KR800001567B1 - Preparing process for meta-sulfonamide-benzamide derivatives - Google Patents

Abstract

Title compds. (I; R = H, lower alkyl, cyano; R1 = alkyl, Ph, amino; R2 = H, halogen, alkoxy; R3 = H, Me, methoxy; R4 = H, halogen; R5 = alkyl, Bz, C3-5 cycloalkyl; n = 0, 1), useful medicine for depressing vomit, were prepd. by reaction of dihalogeno compd.(II; X, X1 = halogen) and R5-NH2. Thus, N-(1-ethyl-2-pyrrolidinyl methyl)-2-pyrrolidinyl methyl)-2-methoxy-4-chloro-5-nitrobenzamide(I') was prepd. from 2,4-dichlorobenzoic acid, anhydrous MeOH, Cu powder under gaseous dimethyl amino followed by adding fuming sulfuric acid thionyl chloride, (CH2)3N, anhydrous methylene chloride, and 1-ethyl-2-aminomethylpyrrolidine to give I'.

Description

Method for preparing meta-sulfonamide-benzamide derivative

The present invention relates to a process for the preparation of meta-sulfonamide-benzamide derivatives.

The meta-sulfonamide-benzamide derivatives produced by the process of the invention are acid addition salts of the following formula (I) compounds.

Where

R is a hydrogen atom or a lower alkyl, cyano or lower alkanesulfonyl group,

R ¹ is lower alkyl, phenyl, amino, lower alkylamino, di (lower) alkylamino group, or C ₄ -C ₅ alkylene amino group,

R ² is hydrogen or a halogen atom or lower alkyl, di (lower) alkylamino, or lower alkoxy group,

R ³ is a hydrogen atom or a methyl or methoxy group,

R ⁴ is hydrogen or a halogen atom,

R ⁵ is lower alkyl, lower alkenyl, C ₃ -C ₅ cyclo alkyl, benzyl, or halogenobenzyl group,

n is 1 or 0.

As used herein, the term "lower alkyl" refers to straight or branched chain alkyl groups, preferably containing 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl , Hexyl, etc.). Methyl groups are preferred, except that ethyl groups are preferred as lower alkyl groups for R ⁵ . The term "lower alkoxy" means a straight or branched chain alkoxy group containing preferably 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy group). Preferred lower alkoxy groups are methoxy groups. "Lower alkanesulfonyl" means a straight or branched chain alkanesulfonyl group having 1 to 6 carbon atoms (e.g., methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentasulfonyl, etc.) do. Methanesulfonyl is a preferred lower alkanesulfonyl group. "Lower alkylamino" means a straight or branched chain alkylamino group having 1 to 6 carbon atoms (e.g., methylamino, ethylamino, methylethylamino, propylamino, isopropylamino, butylamino, pentylamino, etc.); Among them, methyl amino group is preferred. 저 Di (lower) alkylamino˝ means a C ₂ -C ₁₂ dialkylamino group in which two alkyl groups are the same or different from one another (e.g., dimethylamino, diethylamino, ethylpropylamino, methylbutylamino, dibutylamino, di Hexylamino, etc.). Dimethylamino group is good. “Lower alkenyl” means a straight or branched chain alkenyl group having 2 to 6 carbon atoms, preferably vinyl, altyl, butenyl, phenphenyl, and the like. Halogen means fluorine, chlorine, cancelled or oxo. Preferred halogen for R ² is chlorine or fluorine. The term “C ₃ to C ₆ cycloalkyl” means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Among them, cyclohexyl is preferable as the cycloalkyl group. The term “C ₄ to C ₅ alkylene” refers to a pyrrolidino or a pyrredino group, and piperidino is preferable. The term “halogenobenzyl” denoted by R ⁵ includes o-halogenobenzyl, such as o-chlorobenzyl or o-fluorobenzyl, and p-halogenobenzyl, such as p-chlorobenzyl or p-fluorotobenzyl. .

Preferred compounds of the above formula (I) are the compounds of the following formula (Ia) and acid addition salts thereof.

Where

R is a hydrogen atom or a lower alkyl, cyano or lower alkanesulfonyl group,

R ¹ is lower alkyl, phenyl, amino, lower alkylamino, di (lower) alkylamino group,

R ² is hydrogen or a halogen atom or lower alkyl, di (lower) alkylamino, or lower alkoxy group,

R ³ is a hydrogen atom or a methyl or methoxy group,

R ⁴ is hydrogen or a halogen atom,

R ⁵ is lower alkyl, lower alkenyl, C ₃ -C ₅ cycloalkyl, benzyl, or halogenobenzyl group,

More preferred compounds of the above formula (Ia) are those wherein R, R ³ and R ⁴ are each hydrogen atoms, R ¹ is a lower alkyl, phenyl, amino, methylamino or dimethylamino group, and R ² is hydrogen or a chlorine atom or a methyl group And R ⁵ is an ethyl or halogenobenzyl group.

Examples of the compound of formula (I) described above are as follows.

According to the present invention, the meta-sulfonamide-benzamide derivatives (ie, the compounds of formula (I) and acid addition salts thereof)

(A) reacting a dihalogeno compound of formula (II) with an amine of formula (III):

(B) reacting the anilino compound of formula (IV) with a sulfonating agent of formula (V), or

(C) reacting the benzoic acid derivative of the following formula (VI) with a diamino compound of the following formula, converting the resulting organic base to an acid addition salt or converting the resulting acid addition salt to a free base or a different acid addition salt Manufacture.

In each formula above,

X and X ₁ are each a halogen atom,

R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined above,

A and A 'are reactive moieties.

The reaction of the dihalogeno compound of formula (II) with the amine of formula (III) is carried out at a temperature above room temperature (eg, 15 ° C. to 100 ° C. with a suitable solvent (eg water, ethanol, methylene chloride, pyridine or triethylamine). It can be carried out in the presence or absence of.

