JP2826843B2 - Gastrointestinal motility enhancer - Google Patents

Description

The present invention relates to a novel gastrointestinal motility activator.

[Background of the Invention] Anorexia, nausea, vomiting, abdominal distention, upper abdominal discomfort,
One of the causes of indefinite complaints of digestive system complaints, such as heartburn, is a decrease in gastrointestinal motility. Therefore, in order to eliminate these symptoms, it is considered effective to administer a drug having a gastrointestinal motility activating effect that enhances stomach and intestinal motility.

As a drug having a gastrointestinal motility stimulating action, for example, common name metoclopramide, common name domperidone,
Although the amide compound described in 93568 is known, it cannot be said that the amide compound is always sufficiently satisfactory in terms of drug efficacy, safety and the like.

The present inventors have made intensive studies on the motility of the gastrointestinal tract, and as a result, have been found to selectively inhibit the neuroexcitatory effect of N-methyl-D-aspartate, which is a glutamate antagonist and an active substance of glutamate receptors. The present inventors have found that a substance of an antagonistic mode that can be suppressed has an excellent gastrointestinal motility activating action, and completed the present invention.

Various studies have been made on substances involved in the function of the glutamate receptor, but it is not known that these substances have any effect on gastrointestinal motility.

[Means for Solving the Problems] The present invention is characterized in that it contains, as an active ingredient, a substance that is a glutamate antagonist and that can selectively inhibit the nerve stimulating action of N-methyl-D-aspartic acid. Gastrointestinal motility activator.

The active ingredient in the present invention is a glutamate antagonist and a substance capable of selectively inhibiting the neuroexcitatory action of N-methyl-D-aspartate. (RLJo
hnson et al., Journal of Medicinal Chemistry, 1988, vol. 3
1, No. 11, p. 2057-2066 and JC Watkins, Neurotox'88:
Molecular Basis of Drug & Pesticide Action, p.445-
459). The active ingredient in the present invention may be any substance having such properties. Particularly preferred examples of the substance include 3-((±) -2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid DL-2-amino-7-phosphonoheptanoic acid, DL-2-amino-5-phosphonoheptanoic acid, D-α-aminoadipic acid, 2- (2-chlorophenyl) -2- (methylamino)
Cyclohexanone, (±) -10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, and cis-4-phosphonomethyl-2-piperidinecarboxylic acid. .

The active ingredient in the present invention may be in a free form or a pharmacologically acceptable salt thereof. Such salts include inorganic acids (eg, hydrochloric acid, sulfuric acid,
Phosphoric acid) or organic acids (eg, acetic acid, propionic acid, citric acid, tartaric acid, malic acid, oxalic acid, methanesulfonic acid)
And the like, and basic salts such as sodium salt, potassium salt, triethylamine salt and the like.

The active ingredient in the present invention is a known substance, and can be produced or obtained by a method known per se.
For example, 3-((±) -2-carboxypiperazine-4
-Yl) -propyl-1-phosphonic acid is disclosed in European Patent Application No. 159889, DL-2-amino-7-phosphonoheptanoic acid is disclosed in JP-A-58-131958, and (±) -10,11-dihydro. -5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine is disclosed in JP-A-54-63100, and
2- (2-chlorophenyl) -2- (methylamino) cyclohexanone can be obtained by the method described in U.S. Pat. No. 3,254,124. However, it is not known that these substances have a gastrointestinal motility activating effect.

The following experiment shows that the active ingredient in the present invention has an excellent gastrointestinal motility activating effect.

[Experimental method] Male Wistar rats were fasted for 24 hours and urethane (1.2 g)
/ kg, sc). The abdomen was incised along the midline to expose the stomach, a stoma was opened in the forestomach, and a small balloon was inserted. After applying a pressure load of 5 cmH ₂ O to the balloon and allowing it to stand for 15 to 30 minutes, the spontaneous movement of the stomach was measured as a change in the internal pressure of the balloon via a pressure transducer.

The drug (active ingredient) is dissolved in physiological saline and NaOH
After adjusting the pH to 7, the solution was administered through the femoral vein.

[Experimental Results] Each of the active ingredients of the present invention enhanced spontaneous movement of the stomach at a low dose. The minimum effective dose for enhancing the spontaneous movement of the stomach was as shown in Table 1 below.

A: 3-((±) -2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid B: DL-2-amino-7-phosphonoheptanoic acid C: (±) -10,11-dihydro -5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine D: 2- (2-chlorophenyl) -2- (methylamino)
Cyclohexanone The substance, which is an active ingredient of the present invention, has an excellent gastrointestinal motility stimulating action, and has intestinal dysfunction such as anorexia, nausea, vomiting, abdominal bloating, upper abdominal discomfort, heartburn, etc. It has excellent efficacy for complaints.

Further, the active ingredient of the present invention has excellent persistence of the effect, and has few side effects upon administration.

The active ingredient of the present invention can be administered as a free form or a salt thereof. Regardless of the dose, the dose of the free form is generally in the range of 0.5 mg to 500 mg / day for oral administration. The active ingredient of the present invention is administered orally or parenterally (eg, intravenous or subcutaneous injection, nasal administration, rectal administration).

The dosage form may be, for example, injections, suppositories, powders, nasal drops, pills, tablets, syrups and the like, excipients known per se, disintegrants, binders, lubricants, It can be formulated together with coating agents, substrates, etc.

 Examples will be described below.

[Example 1] Formulation example (tablet) One tablet (210 mg) contains the following components.

Active ingredient 40 mg Lactose 103 mg Starch 50 mg Magnesium stearate 2 mg Hydroxypropylcellulose 15 mg [Example 2] Formulation example (capsule) One gelatin hard capsule contains the following components (330 mg).

Active ingredient 20 mg Lactose 200 mg Starch 70 mg Polyvinylpyrrolidone 5 mg Crystalline cellulose 35 mg [Example 3] Formulation example (granules) 1 g of granules contains the following components.

Active ingredient 100mg Lactose 450mg Maize starch 400mg Hydroxypropyl cellulose 50mg

Claims (2)

(57) [Claims] 1. A gastrointestinal motility stimulant comprising, as an active ingredient, a substance that is a glutamate antagonist and that can selectively inhibit the neuroexcitatory action of N-methyl-D-aspartic acid. 2. A method according to claim 1, wherein said substance is 3-((±) -2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid.
DL-2-amino-7-phosphonoheptanoic acid, DL-2-amino-5-phosphonopentanoic acid, D-α-aminoadipic acid, 2- (2-chlorophenyl) -2- (methylamino) cyclohexanone, (±) -10,11-dihydro-5
-Methyl-5H-dibenzo [a, d] cycloheptene-5,10
The gastrointestinal motility activator according to claim 1, which is a compound selected from the group consisting of -imine and cis-4-phosphonomethyl-2-piperidinecarboxylic acid.