JP3242975B2 - Gastrointestinal motility improver - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the application of the following compounds, which are novel benzamide derivatives, for use as gastrointestinal motility function improving agents.

Embedded image

[0002]

2. Description of the Related Art Benzamide derivatives are known as drugs for improving digestive system functions. For example, the common name metoclopramide has been used for many years as a drug that promotes gastric motility, promotes gastric emptying, exerts excellent effects on gastric hypoactivity, and improves its motility and permeability. I have. However, since the drug is a drug having an effect on the central nervous system, it may cause abnormalities in the secretory function of the diencephalon or cause side effects of extrapyramidal symptoms, so it is not necessarily a preferred drug. . In addition, a gastrointestinal motility activation regulator called cisapride is known. Although the side effect of this drug is reduced because its action point is neuroperipheral, there is still room for improvement such as the appearance of extrapyramidal symptoms even with this drug. The emergence of a drug that has good absorption from the gastrointestinal tract and has a small effect on the central nervous system is desired, and the search for that purpose is being conducted by trial and error.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have provided a medical agent which has no or very weak effect on the central nervous system and can improve the motor function of the stomach. What we are trying to do is

Embedded image Or an acid addition salt as an active ingredient.

[0004]

The agent for improving gastrointestinal motility of the present invention is prepared as follows. That is, the expression

Embedded image There are various preparations containing a compound represented by the formula or an acid addition salt thereof as an active ingredient, and the compound represented by the above formula or an acid addition salt thereof is mixed orally with a excipient, a binder, a lubricant, a flavoring agent, and the like. This can be achieved by preparing an appropriate formulation (eg, tablet, capsule, granule, fine granule, etc.). Adjusting the dosage form suitable for administration can be seen in many other cases, but even in the present invention, injections, syrups, etc. are adjusted in addition to the above formulation examples. Of course, it can be done. Here, the compound represented by the formula (I) is a novel compound created by the present inventors, and this compound is produced as follows. Compound represented by formula (III)

[0005]

Embedded image Or a reactive derivative thereof and a compound represented by the formula (IV)

Embedded image Are appropriately reacted in a solvent. Here, the compound represented by the formula (III) and the compound represented by the formula (I)
When directly reacting with the compound represented by V), the reaction is preferably carried out while removing generated water to the outside of the system or proceeding in the presence of a condensing agent, and the condensing agent used is dicyclohexyl. Carbodiimide is preferably used.

When the reactive derivative of the compound represented by the formula (III) is used, the reactive derivative means a compound obtained by converting a carboxyl group into an active acylating agent, and includes an acid halide, N-benzoylimidazole. And mixed acid anhydrides with carbonic acid monoesters, active esters, Woodward reagents and the like. The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, but preferably, tetrahydrofuran, dioxane,
Pyridine, triethylamine, acetonitrile, chloroform and the like are used.

When the reaction is carried out using an acid halide as a reactive derivative of the compound represented by the formula (III), the reaction proceeds by coexisting a tertiary amine such as pyridine, triethylamine and dimethylaniline. It will be good. Since the compound used for the present invention has two asymmetric carbon atoms on the pyrrolidine ring, there are a total of four isomers having different configurations, For this purpose, compounds having the configuration of formula (II) are preferred. When the compound represented by the formula (II) is synthesized by a reaction between the compound represented by the formula (III) and the compound represented by the formula (V), the synthesis reaction is performed by the formula (IV) instead of the formula (IV). Compounds represented by V)

Embedded image Is the same as the method for synthesizing the compound of the formula (I) described above, except that Since the compound used in the present invention contains a nitrogen atom, it naturally forms an addition salt with various acids, but is used without any problem if it is pharmaceutically acceptable. Hydrochloride, hydroiodide, carbonate, methanesulfonate, lactate, succinate, citrate and the like. In order to achieve the object of the present invention, various pharmaceutical products containing the compound represented by the formula (II) as an active ingredient are considered, for example, tablets,
They are shaped in relation to the administration method such as capsules, fine granules, granules, injections, syrups and the like.