Examples of the amine of formula (III) include methylamine, ethylamine, propylamine, butylamine, altylamine, butenylamine, cyclopropylamine, cyclohexylamine, benzylamine, o-chlorobenzylamine and p-fluorobenzylamine There is this.

The reaction of the anilino compound of formula (IV) with the sulfonating agent of formula (V) can proceed according to known methods. Examples of sulfonating agents of the formula (V) include halides of the aforementioned sulfonic acids (such as chlorides, hydrates, oxides), active esters (such as P-nitrophenylesters, benzyl esters, trityl esters) and anhydrides of the aforementioned sulfonic acids with a R ¹ framework. For example methanesulfonic anhydride or ethanesulfonic acid inorganic). Sulfonation is an inert solvent in the presence of an organic base (e.g. triethylamine or pyridine) or an inorganic base (e.g. potassium carbonate or sodium carbonate) at a temperature below room temperature or above room temperature (e.g., a temperature range of 0 ° C to 100 ° C). (Eg, methylene chloride, bezene, tetrahydrofuran or dioxane). Alternatively, the organic base may be used in the form of a solvent. The reaction usually proceeds in high yield. When R is a lower alkyl, cyano or lower alkanesulfonyl group, only 1 molar equivalent of -S ₂ OR ¹ can be introduced under the sulfonation reaction of the present invention. However, when R is a hydrogen atom, 2 molar equivalents of -SO ₂ R ¹ can optionally be introduced, but the product must be treated with an inorganic base such as an aqueous alkali hydroxide (e.g. sodium or potassium hydroxide) solution to form the secondary group. It can be easily replaced by hydrogen.

The compound of formula (I) described above wherein R is a hydrogen atom may be subjected to an alkylation reaction according to a known method. However, compounds of formula (I) wherein R is a lower alkanesulfonyl group and R ¹ is a di (lower) alkylamino group may be used if necessary to remove lower alkanesulfonyl groups that can be hydrolyzed, such as aqueous solutions of alkyl hydroxides (e.g., hydroxides). Aqueous sodium solution). In addition, the product of the above-mentioned formula (I) wherein R ¹ is a t-butylamino group can be treated with trifluoroacetic acid to remove the tertiary butyl group, whereby the compound of the above-mentioned formula (I) wherein R ¹ is an amino group Can be obtained.

The reaction of the benzoic acid derivative of formula (VI) with the diamino compound of formula (VII) can be carried out by methods known in peptide chemistry, such as mixed anhydrides, azides, esters or acid chlorides. For example, benzoic acid derivatives of formula (VI) wherein the reactive moiety is of ester type (e.g., lower alkyl, p-nitrophenyl or 2,4-dinitriphenyl esters), are formulated at room temperature (e.g. In other methods, suitable benzoic acid derivatives of formula (IV), wherein the reactive moiety is in the acid chloride form, may be organic bases (eg triethylamine or pyridine) or inorganic bases (eg sodium carbonate, hydrogen). Condensation with the diamino compound of formula VII at room temperature in the presence of a base such as sodium carbonate or sodium hydroxide).

The starting materials of the compounds of the above formula (II) can be prepared, for example, by reacting the compounds of the following formula (VIII) with a halogenating agent (eg thionyl chloride) according to known methods.

Wherein R, R ¹ , R ² , R ³ , R ⁴ and n are the same as defined above.

The halogenation reaction can be run in an inert solvent at a temperature above room temperature (eg, about 25 ° C. to about 200 ° C.).

The tetrahydrofuryl compound of formula (VIII) can be prepared by reacting a compound of formula (IX) with a tetrahydrofuran derivative of formula (X) according to a known method.

In each formula above,

A ² is a reactive moiety,

R ² , R ³ , R ⁴ and n are as defined above. This condensation reaction can be carried out in an inert solvent (eg benzel, toluene, methylene chloride, dimethylformamide or tetrahydrofuran) at or below room temperature or above (eg 0 ° C. or about 100 ° C.).

Compounds of formula (IX) can be prepared by combining the compounds of formula (XI) with nitration reactions, reduction of nitro groups to amino groups, introduction of R groups, and the sulfonation reactions mentioned above.

Where

A ³ is a hydroxy group or a reactive moiety,

R ² , R ³ and R ⁴ are as defined above.

The starting materials of the above-mentioned structural formula (IX) include, for example, the conversion of known nitro groups to amino groups, for example, contact hydrogenation on buck / carbon, platinum oxide, or renney nickel, tin / hydrochloric acid or iron / hydrochloric acid reduction. It can be prepared by reducing the nitro compound of the formula (XII) by the reaction.

Where

R ² , R ³ , R ⁴ , R ⁵ and n are as defined above.

If necessary, the resulting anilino compound is introduced to the R group by known methods. Therefore, the lower alkyl group represented by R can be introduced by mono alkylation of aromatic primary amine by adopting lower alkyl oxide or di (lower) alkyl sulfate method or a combination of acylation and reduction of carbonyl group.

The lower alkylsulfonyl group represented by R can be introduced according to the method used previously for the introduction of the -SO ₂ R ¹ group. The cyano group represented by R, for example, reacts the corresponding anilino compound with ethyl orthoformate and sodium azide in acetic acid, and the resulting tetrazolyl compound is reacted with a base (e.g., from about 15 ° C to about 120 ° C). , Sodium hydroxide solution).

The nitro compound of formula (XII) is used in the condensation of a benzoic acid derivative of formula (VI) with a diamine of formula (VII) by nitrating the compound of formula (XI) according to a known method. According to the foregoing method, it can be prepared by condensation with the diamine of formula (VII).

