JP2007008815A - Therapeutic agent for respiratory disease comprising n-(benzoyl)amino acid derivative as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a highly safe and excellent prophylactic and/or therapeutic agent for respiratory diseases having excellent antitussive effects with slight adverse effects, especially an antitussive. <P>SOLUTION: The prophylactic and/or therapeutic agent for the respiratory diseases are characterized as comprising a compound represented by formula (I) äwherein, Z is a -C(CH<SB>3</SB>)<SB>2</SB>- or a -CH(CH(CH<SB>3</SB>)<SB>2</SB>)-; n is 0-2; R<SP>1</SP>is a 1-4C alkyl, a hydroxy, a trifluoromethyl or an acetoxy; and R<SP>2</SP>is an H or a 1-4C alkyl} or a pharmaceutically acceptable salt thereof as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a prophylactic and / or therapeutic agent for respiratory diseases comprising an N- (benzoyl) amino acid derivative or an optically active isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, In particular, it relates to antitussives. The present invention also relates to a screening method for a cough suppressant, characterized by using a guinea pig administered with thiorphan before inhaling citric acid in a citric acid-induced guinea pig cough model.

The respiratory organ is a collective term for organs and tissues related to respiration, and plays an important role for life support by taking in necessary oxygen and discharging carbon dioxide generated as a result of substance metabolism.
Among the respiratory diseases, typical diseases exhibiting cough symptoms include, for example, lung cancer, cancerous lymphangiopathy, rib fracture, spontaneous pneumothorax, cold syndrome, pulmonary tuberculosis, interstitial pneumonia, pleurisy, pneumonia, acute bronchitis, chronic Examples include bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, and pulmonary infarction.

Cough refers to a phenomenon in which the lungs are expanded by deep inspiration, the larynx is closed, then the intrapulmonary pressure is increased by strong contraction of the respiratory muscles, the laryngeal muscles are suddenly relaxed, the larynx opens, and air is rapidly called. At this time, secretions in the respiratory tract are exhaled. If secretions or foreign bodies accumulate in the airway mucosa, or there is an abnormality in the pleura, lungs, diaphragm, etc., the stimulus from there reaches the cough center behind the medulla and causes cough attacks reflexively (the latest medicine) Science, 10.3 Antitussives, Sumiko Fujino, 1990, Kodansha).
The main causes of cough are excessive secretion from the airway mucosa, chemical irritation such as smoke and gas, foreign body, respiratory tract inflammation, allergic reaction, bronchial compression due to intrathoracic tumor, psychogenicity and the like. This worsening and chronicity of cough symptoms consumes respiratory muscle energy, exhausts physical strength, and prevents recovery of the underlying disease.

  Antitussive drugs include central antitussive drugs that exert an antitussive action by blocking the cough center and peripheral antitussive drugs that exert an antitussive action by reducing stimulation of peripheral cough receptors. Central antitussives such as codeine phosphate are generally sharp, but side effects include respiratory depression, constipation, nausea, vomiting, headache, sleepiness, and rash. It is also known that tolerance and dependence are caused by repeated use. Peripheral antitussives such as methylephedrine can only exert mild antitussive action. In recent years, antagonists selective for opioid δ receptors appear to be developed as antitussives, but δ receptors have been suggested to be deeply involved in mental and emotional behavior, and there are concerns about side effects (Nature. Genet. 25, 2, 195, 2000). Therefore, there is a need for antitussives that are more effective and have fewer side effects.

As prior art, Patent Document 1 discloses an amide derivative useful as a therapeutic agent for neuroretinal degenerative diseases. In addition, Patent Document 2 discloses that 2-methyl-N- (4-trifluoromethylbenzoyl) alanine was produced as a synthetic intermediate of a novel acylamino-substituted acylanilide derivative useful as an antiandrogen. . Moreover, it is known from patent document 3 that N-benzoyl-2-methylalanine was manufactured as a synthetic intermediate of an anticonvulsant. In addition, Reinaud et al. Reported that N-4-methylbenzoyl-2-methylalanine was produced as an intermediate in the conversion reaction from a benzoic acid derivative to a salicylic acid derivative. Are known. Patent Document 4 discloses a salicylamide derivative having an analgesic action. However, these prior arts do not disclose any preventive and / or therapeutic agents for respiratory diseases or antitussives. Also,
There are no reports of successful development of these compounds as pharmaceuticals.

