JPS59186915A - Psychotropic agent of meta-(sulfonamido)benzamide - Google Patents

Abstract

PURPOSE:A pyschotropic agent containing a meta-(sulfonamido)-benzamide derivative. CONSTITUTION:A psychotropic agent usable orally or parenterally, containing a compound shown by the formula I (Et is ethyl; R is H, or alkyl; R<1> is alkyl, alkylamino, or dialkylamino; R<2> is H, halogen, or alkyl) or its salt alone or it and a carrier (e.g., wheat starch, maize starch, potato starch, gelatin, water, etc.). A dose is 1-350mg/day/person by oral medication. The compound shown by the formula I , an active ingredient, is obtained by reacting an aniline shown by the formula II with a sulfonating agent shown by the formula A-SO2R' [A is reactive group (e.g., halogen, ester residue, etc.)] in the presence or absence of an inert solvent such as methylene chloride, etc. usually at room temperature.

Description

Detailed Description of the Invention (In the formula, R is hydrogen or an alkyl group; R/ is an alkyl group, alkylamino group, or dialkylamino group; R2 represents hydrogen, a halogen, or an alkyl group, respectively;
'Ell, has the same meaning as above. ) or a pharmaceutically acceptable salt thereof.

Here are some specific examples of the terms used in the definition of target substance (1) above.

Methyl is an alkyl group. Ethyl, Provil.

Dimethylamino is a dialkylamino such as isopropyl, butyl, isobutyl, pentyl, etc.

Diethylamino, methylethy4-amino, ethylpropylamino. Examples of halogens include fluorine, chlorine, bromine, and iodine, such as methyl butylamino.

The target substance (1) is as shown in the diagram below.

Raw material anilines (II) are sulfonated (Route A) or benzoic acids or their reactive derivatives (IV
) with amines (V) (route D).

If necessary, it can be obtained by further chemical modification such as deicing (roux) B) or alkylation (route C).

(Left below) 3-96- (It)) (K-alkyl group) [In the formula, A is a reactive group (e.g., halogen, ester residue, -0502R/group), A' is hydroxy represents a group or a reactive group (eg, halogen, ester residue), and Et, R, R', and moieties have the same meanings as above. ] Route A This reaction involves adding a sulfonating agent (nl) to the raw material anilines (It).
) is reacted to form sulfonamide (1). The sulfonating agent (I[[) is a halide of a given sulfonic acid (eg, chloride, bromide).

Active esters (e.g. p-nitrophenyl ester,
benzyl ester, trityl ester) and anhydride (
For example, it contains methanesulfonic anhydride, ethanesulfonic anhydride). This reaction may be carried out by a conventional sulfonation method, and is generally carried out in the presence or absence of a suitable inert solvent (e.g. methylene chloride, benzene, tetrahydrofuran, dioxane) and, if necessary, a suitable deoxidizing agent. (e.g., organic amines such as triethylamine, pyridine, inorganic bases such as potassium carbonate, sodium bicarbonate)
Alternatively, an organic amine (such as pyridine) can be used as both a solvent and a deoxidizing agent.

Triethylamine) may be used.

The reaction temperature is usually room temperature or under cooling or heating. Generally, this reaction proceeds with good yield.

Depending on the type of solvent and deoxidizing agent used, a monosulfonated product, a disulfonated product, or a mixture of the two may be produced, but any of these products may produce a monosulfonated product, a disulfonated product, or a mixture of the two.
included in

Route B The disulfonated product of the product (I) in route A above can be hydrolyzed, if necessary, to form the monosulfonated product (Ia
) can be converted to This reaction is carried out using a conventional method using an inorganic or organic base (eg, sodium hydroxide).

Potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium methoxide, potassium ethoxide) in a suitable solvent (eg, water, methanol, ethanol, acetone, dioxane) at room temperature or under heat.

Route C 3- Compounds having active hydrogen (R-hydrogen) among the products (1) in Route A above can be alkylated to N- if necessary.
It can be converted into an alkylsulfonamide (Ib:R=alkyl group). This reaction may be carried out by a conventional method for alkylating an amino group.

Usually dialkyl sulfates (e.g. dimethyl sulfate, diethyl sulfate) or alkyl halides (e.g.

alkylating agents/alkali such as methyl iodide, ethyl bromide, propyl chloride) (e.g. sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate) and a suitable solvent (e.g. water, acetone, dioxane, tetrahydrofuran). , dimethyl sulfoxide) at room temperature or under heating.