Wherein R ² , R ³ , R ⁴ and A ³ are as defined above.

The starting material of the above-mentioned structural formula (VI) is, for example, according to the previous method in which the compound of the following formula (XIV) is used in the condensation of the anilino compound of the formula (IV) with the sulfonating agent of the formula (V), Can be prepared by reacting with a sulfonating agent.

Wherein R ¹ , R ² , R ³ , R ⁴ and A are as defined above.

Compounds of formula (XIV) can be prepared by reducing the compound of formula (XIII) to the corresponding anilino compound and, if necessary, introducing the R group into the amino group of the anilino compound according to the methods previously used.

The compounds of formula (I) described above include inorganic acids (eg hydrochloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, thiocyanic acid, etc.) and organic acids (eg acetic acid, oxalic acid, succinic acid, maleic acid, malic acid, phthalic acid, tartaric acid, citric acid). , Methanesulfonic acid, toluenesulfonic acid, etc.) and acid addition salts. These acid addition salts can be prepared by known methods, such as by treating the base of formula (I) using a suitable acid. Acid addition salts may be converted to different acid addition salts according to known methods. Of course, the acid addition salt is preferably a pharmacologically acceptable acid addition salt.

The compounds of formula (I) described above and acid addition salts thereof have a clay action and a mental action.

It is known that the nausea action of meta-sulfonamide benzamide in the present invention is administered orally to a hunting dog (male) of 10 to 20 months, and subcutaneously treated with apomorphine 0.1 mg / kg to examine the number of vomiting after 30 minutes. Can be. The result is expressed as ED ₅₀ (mg / kg), which means a dose to convert to 50% vomiting and inhibition. [Janssen, co-investigator, PAJ Arzneim. -Forsch. 18 (3) 261-279 (1968).

Psychological function is shown as antagonistic activity in DS male rats against apomorphine-induced hyperactivity in spontaneous exercise. This test is performed by oral administration of the disclosed compound to the mice, reviewing the amount of spontaneous exercise for 15 minutes after 1 hour, subcutaneously administering 2.5 mg / kg of metapetamine, and examining the other amount of spontaneous exercise for 10 minutes. The results are expressed as ED ₅₀ (mg / kg), which means the dose to convert to 50% inhibition of vomiting (same co-worker of Sen, PAJ cited above).

The compounds of formula (I) and their pharmacologically acceptable acid addition salts can be used in formulations containing them in a mixture with a medicament, for example a pharmacologically acceptable carrier. As the carrier material, organic or inorganic carriers suitable for oral or parenteral administration (e.g., water, lactose, gelatin, starch, magnesium stearate, talc, vegetable oil, gum, polyalkylene glycols, petroleum jelly, etc.) may be used. have. Such formulations may be in solid form (eg, tablets, dragees, capsules, etc.) or liquid form (eg, liquids, suspensions or emulsions). Formulations suitable for injection may be subjected to conventional pharmaceutical conditions such as sterilization, or may contain conventional pharmacological adjuvants such as preservatives, stabilizers, hydrating agents, emulsifiers, buffers and the like.

The dosage of the compound of formula (I) and its pharmacologically acceptable acid addition salt can be altered according to the condition of the patient and the prescription of the pharmacist. Suitable daily dosages for adults are about 30 mg to about 350 mg when administered orally.

Benzamide derivatives, including N- (1-ethyl-2-phytolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide (sulpyride), are anti-inflammatory ulcers or antidepressants. It has been known.

When the present invention is described as an embodiment as follows.

Example 1

(1) A mixture of 2,4-dichlorobenzoic acid (67.4 g), anhydrous methanol (135 ml) and copper powder (3.37 g) was refluxed for 6-7 hours while introducing gaseous dimethylamine. The reaction mixture is mixed with a large amount of water, acidified with hydrochloric acid and shaken with addition of ether. The organic layer is washed with water and dried over sodium sulfate to evaporate off the solvent. The residue is washed with isopropyl ether and filtered to give 2-methoxy-4-chlorobenzoic acid (43.6 g) which is a crystal having a melting point of 139.5 to 141 ° C.

(2) The product (3.25 g) was added dropwise to the fuming sulfuric acid (specific gravity: 1.52) (10 ml) under stirring at −30 ° C., and the resulting mixture was stirred for 10 minutes. The reaction mixture is poured into ice water and washed with chloroform / methanol. The organic layer is washed with water and dried over sodium sulfate to evaporate off the solvent. The residue was washed with isopropyl ether and filtered to give 2-methoxy-4-chloro-5-nitrobenzoic acid (2.85 g) as a crystal having a melting point of 184 to 185 DEG C. (Helv. Chim. Acta. 40. 369 (1957). ).

(3) A mixture of 2-methoxy-4-chloro-5-nitrobenzoic acid (900 mg) and thionyl chloride (5 ml) was refluxed for 30 minutes, and the resulting mixture was evaporated to remove thionyl chloride. The residue is mixed with benzene and evaporated to remove benzene. The residue was mixed with triethylamine (790 mg) and anhydrous methylene chloride (9 ml), and thereto were added dropwise a solution of 1-ethyl-2-aminomethylpyrrolidine (750 ml) and methylene chloride (4 ml) with ice cooling and stirring. do. The resulting mixture is stirred at room temperature for 15 minutes. The reaction product is mixed with aqueous sodium hydrogen carbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and the solvent is evaporated off. The residue is mixed with ether and shaken with dilute hydrochloric acid. The aqueous layer is treated with an aqueous sodium hydrogen carbonate solution to make it alkaline and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and the solvent is evaporated off. The residue was recrystallized from ethyl acetate / isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-nitrobenzamide (679 mg) as a crystal having a melting point of 107 to 108 캜. Get)

