WO1997010207A1

WO1997010207A1 - Novel benzamide derivatives

Info

Publication number: WO1997010207A1
Application number: PCT/JP1996/002605
Authority: WO
Inventors: Masanori Takadoi; Fumiyoshi Kobayashi; Haruo Sekiguchi
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 1995-09-12
Filing date: 1996-09-12
Publication date: 1997-03-20
Also published as: AU6944596A; JPH0977742A

Abstract

Novel benzamide derivatives represented by general formula (I) or pharmacologically acceptable acid addition salts thereof; a process for producing the same; and an enterokinesis regulator comprising the same as the active ingredient which has the action of stimulating 5-HT4 and also acts directly on the digestive tract smooth muscles.

Description

Itoda Novel benzamide derivatives Technical field

The present invention provides a benzamide derivative and a pharmacologically acceptable acid addition salt having both 5-HT stimulatory action and direct action on gastrointestinal smooth muscle, a process for producing the same, and a gastrointestinal motility regulator containing them as active ingredients. Regarding. Background technology

4-amino-5-amino-N-[(2-dethylamino)ethyl]-2-methoxybenzamide (generic name: Metoku oral pramid: see Merck Index, 10, 6019 (1983)) is Since their development in the mid-1960s as antiemetics or gastrointestinal prokinetic agents, various substituted benzamide derivatives have been developed and their pharmacological properties have been studied and clinically applied. .

On the other hand, serotonin (5-ΠΤ) receptors have recently been recognized to have multiple subtypes, 5-II Tj, 5- _ΠΤ2 , 5- _ΗΤ3 and 5- It is classified as a _ΗΤ4 receptor. Of these, 5-II _τ4 receptors _are widely distributed in the central and peripheral nervous systems, as well as in the digestive system. It is known that the liberation indirectly promotes gastrointestinal motility.

In addition to ulcers, non-ulcer gastrointestinal symptoms (abdominal bloating, abdominal pain, heavy stomach, etc.), so-called indefinite complaints, are increasing both domestically and internationally due to the aging population and various stresses. Drugs that improve these symptoms are gastrointestinal motility regulators, and the above-mentioned cisapride and trimebutine are frequently used. death However, especially in the elderly, there is also the problem of functional deterioration of the gastrointestinal wall nerves, and the current situation is that the rate of improvement is low with any of the drugs.

An object of the present invention is to provide a 5- _HT4 stimulating action and a direct action on gastrointestinal smooth muscle in consideration of the current state of gastrointestinal motility regulators that provide only insufficient clinical effects. The object of the present invention is to provide a gastrointestinal motility regulator that is highly safe and has both of these points. Invention disclosure

In view of the above problems, the inventors of Ki, as a result of extensive research, found that the benzamide derivative of the Ki invention and its acid addition salt have an excellent gastrointestinal motility regulating action. That is, according to the present invention, the general formula (I)

(In the formula, represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group and a lower acyl group; _R2 represents a lower alkoxy group and a fluorine atom; _R3 represents a hydrogen atom and a lower alkyl group; R ₄ are the same or different and represent a lower alkyl group, X is a single bond, or 0,

represents a group represented by 3, A is (CH ₂ )

m is an integer from 1 to 3, n is an integer from 0 to 2, p is an integer from 0 to 3, q is an integer from 1 to 3, r is is an integer from 0 to 2, and s is an integer from 2 to 4), or a pharmacologically acceptable acid addition salt thereof, has surprisingly excellent gastrointestinal motility control action. It was found that there is a certain thing, and it came to complete the present invention.

