WO2005032540A1 - Remedy for respiratory diseases comprising n-(benzoyl)amino acid derivative as the active ingredient - Google Patents

Abstract

A preventive/remedy for respiratory diseases characterized by containing a compound represented by the following general formula (I), its optically active form or a pharmaceutically acceptable salt thereof as the active ingredient: (I) wherein Z represents -C(CH3)2- or -CH(CH(CH3)2)-; n is from 0 to 2; R1 represents C1-4 alkyl, hydroxyl, trifluoromethyl or acetoxy; and R2 represents H or C1-4 alkyl. This drug, which aims at achieving an antitussive effect, shows excellent effects as a preventive/remedy for respiratory diseases such as lung caner, common cold syndrome, lung tuberculosis, pneumonia, acute bronchitis and chronic bronchitis.

Description

 Specification

 Respiratory disease therapeutic agent containing N- (benzoyl) amino acid derivative as active ingredient

 [0001] The present invention provides a method for preventing Z- or Z- or respiratory diseases characterized by containing an N- (benzoyl) amino acid derivative or an optically active form thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to therapeutic agents, especially antitussives. The present invention also relates to a method for screening for a cough suppressant, which comprises using a guinea pig to which thiolphan is administered before inhaling citrate in a guinea pig induced guinea pig cough model.

 Background art

 [0002] The respiratory organ is a general term for organs and tissues related to respiration, and plays an important role for sustaining life by taking in necessary oxygen and discharging carbon dioxide generated as a result of metabolism. Is going.

 Among the respiratory diseases, representative diseases that show cough symptoms include, for example, lung cancer, cancerous lymphangiosis, rib fracture, spontaneous pneumothorax, Kaz ゝ syndrome, pulmonary tuberculosis, interstitial pneumonia, pleurisy, pneumonia, acute bronchi Inflammation, chronic bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, pulmonary infarction and the like.

[0003] Cough is a phenomenon in which the lungs are expanded by deep inhalation, the throat is closed, and then the pressure in the lungs is increased due to strong contraction of the respiratory muscles, the laryngeal muscles are suddenly relaxed, the throat is opened, and air is rapidly exhaled. It means. At this time, secretions in the respiratory tract are exhaled. If secretions or foreign bodies accumulate in the respiratory tract mucous membrane, or if there is an abnormality in the pleura, lungs, diaphragm, etc., the stimulation from the mucous membrane reaches the cough center on the posterior side of the medullary medulla, causing a reflex cough attack (latest Pharmacology, 10.3 Antitussives, Sumiko Fujino, 1990, Kodansha).

 The main causes of cough are excessive secretion from airway mucous membranes, chemical irritation such as smoke and gas, foreign bodies, airway inflammation, allergic reactions, bronchial compression due to intrathoracic tumors, and psychogenicity. The illness and the chronic illness of the cough symptoms consume energy of respiratory muscles, deplete physical strength, and hinder the recovery of the underlying disease.

[0004] Antitussives include central antitussives that exert an antitussive action by blocking the cough center. There are peripheral antitussives that exert an antitussive effect by reducing irritation to peripheral cough receptors. Central antitussives represented by codin phosphate are generally sharp, but side effects include respiratory depression, constipation, nausea, vomiting, headache, drowsiness, and rash. It is also known that repeated use causes tolerance and dependence. Peripheral antitussives represented by methylephedrine can only exert a mild antitussive effect. In recent years, it appears that opioid δ receptor selective antagonists have been 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. (Natya Genet., Vol. 25, No. 2, p. 195, 2000). Therefore, there is a need for an antitussive that is more effective and has fewer side effects.

 [0005] As a prior art, Patent Document 1 discloses an amide derivative useful as a therapeutic agent for a neuroretinal degenerative disease. Patent Document 2 discloses that 2-methyl-N- (4 trifluoromethylbenzoyl) alanine was produced as a synthetic intermediate of a novel acylamino-substituted acyl-lide derivative useful as an anti-androgen drug. Have been. It is known from Patent Document 3 that N-benzoyl-2-methylalanine was produced as a synthetic intermediate of an anticonvulsant. Also, Reinaud et al.'S paper (Non-Patent Document 1) discloses 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. . Patent Document 4 discloses a salicylamide derivative having an analgesic effect. However, none of these conventional techniques discloses any prophylactic and / or therapeutic agents for respiratory diseases, and some do not disclose antitussives. Also, there is no report that these compounds have been successfully developed as pharmaceuticals.