Elemental Analysis Value: C ₁₅ H ₂₀ O ₄ N ₃ Cl

This launch: C 52.71, H 5.90, N 12.29, Cl 10.37

Found: C 52.90, H 6.00, N 12.28, Cl 10.63

(4) The product (7.33 g) was mixed with a solution of concentrated hydrochloric acid (36.7 ml) and water (73.3 ml), and the mixture was heated at 50 ° C. and mixed with tin pieces (7.7 g) for 4 hours at 50 ° C. Stir. After cooling, the reaction mixture is made alkaline with aqueous sodium hydroxide solution and shaken with methylene chloride. The organic layer is hydrated and dried over sodium sulfate to evaporate the solvent. The residue is chromatographed on an alumina column and eluted with methylene chloride. The eluate is evaporated to remove the solvent. The residue is washed with isopropylether petroleum ether to give N- (1-2-ethylpyrrolidinylmethyl) -2-methoxy-4-chloro-5-aminobenzamide (5.38 g). The product is recrystallized in isopropyl ether / petroleum ether to obtain crystals having a melting point of 85 to 86.5 ° C.

Elemental Analysis Value: C ₁₅ H ₂₂ O ₂ N ₃ Cl

This launch: C 57.78, H 7.11, N 13.48, Cl 11.37

Found: C 57.63, H 7.18, N 13.55, Cl 11.66

(5) A solution of methanesulfonyl chloride (3.18 g) and anhydrous methylene chloride (8.2 ml) was added dropwise to a dry methylene chloride (41 ml) solution of the product (4.1 g) and triethylamine (2,93 g). do. After removing the ice bath, the reaction mixture is stirred for 45 minutes at room temperature. The reaction mixture is made alkaline with aqueous sodium hydrogen carbonate solution and shaken by addition of methylene chloride. The organic layer is washed with water and dried over sodium sulfate to evaporate off the solvent. The residue was washed with ethyl acetate / isopropyl ether to form N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-N, N-bis, a crystal having a melting point of 153 to 155 占 폚. (Methanesulfonyl) aminobenzamide (5.83 g) is obtained.

Elemental Analysis Value: C ₁₇ H ₂₆ O ₆ N ₃ S ₂ Cl

This launch: C 43.37, H 5.73, N 8.68, S 13.70, Cl 7.58

Found: C 43.37, H 5.73, N 8.98, S 13.79, Cl 7.72

(6) A 10% sodium hydroxide (57.5 ml) suspension of the product (5.75 g) was heated and stirred at 50 ° C. for 30 minutes. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid, made alkaline with aqueous sodium hydrogen carbonate solution, saturated with sodium chloride and shaken by addition of methylene chloride. The organic layer is washed with saturated brine and dried over aluminum sulfate to distill methylene chloride. The residue is chromatographed on an alumina column, eluted with methylene chloride alone and 2% methanol / methylene chloride and the solvent is distilled off. The residue was washed with ethyl acetate / isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-methanesulfonamidobenzamide (4.3 g), This was recrystallized in ethyl acetate / isopropyl ether to obtain colorless prism crystals having a melting point of 126 to 127.5 ° C.

Elemental Analysis Value: C ₁₆ H ₂₄ O ₄ N ₃ SCl

This launch: C 49.29, H 6.20, N 10.78, S 8.22, Cl 9.09

Found: C 49.17, H 6.22, N 10.77, S 8.28, Cl 9.26

Example 2

(1) To a mixture of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-aminobenzamide (700 mg), triethylamine (1.02 g) and methylene chloride (14 ml), Methanesulfonyl (870 mg) is added dropwise under room temperature stirring, and the resulting mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with water and rendered alkaline with aqueous sodium hydrogen carbonate solution and shaken with methylene chloride. The organic layer was washed with water and dried over sodium sulfate to distill methylene chloride. The residue is chromatographed on an alumina column, which is eluted with methylene chloride. After distilling off the solvent from the eluate, the residue was recrystallized from ethyl acetate isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-N, N-bis (methanesulfonyl) Obtain aminobenzamide (582 mg). The product is recrystallized in ethyl acetate to obtain crystals having a melting point of 160 to 161 占 폚.

Elemental Analysis Value: C ₁₇ H ₂₇ O ₆ N ₃ S ₂

This launch: C 47.0, H 6.28, N 9.69, S 14.79

Found: C 47.25, H 6.30, N 9.55, S 14.99

Thus, N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-methanesulfonamidobenzamide is obtained by using 3% methanol methylene chloride as the eluent. The eluate was evaporated and the residue was precipitated in ethyl acetate / isopropyl ether to give the product (148 mg), which was recrystallized in ethyl acetate to obtain crystals having a melting point of 170 to 175.5 ° C.

Elemental Analysis Value: C ₁₆ H ₂₅ O ₄ N ₃ S

This launch: C 54.06, H 7.09, N 11.82, S 9.02

Found: C 54.35, H 7.18, N 11.74, S 9.29

(2) 10% sodium hydroxide suspension (2.9 ml) of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-N, N-bis (methanesulfonyl) aminobenzamide (290 mg) Warm) and warm for 5 minutes to obtain a clarification liquid. After distilling off the solvent, the residue is mixed with ice water, acidified with 6N hydrochloric acid and made slightly alkaline using an aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was washed with ethyl acetate / isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-methanesulfonaminobenzamide (148 mg), which was ethyl acetate / isopropyl Recrystallization with ether gives crystals having a melting point of 170 to 171.5 ° C.

Example 3

(1) To a mixture of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-aminobenzamide (700 mg), methylene chloride (14 ml) and triethylamine (1.03 g), chloride Benzenesulfonyl (1.35 g) is added at room temperature and the resulting mixture is mixed with water to make alkaline with aqueous sodium carbonate solution and shaken with methylene chloride. The organic layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue is dissolved in methylene chloride and chromatographed on an alumina column, which is eluted with methylene chloride. The methylene chloride was organic in the eluate, and the residue was recrystallized from ethyl acetate / isopropyl ether to obtain N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-N, a crystal having a melting point of 166 to 170 ° C. , N-bis (benzenesulfonyl) aminobenzamide (839 mg) is obtained.