Anilines (
II) is synthesized by the method described in Japanese Patent Publication No. Sho'l'l-23119 O.

(The following is a blank space) 6- [In the formula, A' and R2 have the same meanings as above. ]Route D This reaction is performed using benzoic acids or their reactive derivatives (IV).
and amines (V), and is carried out according to conventional methods for this type of reaction. Generally, an alkyl ester of benzoic acids or an acid halide and an amine (V) are combined, if necessary, with a suitable deoxidizing agent (eg, triethylamine, pyridine, picoline).

Sodium hydroxide, potassium carbonate) in the presence of an inert solvent (e.g., ethanol, propatool).

Dioxane, dimethylformamide, benzene.

The reaction may be carried out by heating in methylene chloride).

The benzoic acids or their reactive derivatives (IV) used as raw materials in route D can be obtained, for example, by sulfonating the corresponding aminobenzoic acids (■).

(■) (■) [In the formula, A, Et, R, R/ and R2 have the same meanings as above. ] The target substance (I) of the present invention is an inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid) for the purpose of improving formulation, crystallization, solubility or stability.

thiocyanic acid) and organic acids (e.g. acetic acid, succinic acid, oxalic acid, maleic acid, malic acid, phthalic acid).

This can lead to pharmaceutically acceptable acid addition salts such as acid addition salts such as methanesulfonic acid, citric acid, toluenesulfonic acid, tartaric acid, and the like.

The target substance (I) of the present invention contains dextrorotatory and levorotatory optical isomers, and these can be easily separated from a racemic compound by a conventional method.

Target substances 0) and their pharmaceutically acceptable acid addition salts are useful as anti-gastric ulcer agents or psychotropic agents, particularly antipsychotic agents (Major tranquilizers). for example,
N-(/-Ethylleucopyrrolidinylmethyl)-nomethoxy-gochloro-t-methanesulfonamide benzamide was effective at 0θ/vty/ky (oral administration) in an antiemetic test of apomorphine antagonism in adults. . Other target substances (I) also showed similar pharmacological effects.

Sulfonamide benzamides (1) and their pharmaceutically acceptable acid addition salts may be used alone or in combination with a pharmaceutically appropriate carrier such as wheat starch, corn starch, potato starch, gelatin, water, etc. It is used orally or parenterally.

The choice of carrier is determined by the preferred method of administration, the solubility of the material used, and standard pharmaceutical practice. Examples of dosage forms to be prepared include single tablets, capsules, pills, suspensions, syrups, powders, and solutions. These compositions can be formulated by conventional methods. For example, when used as an antipsychotic, a suitable dosage for adults of sulfonamide benzamides (I) and their pharmaceutically acceptable acid addition salts is about 3 jθmy/day when administered orally.

Examples of the present invention are shown below.

Examples/(1) 2-methoxy-t-chloro-j-nitrobenzoic acid (He1v, Chim, Acta, 4tO,
3 Otsu9 (/9j9))90θ~ and thionyl chloride 3
;tttl is refluxed for 3θ minutes and thionyl chloride is distilled off. Benzene is added to the residue and the benzene is distilled off. To the residue were added 79θq of triethylamine and 9~ of dry methylene chloride, and to this was added /-ethyl-2-
Aminomethylpyrrolidine 7jO■ and methylene chloride 4
Add dropwise 1 ml of the solution and stir for 13 minutes at room temperature. Add an aqueous sodium hydrogen carbonate solution to the reaction mixture, and extract with methylene chloride. The organic layer was washed with water, dried with Glauber's salt,
The solvent is distilled off. Add ether to the residue and extract with dilute hydrochloric acid. The aqueous layer was made alkaline with an aqueous sodium bicarbonate solution.

Extract with methylene chloride. Wash the organic layer with water, dry it,
The solvent is distilled off. The residue was recrystallized from ethyl acetate/isopropyl ether to give N-(/-ethyl-2-pyrrolidinylmethyl)-2- as crystals with a melting point of 107-/θ°C.
Methoxy-goochloro-5-nitrobenzamide 679
Obtain 1Rg.

(2) Add 733 g of the above product to a solution consisting of 3 oz of concentrated hydrochloric acid, 7 vgl and 73.3 tttl of water, and heat at 50°C.
Add tin pieces 77f and stir at 10°C for t hours. After cooling, one reaction solution was made alkaline with an aqueous sodium hydroxide solution and extracted with methylene chloride. The organic layer was washed with water, dried over Glauber's salt, and the solvent was distilled off.