 [0006] In drug development, long-term safety that is not limited to the intended pharmacological activity is required. In addition, it is required to meet strict criteria in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, gastrointestinal absorption during oral administration, rate of entry into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction of drug-metabolizing enzymes, excretion pathways and body clearance In addition, various issues to be studied are required in application methods (application site, method, purpose), etc., and it is difficult to find one that satisfies these. Drugs with better pharmacokinetic properties with a wider safety margin are desired.

[0007] In recent years, the proarrhythmic action of drugs, particularly the QT interval prolongation action in electrocardiograms, Is attracting attention. As an evaluation method for predicting the effect of extending the QT interval, a method of examining the effect on a human ether-a-go-go related gene (HERG) channel is known. Recognition of the importance of cardiac side effects, finding a drug that has no effect on the HERG current is one of the important issues in drug development.

 There are always comprehensive issues in drug development for respiratory diseases. For respiratory diseases, for example, antitussives, it is more likely to be more potent than the above-mentioned currently used central antitussives, peripheral antitussives, or antagonists selective for opioid δ receptors. There is a need for an antitussive with less side effects and high utility. In the cough-inhibiting substance screening method, the cough-inducing model that has been used in the conventional evaluation includes, for example, 1) three times of citric acid inhalation, and the test period is several times as long as two to three weeks. Desensitization may occur due to inhalation of citrate, which may significantly reduce the number of coughs in the control group.2) Coughing among animals varies widely. It is generally known that it is necessary to carry out a test, and therefore it is necessary to purchase a large number of animals, and there are many cases where tests with good reproducibility and sensitivity cannot be performed. Performing stable and pharmacological evaluation with high reproducibility and sensitivity in a short period of time is one of the important issues in drug development (Non-Patent Document 2).

Patent Document 1: International Publication No. W099Z21543

 Patent Document 2: International Publication No. W098Z22432

 Patent Document 3: GB752692 published in the UK

 Patent document 4: French publication FR No. 2137

 Patent Document 5: International Publication WO01Z001983

 Patent Document 6: International Publication WO00Z53225

 Non-patent literature l: Synthsis 612—p. 614, 1990

 Non-Patent Document 2: Japanese Pharmacological Journal, 120, 237-243, 2002

 Disclosure of the invention

 Problems to be solved by the invention

[0009] An object of the present invention is to provide an agent for preventing or treating respiratory diseases, which has an excellent antitussive action, has few side effects, and is highly safe, especially an antitussive. In particular The above-mentioned problems in the prior art, more specifically, side effects of central antitussives such as respiratory depression, constipation, nausea, vomiting, headache, drowsiness, and rash, or tolerance or dependence due to repeated use. Drugs that can be administered to mammals, including humans, that have overcome at least one or more of the side effects related to mental and emotional behavior that are concerned with opioid δ receptor selective antagonists, especially The purpose is to provide a prophylactic and / or therapeutic agent for respiratory diseases, especially an antitussive.

 Another object of the present invention is to provide a method for screening for a cough suppressant which can be performed in a short period of time without causing a desensitization phenomenon or coughing among animals due to a large number of inhalations of citric acid and which can be evaluated with high reproducibility and sensitivity. To provide. Means for solving the problem

 [0010] The inventors of the present invention have conducted intensive studies to obtain a highly safe drug having an excellent antitussive action that solves the above-mentioned problems, and as a result, it is represented by the formula (I). Specific Ν- (benzoyl) amino acid derivatives and their optically active forms, and their pharmaceutically acceptable salt powers (1) Have an antitussive effect in a citrate-induced guinea pig cough model; It has been found that it has one or more features such as low safety and high safety, (3) no HERG channel inhibitory action, and (4) good pharmacokinetic properties.

 In addition, the use of a citrate-induced guinea pig cough model, in which thiolphan was administered before inhalation of citrate, was able to generate sufficient cough in all guinea pigs with a single inhalation of citrate, resulting in short-term reproducibility. The present inventors have found that pharmacological evaluation can be performed with high sensitivity and have completed the present invention.

 [0011] In a first aspect of the present invention, a compound represented by the following formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof is effectively used. It is a preventive and / or therapeutic agent for respiratory diseases characterized by containing as an ingredient.