Elemental _{analysis: C 27 H 31 O 6 N} 3 S 2 · 1 / 2H 2 O

This theory: C 57.23, H 5.69, N 7.42, S 11.32

Found: C 57.26, H 5.69, N 7.20, S 11.50

(2) A mixture of the above product (500 mg), 10% sodium hydroxide (7.5 ml) and methanol (7.5 ml) is warmed on a warming bath for 5 minutes. After distilling methanol from the reaction mixture, the residue was mixed with water, acidified with hydrochloric acid, made alkaline again with aqueous sodium hydrogen carbonate solution and shaken with methylene chloride. The organic layer is dried to distill the solvent. The residue was washed with ethyl acetate / isopropylether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-benzenesulfonamidobenzamide (325 mg). This product is recrystallized from ethyl acetate to obtain crystals having a melting point of 177 to 178 캜.

Elemental Analysis Value: C ₂₁ H ₂₇ O ₄ N ₃ S

This launch: C 60.41, H 6.52, N 10.06, S 7.68

Found: C 60.40, H 6.52, N 9.95, S 7.74

Example 4

(1) A mixture of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-nitrobenzamide (1.5 g), platinum oxide (150 mg) and methanol (30 ml) was shaken under hydrogen stream While contact is hydrogenated. The reaction mixture is treated in a conventional manner and the methanol is distilled off. The residue is mixed with sodium azide (500 mg), ethyl orthoformate (5 ml) and acetic acid (5 ml) and the resulting mixture is heated at 80 ° C. for 1 hour. The reaction mixture is mixed with ice water and made alkaline with sodium hydrogen carbonate and then shaken by addition of methylene chloride. The organic layer is washed with water, dried over sodium sulfate and the solvent is distilled off. The residue was precipitated from ethyl acetate / isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5- (1H-tetrazol-1-yl) as a crystal having a melting point of 171 to 174 ° C. ) Benzamide (1.3 g) is obtained.

Elemental Analysis Value: C ₆ H ₂₂ O ₂ N ₆

This launch: C 58.16, H 6.71, N 25.44

Found: C 57.87, H 6.71, N 25.36

(2) A mixture of the product (1.3 g), ethanol (9.8 ml), water (3.3 ml) and 10% sodium hydroxide (6.5 ml) is heated at 80 ° C. for 40 minutes. The ethanol is distilled off, then the residue is acidified with 6N hydrochloric acid, made alkaline with triethylamine, salted with sodium chloride and shaken with 5% methanol / methylene chloride. The organic layer is dried over sodium sulfate and the solvent is distilled off. The residue was washed with ethyl acetate to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-cyanoaminobenzamide (641 mg), which was recrystallized from ethyl acetate to have a melting point of 134 to 139. Crystals at 占 폚 are formed.

Elemental Analysis Value: C ₁₆ H ₂₂ O ₂ N ₄

This launch: C 63.55, H 7.30, N 18.53

Found: C 63.53, H 7.40, N 1.37

(3) A solution of the product (300 mg) and pyridine (1.5 ml) is mixed with methanesulfonyl chloride (340 mg) at room temperature, and the resulting mixture is stirred at room temperature for 2 hours and at 50 ° C. for 30 minutes. The reaction mixture is mixed with aqueous sodium carbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and the solvent is distilled off. The residue is dissolved in methylene chloride, chromatographed on an alumina column, and eluted with methylene chloride. After distilling methylene chloride from the eluate, the residue was washed with ether / isoproether and recrystallized to form N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5, a crystal having a melting point of 50 to 50 ° C. -(N-cyanomethanesulfonamido) benzamide (99 mg) is obtained.

Elemental Analysis Value: C ₁₇ H ₂₄ O ₄ N ₄ S ₄

This launch: C 53.67, H 6.36, N 14.73, S 8.3

Found: C 53.27, H 6.39, N 14.40, S 8.5

Example 5

To a dry acetone (7 ml) solution of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-ethanesulfonamidobenzamide (266 mg) was added potassium carbonate and dimethyl sulfate (100 mg). The resulting mixture is refluxed for 30 minutes. After acetone is distilled off, the residue is mixed with water and shaken by addition of methylene chloride. The organic layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue is dissolved in methylene chloride and the resulting mixture is chromatographed on an alumina column to elute with methylene chloride. The eluate was evaporated to distill methylene chloride, and the residue was washed with isopropyl ether and recrystallized from ethyl acetate / isopropyl ether to crystallize N- (1-ethyl-2-pyrrolidinyl with a melting point of 85 to 87 ° C. Methyl) -2-methoxy-5- (N-methyl-ethanesulfonamido) benzamide (74 mg) is obtained.

Elemental Analysis Value: C ₁₈ H ₂₉ O ₄ N ₃ S

This launch: C 56.37, H 7.62, N 10.96, S 8.36

Found: C 56.55, H 7.68, N 10.80, S 8.61

[Examples 6-23]

The reaction was carried out in the same manner as in Example 1 using the following starting material (IV) to give the corresponding product (I).

Note: The symbols in the table have the following meanings respectively.

Et (ethyl), Da (dimethylamino), Bu (butyl), Me (methyl), Met (methoxy), F (fluorine), H (hydrogen), Cl (chlorine)

* The melting point of the hydrochloride salt of this product is 202-203 degreeC (decomposition).