  In drug development, not only intended pharmacological activity but also long-term safety is required. Furthermore, it is required to satisfy strict criteria in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, digestive tract absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction of drug metabolizing enzymes, excretion route and clearance in the body Various studies are required in the application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies these. Drugs with a wider safety margin and better pharmacokinetic properties are desired.

In recent years, the proarrhythmic action by pharmaceuticals, particularly the QT interval prolonging action in the electrocardiogram, has attracted attention. As an evaluation method for predicting the QT interval prolonging effect, a method of examining the effect on a HERG (human ether-a-go-go related gene) channel is known. Finding drugs that have no effect on the HERG current, which is recognized for its importance in cardiac side effects, is one of the important issues in drug development.
There is always a comprehensive problem in the development of these drugs for respiratory diseases. And for respiratory disease drugs, such as antitussive drugs, in addition to the above-mentioned central antitussive drugs, peripheral antitussive drugs or antagonists selective for opioid δ receptors, etc. There is a need for antitussives that are both low and highly useful.
In addition, in the method for screening cough suppressants, the cough induction model that has been used for the conventional evaluation, for example, 1) requires 3 inhalations of citric acid, and the test period is as long as 2 to 3 weeks. Desensitization may occur due to inhalation of citric acid, and the number of coughs in the control group may be significantly reduced. 2) There is a large variation among animals with coughing, and animals with sufficient coughing are selected in advance. It is generally known that there is a need to purchase a large number of animals. Therefore, there are many cases in which a test with good reproducibility and sensitivity cannot be performed. Performing a stable pharmacological evaluation with high reproducibility and sensitivity in a short period is one of the important issues in drug development (Non-patent Document 2).

International Publication No. WO99 / 21543 International Publication No. WO 98/22432 UK publication GB752692 French Open FR M2137 International Publication WO01 / 001983 International Publication WO00 / 53225 Synthesis 612-614, 1990 Journal of Japanese Pharmacology, 120, 237-243, 2002

An object of the present invention is to provide an excellent preventive and / or therapeutic agent for respiratory diseases, particularly an antitussive agent, which has an excellent antitussive action and has few side effects. In particular, the above-mentioned problems in the prior art, more specifically, side effects such as respiratory depression, constipation, nausea, vomiting, headache, drowsiness, rash, etc. possessed by central antitussive drugs or tolerance and dependence due to repeated use Drugs that can be administered to mammals including humans who have overcome at least one of the side effects related to mental and emotional behaviors that are concerned about antagonists selective for opioid δ receptors, especially respiratory organs It is to provide a preventive and / or therapeutic agent for diseases, especially an antitussive agent.
In addition, the problem of the present invention is to provide a screening method for a cough suppressant that can be pharmacologically evaluated with high reproducibility and sensitivity in a short period of time, without causing variations in desensitization and coughing by inhalation of citric acid. Is to provide.

In order to solve the above-described problems, the present inventors have conducted extensive research to obtain a drug having an excellent antitussive action and high safety. As a result, the specific N represented by the formula (I) -(Benzoyl) amino acid derivatives and optically active isomers thereof, and pharmaceutically acceptable salts thereof have (1) an antitussive action in a citric acid-induced guinea pig cough model, and (2) safety with few side effects. It has been found that it has one or more features such as high, (3) no HERG channel inhibitory action, and (4) good pharmacokinetic properties.
In addition, by using a citric acid-induced guinea pig cough model in which thiorphan was administered before citric acid inhalation, a single inhalation of citric acid can generate sufficient cough in all guinea pigs, and reproducibility and sensitivity in a short period of time. The inventors have found that pharmacological evaluation is possible and completed the present invention.

（式中、Ｚは、−Ｃ（ＣＨ₃）₂−、または−ＣＨ（ＣＨ（ＣＨ₃）₂）−を表し；
ｎは、０〜２の整数を表し；
Ｒ¹は、Ｃ１−４アルキル基、ヒドロキシル基、トリフルオロメチル基またはアセトキシ基を表し、ｎが２である場合には、Ｒ¹は同一であっても異なっていても良く；
Ｒ²は、水素原子またはＣ１−４アルキル基を表す。） The first aspect of the present invention comprises a compound represented by the following formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Is a preventive and / or therapeutic agent for respiratory diseases.

(Wherein Z represents —C (CH ₃ ) ₂ — or —CH (CH (CH ₃ ) ₂ ) —);
n represents an integer of 0 to 2;
R ¹ represents a C 1-4 alkyl group, a hydroxyl group, a trifluoromethyl group or an acetoxy group, and when n is 2, R ¹ may be the same or different;
R ² represents a hydrogen atom or a C1-4 alkyl group. )

R ¹ in the formula (I) is preferably a methyl group, a hydroxyl group, a trifluoromethyl group or an acetoxy group, and more preferably a methyl group, a hydroxyl group or a trifluoromethyl group. The substitution position of R ¹ is expressed with the carbon atom of the benzene ring to which —CONH— is bonded as the 1-position. A compound of n = 0 is preferable, and when n = 1, the 4-position is preferable, and when n = 2, the 2-position, the 3-position, the 2-position, the 4-position, the 2-position, the 5-position, the 2-position, Position, 6th position, 3rd position and 4th position, 3rd position and 5th position, 3rd position and 6th position, and the like.
R ² in the formula (I) is preferably a hydrogen atom.
Z in the formula (I) is preferably —C (CH ₃ ) ₂ —.

Preferable examples of the compound represented by the formula (I), optically active isomers thereof, pharmaceutically acceptable salts thereof, and solvates thereof include the following.
N- (4-acetoxybenzoyl) -2-methylalanine ethyl ester, pharmaceutically acceptable salt thereof, and solvates thereof;
N- (4-hydroxybenzoyl) -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- (4-acetoxybenzoyl) -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- [3,5-bis (trifluoromethyl) benzoyl] -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- [4- (trifluoromethyl) benzoyl] -D-valine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- [4- (trifluoromethyl) benzoyl] -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N-benzoyl-2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- (p-toluoyl) -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;
N- [3,5-bis (trifluoromethyl) benzoyl] -valine, pharmaceutically acceptable salts thereof, and solvates thereof.

The second aspect of the present invention contains the compound represented by the formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. An antitussive agent characterized by
The third aspect of the present invention contains the compound represented by the formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Is an agent for improving dry cough.
In the second and third aspects, preferred substituents in the compound represented by the above formula (I), or a combination thereof, is the same as in the first aspect.

According to a fourth aspect of the present invention, there is provided a method for screening a cough suppressant, characterized by using a guinea pig administered with thiorphan before inhaling citric acid in a citric acid-induced guinea pig cough model. Specific steps in this embodiment include
(1) A step of administering thiorphan to a guinea pig,
(2) a step of administering a test substance to a guinea pig;
(3) Inhaling citric acid to induce cough,
(4) a step of observing and measuring the number of occurrences of cough reaction,
(5) a step of determining the cough suppression rate of the test substance,
Is mentioned.
The animal used in the screening method of the present invention is not limited to any animal species as long as it can observe cough, but is preferably a guinea pig.

In the present invention, thiorphan represents N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] glycine. The administration route of thiorphan is not particularly limited, but intraperitoneal administration is preferable. The timing of thiorphan administration is not particularly limited as long as it is before inhalation of citric acid used for cough induction, but it is preferably within 30 minutes before inhalation of citric acid.
The test substance is administered before inhalation of citric acid, and the timing can be appropriately set depending on the administration route, the kinetics of the substance, and the like. It is preferable to administer the test substance within about 1 hour before citric acid administration.
For cough reaction, the peak detected by plethysmograph and what is audibly judged as cough can be measured, and the inhibition rate of the test compound against the citric acid-induced cough reaction can be determined by the following equation.
[(A−B) / (A)] × 100 (%)
A: Number of cough reactions occurring in the control group B: Number of cough reactions occurring in the test compound administration group

In the present invention, the “C1-4 alkyl group” means an alkyl group having 1 to 4 carbon atoms, which may be a straight chain structure or a branched structure, and may be a methyl group, an ethyl group, a propyl group. Group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, and the like. A methyl group or an ethyl group is preferable, and a methyl group is more preferable.

The compound represented by the formula (I) used in the present invention may form a salt with a base. Examples of such bases are not particularly limited as long as they are pharmaceutically acceptable salts. Specifically, metal bases such as sodium, potassium, magnesium, calcium, and aluminum, methylamine, ethylamine, and ethanolamine , Salts with organic bases such as pyridine, lysine, arginine, ornithine, ammonium salts and the like.
These salts can be obtained by a conventional method, for example, by mixing a solution containing an equivalent amount of the compound of the present invention and the desired base, and collecting the desired salt by filtration or distilling off the solvent.
In addition, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol. The compound of the present invention or a salt thereof includes these solvates.

The compound of the present invention may be crystalline or amorphous. That is, the compound represented by the formula (I) of the present invention, or an optically active form thereof, or a salt thereof, or a solvate thereof includes a crystalline form, an amorphous form, and an embodiment thereof. Further, this crystal includes a crystal polymorph.
The present invention also includes crystal polymorphs of the compound of formula (I) or a salt thereof, or a solvate thereof.
The compound represented by the formula (I) may have an asymmetric carbon, and various mixtures such as all optically active isomers (enantiomers, etc.) and isolated substances may exist. All of these are included. Such isolation and purification of optical isomers can be achieved through optical resolution or asymmetric synthesis using preferential crystallization or column chromatography.

[Production method]
Next, the manufacturing method of the compound of this invention is demonstrated. The compound represented by the formula (I) in the present invention can be produced by using the method described in Japanese Patent Application No. 2003-292918 or a method analogous thereto.
For example, an amino acid derivative represented by the formula (II) corresponding to the right part of the formula (I): H ₂ NZ-COOR ² or a salt thereof, and a benzoic acid derivative corresponding to the left part, for example, A compound of the formula (I) can be obtained by condensing by a method generally used in amide synthesis or peptide synthesis to form an amide bond to obtain a compound in which both are bonded, and if necessary, converting a substituent. it can.

[Experimental example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.

Experimental Example 1-1 [Inhibitory effect on citric acid-induced guinea pig cough model]
A guinea pig fasted overnight is fixed to a plethysmograph, and changes in the internal pressure of the plethysmograph (guinea pig body side) are measured with a differential pressure transducer (Nihon Kohden, TP-602T) and a respiratory amplifier (Nihon Kohden, AR- 601G), the cough reaction can be recorded on ink-written recording paper (Nihon Kohden, WI-642G), and a 20 W / V% aqueous citric acid solution is used with a nebulizer (OMRON, NE-U12). (Head side) was sprayed for 2 minutes (about 1 mL / min), and the number of cough reactions of guinea pigs was observed and measured for 15 minutes from the start of spraying.
The cough reaction was measured 3 hours before and 1 hour after oral administration of the test compound. In addition, administration was not performed to an individual whose cough reaction was observed 5 times or less as measured before administration. And the cough reaction expression ratio (Post / Pre * 100) before and behind administration was computed, and the suppression rate (C1) with respect to the cough reflex induced by the citric acid of a test compound was calculated | required by following Formula.

Y1 = [(CRRcontrol−CRRtest) / (CRRcontrol)] × 100 (%)
CRRcontrol: Cough reaction expression ratio of control group (%)
CRRtest: Test compound administration group cough response expression ratio (%)

Vehicle was used as a control, and the compound of Example 9 was used as the test compound. The results are shown in Table 1.

薬物投与群の咳嗽反応発現比をDunnettによる多重比較検定法により溶媒投与群の咳嗽反応発現比と比較し、統計的有意差を＊：ｐ＜０．０５，＊＊：ｐ＜０．０１，＊＊＊：ｐ＜０．００１で表した。

以上により、実施例９に代表される本発明化合物は、経口投与によりクエン酸誘発による咳嗽を抑制することが認められた。同時に、一般症状に何ら異常が認められなかったことから、本発明化合物の低い毒性が示された。

The cough response expression ratio of the drug administration group was compared with the cough reaction expression ratio of the solvent administration group by a multiple comparison test by Dunnett, and statistical significance was calculated as *: p <0.05, **: p <0.01, ***: Expressed as p <0.001.

From the above, it was confirmed that the compound of the present invention represented by Example 9 suppresses citric acid-induced cough by oral administration. At the same time, no abnormality was observed in general symptoms, indicating that the compound of the present invention had low toxicity.

Experimental Example 1-2 [Inhibitory effect on citric acid-induced guinea pig cough model]
Thiorphan was intraperitoneally administered to a guinea pig fasted overnight at a dose of 1 mg / kg, and 30 minutes later, the guinea pig was fixed to a plethysmograph, and changes in the internal pressure of the plethysmograph (body side) were measured using a differential pressure transducer (Nippon Koden). Nasal inhalation exposure device for small animals (Inc., TP-602T) and a recording amplifier (Nihon Koden Kogyo, WR7200) capable of recording cough reaction through a respiration amplifier (Nihon Koden Kogyo, AR-601G). M.I.P.S) was used to spray a 0.9 mol / L citric acid aqueous solution into the plethysmograph (head side) for 20 minutes, and the number of cough reactions occurring during the 20 minutes of spraying was observed and measured. The cough reaction was measured by a peak detected by a plethysmograph and an auditory judgment of cough. The test compound was orally administered 30 minutes before inhalation of citric acid. The inhibition rate (Y2) of the test compound against the citric acid-induced cough reaction was determined by the following equation.

Y2 = [(A−B) / (A)] × 100 (%)
A: Number of cough reactions occurring in the control group
B: Number of cough reactions occurring in the test compound administration group

The results are shown in Table 2.

薬物投与群の咳嗽反応発現比をDunnettによる多重比較検定法により溶媒投与群の咳嗽反応発現比と比較し、統計的有意差を＊：ｐ＜０．０５，＊＊：ｐ＜０．０１，＊＊＊：ｐ＜０．００１で表した。

以上により、実施例２に代表される本発明化合物は、経口投与によりクエン酸誘発による咳嗽の抑制が認められた。また、実施例７及び実施例８の化合物も咳嗽反応を抑制した。同時に、一般症状に何ら異常が認められなかったことから、本発明化合物の低い毒性が示された。

The cough response expression ratio of the drug administration group was compared with the cough reaction expression ratio of the solvent administration group by a multiple comparison test by Dunnett, and statistical significance was calculated as *: p <0.05, **: p <0.01, ***: Expressed as p <0.001.

As described above, the present compound represented by Example 2 was found to suppress cough induced by citric acid by oral administration. In addition, the compounds of Example 7 and Example 8 also suppressed the cough reaction. At the same time, no abnormality was observed in general symptoms, indicating that the compound of the present invention had low toxicity.

Experimental Example 2 [Toxicity test]
When the compounds of Example 2, Example 4, Example 5 and Example 6 were orally administered to 6-week-old Wistar Hannover female rats at a dose of 1000 mg / kg, no abnormalities were observed in general symptoms and death occurred. There were no cases.
Six-week-old Wistar Hannover female rats were orally administered by gavage once daily for 14 days at doses of 250, 500 and 1000 mg / kg / day of the compounds of Example 2, Example 4, Example 5 and Example 6. As a result, none of the doses died until 24 hours after the end of the last administration, and no abnormalities were observed in general symptom observation, body weight and food intake measurement. No toxic findings were observed in hematology, blood biochemistry, major organ weights, and pathologic composition.

Experimental Example 3 [Influence on HERG K ⁺ Channel]
Patch clamp (patch-) using Example 2 (300 μmol / L), Example 5 (300 μmol / L) and Example 6 (100 μmol / L) using the CHO-K1 / HREG cell line at the indicated concentrations, respectively. As a result of examination by the clamp) method, inhibition against the HERG K ⁺ channel was not observed.

Experimental Example 4 [Pharmacokinetics]
Plasma after oral single administration of the compounds of Example 2, Example 4, Example 5 and Example 6 using 8-week-old Wistar Hanover female rats and 2- or 3-year-old male beagle dogs When the transition of the concentration was examined, the bioavailability of all the compounds was good. In addition, none of the compounds showed an inhibitory effect on human drug-metabolizing enzymes. Therefore, drug interaction is unlikely to occur. Furthermore, it was difficult to undergo metabolism in human, monkey, dog and rat liver microsomes. Therefore, it is considered difficult to undergo metabolism in the liver.

From the above experimental results, it was confirmed that the compound of the present invention has an inhibitory effect in a citric acid-induced guinea pig cough model. Further, since no abnormality was observed in the toxicity test, the compound of the present invention was judged to have extremely low toxicity. In addition, the compound of the present invention did not show an inhibitory effect on the HERG channel. The compounds of the present invention were also shown to have good pharmacokinetic properties.
Therefore, the compound of the present invention can be expected as an excellent antitussive agent because it has an excellent antitussive effect in an animal cough model and has high safety and good pharmacokinetic properties.
In addition, the screening method of the present invention uses a citric acid-induced guinea pig cough model in which thiorphan is administered prior to inhalation of citric acid, so that the desensitization phenomenon caused by multiple inhalations of citric acid and the variation in the occurrence of cough due to animals among animals. Since all coughs can be stably generated by a single inhalation of citric acid, there is no need to select animals that cough in advance, and pharmacology is highly reproducible and sensitive in 3 days. Since evaluation is possible, it can be expected as an animal model for evaluating cough suppressant substances.

  The compound of the present invention has the following respiratory diseases for the purpose of antitussive effect, such as lung cancer, cancerous lymphangiopathy, rib fracture, spontaneous pneumothorax, cold syndrome, pulmonary tuberculosis, interstitial pneumonia, pleurisy, pneumonia, acute bronchitis, Can be used for chronic bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, pulmonary infarction, etc. In these respiratory diseases, the worsening and chronicity of cough symptoms consumes energy of respiratory muscles, exhausts physical strength and prevents recovery of the underlying diseases. It is possible to promote treatment. Therefore, the compound of the present invention can be used as a preventive and / or therapeutic agent for respiratory diseases. However, it can be applied to similar pathologies and symptoms without being limited thereto.

  Cough is classified into wet cough and dry cough. A wet cough is a cough that occurs because increased secretions in the respiratory tract irritate the respiratory tract and produce sputum. In addition, dry cough is a cough caused by airway hypersensitivity without sputum, and it is also called “empty cough” because it shows concon and dry cough. The compound used in the present invention is effective for any cough, but when used particularly for dry cough, the symptoms can be improved and the respiratory diseases can be treated.

The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive. More specifically, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbox Methyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer) LD), plasticizers (eg triethyl citrate, macrogol), masking agents (eg titanium oxide), colorants, flavoring agents, preservatives (eg benzalkonium chloride, paraoxybenzoate esters), isotonic. Agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH regulators (eg, buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilization Agent (eg, sugar, sugar al) Coal, xanthan gum), dispersants, antioxidants (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffers, preservatives (eg; parabens, benzyl alcohol, benzal chloride) Luconium), fragrance (eg, vanillin, l-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancer (E.g., sodium glycolate, sodium edetate, sodium caprate, acylcarnitines, limonene), gelling agents, suspending agents or emulsifiers, commonly used suitable additives or solvents Various dosage forms can be obtained by appropriately combining with the compounds of the invention. That.

Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir. Oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
When the compound of the present invention is administered as a powder inhaler, it is desirable to use it by refining into particles of 10 μm or less. In miniaturization, it can be obtained by pulverization using a commonly used apparatus, for example, a dry pulverizer such as a jet mill, a roller mill, a high-speed rotation mill, a container drive medium mill, a medium agitation mill. Specific examples include a jet mill, a hammer mill, a pin mill, a turbo mill, a supermicron mill, a rolling ball mill, a vibrating ball mill, a planetary mill, and a centrifugal fluidizing mill. Carriers for powder inhalants include monosaccharides such as mannitol, arabinose, xylitol and dextrose and their monohydrates, disaccharides such as lactose, maltose and sucrose, and many such as starch, dextrin or dextran. Examples include sugars.
The dose of the compound of the present invention is usually 0.05 mg to 30.0 g, preferably 0.5 mg to 25 g, more preferably 1 mg to 15 g per day for an adult, but can be appropriately increased or decreased depending on symptoms or administration route.
The total amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously, such as intravenous infusion.

Examples are given below to describe the present invention in more detail, but the present invention is not limited thereto. Production examples and physical properties of these Example compounds are described in Japanese Patent Application No. 2003-292918. In the following, Ac represents an acetyl group, and Et represents an ethyl group.
Any of the compounds shown in Examples 1 to 9 could be formulated into a required dosage form by a conventional formulation method, and good results were obtained as shown in the above test examples. The compound form is omitted and only the compound is shown.

ｍ．ｐ．：１０１．２〜１０２．２℃
［実施例２］Ｎ−（４−ヒドロキシベンゾイル）−２−メチルアラニン

ｍ．ｐ．：２２５．８〜２２７．９℃ [Example 1] N- (4-acetoxybenzoyl) -2-methylalanine ethyl ester

m. p. : 101.2-102.2 ° C
[Example 2] N- (4-hydroxybenzoyl) -2-methylalanine

m. p. : 225.8 to 227.9 ° C

ｍ．ｐ．：１７１．０〜１７３．８℃
［実施例４］Ｎ−［３，５−ビス（トリフルオロメチル）ベンゾイル］−２−メチルアラニン

ｍ．ｐ．：１８０．４〜１８４．７℃ [Example 3] N- (4-acetoxybenzoyl) -2-methylalanine

m. p. : 171.0-173.8 ° C
[Example 4] N- [3,5-bis (trifluoromethyl) benzoyl] -2-methylalanine

m. p. : 180.4 to 184.7 ° C

ｍ．ｐ．：１２２．６〜１２４．８℃
［実施例６］Ｎ−[４−（トリフルオロメチル）ベンゾイル]−２−メチルアラニン

ｍ．ｐ．：２１５．４〜２１９．３℃ [Example 5] N- [4- (trifluoromethyl) benzoyl] -D-valine

m. p. : 122.6-124.8 ° C
[Example 6] N- [4- (trifluoromethyl) benzoyl] -2-methylalanine

m. p. : 215.4 to 219.3 ° C

ｍ．ｐ．：１９２．３〜１９５．８℃
［実施例８］Ｎ−（ｐ−トルオイル）−２−メチルアラニン

ｍ．ｐ．：２００．１〜２０３．０℃
［実施例９］Ｎ−[３，５−ビス（トリフルオロメチル）ベンゾイル]−バリン

ｍ．ｐ．：１７５〜１７６℃ [Example 7] N-benzoyl-2-methylalanine

m. p. 192.3 to 195.8 ° C
[Example 8] N- (p-toluoyl) -2-methylalanine

m. p. : 200.1-203.0 ° C
[Example 9] N- [3,5-bis (trifluoromethyl) benzoyl] -valine

m. p. : 175-176 ° C

[Formulation example]
Next, although the formulation example containing the compound of this invention is shown, this invention is not limited to these.
Formulation Example 1 Compound of Tablet Example 2 100 g
137g of lactose
Crystalline cellulose 30g
Hydroxypropylcellulose 15g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
Weigh the above ingredients and mix evenly. This mixture is compressed into tablets having a weight of 150 mg.

Formulation Example 2 Film-coated hydroxypropylmethylcellulose 9g
Macrogol 6000 1g
Titanium oxide 2g
After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.

Formulation Example 3 Capsule Example 4 Compound 50g
Lactose 435g
Magnesium stearate 15g
The above ingredients are weighed and mixed uniformly. The mixture is filled into an appropriate hard capsule in an amount of 300 mg in a capsule encapsulator to obtain a capsule.

Formulation Example 4 Capsule Example 2 Compound 100 g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 2, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation. Talc is uniformly mixed with the granules, and 200 mg each is filled into a suitable hard capsule to form a capsule.

Formulation Example 5 Powder Example 1 Compound 200g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to form a 20% powder.
Formulation Example 6 Granules, Fine Granules Compound of Example 3 100 g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g
After weighing the above components, add the compound of Example 3, lactose, crystalline cellulose, and partially pregelatinized starch, mix uniformly, add an aqueous solution of hydroxypropylcellulose (HPC), and granulate or fine granules by wet granulation method Manufacturing. The granules or fine granules are dried to obtain granules or fine granules.

Formulation Example 7 Injection 2 Compound of Example 2 2g
Propylene glycol 200g
Distilled water for injection Appropriate amount After weighing the above components, the compound of Example 2 is dissolved in propylene glycol. Sterile water for injection is added to make a total volume of 1,000 mL. After sterilizing by filtration, 5 mL each is dispensed into a 10 mL ampoule and sealed to make an injection.
Formulation Example 8 Dry Powder Inhalant Compound of Example 7 5g
Lactose 95g
The compound of Example 7 is pulverized to a particle size of 10 μm or less by a conventional method and uniformly mixed with lactose, and then this mixture is added to a dry powder inhaler.

The compound used in the present invention showed an excellent inhibitory effect in a citric acid-induced guinea pig cough model, and no abnormality was observed in the toxicity test. In addition, since no inhibitory action on the HERG channel was observed, unlike existing drugs, it not only has an excellent antitussive effect, but also has good pharmacokinetic properties and an excellent safety side effect. Can be used as a drug with little
The pharmaceutical composition of the present invention has the following respiratory diseases for the purpose of antitussive effect, such as lung cancer, cancerous lymphangiopathy, rib fracture, spontaneous pneumothorax, cold syndrome, pulmonary tuberculosis, interstitial pneumonia pleurisy, pneumonia, acute bronchial Can be used for inflammation, chronic bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, pulmonary infarction, etc., useful as an excellent preventive and / or therapeutic agent for respiratory diseases It is.

Claims (4)

A prophylactic and / or therapeutic agent for respiratory diseases comprising a compound represented by the following formula (I) or an optically active isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

(Wherein Z represents —C (CH ₃ ) ₂ — or —CH (CH (CH ₃ ) ₂ ) —);
n represents an integer of 0 to 2;
R ¹ represents a C 1-4 alkyl group, a hydroxyl group, a trifluoromethyl group or an acetoxy group, and when n is 2, R ¹ may be the same or different;
R ² represents a hydrogen atom or a C1-4 alkyl group. ) The compound represented by formula (I) is:
N- (4-acetoxybenzoyl) -2-methylalanine ethyl ester;
N- (4-hydroxybenzoyl) -2-methylalanine;
N- (4-acetoxybenzoyl) -2-methylalanine;
N- [3,5-bis (trifluoromethyl) benzoyl] -2-methylalanine;
N- [4- (trifluoromethyl) benzoyl] -D-valine;
N- [4- (trifluoromethyl) benzoyl] -2-methylalanine;
N-benzoyl-2-methylalanine;
N- (p-toluoyl) -2-methylalanine; and N- [3,5-bis (trifluoromethyl) benzoyl] -valine;
The agent for preventing and / or treating respiratory diseases according to claim 1, which is a compound selected from the group consisting of:   An antitussive agent comprising the compound represented by formula (I) according to claim 1 or an optically active form thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. A method for screening a cough suppressant, which comprises using a guinea pig administered with thiorphan before inhaling citric acid in a citric acid-induced guinea pig cough model.