 [Chemical 1]

(式中、 Ζίま、 -C (CH ) 一、また ίま CH (CH (CH ) ) を表し；

(Wherein Ζί, -C (CH), or CHCH (CH (CH));

 3 2 3 2

 n represents an integer of 0-2;

R ¹ represents a C ¹⁴ alkyl group, a hydroxyl group, a trifluoromethyl group or an acetyloxy group, and when n is 2, R ¹ may be the same or different;

R ² represents a hydrogen atom or a C14 alkyl group. )

R ¹ in the above formula (I) is more preferably a methyl group, a hydroxyl group, a trifluoromethyl group, or a methyl group, preferably a hydroxyl group or a trifluoromethyl group. preferable. 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. When n = l, it is preferred that the compound is at position 4.When n = 2, it is at position 2 and 3, at position 2 and 4, at position 2 and at position 5. , 2 and ⁶ positions, 3 and 4 positions, 3 and 5 positions, 3 and 6 positions, etc., with 3 and 5 positions being preferred.

R ² in the above formula (I) is preferably a hydrogen atom.

 Z in the above formula (I) is preferably C (CH 2) 1.

 3 2

 Preferred examples of the compound represented by the formula (I), an optically active form thereof, a pharmaceutically acceptable salt thereof, and a solvate thereof include the following. N- (4-acetoxybenzoyl) -2-methylalanine ethyl ester, a pharmaceutically acceptable salt thereof, and a solvate thereof;

 N- (4-hydroxybenzoyl) -2-methylalanine, a pharmaceutically acceptable salt thereof, and a solvate thereof;

 N- (4-acetoxybenzoyl) -2-methylalanine, a pharmaceutically acceptable salt thereof, and a solvate thereof;

 N- [3,5bis (trifluoromethyl) benzoyl] -2-methylalanine, pharmaceutically acceptable salts thereof, and solvates thereof;

 N— [4- (Trifluoromethyl) benzoyl] —D Palin, its pharmaceutically acceptable salts, and solvates thereof;

N- [4- (trifluoromethyl) benzoyl] -2-methylalanine, a pharmaceutically acceptable salt thereof, and a solvate thereof; N-benzoyl-2-methylalanine, a pharmaceutically acceptable salt thereof, and a solvate thereof;

 N- (p-toluoyl) -2-methylalanine, a pharmaceutically acceptable salt thereof, and a solvate thereof;

 N- [3,5-bis (trifluoromethyl) benzoyl] -valine, a pharmaceutically acceptable salt thereof, and a solvate thereof.

[0014] The second aspect of the present invention is to provide a compound represented by the formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is an antitussive characterized by containing as an ingredient.

 A third embodiment of the present invention comprises a compound represented by the above formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is a dry cough improving agent characterized by performing.

 In the second and third embodiments, the compounds represented by the above formula (I) have the same preferred! /, Substituents, or combinations thereof as in the first embodiment.

[0015] A fourth aspect of the present invention is a method for screening a cough suppressant, which comprises using a guinea pig to which thiolphan is administered before ingesting citrate in a guinea pig cough model induced by citrate. Specific steps in this embodiment include:

 (1) a step of administering thiolphan to guinea pigs,

 (2) administering a test substance to a guinea pig,

 (3) a step of inducing cunic acid to induce cough,

 (4) observing the number of occurrences of cough reaction, the step of measuring,

 (5) determining the cough suppression rate of the test substance,

 Is mentioned.

 The animal used in the screening method of the present invention is not particularly limited as long as it can observe cough, but is preferably a guinea pig.

[0016] In the present invention, Thiorphan represents N- [2- (mercaptomethyl) -1 year old xo 3-phenylphenyl] glycine. There is no particular limitation on the route of administration of thiolphan, but intraperitoneal administration is preferred. The timing of administration of thiolphan is used to induce cough. There is no particular limitation as long as it is before the inhalation of citric acid, but it is preferable that the time is within 30 minutes before the inhalation of citric acid.

 The test substance is administered before inhalation of citric acid, and the timing can be set appropriately according to the administration route, kinetics of the substance, and the like. It is preferable to administer the test substance generally within one hour before the administration of citric acid.

 For the cough reaction, the peak detected in the plethysmograph and those caudically judged to be cough are measured, and the inhibition rate of the test compound against the cough reaction induced by citrate can be determined by the following formula.