The residue was subjected to chromatography on an alumina column,
Elute with methylene chloride and evaporate the solvent.

When the residue was washed with isopropyl ether/petroleum ether, N-(/-ethyl-2-pyrrolidinylmethyl)-
2-Methoxy-guchloro-J-aminobenzamide Kei 311 is obtained. When the ice crystals are recrystallized with isopropyl ether/petroleum ether.

It forms a crystal with a melting point of f3~J　5　°C.

(3) The above product 'A/f, triethylamine 2,93
g and dry methylene chloride←-l in a solution.

While cooling with water, a solution consisting of 37 g of methanesulfonyl chloride and 7.2 tttl of dry methylene chloride was added dropwise.

Remove the water bath and stir at room temperature for 4t, 5' minutes. Add sodium bicarbonate aqueous solution to the reaction solution to make it alkaline.
Extract with methylene chloride. Wash the organic layer with water.

Dry with Glauber's salt and evaporate the solvent. The residue was dissolved in ethyl acetate.
Washed with isopropyl ether, melting point /j3~/33
;”As a crystal of Cj, N-(/-ethyl-2-pyrrolidinylmethyl)-2-methoxy=7-chloro-j-N,N
-Bis(methanesulfonyl)aminobenzamide! ;1
Get 3f.

(4) The above product! A suspension consisting of 73-9 and 37.3 ml of 70% sodium hydroxide was stirred for 3θ minutes while heating to 30"C. After cooling, the reaction solution was acidified with concentrated hydrochloric acid, and then sodium bicarbonate was added. The mixture is made alkaline with an aqueous solution, saturated with 1 common salt, and extracted with methylene chloride.

Wash the organic layer with saturated saline.

Dry with Glauber's salt and distill off methylene chloride. The residue was chromatographed on an alumina column.

Elute with methylene chloride alone and 2% methanol/methylene chloride, and evaporate the solvent from the eluate.

Wash the residue with ethyl acetate/isopropyl ether,
443 g of N-(/-ethyl-2-pyrrolidinylmethyl)-2-methoxydarchloroj-methanesulfonamide benzamide are obtained. The ice crystals were recrystallized from ethyl acetate/isopropyl ether.

Melting point /2 oto /27! ; It becomes a colorless prismatic crystal of 'C.

Example 2 N-(/-ethyl-2-pyrrolidinylmethyl)-normethoxy-j-aminobenzamide 7θθ73- ■, triethylamine 102f and methylene chloride/'1
Methanesulfonyl chloride 7θq was added dropwise to the mixed solution consisting of nrl at room temperature while stirring, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, made alkaline with aqueous sodium bicarbonate solution, and extracted with methylene chloride. The organic layer was washed with water, dried over Glauber's salt, and methylene chloride was distilled off. The residue is subjected to column chromatography using alumina and eluted with methylene chloride. The solvent was distilled off from the eluate, and the residue was crystallized from ethyl acetate/isopropyl ether.
-ethyl-2-pyrrolidinylmethyl)-2-methoxy-
5-N,N-bis(methanesulfonyl)aminobenzamide! ; obtain r211Ig. The ice crystals are recrystallized from ethyl acetate to obtain crystals with a melting point of lO~/l,/°C.

The eluate was then diluted with 3% methanol/methylene chloride to give N-(/-ethyl-2-pyrrolidinylmethyl)-2-
This gives methoxy-5-methanesulfonamide benzamide. After concentrating the eluate, the residue is crystallized from ethyl acetate/isopropyl ether to give the product/fusa η. When the ice crystals are recrystallized from ethyl acetate, they become crystals with a melting point of /70 to 17/°C.

(2) N-(/-ethyl-2-pyrrolidinylmethyl)-
No methoxy, j-N, N-bis(methanesulfonyl)aminobenzamide 2? A suspension consisting of θ Misaki, 2.9 tttl of 70% aqueous sodium hydroxide solution and ml of methanol becomes a transparent solution when heated on a water bath for 5 minutes. After evaporating the solvent, ice water was added to the residue, acidified with 6N hydrochloric acid, and then made weakly alkaline by adding an aqueous sodium bicarbonate solution.