Tablets are prepared by adding a compound represented by the formula (II) or a salt thereof, which is a main drug, to an excipient (eg, lactose, glucose,
Starch, microcrystalline cellulose, etc.) and, if necessary, further mixed with disintegrants (eg, starch, carboxymethylcellulose calcium, etc.) and lubricants (eg, magnesium stearate, purified talc, calcium stearate, etc.) A binder (for example, starch paste, hydroxypropylcellulose solution, carboxymethylcellulose solution, gum arabic, gelatin solution, etc.) is added to produce granules having a binding force, and the granules are compressed into tablets. Capsules are prepared using the active ingredient of formula (I)
A compound represented by I) or a salt thereof was evenly mixed with the excipient and other additives, or the mixture was granulated by an appropriate method, or the granulated product was coated with a coating agent using a coating agent. It is then made by filling into capsules made of gelatin. In addition, a pharmaceutical dosage form suitable for the administration route is produced in accordance with the provisions of the Pharmacopoeia General Rules for Preparations. Where the content of the drug in these formulations is related to the total drug dose per day,
The dose is preferably 0.5 to 10 mg / single dose. The number of administrations may be adjusted depending on symptoms, administration period, individual sensitivity to the main drug, and the like, but is generally administered 1 to 3 times a day.

[0009] The effect of the present invention for improving gastrointestinal tract function was confirmed as follows. Example 1 Gastric emptying stimulatory action A predetermined amount of a compound (base) represented by the formula (II) was suspended in a 0.5% aqueous solution of methylcellulose and orally administered to a mouse (body weight: about 20 g). Thirty minutes later, 0.1 ml of a 1.5% carboxymethylcellulose aqueous solution containing 0.05% phenol red was orally administered. 15 minutes later,
The stomach was excised, the amount of phenol red remaining in the stomach was measured, the remaining rate was determined, and the excretion rate was determined by 100-residual rate. As a control, only a 0.5% aqueous solution of methylcellulose (0.1 ml) was administered, and then the same treatment as in the test group was performed for comparison. The results are shown in "Table 1".

[Table 1]

[0010] The known compounds metoclopramide and cisapride were evaluated for their stomach excretion-promoting activity in the same manner as above. The results are shown in "Table 2".

[Table 2] Example 2 Example 1 was performed using the hydrochloride of the compound represented by the formula (II).
The effect of the compound hydrochloride on the stomach excretion motility was examined in the same manner as described above. The results are shown in "Table 3".

Example 3 Antiemetic Action Using a dog (having a body weight of about 10 kg), a prescribed amount of a test compound (base) represented by the formula (II) was packed in a gelatin capsule in a drug-administered group. After oral administration, apomorphine was dissolved in physiological saline 30 minutes later (1 mg / c
c) This was injected subcutaneously at 0.1 mg / kg. The time until the beginning of vomiting (latency) was measured, and the time during which vomiting continued (duration) was measured. The number of vomiting during the duration was also counted. The control, in which apomorphine was administered without administration of the test compound, was used as a control, and the latency, duration, and number of vomiting in this control were defined as 100, and the change in the drug administration group was expressed as a percentage. It was used as an indicator of effectiveness. The results are shown in "Table 4".

Example 4 Acute toxicity SD strain male (weight 120-140 g), female (weight 110-140 g)
130 g) was used in each group of 10 animals per group, and the dose (mg / kg) was 2000, 1600, 1280, 10 mg / kg.
The hydrochloride of the compound represented by the formula (II) is dissolved in a concentration of 10 w / v% (using distilled water) in five steps of 24,819, and the sonde is adjusted to a predetermined dose. performs gavage into the stomach using, and observed over 14 days after administration to count the number of deaths, than the number of cumulative deaths were calculated LD ₅₀ value at probit (probit) method.
(Note that given the confidence limits of 95%.) _{LD 50} values: male rats ··· 1341mg / kg (95% confidence limits 1205-1491mg / kg) confidence limits female rats ··· 1335mg / kg (95% 1209-1472 mg / kg).

Example 5 Preparation of tablet a) 50 g of the compound obtained in Reference Example 1, 650 g of lactose, and 200 g of crystalline cellulose were weighed and placed in a fluidized bed granulator, and 30 g of hydroxypropylcellulose binder was added.
% Aqueous solution and sprayed to obtain granulated powder. Next, 50 g of disintegrant calcium carboxymethyl cellulose and 20 g of magnesium stearate were added to the previously obtained granulated powder and mixed. The obtained granulated powder for tableting was subjected to pressure molding so that one tablet weighed 100 mg to obtain a tablet. Separately, using the uncoated tablets obtained in the above procedure, 48 g of hydroxypropyl methylcellulose and
0 g of talc, 1.8 g of talc, 3 g of titanium oxide, and 550 cc of purified water were coated with a film coating solution until the weight of one tablet reached 105 mg to obtain a film-coated tablet.