 [(A-B) / (A)] X 100 (%)

 A: Number of cough reactions in the control group

 B: Number of cough reactions occurring in the test compound administration group

[0017] In the present invention, the "C14 alkyl group" means an alkyl group having 1 to 4 carbon atoms, and may be a methyl group or an ethyl group which may have a linear structure or a branched structure. Propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, _t- butyl group, etc., and more preferably a methyl group, preferably a methyl group or an ethyl group.

[0018] The compound represented by the formula (I) used in the present invention may form a salt with a base. Examples of strong bases are not particularly limited as long as they are pharmaceutically acceptable salts. Specifically, bases of metals such as sodium, potassium, magnesium, calcium, and aluminum, methylamine, ethylamine, ethanolamine Examples thereof include salts with organic bases such as min, pyridine, lysine, arginine, and ol-tin, and ammonium salts.

 These salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention and a solution containing a desired base, and distilling off and collecting a solvent used for filtering a desired salt. Further, the compound of the present invention or a salt thereof may form a solvate with a solvent such as water, ethanol and glycerol. The compound of the present invention or a salt thereof also includes these solvates.

[0019] The compound of the present invention may be crystalline or amorphous. That is, the compound represented by the above formula (I) of the present invention, its optically active form, or a salt or a solvate thereof also includes embodiments of crystal, non-crystal, and their solvates. . Also this crystal Also includes those of polymorphism.

 The present invention also includes the polymorph of the compound of the formula (I), a salt thereof, and a solvate thereof.

 The compound represented by the formula (I) may have an asymmetric carbon atom, and various mixtures and isolated substances such as all optically active isomers (enantiomers and the like) may exist. Includes all of these. The isolation and purification of such optical isomers can also be achieved through optical resolution using preferential crystallization-column chromatography or asymmetric synthesis.

 [0020] [Manufacturing method]

 Next, a method for producing the compound of the present invention will be described. 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, the formula (II) corresponding to the right part of the formula (I): Amino represented by HN—Z—COOR ²

 2

 An acid derivative or a salt thereof and a benzoic acid derivative corresponding to the left portion are condensed by, for example, a method generally used in amide synthesis or peptide synthesis to form an amide bond, thereby forming a conjugated product in which both are bonded. The compound of the formula (I) can be obtained by converting the substituent if necessary.

[Experimental example]

 The power of explaining the present invention concretely with reference to the following experimental examples The present invention is not limited by these.

[0022] Experimental example 1 1 [Inhibitory effect on the model of guinea pig cough induced by taenoic acid]

-Fix the fasted guinea pig to a plethysmograph and use a differential pressure transducer (Nihon Kohden, TP-602T) and a respiratory amplifier (Nihon Kohden, AR-601G) to measure changes in the internal pressure of the plethysmograph (body side of the guinea pig). The cough response can be recorded on the ink writing recording paper (Nihon Kohden Kogyo, WI-642G) via a plethysmograph (head side) using a nebulizer (Omron, NE-U12) with a 20 WZV% aqueous solution of citric acid. Within 2 minutes (approximately 1 mL / min), the number of coughing reactions in guinea pigs for 15 minutes from the start of spraying was observed and measured. Cough response was measured 3 hours before and 1 hour after oral administration of the test compound. It should be noted that administration was not performed for individuals having a cough reaction frequency of 5 or less as measured before the administration. Then, the cough reaction expression ratio before and after administration (PostZPre X 100) was calculated, and the inhibition rate (Y1) of the test compound against the citrate-induced cough reflex was calculated by the following formula.

 Yl = [(CRRcontrol-CRRtest) / (CRRcontrol)] X 100 (%)

 CRRcontrol: ratio of cough reaction expression in control group (%)

 CRRtest: Cough reaction expression ratio (%) in the test compound administration group

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

[Table 1]

 table 1

( 15分） xj t (%) 抑制率 （％) r e p o s tJorudo ^ J dose (mgZl ί g)

(15 minutes) xj t (%) Suppression rate (%) repost

 ehicle 1 1 ± 1 1 1 ± 1 102 ± 8 — Difficult case 9 100 1 1 ± 16 ± 1 49 ± 3 52 *** The ratio of coughing reaction onset in the drug administration group was determined by Dunnett's multiple comparison test using the vehicle administration group. The statistically significant difference was expressed by *: ρ <0.05, **: ρ <0.01, ***: ρ <0.001.

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

Experimental Example 1 2 [Inhibitory effect on taenoic acid-induced guinea pig cough model]

ー 晚 Intraperitoneal administration of Thiorphan at a dose of lmgZkg to a fasted guinea pig, 30 minutes after that, 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 (Nihon Kohden, TP-602T). ) And a respiratory amplifier (Nippon Koden Kogyo, AR-601G) to enable recording of cough reaction on ink recording paper (Nihon Kohden WR7200), and a nasal inhalation exposure device for small animals (M · I · Spray a 0.9 mol ZL aqueous solution of citric acid into the plethysmograph (head side) for 20 minutes using The number of coughing reactions that occurred during a 20-minute fog period was observed and measured. The cough response was measured by the peak detected in the plethysmograph and those that were judged to be cough audibly. The test compound was orally administered 30 minutes before inhalation of citric acid. The inhibitory rate (Y2) of the test compound against the citrate-induced cough reaction was determined by the following formula.

 Y2 = [(A-B) / (A)] X 100 (%)

 Α: Number of cough reactions in control group

 B: Number of cough reactions occurring in the test compound administration group

 Table 2 shows the results.

[Table 2]

 Table 2

 Sadani compound dose (mg z kg) mouth (0/20 min) inhibition rate (%)

V e h i c l e 1 9 ± 1

 Factory p> *

 Wei Example 2 1 0 0 7 ± 1 The cough response ratio in the drug-administered group was compared with the cough response ratio in the vehicle-administered group by the Dunnett multiple comparison test, and the statistically significant difference was calculated as *: ρ <0.05, * *: ρ <0.01, * * *: ρ <0.001

 As described above, the compound of the present invention represented by Example 2 was found to inhibit cue acid-induced cough by oral administration. Further, the compounds of Example 7 and Example 8 also suppressed the cough reaction. At the same time, no abnormalities were observed in the general symptoms, indicating low toxicity of the compound of the present invention.

Experimental Example 2 [Toxicity test]

 Oral administration of the compound of Example 2, Example 4, Example 5, or Example 6 to a 6-week-old Wistar Hannover female rat at a dose of lOOmgZkg showed no abnormalities in general symptoms and died. The case was unrecognizable.

6-week-old Wistar Hannover female rats were treated with the conjugate of Example 2, Example 4, Example 5, and Example 6 at 250, 500, and 100mgZkgZ at a dose of 1 time and 1 time for 14 times. Oral administration showed no abnormalities in the general symptoms observed and body weight and food consumption measurements, although there were no deaths up to 24 hours after the end of the last dose, even when the dose was shifted by V or vice versa . Outstanding toxic findings in hematology, blood chemistry, major organ weighing, and pathologic examination were not observed.

 [0027] Experimental example 3 [Effect on HERG K + channel]

 The compounds of Example 2 (300 μmol / L), Example 5 (300 μmol / L) and Example 6 (100 μmol / L) were added to the indicated concentrations, respectively, using the CHO-K1ZHREG cell line. As a result of examination by the patch-clamp method using E. coli, no inhibition of the HERG K + channel was observed.

 [0028] Experimental Example 4 [Pharma kinetics]

 Plasma after single oral administration of the compounds of Examples 2, 4, 5, and 6 in 8-week-old female Wistar Hannover rats and 2- or 3-year-old male beagle dogs Examination of the changes in the concentrations revealed that all compounds had good bioavailability. In addition, all compounds showed no inhibitory effects on human drug-metabolizing enzymes. Therefore, drug interaction is unlikely to occur. In addition, it was poorly metabolized in human, monkey, dog and rat liver microsomes. Therefore, it is considered that the metabolism in the liver is less likely to occur.

 From the above experimental results, it was confirmed that the compound of the present invention has an inhibitory effect in a guinea pig cough model induced by citrate. In addition, since any abnormalities were observed in the toxicity test, it was determined that the compounds of the present invention had extremely low toxicity. Further, the compound of the present invention exerted no 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 since it has an excellent antitussive effect in an animal cough model and also has good pharmacokinetic properties with high safety.

In addition, the screening method of the present invention uses a citrate-induced guinea pig cough model in which thiolphan was administered before inhalation of citrate, and thus the desensitization phenomenon due to multiple inhalation of citrate and coughing by animals. The cough can be stably generated in all animals by a single inhalation of citric acid.Therefore, it is not necessary to select animals that cough in advance.Reproducibility and sensitivity are as short as 3 days. Because pharmacological evaluation is possible, It can be expected as an animal model for evaluating cough suppressants.

 [0030] The compound of the present invention has the following respiratory diseases for the purpose of an antitussive effect, for example, lung cancer, cancerous lymphangiosis, rib fracture, spontaneous pneumothorax, Kazusa syndrome, pulmonary tuberculosis, interstitial pneumonia, pleurisy, lung It can be used for inflammation, acute bronchitis, chronic bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, pulmonary infarction, etc. In these respiratory diseases, exacerbation and chronicity of cough symptoms can be achieved by alleviating cough symptoms, as it consumes respiratory muscle energy, depletes physical strength, and impedes the recovery of the underlying disease. It is possible to promote the treatment of the disease. Therefore, the compounds of the present invention can be used as prophylactic and / or therapeutic agents for respiratory diseases. However, it can be applied to similar conditions and symptoms without limitation.

 [0031] Cough is classified into wet cough and dry cough! Wet cough is a cough caused by increased secretions in the respiratory tract irritating the respiratory tract and expectorating sputum. Dry cough is a cough caused by airway irritation without sputum, and is also called “empty cough” because of dry skin and cough. Although the compound used in the present invention is effective for any cough, it can improve its symptoms especially when used for dry cough, and is useful for treating the respiratory diseases.

 [0032] The medicament of the present invention is administered in the form of a pharmaceutical composition.

The pharmaceutical composition of the present invention is prepared in combination with a pharmaceutically acceptable excipient containing at least one of the compounds represented by the formula (I) of the present invention. More specifically, excipients (eg, lactose, sucrose, mannitol, crystalline cellulose, caic acid, corn starch, potato starch), binders (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropyl Methylcellulose (HPMC)), microcrystalline cellulose, sugars (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, corn starch), pregelatinized starch, dextrin, polybutylpyrrolidone (PVP), macro Gall, polyvinyl alcohol (PVA)), lubricants (eg, magnesium stearate, calcium stearate, talc, carboxymethyl cellulose), disintegrants (eg, starches (corn starch, potato starch), carboxymethyl starch Potassium, carmellose, carmellose calcium, croscarmellose sodium, click Rospopidone), coating agents (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plasticizers (eg, triethyl taenoate, macrogol) A masking agent (eg, titanium oxide), a coloring agent, a flavoring agent, a preservative (eg, salted benzalco-pam, paraoxybenzoate), an isotonic agent (eg, glycerin, salted sodium), Shioi匕calcium, Ma emissions - tall, dextrose), _P H modifiers (eg, Mizusani匕sodium, Mizusani匕potassium carbonate sodium © beam, hydrochloric acid, sulfuric acid, buffers such as phosphate buffer) , Stabilizers (eg, sugar, sugar alcohol, xanthan gum), dispersants, antioxidants (eg, ascorbic acid, butylhydroxysole (BHA), propyl gallate) Buffer, preservative (eg, paraben, benzyl alcohol, benzalco-dimethyl), fragrance (eg, vanillin, 1-menthol, rose oil), solubilizer ( Examples: Polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg, sodium glycolate, sodium edetate, sodium power prinate, acylcarnitines, limonene) ), A gelling agent, a suspending agent, or an emulsifying agent, and commonly used appropriate additives or solvents, can be suitably combined with the compound of the present invention to give various dosage forms.

 Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, solutions, spirits, suspensions, Extracts, elixirs and the like can be mentioned. Oral, subcutaneous, intramuscular, intranasal, transdermal, intravenous, intraarterial, perineural, epidural, intradural, intraventricular, rectal It can be administered to patients by inhalation or the like.

When administering the compound of the present invention as a powder inhalant, it is preferable to use the compound in the form of fine particles of 10 m or less. In the case of 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 driving medium mill, and a medium stirring 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, a centrifugal fluidizing mill, and the like. Carriers for powder inhalants include monosaccharides such as mannitol, arabinose, xylitol and dextrose and their monohydrates. And disaccharides such as ratatose, maltose and sucrose, and polysaccharides such as starch, dextrin or dextran.

 The dose of the compound of the present invention can be appropriately increased or decreased depending on the symptoms or the administration route, which is usually 0.05 mg to 30. Og, preferably 0.5 mg to 25 g, more preferably 1 mg to 15 g per adult per day.