In the present invention, "lower alkyl" includes linear or branched C 1-6 alkyl such as methyl, ethyl, n-propyl and iso-propyl, and "lower alkoxycarbonyl" Examples include those having 1 to 4 carbon atoms such as methoxycarbonyl and ethoxycarbonyl, "lower acyl" includes those having 1 to 4 carbon atoms such as acetyl and propionyl, and "lower alcokyne" includes Linear or branched ones having 1 to 4 carbon atoms such as methoxy and ethoxy can be mentioned. Examples of "protecting group for amino group" include lower acyl groups such as acetyl and propionyl, lower alkoxycarbonyl groups such as ethoxycarbonyl and lerl-butoquincarbonyl, and benzyl groups. _"3 and _R5 together form an amino-protecting group" includes, for example, a phthaloyl group and the like. "Acid addition salts" are pharmacologically acceptable salts such as, for example, inorganic acid salts such as hydrochloric-acetic acid, sulfuric acid, and organic acid salts such as citric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, and the like. It is salt. When the compound of the present invention has an asymmetric carbon atom or an asymmetric sulfur atom, optical isomers may exist, and these optical isomers and mixtures thereof are included in the compound of the present invention. is. The compound of the present invention can be synthesized, for example, by the method shown below.

The compound of general formula (I) is a compound represented by the following general formula (111) (wherein _R2 is as described above) or a reactive derivative thereof, and the following general formula (11) (wherein _R3 , , X, A, m, n, p, q, r, and s are as described above) and the compound represented by benzene, toluene, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, triacid In an appropriate solvent such as ethyl or acetonitrile or in the absence of a solvent, if necessary, an inorganic base such as sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydride. Alternatively, it can be obtained by reacting at -20 to 150°C for 1 to 12 hours in the presence of an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or the like.

R, _C02II (ΠΙ)

The "reactive derivative" of the compound of formula C1 (111) includes, for example, lower alkyl esters, active esters, acid anhydrides, acid halides (especially acid chlorides) and the like. Specific examples of active esters include p-ditrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N —Hydroxysuccinimide Ester, N—Hydroxyphthalimide Ester, N—Hydroxyl 5_Norbornene_ 2, 3—Dicarboxyimide Ester, 8—Hydroxyquinoline Ester, 2—Hydroxyphenyl Ester, 2 — hydroxy-4,5-dichlorophenyl ester, 2-hydroxypyridine ester, 2-pyridinethiol ester and the like. Examples of acid anhydrides include symmetrical acid anhydrides and mixed acid anhydrides, and specific examples of mixed acid anhydrides include chloroethyl carbonate, isobutyl chloroethyl carbonate, and benzyl chloroethyl carbonate. Mixed acid anhydrides with cyclocarbonic acid alkyl esters or cyclocarbonic acid aralkyl esters, mixed acid anhydrides with chlorocarbonic acid aryl esters such as cyclophenylcarbonate, isovaleric acid, bivalic acid, etc. and mixed acid anhydrides with alcarboxylic acids.

For the compound of formula (111), N,N'-dicyclohexane carbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide' hydrochloride (EDCI) , N,N'—Lponyldimidazol (CDI) or the like can be reacted in the presence of a condensing agent. In this case, a reaction accelerator such as N-hydroxysuccinimide, 1-hydroxybenzotriazol, or the like may be added to cause the reaction.

In addition, compounds of general formulas (1d) and (IV) can be prepared, for example, according to the following scheme. 6

H.

(IV)

(Π') That is, the above compound (1) (wherein X, _R4 , m, π, p, and q are as described above) and the above compound (2) (wherein A is as described above and Y is (representing a leaving group) is tetrahydrofuran, 1,4-dioxane, N.N-dimethylformamide, acetonitrile, ethyl acetate, benzene, methylene chloride, chloroform, etc. In a solvent or in the absence of a solvent, if necessary, an inorganic base such as sodium bicarbonate, sodium carbonate, lithium carbonate or sodium hydride, etc. In the presence of an organic base such as amine, diisopropylethylamine, N-methylmorpholine, etc., the compound of general formula (IV) (wherein _R3 , _R4 , X, m, n, p, and q are as described above, and _R5 represents a hydrogen atom, an amino group-protecting group, or _R3 and _R5 together form an amino group. (which may form a protective group), and then with hydrazine hydrate or an inorganic acid such as hydrochloric acid or sulfuric acid in a suitable solvent such as methanol, ethanol or ethyl acetate at 0-150°C. The compound of general formula (1) (wherein _R4 , X, A, m, n, p, and q are as described above) can be synthesized by reacting for 1 to 10 hours at . Further, the compound of the general formula (1d) (wherein _R4 , X, A, m, n, p and q are as described above) was converted to the following compound (3) (wherein _R6 represents a lower alkyl group , Y represents a leaving group) and tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, ethyl acetate, benzene, methylene chloride, chloroform, etc. In a suitable solvent or in the absence of a solvent, if necessary, an inorganic base such as sodium bicarbonate, sodium carbonate, sodium carbonate or sodium hydride, triethylamine, diisopropylethyl In the presence of an organic base such as amine, N-methylmorpholine, etc.-2! ) to react at 150°C for 1 to 10 hours