Example 6 Preparation of Tablet 50 g of the compound obtained in Reference Example 1, 250 g of lactose, 187 g of crystalline cellulose, 0.5 g of light anhydrous silicic acid, 5 g of magnesium stearate and 7.5 g of talc were weighed and mixed.
Using a capsule filling machine, Japan Pharmaceutical Capsule (No. 3) is filled with 100 mg of powder per capsule.

Reference Example 1 Synthesis of compound used in the present invention 4-amino-5-chloro-2-methoxybenzoic acid
0 g was suspended in 300 ml of chloroform, and the suspension was cooled with water (2
20 g of (S, 4S) -4-amino-N-ethyl-2-hydroxymethylpyrrolidine was dissolved in 20 ml of chloroform and added dropwise. After stirring for 30 minutes, 1-hydroxy-
2.12 g of 1H-benzotriazole-hydrate was added,
A solution prepared by dissolving 30 g of DCC in 30 ml of chloroform was added dropwise. The mixture was stirred for 14 hours while cooling with water, and DCU precipitated.
After filtration, the chloroform layer was washed with water and diluted hydrochloric acid was added.
The obtained aqueous layer was washed with chloroform and neutralized by adding potassium carbonate. Chloroform was added for extraction, and the chloroform layer was washed with water, dried and concentrated under reduced pressure. 60 ml of acetone was added to the residue, the mixture was cooled with ice water, and the precipitated crystals were collected by filtration.
Recrystallization from acetone gave (2'S, 4'S) -4-amino-5-chloro-2-methoxy-N- (N'-ethyl-
2'-Hydroxymethylpyrrolidin-4'-yl) benzamidase (base) was obtained.

Yield 26.3 g mp 113-114
C. When this product was recrystallized with ethyl acetate and methyl ethyl ketone, its mp was 137-138.degree. NMR spectrum (CDCl ₃ ) δ (TMS, pp
m): 1.05 (3H, t) 1.4 to 3.8 (10
H) 3.83 (3H, s) 4.2-4.8 (3H)
6.27 (1H, s) 8.07 (1H, s) 8.1
7 (1H, d) [α) D ²⁰ = −28.39 ° (C = 1 MeOH) HCl gas was blown in isopropyl alcohol to obtain a hydrochloride of the compound. The water content of the compound hydrochloride changes due to hygroscopicity or a change in the outside air humidity. As an example, the compound hydrochloride was dried with warm air (at 60 ° C. overnight) and stored for 24 hours in a desiccator adjusted to a relative humidity of 75%, and the water content was measured by the Karl Fischer method. However, 4.
It showed a water content of 00%. mp 168-169 ° C. [α] D ²⁰ = 11.3 ° (C = 1, H ₂ O)

REFERENCE EXAMPLE 2 Synthesis of raw materials for compound used in the present invention (1) 4-hydroxy-L-proline, [α] D ²⁰ =
To a mixture of −76.5 ° (C = 2.5, H ₂ O) 100 g and ethanol 380 ml, 109 g of thionyl chloride was dropped. The reaction was carried out under reflux for 4 hours, cooled, and the precipitated crystals were collected by filtration to obtain (2S, 4R) -2-ethoxycarbonyl-4-hydroxypyrrolidine hydrochloride. Obtained amount 143.8 g mp 153.5-154 ° C. [α] D ²⁰ = −29.85 ° (C = 1.0, H ₂ O) NMR (DMSO-d ₆ ) δ (TMS, ppm): 1.
25 (3H, t) 1.9 to 2.4 (2H) 2.8 to
4.7 (4H) 4.23 (2H, q)

