 mmol) of the compound obtained in 3), triethylamine (2 ml) -dichloromethane (10 ml)
The solution was gradually added, and the mixture was stirred overnight while warming to room temperature. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform / methanol = 30: 1 → 10: 1) to give N- [2 -(N-tert-butoxycarbonyl) aminophenyl] -4-[(pyridine-3-
Yl) sulfonylaminomethyl] benzamide 0.26
g (13.4% yield) as a brown solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 1.46 (9H, s), 4.18 (2H,
s), 7.14-7.23 (2H, m), 7.40 (2H, d, J = 7.9Hz), 7.52-7.63
(3H, m), 7.87 (2H, d, J = 7.9Hz), 8.16 (1H, d, J = 7.9Hz), 8.
56 (1H, br s), 8.69 (1H, s), 8.79 (1H, d, J = 4.9Hz), 8.96
(1H, d, J = 2.3Hz), 9.81 (1H, br s).

(28-2) 0.21 g (0.44 mmol) of the compound obtained in step (28-1) in dioxane (2
ml) -methanol (1 ml) solution at room temperature was added with 4N hydrochloric acid-dioxane (2 ml), and the mixture was stirred at room temperature for 2 hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate-methyl ethyl ketone (2: 1). The organic layer was washed with saturated saline, dried, and the solvent was distilled off. Diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to give N- (2-aminophenyl) -4-. [(Pyridin-3-yl) sulfonylaminomethyl] benzamide 9
3 mg (55% yield) was obtained as a brown solid. ^{1 H-NMR (270MHz, DMSO} -d6) δppm: 4.15 (2H, d, J = 5.9Hz),
4.87 (2H, s), 6.60 (1H, dd, J = 7.3,7.6Hz), 6.78 (1H, dd, J =
1.3,8.3Hz), 6.97 (1H, ddd, 1.3,7.3,7.9Hz), 7.16 (1H, d,
6.9Hz), 7.36 (2H, d, J = 8.2Hz), 7.61 (1H, dd, J = 4.9,7.9H
z), 7.90 (2H, d, J = 8.3Hz), 8.17 (1H, ddd, J = 1.3,1.5,8.1H
z), 8.52 (1H, t, J = 5.9Hz), 8.80 (1H, dd, J = 1.5,4.6Hz),
8.95 (1H, d, J = 1.5Hz), 9.63 (1H, s).

Example 29 N- (2-aminophenyl)
Synthesis of -4- [N-methyl-N- {3- (N, N-dimethylamino) benzene} sulfonylamino] benzamide hydrochloride (Table 1, hydrochloride of compound 45) (29-1) Example 20 0.40 g (0.83 mmol) of the compound obtained in the step (20-1) in acetone (10
0.68 g (4.92 mmol) of potassium carbonate in the solution.
l), and further added methyl iodide (0.3 ml, 4.9 m).
mol)), and the mixture was heated under reflux for 1 hour, allowed to cool, again added with the same amount of methyl iodide, and heated under reflux for 1 hour. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 5: 1) to give N- [2- (N-tert-butoxycarbonyl) aminophenyl] -4- [ N-methyl-N- ｛3-
0.12 g (28% yield) of (N, N-dimethylamino) benzenesulfonyl {amino] benzamide was obtained as a light brown solid. ¹ H-NMR (270 MHz, DMSO-d6) δ ppm: 1.44 (9H, s), 2.87 (6H,
s), 3.18 (3H, s), 6.62 (1H, s), 6.76 (1H, d), 6.99 (1H,
d), 7.12-7.23 (2H, m), 7.31-7.39 (3H, m), 7.50-7.56 (2
H, m), 7.92 (2H, d), 8.66 (1H, br s), 9.84 (1H, br s).

(29-2) 0.08 g (0.15 mmol) of the compound obtained in the step (29-1) was treated with dioxane (3
ml) -methanol (2 ml) solution, 4N hydrochloric acid-dioxane (5 ml) was added, and the mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the residue was washed with diisopropyl ether to give N- (2-aminophenyl) -4- [N-methyl-
N- {3- (N, N-dimethylamino) benzenesulfonyl} amino] benzamide hydrochloride 0.06 g (yield 8
7%) as a light brown solid. ^{. amorphous solid 1 H-NMR (} 270MHz, DMSO-d6) δppm: 2.90 (6H, s), 3.20 (3H,
s), 6.70 (1H, s), 6.76 (1H, d, J = 8.1Hz), 7.01 (1H, dd, J =
2.1,8.1Hz), 7.32-7.50 (7H, m), 7.55 (1H, d, J = 6.6Hz),
8.08 (2H, d, J = 8.1Hz), 10.57 (1H, br s) .IR (KBr) cm ^-1 : 3367,2858,1607,1497,1346,1177,870,76
0.

Pharmacological Test Example 1 A2780 derived from human ovarian cancer
Test for Differentiation-Inducing Action on Cells An increase in alkaline phosphatase (ALP) activity is known as an indicator of human colon cancer cell differentiation, and it is known that, for example, sodium butyrate increases ALP activity [Young et al .; Cancer] Res. , Vo
l. 45, 2976 (1985); Morita et al .; C
cancel Res. , Vol. 42, 4540 (19
82)]. Therefore, the differentiation inducing action was evaluated using ALP activity as an index. (Experimental method) 15000 / well in 96-well plate
0.1 ml of A2780 cells at a time,
The next day, 0.1 ml of the test drug solution serially diluted with the medium was added. After culturing for 3 days, the cells on the plate were
Buffer solution (20 mM Tris, 137 mM NaCl, p
H7.6) twice. Then 0.6 mg / ml
p-Nitrophenyl phosphate (9.6% diethanolamine, 0.5 mM MgCl ₂ (pH 9.
6)) was added in 0.05 ml portions, and incubated at room temperature for 30 minutes. After stopping the reaction with 0.05 ml of a 3N NaOH solution, the absorbance at 405 nm was measured to determine the minimum concentration (ALPmin) of the drug that causes an increase in ALP activity. (Experimental results) Table 2 [Table 31] shows typical examples of the experimental results.
It was shown to.