(II*) (wherein R ₄ , R ₆ , X, A, m, n, p, and q are as described above) can be converted to. The "leaving group" as used herein includes, for example, halogen atoms such as fluorine, chlorine, bromine and iodine, p-toluenesulfonyloxy group, methanesulfonyloxy group and the like.

(Π' )

Alternatively, as in the scheme below, conventional reductive alkylation conditions, i.e., a compound of general formula (I) (wherein RX, A, m, n, p, and q are as described above) and an aldehyde Form (4) (wherein _R6 represents a lower alkyl group) was treated with tetrahydrofuran, 1,4-dioxane, meta In the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as ethanol or toluene at 20°C to the boiling point of the solvent for 1 to 6 hours, or ethanol or acetic acid. In a suitable solvent such as ethyl or water, in the presence of a suitable catalyst such as palladium carbon, platinum oxide, Raney nickel or the like, catalytic reduction is carried out under normal pressure to high pressure conditions for 1 to 6 hours to give the compound of general formula (I) (wherein R 4 R 6 X, A, m, n, p, and q are as described above)

(Π') In addition, compound (1) (wherein X, _R4 , m, n, p, and q are as described above) and compound (5) (wherein _R3 , A, Y is as described above) in a suitable solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, ethyl acetate, benzene, methylene chloride, chloroform, etc. In the medium or in the absence of a solvent, if necessary, an inorganic base such as sodium bicarbonate, sodium carbonate, sodium carbonate, or sodium hydride, triethylamine, or diisopropionate is added. In the presence of an organic base such as piruetylamine or Ν-methylmorpholine, the compound of general formula (11) (wherein R, , R ₄ , X, A, m, n, p , q are as described above) can be synthesized.

(1)

Further, as shown below, the compound of general formula (1d) (wherein R ₄ , X, A, m, n, P, and q are as described above) is compound (1) (wherein X, , m, n , p and q are as described above) and compound (6) (wherein A and Y are as described above) were mixed with tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetonitrile in a suitable solvent such as ethyl acetate, benzene, methylene chloride, chloroform or the like, or in the absence of a solvent, if necessary sodium bicarbonate, sodium carbonate, sodium carbonate or sodium hydride. In the presence of an inorganic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, or another organic base, the compound (7) (In the formula, R, α, X, m, n, p, and q are as described above), and then in a suitable solvent such as ethanol, ethyl acetate, water, etc., a suitable solvent such as palladium carbon, platinum oxide, Raney nickel, etc. In the presence of a catalyst, catalytic reduction under normal pressure to high pressure conditions, or lithium aluminum hydride, a borane complex (e.g., borane It can also be synthesized by reacting for 1 to 10 hours at 0°C to the boiling point of the solvent in the presence of a reducing agent such as a monohydrofuran complex. ,

Furthermore, a compound of the general formula (IV) [wherein R ₃ , R ₄ , R ₅ , m, n, p, and q are as described above, and X′ represents X (excluding single brackets)] Objects can also be synthesized as follows.

(CH - Z

': .

