JP2700799B2 - Antitussive - Google Patents

Description

The present invention relates to an antitussive.

BACKGROUND OF THE INVENTION Since the discovery of opioid peptides such as methionine- and leucine-enkephalin, many analogs of these substances have been synthesized. Among them, Lippkowski et al. [“Peptides”, 3 , 6
97-700 (1982)] and a compound which can be called double-enkephalin (biphalin) represented by the above formula (1).

[Summary of the Invention] The present invention is based on the finding that this compound has an excellent antitussive effect as a result of various studies on the compound represented by the formula (1).

That is, the present invention relates to an antitussive containing a compound represented by the formula (Tyr-D-Ala-Gly-Phe-NH) ₂ ... (1) or a pharmaceutically acceptable salt thereof.

The compound of formula (1), which is an active ingredient used in the present invention, is obtained by replacing the C-terminal methionine or leucine residue of methionine- and leucine-enkephalin with a second active fragment of an enkephalin analog, and obtaining D-Ala ^2-.
Two fragments of an enkephalin analog are linked by a diamine. This compound can be produced by a known amino acid synthesis method. For example, as one of the methods, “Peptides”, 3 , 697
-700 (1982). In this method, benzyloxycarbonyl-Phe is used as a starting material.
With 4-nitrophenyl, benzyloxycarbonyl -Phe-NH-NH _2, (benzyloxycarbonyl -Phe
-NH-) ₂ , (HBr-Phe-NH-) ₂ , (tetra-butyloxycarbonyl-Tyr-D-Ala-Gly-Phe-NH-) ₂
To obtain the desired compound. Equation (1) obtained
The melting point of the hydrochloride of the compound of the formula is 176-178 ° C., ▲ [α] ²⁴ _D ▼ + 7.9 (c1, DMF), Rf (I) = 0.85, Rf
(III) = 0.72.

Examples of the pharmaceutically acceptable salt of the compound of the formula (1) include inorganic acid salts such as hydrochloride, sulfate, acetate, fumarate and maleate, and organic acid salts.

The antitussives of the present invention are prepared by mixing a compound of formula (1) or a pharmaceutically acceptable salt thereof with suitable additives.

Preferably, the antitussive is in unit dosage form and is in a form adapted to be used in the pharmaceutical field.

The antitussives of the present invention are formulated to be administered by any route, examples of which are oral, parenteral, rectal, topical and the like. Dosage forms include, for example, tablets, capsules,
In the form of vials, powders, granules, troches, powders or solutions which can be redissolved, for example solutions or suppositories.

Suitable for oral administration are conventional additives such as binders (eg syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone); fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerin). Disintegrants (eg, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose); tableting lubricants (eg, magnesium stearate) or pharmaceutically acceptable hardeners (eg, sodium lauryl sulfate)
May be included.

Solid oral dosage forms can be obtained by conventional methods such as mixing, filling, tableting and the like. By repeating the mixing operation, the compound of formula (1) or a pharmaceutically acceptable salt thereof can be distributed throughout the drug using a large amount of filler. The antitussive is, for example, in the form of a digestible capsule, for example a capsule made of gelatin, containing, if desired, carriers or other additives.

Liquid oral preparations are provided, for example, in the form of emulsions, syrups or elixirs, or as a dry product, which can be redissolved in water or other suitable vehicle before action. Such solutions may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fat; emulsifiers such as lecithin, sorbitan monooleate, polyglycerol Or gum arabic; aqueous or non-aqueous media (including edible oils) such as almond oil, fractionated coconut oil, oily esters such as glycerin or propylene glycol or ethanol, glycerin, water or normal saline; preservatives such as Methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired, conventional flavoring or coloring agents.

The antitussives of the present invention may also be administered by parenteral routes, such as subcutaneous or intravenous routes. It may be an aqueous or non-aqueous solution, suspension in a pharmaceutically acceptable liquid or a mixture of pharmaceutically acceptable liquids such as sterile and pyrogen-free water or parenterally acceptable oils. Or formulated in an injectable form in an emulsion. For liquids,
Contains bacteriostats, antioxidants or other preservatives, substances that render the buffer or solution isotonic with blood, thickeners or other pharmaceutically acceptable additives. Such forms include unit dosage forms, such as ampules or disposable injection devices or concentrates or bottles from which the appropriate dose is drawn. The antitussives of the present invention can also be formulated for rectal administration according to conventional pharmaceutical methods, for example, as suppositories.

These dosage forms can also be in a controlled release form, if desired.

The dosage of the antitussives of the invention will depend on the condition of the patient and the frequency and route of administration. And once a day or more, for example, 1
It is administered two, three or four times a day and the total daily dose for an adult is usually 2 to 300 mg, preferably 5 to 100 mg, of the active ingredient. The unit dosage contains 2 to 20 mg of the compound of formula (1) or a pharmaceutically acceptable salt thereof.

No toxicity of the antitussives of the present invention was observed during the experiments shown in the examples below.

Example Next, an example of the present invention will be described.

Example 1 Methods and Materials For the experiments, male Sprague-Dawley rats (body weight 230
380 g).

The analgesic effect was evaluated using a hot plate. That is, a rat was placed on a copper plate heated to 55 ° C., and the rats waited until they licked their footpads. The response was used as an index to measure the time delay (latency) until the onset of the reaction due to drug administration. Latency measurements were taken 30 minutes before and 15,
Performed after 30 and 60 minutes. All drugs were administered intraperitoneally. Naloxone was administered intraperitoneally 5 minutes before the administration of morphine or the hydrochloride of the compound of formula (1) (hereinafter referred to as D-Enk).

The measurement of respiration was performed as follows. Rat is α
-Anesthetized with chloralose (70 mg / kg, ip). The trachea was removed by incising the neck and a tracheal cannula was inserted into the caudal site of the incised trachea. Breathing is 1
Floor ventilation and respiratory rate were assessed by measuring with a respiratory flow meter connected to a polygraph. The drug was administered intravenously via a cannula inserted into the femoral vein.

The cough reflex was triggered as follows. Animals were fixed in a dorsal position under α-chloralose anesthesia. The cough reflex was measured by the insertion electrode method [Kamei et al., Arch. Int. Pharmacoodyn., 290 , 117-127.
(1987)]. The condition of the electrical stimulation used to elicit the cough reflex consisted of a rectangular pulse with a frequency of 40 Hz, the duration of the pulse was 1 ms, the voltage was 2-4 V, the duration of application was 10 Seconds. Rat chest movement was measured by an isometric transducer and used as an indicator of the cough reflex. The electrical stimulation for inducing the cough reflex is performed at 5 minute intervals before the administration of the drug, and after a certain cough reflex is obtained, the drug is administered, and the administration of the drug is performed 5, 10, 15, 30, 45, and 60. Made a minute later. When a cough reflex did not occur with one stimulus after drug administration, the drug was considered effective. A minimum of six animals were used for each dose of each drug. All drugs were administered intraperitoneally. Naloxone was administered intraperitoneally 5 minutes before the administration of morphine or D-Enk.

The drug was dissolved in physiological saline immediately before use using D-Enk, morphine hydrochloride, and naloxone hydrochloride.

Results 1. Effect on nociceptive threshold The average control latency in the hot plate test was 7.07 ± 0.62 seconds. Morphine and D-Enk
The nociceptive threshold after administration of is shown in FIG. D-Enk
Produced a statistically significant analgesic effect 15, 30, and 60 minutes after administration at doses of 10 and 20 mg / kg. A higher dose of D-Enk (20 mg / kg) increased the latency of the reaction 60 minutes after administration, with a control value of 177.4% before injection, the effect being 92.2 times that of that of morphine (10 mg / kg). %, And the effect when converted to a molar concentration almost doubled. D-
The analgesic effect of Enk was antagonized by pretreatment with naloxone (5 mg / kg, ip).

2.1 Effects of D-Enk and morphine on tidal volume and respiratory rate D-Enk and morphine reduced tidal volume (Vt) and respiratory rate (RF). These effects were greatest 15 minutes after administration of either drug. Therefore, changes 15 minutes after dosing were chosen to quantify the effects of D-Enk and morphine on respiration.

FIG. 2 shows the effects of D-Enk and morphine on RF. D-Enk and morphine dose-dependently reduced RF at doses of 0.1-30 mg / kg. As shown in FIG. 3, intravenous administration of D-Enk and morphine reduced Vt in a dose-dependent manner. However, the reduction in RF and Vt caused by D-Enk was significantly smaller than those caused by morphine.

3. Effect of D-Enk and morphine on cough reflex FIG. 4 shows dose response data on the effect of D-Enk and morphine (intraperitoneal administration) on cough reflex. The 50% antitussive dose of D-Enk and morphine (AtD50) (the dose required to suppress the cough reflex in 50% of the tested rats) was the first.
As shown in the table, they were 0.63 and 0.48 mg / kg, respectively.

AtD50 was determined by probit analysis of the dose response data. Naloxone was administered 5 minutes before the administration of D-Enk and morphine.

Pretreatment with naloxone translated the D-Enk and morphine dose response curves to the right (FIG. 4). D-Enk of rats pre-treated with naloxone (0.4 mg / kg, ip)
And the morphine AtD50 was 3 times higher in each case than the corresponding AtD50 in rats not receiving naloxone pretreatment.

[Effect] As is clear from the above-mentioned Examples, the antitussive of the present invention has a potent and naloxone reversible antitussive and analgesic effect. The antitussives of the present invention and morphine are active in the same range of antitussive doses and their efficacy is not significantly different. It should be noted, however, that the antitussive and analgesic potency of the antitussives of the present invention is about twice as high as their potency of equimolar amounts of morphine.

The antitussive of the present invention reduces Vt and RF in a dose-dependent manner. And the ED50 of the antitussive of the present invention with respect to the reduction of Vt (13.6 mg / kg) and RF (10.2 mg / kg) are not much different from each other. On the other hand, morphine also has dose-dependent Vt and
Reduce RF. However, morphine is more potent in lowering RF than it is in lowering Vt. RF (5.
The morphine ED50 for a 5 mg / kg reduction is Vt (1.6 mg / kg).
kg) is about 3 times higher than the ED50 for reduction.

As can be seen from the above, the antitussives of the present invention administered systemically show a much greater antitussive effect compared to morphine when both are compared in molar concentration. Moreover, the antitussives of the present invention have a significantly lower respiratory depression effect than morphine. Therefore, the antitussive of the present invention exhibits a remarkable antitussive effect with little effect on respiration.

[Brief description of the drawings]

FIG. 1 shows pain threshold values after administration of morphine and D-Enk. FIG. 2 shows the effect of intravenous administration of D-Enk and morphine on RF. FIG. 3 shows the effect of intravenous administration of D-Enk and morphine on Vt. 4th
The figure shows dose response data on the effect of D-Enk and morphine (intraperitoneal administration) on the cough reflex. In the figure, * indicates p <0.05 of the t-student test, and ** indicates p <0.01.

Claims (1)

(57) [Claims] 1. An antitussive comprising a compound of the formula (Tyr-D-Ala-Gly-Phe-NH) ₂ ... (1) or a pharmaceutically acceptable salt thereof.