JPH06211669A - Agent for treating abnrmal accentuation of intestinal peristalsis - Google Patents

Abstract

PURPOSE:To provide the subject medicine containing an adenosine derivative having a specific structure as an active ingredient, and exhibiting an excellent therapeutic effect on intestinal peristalsis-abnormal sthenia diseases such as acute diarrhea, sitotoxism, hypersensitive intestinal syndromes, and nervous diarrhea. CONSTITUTION:The objective medicine contains an adenosine derivative of the formula (the double bond consisting of a full line and a dashed line is single bond or double bond; Y is single bond or alkylene) or its salt as an active ingredient. The compound of the formula is usually administered at a dose of 0.001-25mg/kg twice or four times a day. The medicine is prepared e.g. by adding distilled water for injections and NaCl to the compound of formula, subjected the mixture to an aseptic filtration with a disposable membrane filter, and subsequently aseptically charged the filtrate into glass ampoules for injections.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for abnormally elevated intestinal motility.

[0002]

2. Description of the Related Art Equation (1)

[0003]

[Chemical 3]

It is known that an adenosine derivative represented by (abbreviated as compound 1 hereinafter) is a selective agonist for the adenosine A1 receptor [J. Med. Chem), 32
Vol. 8, p. 1989]. On the other hand, the formula (A)

[0005]

[Chemical 4]

It is known that an adenosine derivative represented by the formula (hereinafter abbreviated as compound A) has a therapeutic effect on gastrointestinal motility disorder (JP-A-3-145423).

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide an excellent therapeutic agent for abnormally enhanced intestinal motility.

[0008]

According to the invention, the formula (I)

[0009]

[Chemical 5]

(Where

[0011]

[Chemical 6]

Represents a single bond or a double bond, and Y represents a single bond or an alkylene) and an adenosine derivative [hereinafter abbreviated as compound (I)] or a pharmacologically acceptable salt thereof as an active ingredient. It is possible to provide a therapeutic agent containing an abnormally increased intestinal motility. Compound (I)
In the definition of, alkylene includes linear or branched C1-C4, for example, methylene, ethylene, trimethylene, tetramethylene, methylmethylene, ethylmethylene, propylene, ethylethylene and the like.

The abnormal enhancement of intestinal motility in the present invention means, for example, acute diarrhea [1. Acute infectious diarrhea (bacterial diarrhea, fungal diarrhea, protozoal diarrhea, parasitic diarrhea, or diarrhea secondary to systemic infection) 2. Acute non-infectious diarrhea [simple diarrhea, nervous diarrhea, allergic diarrhea (allergic gastroenteropathy, Henoch purpura, food), chemical food poisoning (animal,
Botanical), or diarrhea caused by drugs and heavy metals]] and chronic diarrhea {1. Chronic infectious diarrhea (bacterial diarrhea, fungal diarrhea, viral diarrhea, protozoal diarrhea, parasitic diarrhea, or diarrhea associated with systemic infection) 2. Chronic non-infectious diarrhea [organic bowel disease-induced diarrhea [ulcerative colitis, Crohn's disease, intestinal tumors (cancer, sarcoma, polyposis, malignant lymphoma,
Carcinoid tumors or colon endometriosis), colon diverticulosis, intestinal adhesions / scarring mesenteritis, or intestinal disorders caused by chemical substances / radiation], irritable bowel syndrome, neural diarrhea, malabsorption syndrome, lactate Diarrhea associated with systemic disease after decomposing enzyme deficiency, protein leaky gastroenteropathy, bowel surgery [endocrine disease (hyperthyroidism, Addison's disease, diabetes, etc.), pancreatic disease (chronic pancreatitis, pancreatic tumor, after pancreatectomy) Etc.), liver / biliary tract diseases (hepatitis, cirrhosis,
Other systemic diseases (such as common bile duct obstruction) (uremia, abetalipoproteinemia, scleroderma, amyloidosis, heart failure, intestinal lymphangiectasia, acquired immunodeficiency syndrome, carcinoid syndrome, etc.)] Diarrhea (mercury, arsenic,
Cadmium, colchicine, quinidine, etc.)]}
And so on.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The pharmacologically acceptable acid addition salt of compound (I) includes a hydrochloride salt,
Sulfates, inorganic salts such as phosphates, acetates, maleates, fumarates, tartrates, organic acid salts such as citrate, and the like, pharmacologically acceptable metal salts are sodium salts, Alkali metal salts such as potassium salts, magnesium salts,
Examples thereof include alkaline earth metal salts such as calcium salts, aluminum salts, and zinc salts. Examples of the pharmacologically acceptable ammonium salts include ammonium, salts such as tetramethylammonium, and pharmacologically acceptable organic amine addition salts. Are addition salts such as morpholine and piperidine,
Examples of pharmaceutically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.