HX—(CH[OR,)

2'P

(Ten)

Y- (CHJ 0RJ

(11) R. That is, first, compound (2) (formula A is as described above, Y represents a leaving group) is converted to compound (8) (wherein Z represents ΟΙΪ, _IIR3 , _C02H ) and a suitable solvent such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, ethyl acetate, benzene, methylene chloride and chloroform, or in the absence of a solvent, If necessary, inorganic bases such as sodium bicarbonate, sodium carbonate, sodium carbonate or sodium hydride, triethylamine, diisopropylethylamine, N-methylmorphol. In the presence of organic base such as Reaction conditions (for example, if X' is an ester bond, normal esterification conditions are used; if X' is an ether bond, normal etherification conditions are used; if X' is an amide bond, normal esterification conditions are used; are amidation conditions) to react with compound (10) or compound (11) to obtain general formula (IV) (wherein RJ, _R4 , _R5 , X', m, π , ρ, and q are as described above).

The terms "usually esterified" and "usually amidated" as used herein refer, for example, to a compound represented by (10) (wherein R ₄ , X', p and q are as described above). benzene, toluene, diethyl ether, tetrahydrofuran, Ν, Ν— in a suitable solvent such as dimethylformamide, methylene chloride, chloroform, ethyl acetate, acetonitrile, or in the absence of a solvent, if necessary sodium bicarbonate or sodium carbonate, In the presence of an inorganic base such as lithium carbonate or sodium hydride, or an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc. Means to react for ~12 hours. Examples of the "reactive derivative" of compound (10) include lower alkyl esters, active esters, acid anhydrides, acid halides (especially acid chlorides) and the like. Specific examples of active esters include p-ditrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide N-Hydroxyphthalimide Ester, N-Hydroquino-5-Norbornene-2,3-Dicarboximide Ester, 8-Hydroxyquinoline Ester, 2-Hydroxyphenyl Ester, 2-Hydroxy -4,5-dichlorophenyl ester, 2-hydroxypyridine ester, 2-pyridinethiol ester and the like. Examples of acid anhydrides include symmetrical acid anhydrides and mixed acid anhydrides, and specific examples of mixed acid anhydrides include chloroethyl carbonate, chloroisobutyl carbonate, chlorobenzyl carbonate Mixed acid anhydrides with chloroalkyl alkyl esters or aralkyl carboxylic acid esters such as cyclophenyl carbonate, mixed acid anhydrides with cyclophenyl carbonates such as phenyl phenyl carbonate, isovaleric acid, Mixed acid anhydrides with alkanoic acids such as bivalic acid can be mentioned.

In the case of compound (10), N,N'--dimclohekinylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N , N'--Carbonyldimidazole (CDI) or the like can be reacted in the presence of a condensing agent. In this case, reaction accelerators such as N-hydroxysuccinimide and 1-hydroxybenzotriazol may be added for reaction.

In addition, "ordinary etherification conditions" are, for example, compound (9) (formula ι|ιΛ, Z, m, n are as described above) and compound (11) (in formula 1^, Y, P and q are as described above), benzene, toluene, diethyl ether in a suitable solvent such as tel, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, acetonitrile, or in the absence of a solvent, if necessary, sodium bicarbonate, sodium carbonate, sodium carbonate or hydrogen. In the presence of an inorganic base such as sodium chloride, etc., or an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, etc., the reaction rate is 1-12 at -20-150°C. Some of the compounds of general formula (1) are known, and are described in J. Med. Chem., 14 (4), 357 (1971). Chem. Pharm. Bull. , 42 (3), 541 (1994), French patent Π50341, JP-A-6-Π0626, JP-A-6-211839, JP-A-60-, JP-A-H9- J. Med. Chem., 11 (5), 1034 (1968), etc.

Also, the Υ force

0

When m is 2, n is 1, and p is 0, it can be synthesized, for example, according to the following production method. That is, the compound (12) (in the formula, R ₄ and q are as described above) prepared according to JP-A-60-58981, etc. is treated with palladium in a solvent such as ethanol, ethyl acetate, or water. In the presence of a suitable catalyst such as monocarbon, platinum oxide, rhodium-alumina, Raney-nickel, etc., catalytic reduction can be performed under normal pressure to high pressure conditions to convert to compound (1') (in the formula, R and q are as described above). .

Alternatively, compounds of general formula (I) can be synthesized by the route shown below.

That is, first, a compound represented by the general formula (111) (wherein R _} and R are as described above) or a reactive derivative thereof and a compound (13) (wherein A is as described above, _R8 , Rg represents a protective group for the aldehyde group) is converted to amide (14) according to the usual amidation method. The acetyl group is then treated with or without a suitable solvent such as benzene, toluene, diethyl ether, tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, acetonitrile, methanol or ethanol. In a solvent, an acid such as hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, or another catalyst is used to form an aldehyde (15). This was reacted with compound (1) under normal reductive alkylation conditions, i.e., sodium borohydride, sodium cyanoborohydride, in a solvent such as tetrahydrofuran, 1.4-dioxane, methanol, or toluene. In the presence of a reducing agent such as lithium, the reaction is carried out at 20°C to the boiling point of the solvent for 1 to 6 hours, or in a suitable solvent such as ethanol, ethyl acetate, water, etc., palladium-on-carbon, platinum oxide, rhodium. - In the presence of a suitable catalyst such as alumina or Raney nickel, catalytic reduction under normal pressure to high pressure conditions can be reacted for 1 to 6 hours to give the compound of general formula (I). As used herein, the term "protecting group for aldehyde group" includes, for example, cyclic or non-cyclic acetaryl, cyclic or non-cyclic dithioacetyl, and the like. HN Next, the compound of general formula (111) (wherein R ₂ is as described above) can be prepared according to, for example, ed. Chera.. 34 (2). 616 (1991). In this case, a compound in which R _t is a hydrogen atom and R ₂ is a fluorine atom is a novel compound.

The compound of general formula (I) produced by the above production method is isolated and purified by a common purification method such as chromatography, recrystallization, and reprecipitation. The compound of general formula (I) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, reaction conditions, treatment conditions, and the like. Acid addition salts can be converted to the free bases by conventional methods, for example, by treatment with a base such as alkali carbonate, alkali hydroxide. On the other hand, a pharmaceutically acceptable acid addition salt is required, and the free base can be treated with an inorganic acid such as hydrochloric acid or an organic acid such as succinic acid in accordance with a conventional method to obtain an acid addition salt. can lead to Best Mode for Carrying Out the Invention

The present invention will be described in more detail below by describing examples of the compound of the present invention.

(Example 1)

4-amino 5-chloro 2-methoxy-N-[2-[4-(3,4,5-trimethoxybenzyloquine)-1-piperidyl]ethyl]benzamide

300 ml Nascor 1-(2-phthaloylethyl)-4-(3,4,5-trimethyloxybenzyloxy) piperidine 6.34 g (13.95 mmol) was dissolved in 200 ml of ethanol solution. About 1 OmI of drazine monohydrate was added and incubated at room temperature for 3 hours. The reaction mixture was filtered by suction, the filtrate was concentrated under reduced pressure, 150 ml of dilute aqueous sodium hydroxide solution was added, and the mixture was extracted five times with 31 of methylene chloride. After the organic matter was combined and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 4.57 g of 1-(2-aminoethyl)-4-(3,4,5-trimethoxybenzyloxy). Piperidine was obtained. 300 ml of 3 neck Kolben widths of 4-amino-5-chloro-2-methoxybenzoic acid 2.84 g (H. lmraol) of methylene chloride 10 Om! To the suspension, 1.96 ml (1 eq.) of triethylamine and then 1.35 ml (1 eq.) of ethyl chloroformate were added dropwise under an argon atmosphere at 0°C, and the mixture was stirred for 30 minutes. Under the same conditions, a solution of 4.57 g (13.95 mmol) of 1-(2-aminoethyl)-4-(3,4,5-trimethoxybenzyloxy)piperidine in 50 ml of methylene chloride was added. was added dropwise, flushed with argon and left overnight at room temperature. The reaction mixture was washed with saturated brine (150 ml), the aqueous layer was extracted with 20 nil of methylene chloride three times, the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized twice to obtain the 1st crystal of the title compound.

I. Obtained 68 g (24% yield). The mother liquor was also distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (alumina, ethyl acetate, then vinegar). Purified with ethyl acetate: ethanol = 20:1) and recrystallized to obtain 1.95 g of the second crystal (yield 28%).

No. 1- B yak - nip. U3-U4 °C (Hexane-ethyl acetate) Colorless powdery crystal Elemental analysis (%) as C o ₅ H ₃₄ C 1 N 0 ₆

Calculated value; C: 59.11 II: 6.75 N: 8.27

Actual value; C: 58.84 H: 6, 81 N: 8.42

No. 2

_B mp. U2 _~ 134 °C (Hexanemonoethyl acetate) _Colorless powder crystallite Elemental analysis (%) As _C25H34C1N306

Calculated value; C: 59.11 H: 6.75 N: 8.27

Actual value; C: 59.21 H: 6.45 N: 8.01

Similarly, Examples 2 to 58 were synthesized as shown in Tables 1 to 7.

substitution position

»Replacement BR

[Table 2]

[Table 7]

(Example 59)

1 — (2—phthaloylethyl) - 4 — ( 3. 4, 5 — trimethylbenzyloxy) piperidine

To a solution of 7.01 g (24.92 mmol) of 4-(3.4,5-trimethyloxybenzyloxy)piperidine in 150 ml of acetonitrile, N-( 2-Phromoethyl)phthalimide 5.07 g (0.8 eq.) and potassium carbonate 3.45 g (1 eq.) were added, and the mixture was heated under reflux for 8 hours. The reaction solution was returned to room temperature, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, ethyl acetate) to give a yellow oil: 1-(2-phthaloylethyl)-4 of IX. 7.27 g (64% yield) of -(3,4,5-trimethoxybenzyloxy)piperidine were obtained.

lH-NMR (90MHz, CDC1,); 1.41-2.38 (611, m) 2.62 (211, 6.6) 2.51-3.08 (211, m) 3.23 - 3.59 (1H, m) 3.82, 3.86 (911 + 211, s) 4.45 (211, s) 6.56 (211, s) 1.59 - 7.95 (4 H, m)

A compound of general formula (IV) was synthesized in the same manner.

Some examples of Ψ are given below.

anonymity

] ¾8 2 7

— Yaichi

" -X_ (C

Substitution ho 9]

Parentheses indicate corresponding Examples 1-57

Test method

O 5 - H τ ^ stimulus m

Male Wistar rats _weighing 20 (!~500 g) were used _. (°C), and the outer muscle layer was peeled off and suspended on a Magnus apparatus.The initial tension was set to 0.5 g, and the contractile force was recorded isometrically. Clomipramine 3×1 (Γ ⁷ μ, pargyline 1 Γ ⁵ μ) was mixed in. The relaxant effect of the wave detection drug was expressed in the state of contraction with carbachol ^10-6 μ.

The EC ₅₀ (M) was calculated by averaging the 2 cases and performing linear regression at 2 points between 50% of the dose-response curve.

Reference: J. Reeves et al., Br. J. Pharmacol.. 103. !067 (1991). , GS Baxter et al., Naunyn-Schmi edeberg's Arch,

Pharmacol., 3U_439 (1991).

〇Direct action on gastrointestinal smooth muscle

Hartley male guinea pigs weighing 300-800 g were used. Stomachs excised from the abdomen of guinea pigs were transferred to modified Krebs solution passed through 95% _02-5 % _C02 , and the gastric antrum was cut into strips in the direction of the circular muscle and suspended in the Magnus apparatus. . Locomotor activity was recorded isometrically with an initial tension of 0.5 g.

The effect was calculated by averaging 2 subjects, expressed as the maximum rate of increase in frequency after addition of the drug to active movement in %. Experiments were performed in the presence (32°C) of atopopin (3 x ¹⁰⁰ M) and tetrodotoxin ( ¹⁰⁰ M), excluding cholinergic and nervous system-mediated responses.

(Reference: Hideyuki Takenaga et al., Journal of the Japanese Pharmaceutical Industry, 1, 163 (1982).)

Table 10 shows some of the test results of Examples.

[Table 10]

5-HT ₄ stimulation JT1 muscle direct action

Example

E C n (M) Maximum rate of increase in frequency

16.5x 10" ^R 53% (10-"M)

^28.6x10-729 % (10" ^7M )

19 2.1 x ^10-7 24% (10" ^7M )

22 2.4 ^10-7 53% (10-"M) Industrial benefits ίίΐ field

As described above, the novel benzamide derivative according to the present invention can provide a gastrointestinal motility regulator excellent in improving non-ulcer gastrointestinal symptoms.

Claims

The scope of the claims

1. General formula (I)

(In the formula, represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group and a lower acyl group; _R2 represents a lower alkoxy group and a fluorine atom; _R3 represents a hydrogen atom and a lower alkyl group; R ₄ are the same or different and represent a lower alkyl group, and X is a single bond, or

represents a group represented by A is one (CII ₂ ) _s

m is an integer from 1 to 3, n is an integer from 0 to 2, p is an integer from 0 to 3, q is an integer from 1 to 3, r is is an integer from 0 to 2, and s is an integer from 2 to 4) and acid addition salts thereof. 3

no.os=

,

2. General formula

(In the formula, R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ is the same or different and represents a lower alkyl group, X is a single bond, or

,0, represents a group represented by, A is - (CH ₂ )

m is an integer from 1 to 3, n is an integer from 0 to 2, P is an integer from 0 to 3, q is an integer from 1 to 3, r is is an integer from 0 to 2, and s is an integer from 2 to 4) and the compound represented by the general formula (111)

C1 (In the formula, represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group and a lower acyl group, and _R2 represents a lower alkoxy group and a fluorine atom)

General formula (I), HN (I) characterized by reacting a compound represented by or a reactive derivative thereof in an appropriate solvent

(In the formula, R _t represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, or a lower acyl group, R ₂ represents a lower alkoxy group, or a fluorine atom, and R ₃ represents a hydrogen atom or a lower alkyl group. 4 are the same or different and represent a lower alkyl group, X is a single bracket, or

,0,

represents a group represented by, A is one (CH ₂ )

m is an integer from 1 to 3, n is an integer from 0 to 2, P is an integer from 0 to 3, q is an integer from 1 to 3, r is is an integer from 0 to 2, and s is an integer from 2 to 4). 33

3. —General Formula (IV)

(In the formula, _R3 represents a hydrogen atom or a lower alkyl group, _R5 represents a hydrogen atom or a protective group for an amino group, or _R3 and _Rr together form an amino group. may form a protecting group, R ₄ is the same or different and represents a lower alkyl group, X is a single bond, or

represents a group represented by, α is one (CH ₂ )

πι is an integer from 1 to 3, n is an integer from 0 to 2, P is an integer from 0 to 3, q is an integer from 1 to 3, r is is an integer from 0 to 2, and s is an integer from 2 to 4) and acid addition salts thereof.

4. 4-Amino 5-Chloro-2-Methyl-N-[2-[2-(3,4,5-Trimethoxybenzoyloxymethyl)-1-Piperidyl]ethyl ] The compound according to claim 1, which is benzamide, and acid addition salts thereof.

5. 4—Amino 5—Black 2—Methoxy-N— [2— [4—

The compound according to claim 1, which is (3,4,5-trimethoxybenzyloxy)-1-piperidyl]ethyl]benzamide and its acid addition salts.

6. General formula (I)

(I) R

(In the formula, Ri represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, or a lower acyl group, _R2 represents a lower alkoxy group, or a fluorine atom, and _R3 represents a hydrogen atom, or a lower alkyl group. , are the same or different and represent a lower alkyl group, and X is a single bracket, or

(o) _r R. 0 0 R. O o

II ^ΓO

,0,

, people 0 N: 0

V'

0R

3 represents a group represented by ^R 3 ^R 3 , and A is -(CH ₂ ) _s -

m is an integer from 1 to 3, n is an integer from 0 to 2, p is an integer from 0 to 3, q is an integer from 1 to 3, r is an integer from 0 to 2, and s is an integer from 2 to 4). Tumor regulator.