Example 24

To a solution of 1.0 g of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-aminobenzamide and 5 ml of dry pyridine, 308 mg of methanesulfonyl chloride under ice-cooling was added and stirred at room temperature for 20 minutes. . This reaction mixture was treated in the same manner as in Example 1 to form N- (1-cyclohexyl-3-pyrrolidinyl) 2-methoxy-5-methanesulfonamidobenzamide (7 31 m) as a crystal having a melting point of 170 to 171.5 ° C. g) is obtained.

Elemental Analysis Value: C ₁₉ H ₂₉ O ₄ N ₃ S

This launch: C 57.70, H 7.39, N 10.26, S 8.11

Found: C 57.89, H 7.47, N 10.45, S 8.37

Example 25

(1) A solution of 300 mg of methyl 2-methoxy-5-aminobenzoate, 6 ml of dry methylene chloride and 368 mg of triethylamine was added dropwise to 4400 mg of methanesulfonyl chloride and 1 ml of dry methylene chloride under ice-cooling, followed by 1 Stir for time. The reaction solution is made alkaline with an aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and methylene chloride was distilled off under reduced pressure. The residue is washed with ethyl acetate / isopropyl ether to give 2-methoxy-5-N, N-bis (methanesulfonyl) aminobenzoate (520 mg). When this product is recrystallized from ethyl acetate, it becomes a crystal of melting | fusing point 169-160.5 degreeC.

Elemental Analysis Value: C ₁₁ H ₁₅ O ₇ NS ₂

This launch: C 39.16, H 4.48, N 4.15, S 19.01

Found: C 39.04, H 4.45, N 4.04, S 19.01

(2) 300 mg of the above product was added to a mixed solution of 3 ml of tetrahydrofuran and 3 ml of 10% aqueous sodium hydroxide solution, and stirred for 1 hour and 15 minutes under heating to 50 ° C. After distilling off the solvent from the reaction solution, the residue was acidified with 6N hydrochloric acid, and salted and extracted with methylene chloride containing salt and a small amount of methanol. The organic layer is washed with saturated brine, dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is washed with isopropyl ether to give 2-methoxy-5-methanesulfonamidobenzoic acid (175 mg) having a melting point of 166 to 167.5 ° C.

(3) The mixture of 150 mg of the product and 3 ml of thionyl chloride was heated to reflux for 30 minutes. Thionyl chloride is distilled off under reduced pressure, dry benzene is added to the residue, and the solvent is distilled off under reduced pressure. The residue is dissolved in 3 ml of dry methylene chloride. Under ice-cooling, a solution of 124 mg of triethylamine and then 90 mg of 1-ethyl-2-aminomethylpyrrolidine and 1 ml of dry methylene chloride was added dropwise and stirred at room temperature for 15 minutes. Aqueous solution of sodium bicarbonate was added to the reaction solution to make it alkaline, salted with salt, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over sodium sulfate and methylene chloride was distilled off under reduced pressure. The residue is chromatographed with an alumina column and eluted with 1% methanol / methylene chloride to 2% methanol / methylene chloride. The solvent is distilled off from the eluate and the residue is recrystallized from ethyl acetate / isopropyl ether to obtain 143 mg of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-methanesulfonamidobenzamide. When this product is recrystallized from ethyl acetate / isopropyl ether, it will become the crystal of melting | fusing point 169-170.5 degreeC.

Example 26

(1) To a solution consisting of 300 mg of 2-methoxy-5-aminobenzoic acid methyl ester and 3 ml of dried pyridine, 210 mg of sulfonyl chloride under ice-cooling was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution is acidified with 6N hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, and methylene chloride was distilled off under reduced pressure. The residue is chromatographed on a silica gel column, eluting with methylene chloride-2% methanol / methylene chloride and distilling off the solvent from the eluate. The residue was determined in ethyl acetate / isopropyl ether to obtain 381 mg of 2-methoxy-5-methanesulfonamide benzoic acid methyl ester as a colorless prism tablet having a melting point of 84 to 86 ° C.

Elemental analysis value: C ₁₀ H ₁₃ O ₅ NS.1 / 10H ₂ O

This launch: C 46.32, H 5.05, N 5.40, S 12.37

Found: C 45.77, H 5.14, N 5.30, S 12.32

(2) A solution of 330 mg of the product, 245 mg of 1-ethyl-2-aminomethylpyrrolidine and 7 ml of n-propane was heated to reflux for 23 hours. After cooling, N-propanol is distilled off under reduced pressure, the residue is dissolved in dilute hydrochloric acid, and the unreacted ester is extracted with methylene chloride. The aqueous hydrochloric acid layer is made alkaline with sodium carbonate, salted with sodium chloride and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over sodium sulfate, and the methylene chloride was distilled off under reduced pressure. The residue is chromatographed on an alumina column to elute 2% methane with methylene chloride and the solvent is distilled off from the eluate. The residue was recrystallized from ethyl acetate / isopropyl ether to give 143 mg of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-methanesulfonamidobenzamide as colorless phosphorus tablet having a melting point of 171 to 72 ° C. Get

Example 27

The reaction was carried out in the same manner as in Example 5 using N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-methanesulfonamidobenzamide and dimethyl sulfate, with a melting point of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5- (N-methylmethanesulfonylamido) benzamide is obtained as a crystal at 140.5 to 142 ° C.

Example 28

T-butylamino chloride in a mixed solution of 1.0 g of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl-5-aminobenzamide, 20 ml of anhydrous methylene chloride and 693 mg of triethylamine A mixture of 707 mg of sulfonyl and 5 ml of methylene chloride is added dropwise under ice-cooling stirring. After stirring for 15 minutes, the reaction mixture is mixed with sodium hydrogen carbonate solution and shaken with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on an alumina column and eluted with 0-2% methanol / methylene chloride. The eluate was recrystallized from ethyl acetate isopropyl ether to give N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-ethyl-5-t-butylamino-sulfone as a crystal having a melting point of 167 to 168 캜. Obtain amidobenzamide (1.0 g).