[0144]

Table 31: Differentiation inducing action on A2780 cells Test compound ALPmin (μM) Compound of Example 1 1 Compound of Example 2 3 Compound of Example 3 3 Compound of Example 4 1 Compound of Example 6 3 Compound of Example 8 3 Compound of Example 10 3 Compound of Example 12 3 Compound of Example 16 3 Compound of Example 17 3 Compound of Example 18 1 Compound of Example 19 0.3 Compound 1 of Example 20 Compound of Example 21 1 Compound of Example 22 3 Compound of Example 24 1 Compound of Example 25 1 Compound of Example 26 10 Sodium butyrate 10,000

[0145]

The novel sulfonamide benzamide derivative of the present invention has a strong differentiation inducing action. Therefore, it is expected to be useful as a therapeutic and / or ameliorating agent for hematopoietic tumors, solid cancers, autoimmune diseases, parasitic infections, and skin diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/425 AEA A61K 31/425 AEA 31/44 31/44 31/505 31/505 31/63 31/63 C07C 311/05 C07C 311/05 311/13 311/13 311/19 311/19 311/21 311/21 311/27 311/27 311/29 311/29 311/35 311/35 311/42 311/42 311/44 311 / 44 C07D 207/333 C07D 207/333 207/36 207/36 213/32 213/32 213/46 213/46 213/52 213/52 213/61 213/61 213/64 213/64 213/65 213 / 65 213/68 213/68 213/70 213/70 213/74 213/74 233/64 104 233/64 104 233/70 233/70 237/08 237/08 237/14 237/14 239/26 239 / 26 239/34 239/34 239/42 239/42 241/12 241/12 241/18 241/18 263/32 263/32 263/40 263/40 277/26 277/26 277/34 277/34 471/04 102 471/04 102 (72) Inventor Osamu Nakanishi 1900-1 Togo, Mobara City, Chiba Pref. Mitsui Pharmaceutical Co., Ltd. (72) Akiko Saito Akiko 1900 Togo, Mobara-shi, Chiba Prefecture Mitsui Pharmaceutical Industry Co., Ltd.

Claims (9)

[Claims] 1. A compound represented by the formula (1): Wherein X is a direct bond, a —CH ₂ — group, —CH ₂ —CH ₂
- group, -CH = CH- group, -O-CH ₂ - group, -NR7-
CH ₂ — group, —CH ₂ —CH ₂ —CH ₂ — group, —O—CH ₂
-CH ₂ - group, -CH ₂ -O-CH ₂ - group, -NR7-CH
₂ -CH ₂ - group, -CH ₂ -NR7-CH ₂ - represents a radical, n
Represents 0 or 1, and A represents an aromatic heterocyclic ring containing one or two optionally substituted nitrogen atoms, or formula (2)
[Chemical 2] [Chemical 2] Wherein R 1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
R2 to R6 each independently represent a hydrogen atom, a halogen atom, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkyl group having 1 to 4 carbon atoms,
4, an alkoxy group, an alkylamino group having 1 to 4 carbon atoms,
Represents a dialkylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, or CO ₂ R 1, wherein R 7 is a hydrogen atom,
To 4 alkyl groups, benzyl groups, COR1 groups, COPh
Represents a group. Or a pharmacologically acceptable salt thereof. 2. A compound of the formula (3) [Wherein, X, A, and R1 to R3 have the same meanings as described above. ] The sulfonamide benzamide derivative of Claim 1 represented by these, or its pharmacologically acceptable salt. 3. A is a pyridyl group which may be substituted, and X is a direct bond, a —CH ₂ — group, —CH ₂ —CH ₂ —.
Groups, -CH = CH- group, -O-CH ₂ - group, -NR7-C
The sulfonamide benzamide derivative according to claim 2, which is an H ₂ group, or a pharmacologically acceptable salt thereof. 4. A compound of the formula (4) [Wherein, A, X and R1 to R3 are as defined above. The sulfonamide benzamide derivative according to claim 1 or a pharmacologically acceptable salt thereof. 5. A is a pyridyl group which may be substituted, and X is a —CH ₂ —CH ₂ — group, a —CH ＝ CH— group,
O-CH ₂ - group, -NR7-CH ₂ - group, -CH ₂ -CH ₂
-CH ₂ - group, -O-CH ₂ -CH ₂ - group, -CH ₂ -O-
CH ₂ — group, —NR ₇ —CH ₂ —CH ₂ — group, —CH ₂ —N
R7-CH ₂ - sulfonamide benzamide derivative or a pharmaceutically acceptable salt thereof pharmacologically according to claim 4 is a group. 6. A compound represented by the formula (5): Wherein A and R1 to R3 are as defined above. The sulfonamide benzamide derivative according to claim 1 or a pharmacologically acceptable salt thereof. 7. A compound represented by the formula (6): [Wherein, R4 to R6 are as defined above. Claim 1 represented by]
Or a pharmacologically acceptable salt thereof. 8. A pharmaceutical comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 9. An anticancer agent comprising the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient.