JPH05320046A - Antitussive - Google Patents

Abstract

PURPOSE:To provide a new antitussive having no side effects, containing, as active ingredient, a specific compound such as L-phenylalanine or a pharmaceuti cally permissible salt thereof. CONSTITUTION:This antitussive containing, as active ingredient, a compound of formula I [R is OH or sialic acid derivative group of formula II (R<1> is H or acetyl; R<2> is H or 1-6C alkyl)] or a pharmaceutically permissible salt thereof. The compound of the formula I is e.g. L-phenylalanine (where, R is OH), methyl[methyl-5-(benzyloxycarbonyl-L-phenylalanylamino)-3,5-dideoxy-be ta-D-glycero- D-galacto-2-nonylopyranoside (where, R is of formula II). This antitussive is an excellent medicine because of having no side effects such as arrhythmia, blood pressure changes, drowsiness, dizziness, nausea, constipation, hypersensitivities such as anthema, or dysuria.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel antitussive agent.

[0002]

2. Description of the Related Art Conventionally, there is codeine (codeine phosphate) which has been practically used as an antitussive. Codeine acts on the central nervous system to stop coughing. However, as side effects, arrhythmia, changes in blood pressure, sleepiness, dizziness, nausea, constipation, rashes and other hypersensitivity symptoms, and dysuria may occur.

[0003]

OBJECTS OF THE INVENTION It is therefore an object of the present invention to provide a new antitussive agent which is completely different from codeine and is expected not to have the side effects of codeine.

[0004]

DESCRIPTION OF THE INVENTION The present invention relates to an antitussive containing a phenylalanine derivative represented by the following general formula [I] as an active ingredient.

[0005]

[Chemical 3]

(Wherein R is an OH group or the following general formula [II]
The sialic acid derivative group represented by the formula (wherein R ¹ represents a hydrogen atom or an acetyl group, and R ² represents a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms). )

[0007]

[Chemical 4]

The present invention will be described in detail below. Among the compounds of general formula [I] which are active ingredients of the antitussive agent of the present invention,
The compound in which R is an OH group is L-phenylalanine. L-phenylalanine is an essential amino acid in humans and is not synthesized in the body. What is ingested from the outside is used as a material for protein synthesis in the body or is metabolized. Conventionally, it has been used as a comprehensive amino acid preparation for hypoproteinosis, undernutrition, and amino acid supplementation before and after surgery. As a method of obtaining, a method of separating from protein and a chemical synthesis method are known.

A compound in which R is a sialic acid derivative group represented by the general formula [II] is a compound disclosed in JP-A-60-231690. For example, methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D-glycero-D-galacto-2-nonulopyranoside was synthesized in Example 7. ing.

In the present invention, pharmaceutically acceptable salts of the compounds of general formula [I] are also included as active ingredients. Examples of the pharmaceutically acceptable salt include hydrochloride, mesylate, sulfonate, sulfate, organic acid salt and the like. However,
It is not limited to these.

The antitussive agent of the present invention may be administered orally or parenterally, for example, by intravenous injection, subcutaneous injection or the like in an amount of 0.1 to 500 mg by weight of the active ingredient once a day or 2 to 5 times a day. it can. However, the dose is appropriately changed in consideration of the body weight and symptoms of the patient. For the antitussive agent of the present invention, a suitable carrier can be used depending on the dosage form.

In order to prepare the compound of the present invention for oral administration, for example, an excipient, a binder, a disintegrant, a lubricant, a film-forming agent, etc. are generally used.

As the excipient, for example, glucose, starch, lactose, mannitol, sorbitol, sucrose, kaolin, dextrin, cyclodextrin, titanium oxide, anhydrous calcium phosphate, light anhydrous silicic acid, talc,
One kind or a combination of two or more kinds of natural hydrous magnesium silicate, precipitated calcium carbonate, magnesium aluminometasilicate, crystalline cellulose, calcium carboxymethylcellulose and the like can be attached.

Examples of the binder include starch, dextrin, tragacanth gum, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl starch, crystalline cellulose, pectin, polypectin. Acid, sodium polypectate, polyacrylic acid, sodium polyacrylate, polyacrylic acid copolymer, polymethacrylic acid, sodium polymethacrylate, polyhydroxyethylmethacrylate, carboxymethylcellulose, sodium carboxymethylcellulose, gum arabic, One kind or a combination of two or more kinds such as sodium alginate can be attached. .

As the disintegrant, for example, starch, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch, agar powder, mannan and the like can be attached alone or in combination of two or more.

As the lubricant, for example, talc, stearic acid, magnesium and calcium stearate, hydrogenated oil, sesame oil, paraffin, etc. may be used alone or in combination of two or more kinds. Further, as the film-forming substance, ethyl cellulose (EC), carboxymethyl ethyl cellulose (CM) as a cellulose derivative are used.
EC), cellulose acetate (CA), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), methylcellulose (MC),
Hydroxypropyl cellulose (HPC), polyvinyl acetal as a polyvinyl derivative, diethylaminoacetate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylic acid copolymer, ethyl methacrylate / methacrylic acid trimethylammonium ethyl copolymer, meta Examples thereof include dimethylaminoethyl acrylate / methyl methacrylate copolymer.

In addition, a coating aid usually used in coating the above film-forming substance, for example,
In addition to the plasticizer, addition of various kinds of adjuncts for preventing mutual adhesion of the chemicals during the coating operation can improve the properties of the film forming agent and facilitate the coating operation.

When used in the form of inhalants or injections, the following additives are generally used. Calcium chloride Potassium chloride Sodium chloride Citric acid Sodium citrate Succinic acid Acetic acid Potassium acetate Sodium acetate Tartaric acid Potassium hydroxide Sodium hydroxide Injection Water Saline Lactic acid Potassium phosphate Maleic acid Sulfuric acid Phosphate potassium phosphate Hydrogen phosphate Calcium phosphate Potassium dihydrogen Calcium hydrogen phosphate Sodium dihydrogen phosphate Sodium bisulfite Sodium bisulfite Potassium pyrosulfite Sodium pyrosulfite 1-Arginine Purified egg yolk lecithin Purified gelatin Gelatin Lactose Human serum albumin Polyethylene glycol 4500 Polyethylene glycol 1500 Polyethylene glycol 4 0 0 0 Polyethylene glycol 600 0 Polyoxyethylene hydrogenated castor oil 6 0 Sodium edetate, etc.

[0019]

EXAMPLES The present invention will be further described below with reference to examples.

Example 1 (Method) Male Hartley guinea pigs weighing 300-350 g were used for each dose of phenylalanine from 8 to 19 guinea pigs without anesthesia. Each animal was placed in an acrylic resin plethysmograph consisting of two parts, a head (1177.5 cm ³ ) and a body (1177.5 cm ³ ). The cough reflex was induced by spraying 20% citric acid or 10 ^-8 M capsaicin solution for 2 minutes with an ultrasonic nebulizer (MEP-1100, Nihon Kohden) connected to the head of the plethysmograph. The ultrasonic nebulizer output level was adjusted to 0.2 ml / min. The cough reflex is a respiratory flow meter (TUR-320) connected to the body of the plethysmograph.
(0, Nihon Kohden) was recorded as a respiration curve on a pen recorder, and at the same time, a coughing sound was confirmed by a microphone. Coughing and sneezing could be distinguished from coughing sounds and animal movements. Blinding was performed between administration and recording of cough reflex, and recording of cough reflex was performed by a trained experimenter. The cough reflex was recorded for a total of 15 minutes during spraying for 2 minutes and then for 13 minutes. And Student's t-test
The results were estimated by comparison. The pre-dose control experiment was performed 4 hours before drug administration. Prior to the experiment, the animals were fasted for 16 hours.

L-Phenylalanine (Hanui) was suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na) solution and orally administered. Codeine (Sankyo) and citric acid (Hanui) were dissolved in distilled water.

(Results) L-Phenylalanine exhibited an antitussive effect on the cough reflex caused by spraying citric acid. Figure 1 is L
-The respiratory curve shows the antitussive effect of three doses of phenylalanine. At a low dose of 1 mg / kg, L-phenylalanine reduced the number of cough reflexes in animals from 15 to 10 but did not alter cough size. The effects were more pronounced at higher doses, but the 100 mg / kg dose did not completely suppress the cough reflex. The dose-response curve of the antitussive effect of L-phenylalanine is shown in FIG. Figure 2
Among them, * and *** are significantly different from the control group to which the solvent was administered (*: P <0.005, ***: P <
0.001). The antitussive effect was dose-dependent, and the effect of 1 mg / kg was also significant as compared with the vehicle-treated control group. The typical antitussive drug codeine showed an antitussive effect of 74.4% at 20 mg / kg, and the intensity of L-phenylalanine action was comparable to that of codeine.

Example 2 (Method) Male Hartley guinea pigs having a body weight of 300 to 350 g were used in an unanesthetized state in 4 to 19 males of one group. Each animal was placed in an acrylic plethysmograph consisting of two parts, a head (1177.5 cm ³ ) and a body (1177.5 cm ³ ). The cough reflex was induced by spraying 20% citric acid for 2 minutes with an ultrasonic nebulizer (MEP-1100, Nihon Kohden) connected to the head of the bretismograph. The output level of the ultrasonic nebulizer was adjusted to 0.2 ml / min. The cough reflex is a respiratory flow meter (TUR-3200, connected to the body of the plethysmograph,
It was recorded as a breathing curve on a pen recorder via Nihon Kohden, and at the same time, a coughing sound was confirmed with a microphone. Coughing and sneezing could be distinguished from coughing sounds and animal movements.
Blinding was performed between administration and recording of cough reflex, and recording of cough reflex was performed by a trained experimenter. The cough reflex was recorded for a total of 15 minutes during spraying for 2 minutes and then for 13 minutes, and the effect was shown as the inhibition rate with the frequency of coughing before administration as 100%. And Student's t test were used to make a stochastic comparison. The pre-dose control experiment was performed 4 hours before drug administration. Prior to the experiment, the animals were fasted for 16 hours.

Methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D-glycero-D-galacto-2-nonulopyranoside and codeine were distilled water. In addition, L-phenylalanine (Hanui) was suspended in 0.5% carboxymethylcellulose sodium salt (CMC-Na) solution and orally administered, and citric acid (Hanui) was dissolved in distilled water.

(Results) Methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino)-
3,5-Dideoxy-β-D-glycero-D-galacto-2-nonulopyranoside showed an antitussive effect on the cough reflex caused by citric acid spraying. Figure 3 shows methyl (methyl-5
-(Benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D-glycero-D
Fig. 3 is a breathing curve showing a typical example of the antitussive action of galacto-2-nonulopyranoside at 30 mg / kg. Methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D
-Glycero-D-galacto-2-nonulopyranoside showed an inhibitory effect of 64% when the frequency of coughing due to citric acid before administration was 100%, and this effect was statistically significant. It was

Methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,
5-dideoxy-β-D-glycero-D-galacto-2
-Oral administration of nonuropyranoside did not change the behavior of guinea pigs, nor did it change general symptoms such as muscle tone and respiration. L-phenylanine also showed an antitussive effect on the cough reflex caused by citric acid spraying. That is, 44% at 1 mg / kg, 59% at 10 mg / kg, and 100% at 100 mg / kg
The number of occurrences of 81% cough reflex was suppressed, and both were significantly different from the control before administration. A typical antitussive drug, codeine, at 20 mg / kg suppressed the pre-dose cough frequency by 74%, which was also significant.

Thus, methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino))
-3,5-Dideoxy- [beta] -D-glycero-D-galacto-2-nonulopyranoside showed an antitussive action comparable to codeine and phenylalanine against citric acid-induced cough in conscious guinea pigs.

[0028]

The antitussive agent of the present invention has an antitussive effect comparable to that of codeine.

[Brief description of drawings]

FIG. 1 represents the antitussive effect of three doses of L-phenylalanine on a respiratory curve.

FIG. 2 shows a dose-response curve of antitussive action of L-phenylalanine.

FIG. 3: Methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D-glycero-D-galacto-2-nonulopyranoside 30 mg / A typical example of the antitussive effect by kg is shown by a respiratory curve.

Claims (3)

[Claims] 1. An antitussive containing a compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient. [Chemical 1] (In the formula, R represents an OH group or a sialic acid derivative group represented by the following general formula [II] (wherein R ¹ represents a hydrogen atom or an acetyl group, R ² represents a hydrogen atom or a carbon number of 1 to 6). Represents a lower alkyl group of).) 2. The antitussive according to claim 1, wherein the compound represented by the general formula [I] is L-phenylalanine. 3. A compound represented by the general formula [I] is methyl (methyl-5- (benzyloxycarbonyl-L-phenylalanylamino) -3,5-dideoxy-β-D-.
The antitussive according to claim 1, which is glycero-D-galacto-2-nonopyranoside.