(2) 10.0 g of (2S, 4R) -2-ethoxycarbonyl-4-hydroxypyrrolidine hydrochloride,
9.46 g of diethyl sulfuric acid was added to a mixture of 15.5 g of anhydrous potassium carbonate and 50 ml of chloroform. 40 ℃
After cooling for 4 hours, the reaction solution was washed with water, diluted hydrochloric acid was added, the aqueous layer was taken out, and the aqueous layer was neutralized by adding potassium carbonate. Extract with chloroform, wash the chloroform layer with water,
After drying, the filtrate was concentrated under reduced pressure to obtain an oil of (2S, 4R) -2-ethoxycarbonyl-N-ethyl-4-hydroxypyrrolidine. 8.15 g [α) D ²⁰ = −70.80 ° (C = 1.06, MeO
H) NMR (CDCl ₃ ) δ (TMS, ppm): 1.07
(3H, t) 1.27 (3H, t) 1.9 to 3.1
(5H) 3.1-3.7 (3H) 4.16 (2H,
q) 4.2-4.7 (1H)

(3) (2S, 4R) -2-ethoxycarbonyl-N-ethyl-4-hydroxypyrrolidine 2.5
g, triethylamine 1.76 g, chloroform 10 m
1.84 g of mesyl chloride was added to the mixture (1), and the mixture was stirred for 2 hours. The reaction mixture was poured into ice water and extracted with chloroform. The chloroform layer was washed with sodium bicarbonate water, washed with water, dried and concentrated under reduced pressure to obtain an oily substance of (2S, 4R) -2-ethoxycarbonyl-N-ethyl-4-methanesulfonyloxypyrrolidine. Yield 3.64 g [α) D ²⁰ = −39.92 ° (C = 1.06, MeO
_{H) NMR (CDCl 3) δ} (TMS, ppm): 1.10
(3H, t) 1.30 (3H, t) 2.1-3.1
(5H) 3.03 (3H, s) 3.3 to 3.8 (2
H) 4.20 (2H, q) 5.26 (1H)

(4) A mixture of 3.5 g of (2S, 4R) -2-ethoxycarbonyl-N-ethyl-4-methanesulfonyloxypyrrolidine, 1.54 g of sodium diazotide and 10 ml of dimethylformamide was stirred at 90 ° C. for 4 hours. did. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene-acetic acid ethyl ester as an eluent to obtain an oily substance of (2S, 4R) -4-azido-2-ethoxycarbonyl-N-ethylpyrrolidine. Yield 2.05 g [α) D ²⁰ = −64.70 ° (C = 1.04, MeO
_{H) NMR (CDCl 3) δ} (TMS, ppm): 1.10
(3H, t) 1.28 (3H, t) 1.8-3.5
(7H) 3.7-4.4 (1H) 4.23 (2H,
q)

(5) 0.41 g of lithium aluminum hydride is suspended in 10 ml of tetrahydrofuran,
Under cooling, 1.9 g of (2S, 4S) -4-azido-2-ethoxycarbonyl-N-ethylpyrrolidine was dissolved in 4 ml of tetrahydrofuran, and the solution was dropped. After stirring at the same temperature for 1 hour, the temperature was raised to room temperature and stirred for 2 hours. A mixture of 1 ml of 1N caustic soda and 9 ml of tetrahydrofuran was added,
After decomposing the lithium aluminum hydride, insolubles were collected by filtration, and the filtrate was concentrated under reduced pressure to give (2S, 4S) -4-
Amino-N-ethyl-2-hydroxymethylpyrrolidine was obtained. Obtained amount 1.05 g [α] D ²⁰ = −76.79 ° (C = 1.03, MeO
_{H) NMR (CDCl 3) δ} (TMS, ppm): 1.10
(3H, t) 1.0 to 3.2 (10H) 3.2 to
3.9 (3H)

[Table 3]

[Table 4]

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Hiromichi Fujiwara 5-41 Senmon, Itami-shi, Itami Plant, Teikoku Chemical Industry Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/40 C07D 207/14 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] (1) Formula (1) Or a gastrointestinal motility improving agent comprising an acid addition salt thereof as an active ingredient. 2. A compound of the formula Or a gastrointestinal motility improving agent comprising an acid addition salt thereof as an active ingredient. 3. A compound of the formula A drug which comprises a compound represented by the formula (1) as an active ingredient and is used as a drug for improving digestive tract function. 4. A compound of the formula An emetic suppressant comprising a compound represented by the formula (I) or an acid addition salt thereof as an active ingredient.