Extract with methylene chloride. The organic layer was washed with water, dried over Glauber's salt, and the solvent was distilled off. The residue was washed with ethyl acetate/isopropyl ether, and N-(/-ethyrunopyrrolidinylmethyl)-sumethoxyj-methanesulfonamide benzamide/ll! Get W. Recrystallize the ice crystals from ethyl acetate/isopropyl ether to obtain a melting point of 7θ~
/7/j°C crystal.

Example 3 N-(/-ethyl-2=pyrrolidinylmethyl)-2-methoxy-j-ethanesulfonamide benzamide λ2q, dry acetone 7ml. Mix potassium carbonate λθθq and dimethyl sulfate/θθ and reflux for 3θ minutes. Acetone was distilled off, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over Glauber's salt, and the solvent was distilled off. The residue is dissolved in methylene chloride and subjected to chromatography on an alumina column, eluting with methylene chloride. Distill methylene chloride from the eluate.

The residue was washed with isopropyl ether and then recrystallized from ethyl acetate/isopropyl ether.

N-(/-ethyl-2) as a crystal with a melting point of f3~♂7°C
-pyrrolidinylmethyl)-sumethoxy-! -(N-methylethanesulfonylamino)benzamide 77■ is obtained.

Example 4 Using the following raw material compound (II), a reaction is carried out in the same manner as in Example 1 to obtain the corresponding product (1).

77- Note) Abbreviations in the formula have the following meanings: Et (ethyl), Da (dimethylamino).

Bu (n-butyl), Me (methyl).

～/Za- F (fluorine), ■ (hydrogen), CI (chlorine) * Ice crystal hydrochloride has a melting point of 2θ2~. 203°C (decomposed).

Example / 9 (1) To a solution consisting of 2-methoxy-j-aminobenzoic acid methyl ester 3θθ~, dry methylene chloride and 36 g of triethylamine, methanesulfonyl chloride θθ■ and dry methylene chloride/g were added under water cooling. The solution was added dropwise and stirred at room temperature for 7 hours. The reaction solution was made alkaline with an aqueous solution of bicarbonate and extracted with methylene chloride. The organic layer was washed with water, dried over Glauber's salt, and methylene chloride was distilled off under reduced pressure. The residue was washed with ethyl acetate/isopropyl ether to give 2-methoxy-3-N.

N-bis(methanesulfonyl)aminobenzoic acid methyl ester 32θq is obtained. When ice crystals are recrystallized from ethyl acetate, the melting point is /Otsu9 ~ /Otsu9! ; Becomes a crystal of 'C.

(2) Add 300M4 of the above product to a mixture consisting of 3tttl of tetrahydrofuran and 3tttl of 70% sulfur hydroxide aqueous solution, and heat to 50°C for 1h/h.
Stir for a minute. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was
The mixture is acidified with hydrochloric acid, salted out by adding one common salt, and extracted with methylene chloride containing a small amount of methanol.

The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with isopropyl ether to give niemethoxy-j as crystals with a melting point of 73'C.
-Methanesulfonamidobenzoic acid/73q is obtained.

(3) A mixture consisting of the above product/3θ■ and 3 ml of thionyl chloride is heated under reflux for 3θ minutes. Thionyl chloride is distilled off under reduced pressure, dry benzene is added to the residue, and the solvent is distilled off again under reduced pressure. The residue is dissolved in dry methylene chloride.

To this solution under water cooling, a solution consisting of triethylamine (μ) and then /-ethyl-niaminomethylpyrrolidine (9θ) and dry methylene chloride/tttl was added dropwise, and the mixture was stirred at room temperature for 1S minutes. The reaction solution was made alkaline by adding an aqueous sodium bicarbonate solution, and salted out with 1 common salt.

Extract 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 was subjected to chromatography on an alumina column, and /
Elute between % methanol/methylene chloride and 2% methanol/methylene chloride.

The solvent was distilled off from the eluate, and the residue was recrystallized from ethyl acetate/isopropyl ether to give N-(/-ethyl-2-pyrrolidinylmethyl)-2-methoxy-3-methanesulfonamide benzamide/re3D. get. When the crystal is recrystallized from ethyl acetate/isopropyl ether, it becomes a crystal with a melting point of /O9 to /7θ5'C.