Elemental Analysis Value: C ₂₀ H ₃₄ O ₄ N ₄ S

This launch: C 56.31, H 8.03, N 13713, S 7.52

Found: C 56.23, H 8.11, N 12.84, S 7.70

(2) The solution of 700 mg of the above product mixed with 7 ml of trifluoroacetic acid was stirred at room temperature for 3 hours, and trifluoroacetic acid was evaporated off. The residue is mixed with ammonia solution, salted with saturated brine and shaken with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and then recrystallized from ethyl acetate / ether to be N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl as a crystal having a melting point of 140 to 141 ° C. Obtain 5-5-amino-sulfonamidobenzamide (408 mg).

Elemental Analysis Value: C ₁₆ H ₂₀ O ₄ N ₄ S

This launch: C 51.87, H 7.07, N 15.12, S 8.65

Found: C 51.87, H 7.07, N 14.81, S 8.63

[Examples 29-32]

The reaction was carried out in the same manner as in Example 28 using the following starting material (IV) to give the corresponding products (I) and (Ib).

Example 33

(1) A mixture of 20 g of 2-methoxy-4-methyl-5-methane-sulfonamidobenzoate and thionyl chloride (20 ml) was refluxed for 2.5 hours, and the reaction mixture was evaporated under reduced pressure to remove thionyl chloride. do. The residue was mixed with 10 ml of anhydrous benzene and 1.5 g of triethylamine, and a mixture of 870 mg of tetrahydrofurfurfurylamine and 2 ml of anhydrous benzene was added under ice-cooling stirring. The resulting mixture is stirred at room temperature for 15 minutes, then the reaction mixture is made alkaline with sodium carbonate and shaken with methylene chloride. The organic layer is washed with water and dried over sodium sulfate to evaporate off methylene chloride. The residue was washed with ethyl acetate / isopropyl ether to give N-tetrahydropurofuryl-2-methoxy-4-methyl-5-methanesulfonamidobenzamide (2., 21 g) as a crystal having a melting point of 207 to 208.5 ° C. Get

(2) The solution which consists of 1.5 g of the said products, 9 ml of thionyl chlorides, and 30 ml of chloroform is refluxed for 4 hours. The reaction mixture is poured into ice water and shaken by adding methylene chloride. The organic layer is washed with sodium hydrogen carbonate solution and then with water and dried over sodium sulfate. The residue is dissolved in methylene chloride, chromatographed on silica gel column and eluted with 1% methanol / methylene chloride. The solvent was removed from the eluate and the residue was washed with ethyl acetate / ether to yield N- (2,5-dichloropentyl) -2-methoxy-4-methyl-5-methane-sulfonamido as crystals having a melting point of 132 to 132.5 ° C. Obtain genzamide (1.30 g).

(3) The mixed solution of 100 mg of the product and 70% ethylamine solution is warmed to 60 ° C. for 2.5 hours, and the reaction mixture is ice-cooled, mixed with sodium hydrogen carbonate solution, salted with sodium chloride and shaken with methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on an alumina column and eluted with 1% methane / methylene chloride. After evaporating off the solvent from this eluate, the residue was washed with ethyl acetate / isopropyl ether to obtain N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl as a crystal having a melting point of 131.5 to 133 ° C. 42 mg of 5-5-methanesulfonamidobenzoamide are obtained.

Example 34

(1) The reaction was carried out in the same manner as in Example 33 (1) using 2-methoxy-4-chloro-5-nitrobenzoic acid, to thereby crystallize N-tetrahydrofurofuryl-2-meth having crystals having a melting point of 164 to 165 캜. 3.85 g of oxy-4-chloro-5-nitrobenzamide are obtained.

A solution of 3.65 g of the product, 36.5 ml of concentrated hydrochloric acid, 18 ml of water, 36.5 ml of tetrahydrofuran, and 4.13 g of tin pieces is heated to 50 ° C. for 2 hours, and the solvent is distilled off from the reaction mixture. The residue is mixed with ice water and made strong alkaline with sodium hydroxide and shaken with methylene chloride. The organic layer was filtered off with water, washed with water, dried over sodium sulfate, the solvent was distilled off, and the mixture was recrystallized from ethyl acetate / ether to obtain N-tetrahydrofurfuryl-2-methoxy-4-chloro- as a crystal having a melting point of 109 to 110 ° C. Obtain 5-aminobenzamide.

3.4 g of this product was dissolved in a solution of 36 ml of methylene chloride and 2.85 g of triethylamine, and then 3.08 g of sulfonylmethylsulfonyl and 7.2 ml of methylene chloride were added under ice-cooling, and the resulting mixture was heated to a temperature near the boiling point of the solvent. Heat with stirring for minutes. A sodium hydrogen carbonate solution is added to the reaction mixture and shaken. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is distilled off. The residue is mixed with 61 ml of 10% sodium hydroxide solution and 10 ml of tetrahydrofuran and stirred at 50 ° C. for 1.25 hours. The resulting mixture is acidified with concentrated hydrochloric acid, shaken with methylene chloride, washed with water, dried over sodium sulfate and the solvent is distilled off. The residue was washed with ethyl acetate / ether and recrystallized from methylene chloride / ethyl acetate to yield N-tetrahydrofurfuryl-2-methoxy-4-chloro-5-methane-sulfonamidobenzamide as crystals having a melting point of 159 to 160 ° C. Get 2.82 g

(2) Using the product, the reaction was carried out in the same manner as in Example 33 (2), and the crystal was-(2,5-dichloropentyl) -2-methoxy-4-chloro-5- having a melting point of 105 to 106.5 ° C. Sulfonamidobenzamide is obtained.