The compound (I) can be prepared by a known method [for example, Journal of Medicinal Chemistry (J. Med.
Chem.), 28, 1636, 1985, ibid, 32, 8 198
9 years], and the obtained compound is isolated and purified by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatography. can do.

When it is desired to obtain a salt of compound (I), when compound (I) can be obtained in the form of a salt, it can be purified as it is. When it is obtained in a free form, a suitable solvent can be used. It may be dissolved or suspended in and the acid or base may be added to form a salt. Although compound (I) has stereoisomers, the present invention includes all stereoisomers and mixtures thereof.

Next, the pharmacological action of compound (I) will be described with reference to test examples. Compound 1 used in the following test examples
Journal of Medicinal Chemistry (J. Med. Chem.), 28, 1636, 1985, ibid., 32
Volume, page 8, 1989. Test Example 1 Acute toxicity test Compound 1 [(2S) -N ^6- [2-endo-norbornyl] adenosine] was intravenously administered to 5 male dd strain mice each weighing 20 ± 1 g. The mortality status 7 days after administration was observed and the 50% lethal dose (LD ₅₀ ) value was determined. The LD _{50 of} compound 1 was 5 mg / kg.

Test Example 2 Effect on Glycerol Enema-Induced Proliferative Colonic Contraction Giant migrating contractions; GM
Cs) is a large contraction that travels in the direction of the anus over a long distance in the colon and is known to be closely related to defecation and induction of defecation [Gastroenterology (Gast
roenterology), 101, 1298, 1991]. In recent years, it has become clear that it is a waveform corresponding to colonic peristalsis that is responsible for the rapid transport of colonic contents. Glycerol enema, which is clinically used to treat patients with constipation and paralytic ileus, has been found in humans for a long time to cause a large contraction of the colon (Gut, Vol. 11, p. 41, 1970). ],
It was possible to confirm the occurrence of transmissible colonic contraction by applying glycerol enema to rats (Fig. 1). Figure 1
Shows the contraction of the colon at 4, 6 and 8 cm from the anus by glycerol enema.

The effect of test compounds on transmissible colonic contractions was investigated. Wistar male rats weighing 300-400 g after fasting for one day (Japan Charles River)
Pentobarbital sodium 50 mg / kg and ketamine
After mixed anesthesia with intraperitoneal administration of 10 mg / kg, the animal was fixed on its back on a wooden table. Three catheter pressure transducers [SPC-350, Miller Instruments (Mill
ar Instrument Inc., Houston, Texas, USA)], and then inserted into the descending colon and inserted from the anus 4, 6 and
It was placed at a position of 8 cm. The signal from the transducer is the transducer control unit [tran
sducer control unit ； TCB-500, Miller Instrument Inc., Houston, Texas, U.
SA)], recorder [linear coder (linearcor
der) WR-3701, Graphtec Corp., Toky
o, Japan)] at a speed of 1 cm / min.

Glycerol enema is glycerol (65%, 2 ml / kg) preheated to 37 ° C 40 minutes after anesthesia
A polyethylene tube with a tip placed in the colon 7.5 cm from the anus [PE-50, Clay Adams (Cla Adams
y Adams, Parsippany, NJ, USA)] for 1 minute. An observation time of 30 minutes was set after the start of intracolonic injection of glycerol, and each contraction was visually analyzed.
Normal colonic contractions almost disappeared after intracolonic injection of glycerol, so that a partially transmissible large colonic contraction was easily distinguishable. It was determined whether there was a transmissible colonic contraction according to the following criteria. The sum of the product of the amplitude and duration of the three contractions propagating from the oral side to the anal side at the three measurement sites is 3000 mmHg.
For sec or more, the colonic constriction was interpreted as one transmissible large colonic contraction (GMC). Furthermore, for each contraction, it was judged whether or not it was a large contraction (giant contraction (GC)) of the colon. When the product of the amplitude and duration of a contraction was 1000 mmHg · sec or more, that contraction was recognized as a large colon contraction.

As a test compound, 10 glycerol injections
Minutes before, Compound 1 (dissolved in dimethylsulfoxide at a concentration of 10 mg / ml, then diluted with saline) and N for comparison
⁶ -Cyclohexyladenosine (Compound A; dissolved in physiological saline) was intravenously administered (1 ml / kg). On the other hand, in the control group, physiological saline was intravenously administered (1 ml / kg). The effect of the test compound on the occurrence of colonic contraction and transmissible colonic contraction was evaluated by calculating the total number of colonic contractions and the number of transmissible colonic contractions at the three measurement sites during the observation time. . The test compound administration group was 6 cases per group, and the control group was 15 cases per group. The results are shown in Figure 2. In addition, in FIG. 2, each point represents the average value ± standard error of 6 rats. The part covered by the horizontal line and the diagonal line above is
As a control, 15 in the group in which physiological saline was intravenously administered.
The mean value ± standard error using one rat is shown.