Example θ (1) To a solution consisting of 2-methoxy-j-aminobenzoic acid methyl ester 3θθ and 3 ml of dry pyridine, methanesulfonyl chloride 2/θ was added dropwise with stirring under water cooling, and the mixture was stirred at room temperature for 7 hours. do. The reaction solution was made acidic 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 was chromatographed on a silica gel column,
Methichloride 2% methanol/methhidimethylene chloride.

The solvent is distilled off from the eluate. The residue is recrystallized from ethyl acetate/isopropyl ether to obtain methyl methoxy-j-methanesulfonamide benzoate 3f/q as colorless prismatic crystals with a melting point of ~50C.

(2) A solution consisting of 330 μl of the above product, 2'l 3 Mf/-ethyl-niaminomethylpyrrolidine, and 7 tnl of n-furopanol was heated to reflux for 23 hours. After cooling to zero, n-propanol was distilled off under reduced pressure. The residue was dissolved in dilute hydrochloric acid, and the unreacted ester was extracted with methylene chloride. The hydrochloric acid acidic aqueous layer is made alkaline with sodium bicarbonate, salted out with 9 chloride 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 was subjected to chromatography on an alumina column, eluted with 1.2% methanol/methylene chloride, and the solvent was distilled off from the eluate. The residue was recrystallized from ethyl acetate/isopropyl ether to give a melting point of /7/~/
N-(/-22-ethyl-2-pyrrolidinylmethyl)-2-methyl-xy-methanesulfonamide benzamide/3 is obtained as colorless scales at 72°C.

Example 2 / N-(/-Ethyl-2-pyrrolidinylmethyl)-2-methoxy-glyclaw 5-methanesulfonamide A reaction was carried out as in Example 3 using benzamide and dimethyl sulfuric acid, Melting point/'10! N-(/-ethyl-2-pyrrolidinylmethyl)-2 as crystals at i~/g2°C
-Methoxy-t-relow-5-(N-methylmethanesulfonamido)benzamide is obtained.

Example 2, 2 Using 2-methoxy-3-(N-methylmethanesulfonamido)benzoic acid methyl ester, Example 2θ(2)
The reaction is carried out in the same manner as above to obtain N-(/-ethyl-neepyrrolidinylmethyl)-2-methoxy-5-(N-methylmethanesulfonamido)benzamide as crystals with a melting point of 97 to 9 g°C.

Example 23 Using niemethoxy-t-methyl-5-[(methyl)(dimethylaminosulfonyl)amino]benzoic acid methyl ester, a reaction was carried out in the same manner as in Example 2θ(2), and the melting point was 3 to . As a crystal of S'l'C, N -(/-ethyl-
2-pyrrolidinylmethyl)-,1methoxy-gumethyl-j-[(methyl)(dimethylaminosulfonyl)aminocobenzamide is obtained.

Experimental examples of the compounds of the present invention are shown below.

(Left below) 25-) Rei
h2, Test method: (a) Anti-apomorphine climbing behavior: 2 to 3 groups of DS mice of /group/θ were used.

After subcutaneously injecting avomorphine/MQ/kti, the mice were placed in a stainless steel cage (/θ×/θ×2θm) and made movements to climb the wall by grasping the cage wall mesh with their limbs. 7 hours before apomorphine administration.

The test compound was administered as a gum arabic suspension.

Observation was performed for 3 minutes starting 2θ minutes after apomorphine administration.

The standard of climbing behavior was determined by comparing with control group mice.

The results are shown as ED,,111//[Prok
ais, et al, Psychopharm
acology, ,jQ, /-Otsu.

/97 O].

(b) Acute toxicity: DSS mouse test compounds were orally administered at different doses. 1 mouse weighing 20-23 g/θ for each dose
used. Observations were made for 4 to 72 hours after administration of the test compound. The lethal dose was calculated by the Bliss method [B115
s, AnrLAppl, Biolo, 22,
/ 311-3θ7C/933); Quant,, I
Pharmacol, //, /92 (793g
)].

3. Results: According to Hiro's judgment, the compounds of the present invention (Compounds 2 and 3) exhibited higher activity in anti-apomorphine climbing behavior than the control drug sulpiride.

Patent applicant: Shionogi & Co., Ltd.

Claims (1)

[Claims] (1) A compound represented by the general formula (wherein, Et is an ethyl group, R is hydrogen or an alkyl group, R/ is an alkyl group, an alkylamino group, or a dialkylamino group, and R2 represents hydrogen, a halogen, or an alkyl group, respectively) or a psychotropic drug containing a pharmaceutically acceptable salt thereof.