(3) The reaction was carried out in the same manner as in Example 33 (3), using 1.3 g of the product and 26 ml of a 70% ethylamine solution to obtain N- (1-ethyl-2-pyrrolidinyl, a crystal having a melting point of 126 to 127.5 ° C. 452 mg of methyl) -2-methoxy-4-chloro-5-methanesulfonamidobenzamide are obtained.

Example 35

(1) Ice-cooled a mixture of 4.33 g of tetrahydrofurfuryl amine and 11 ml of anhydrous benzene in a solution of 7.0 g of 2-methoxy-4-methyl-5-nitrobenzoyl chloride, 35 ml of methylene chloride and 7.68 g of triethylamine. It is added under stirring. The resulting mixture was left at room temperature for 20 minutes, after which water was added and shaken with methylene chloride. The organic layer is dried over sodium sulfate to distill the solvent. The residue was washed with ethyl acetate isopropyl ether and recrystallized from methylene chloride / ethyl acetate to yield 7.1 g of N-tetrahydrofurfuryl-2-methoxy-4-methyl-5-nitrobenzamide, a crystal having a melting point of 178 to 179.5 ° C. Get

8.1 g of the product is reduced by conventional methods using 810 mg of platinum oxide and 162 ml of methanol to obtain N-tetrahydrofurfuryl-2-methoxy-4-methyl-5-aminobenzamide (7.81 g) as an oil.

A mixture of 500 mg of the product, 543 mg of dimethylsulfamoyl chloride, 382 mg of triethylamine, and 10 ml of anhydrous benzene was refluxed for 18 hours. The solvent is distilled off from the reaction mixture, alkalized with 10% sodium hydroxide solution and shaken with addition of ether. The alkaline solution is acidified with 6N hydrochloric acid and shaken with addition of methylene chloride. The organic layer is dried over sodium sulfate and the solvent is distilled off to give a gelatinous product which is chromatographed on a silica gel column and eluted with 2% methylol / methylene chloride. The solvent was distilled off from the eluate, and the residue was washed with ethyl acetate isopropyl ether to form N-tetrahydrofurfuryl-2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide as a crystal having a melting point of 130 to 131 캜. Get 315 mg.

(2) The reaction was carried out in the same manner as in Example 33 (2) using 700 mg of the product, 4.2 ml of thionyl chloride, and 14 ml of chloroform to obtain N- (2,5-dichloropentyl) -2-methoxy- as an oil. 4-methyl-5-dimethylaminosulfonamidobenzamide (618 mg) is obtained.

(3) The reaction was carried out in the same manner as in Example 33 (3) using the product and 3.1 ml of a 70% etaamine solution to obtain N- (1-ethyl-2-pyrrolidinylmethyl as a crystal having a melting point of 126 to 128 ° C. ) -2-methoxy-4-methyl-5-dimethylaminosulfonamidobenzamide (305 mg) is obtained.

[Examples 36-39]

The reaction was carried out in the same manner as in Example 33 (3) using the following starting materials (II) and amines (III) to afford the corresponding product (I).

Example 40

500 mg N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl-5-methanesulfonamidobenzamide, 823 mg triethylamine, 1.17 g dimethylaminosulfonyl chloride and methylene chloride The mixture to 20 ml is refluxed for 39 hours and the reaction mixture is washed with sodium hydrogen carbonate solution. The organic layer is washed with water, dried over sodium sulfate and the solvent is distilled off. The residue is chromatographed on an alumina column and 0.5-1% methane is eluted with methylene chloride. 351 mg of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl-5- [N- (dimethylaminosulfonyl) methanesulfonamido] benzoamide as an oily substance by evaporation Get The product is mixed with 3 ml of tetrahydrofuran and 10% sodium hydroxide solution and warmed to 80 ° C. for 1 hour. Tetrahydrofuran is distilled from the reaction mixture, acidified with hydrochloric acid, alkalined again with sodium bicarbonate, salted with sodium chloride and shaken by addition of methylene chloride. The organic layer is washed with saturated brine, dried over sodium sulfate and the solvent is distilled off. The residue is chromatographed on an alumina column and eluted with 3% methanol / methylene chloride. The solvent was distilled off from the eluate and the residue was washed with ether / isopropylether and filtered to give N- (1-ethyl-2-dullolinylmethyl) -2-methoxy-4-methyl-5-dimethylaminosulfonami Obtain dobenzamide (211 mg). This product is recrystallized in acetonitrile / isopropyl ether to obtain crystals having a melting point of 129 to 129.5 ° C.

Example 41

N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-methyl-5-dimethylami

The above components are mixed and kneaded with water and granulated by a conventional method using a granulator. The granules thus obtained were hung on 20 mesh bodies to make 2000 tablets having an active ingredient content of 50 mg and a weight of 200 mg. The tablets were coated with syrup to obtain dragees.

Claims (1)

Reacting a dihalogeno compound of formula (II) with an amine of formula (III), or reacting an anilino compound of formula (IV) with a sulfonating agent of formula (V), or A process for preparing meta-sulfon amido-benzamide derivative (I) characterized by reacting a benzoic acid derivative of) with a diamino compound of formula (VII).

Wherein R is a hydrogen atom or lower alkyl, cyano or lower alkanesulfonyl group, R ¹ is lower alkyl, phenyl, amino, lower alkylamino, di (lower) alkylamino group or C ₄ -C ₅ alkylene amino group, R ² is hydrogen or halogen atom or lower alkyl, di (lower) alkylamino or lower alkoxy group, R ³ is hydrogen atom or methyl or methoxy group, R ⁴ is hydrogen or halogen atom, R ⁵ is lower alkyl, lower alkenyl, C ₃ -C ₆ cycloalkyl, benzyl or halogenobenzyl group, n is 1 or 0.