As shown in FIG. 2, compound 1 is compound A
Colonic contraction induced by glycerol enema, rather than
And significantly suppressed transmissible colonic contractions (Sheffe's multiple comparison test). Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be produced by uniformly mixing, as an active ingredient, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. These pharmaceutical compositions are preferably in unit dose form suitable for oral, injection, or rectal administration.

In preparing the composition in the oral dosage form, any useful pharmacologically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups can be prepared by using water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p. It can be produced by using antiseptics such as hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Powders, pills, capsules and tablets are excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrating agents such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl. It can be produced by using a binder such as cellulose or gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin and the like. Tablets and capsules are the most useful oral unit dosages because they are easy to administer. Solid pharmaceutical carriers are used in the production of tablets and capsules.

The injection can be prepared by using a carrier made of distilled water, salt solution, glucose solution or a mixture of salt water and glucose solution. At this time, it is prepared as a solution, suspension or dispersion using an appropriate auxiliary agent according to a conventional method. The preparation for rectal administration contains an effective amount of compound (I) as a pH adjusting agent, a pharmacologically acceptable carrier, a base, a diluent, a coloring agent, an aromatic agent, a disintegrating agent, an excipient, a softening agent, a wetting agent, And a solubilizing agent to be uniformly dispersed or dissolved in the preparation. Examples of the dosage form of the preparation include so-called rectal suppositories that are solid at room temperature, and soft capsules in which liquid or ointment-like ones are filled in capsules.

Examples of the pH adjuster to be used include those which are usually used in pharmaceutical products and which maintain the pH of the rectal fluid after administration of the formulation at 4.0 to 8.0. Succinic acid-borax, lactic acid-sodium lactate, Examples include potassium citrate-sodium hydroxide, dibasic sodium citrate-sodium hydroxide, monobasic potassium phosphate-dibasic sodium phosphate, and monobasic potassium phosphate-borax. The base used may be either a commonly used oily base or water-soluble base. As the oily base, for example, cacao butter, peanut oil, coconut oil, vegetable oils and fats such as corn oil,
Hard fat (Witepsol: manufactured by Dynamite Nobel Co., Pharmasol: manufactured by NOF CORPORATION, etc.) which is a glycerin ester of saturated fatty acid using natural fatty acid as a raw material, and mineral oil such as petrolatum and paraffin. On the other hand, examples of the water-soluble base include polyethylene glycol-polypropylene glycol copolymer, propylene glycol, glycerin and the like. These bases are used alone or in combination.

Compound (I) or a pharmaceutically acceptable salt thereof can be administered orally in the above-mentioned pharmaceutical form or parenterally as an injection or a preparation by rectal administration, and its effective dose and the number of administrations are It depends on the dosage form, age, weight and symptoms of the patient, but usually 0.01
-Administer -25 mg / kg in 3 to 4 divided doses. Hereinafter, embodiments of the present invention will be described with reference to examples.

[0027]

【Example】

Example 1 Distilled water for injection was added to 1,1 g of the compound and 16 g of sodium chloride to make a total volume of 2000 ml. This is aseptically filtered using a 0.2 μm disposable membrane filter, and aseptically filled in glass vials in 5 ml increments.
Containing 2.5 mg of active ingredient per vial). Example 2 1,40 g of compound, 286.8 g of lactose and potato starch 6
0 g was mixed, and 120 g of a 10% aqueous solution of hydroxypropyl cellulose was added. This mixture was kneaded by a conventional method, granulated, dried and then sized to give granules for tableting. To this, 1.2 g of magnesium stearate was added and mixed, and the mixture was tableted with a tableting machine (RT-15 type manufactured by Kikusui Co., Ltd.) having a punch having a diameter of 8 mm to give tablets (each tablet containing 20 mg of active ingredient. ) Got.

Example 3 Witepsol H15, 678.8 g, Witepsol E7
5,290.9 g were melted at 40-50 ° C. Compound 1,2.5 g, potassium monophosphate 13.6 g, and sodium diphosphate 14.2 g were uniformly mixed and dispersed in this. Then, the mixed and dispersed product is filled in a plastic mold and gradually cooled to rectal suppository (active ingredient per formulation).
Containing 2.5 mg).

[0029]

INDUSTRIAL APPLICABILITY The present invention provides an excellent therapeutic agent for abnormal intestinal motility enhancement.

[Brief description of drawings]

FIG. 1 shows changes in colonic motility after glycerol enema.

FIG. 2 shows the effect of test compounds on glycerol-induced and contractile colonic contractions.

Claims (1)

[Claims] 1. Formula (I): (In the formula, Represents a single bond or a double bond, and Y represents a single bond or an alkylene), and a therapeutic agent for abnormal intestinal motility, containing an adenosine derivative represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.