 Oral or parenteral administration of the whole dose in 1 or 2 to 6 divided doses or continuous administration such as intravenous drip is also possible.

 Example

 Hereinafter, examples will be given in order to explain the present invention in further detail, but the present invention is not limited thereto. The 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. All of the compounds shown in Examples 19 to 19 could be prepared into required dosage forms by a conventional preparation method, and good results were obtained as shown in the above Test Examples. Only the compound is shown, omitting the indication of the formulation.

 Example 1 N- (4-Acetoxybenzoyl) -2-methylalanine ethyl ester

m. p. : 101 2— 102. 2°C [Chemical 2]

mp: 101 2— 102.2 ° C

 [Example 2] N- (4-hydroxybenzoyl) -2-methylalanine

m. p. : 225 8—227. 9°C [Formula 3]

mp: 225 8—227.9 ° C

 Example 3 N- (4-acetoxybenzoyl) -2-methylalanine

[Formula 4]

 m.p .: 171.0-173.8 ° C

Example 4 N— [3,5-bis (trifluoromethyl) benzoyl] -1-2-methylarab

 m.p .: 180.4-1 184.7 ° C

 [Example 5] N- [4- (trifluoromethyl) benzoyl] -D-parin

[Formula 6]

 m.p .: 122.6-124.8 ° C

Example 6 N- [4- (Trifluoromethyl) benzoyl] -2-methylalanine

 m.p .: 215.4-219.3 ° C

 [Example 7] N-benzoyl 2-methinolealanine

[Formula 8]

 m.p .: 192.3-195.8 ° C

m. p. : 200. 1—203. 0°C [Example ⁸ ] N- (p-toluoyl) -1-2-methylara [Formula 9]

mp: 200.1--203.0 ° C

 [Example 9] N- [3,5-bis (trifluoromethyl) benzoyl]

[Formula 10]

m. p. : 175— 176°C

mp: 175— 176 ° C

[Formulation example]

 Next, Formulation Examples containing the compound of the present invention are shown, but the present invention is not limited thereto.

Formulation Example 1 Tablet

 100 g of the compound of Example 2

 Lactose 137g

 30 g of crystalline senorelose

 Hydroxypropinoresenolerose 15g

 Carboxymethyl starch sodium 15g

 Magnesium stearate 3g

 After weighing the above ingredients, mix them uniformly. Compress the mixture into tablets weighing 150 mg.

Formulation Example 2 Film coating

 Hydroxypropinolemethinoresenolerose 9g

 Macro Gonore 6000 lg

 Titanium oxide 2g

After weighing the above components, add hydroxypropyl methylcellulose and macrogol 6000 Dissolve in water and disperse titanium oxide. This solution is film-coated on 300 g of the tablet of Formulation Example 1 to obtain a film-coated tablet.

Formulation Example 3 Capsule

 50 g of the compound of Example 4

 Lactose 435g

 Magnesium stearate 15g

 After the above components are weighed, they are mixed uniformly. The mixture is filled into appropriate hard capsules in a capsule encapsulator at a weight of 300 mg each to obtain capsules.

Formulation Example 4 Capseno ^!

 Compound lOOg of Example 2

 63g lactose

 25g

 Hydroxypropinoresenololose 10g

 2g talc

 After weighing the above components, the compound of Example 2, lactose, and corn starch are uniformly mixed, an aqueous solution of hydroxypropyl cellulose is dried, and granules are produced by a wet granulation method. The talc is evenly mixed with the granules, and the mixture is filled into suitable hard capsules at a weight of 200 mg to give capsules.

 Formulation Example 5 Powder

 200 g of the compound of Example 1

 Lactose 790g

 Magnesium stearate 10g

 After weighing each of the above components, mix them uniformly to make a 20% powder.

 Formulation Example 6 Granules and fine granules

 Compound lOOg of Example 3

 Lactose 200g

 Crystal senorelose lOOg

Part a 50g Hydroxypropinoresenolerose 50g

After weighing the above components, the compound of Example 3, lactose, crystalline cellulose, and e mosquito卩part _α of Den Pung were uniformly mixed, Karoe an aqueous solution of hydroxypropyl cellulose (HPC), by a wet granulation granules Or to produce fine granules. The granules or fine granules are dried to obtain granules or fine granules.

Formulation Example 7 Injection

 Compound of Example 2

 Propylene glycolone

 Distilled water for injection

 After weighing the above components, the compound of Example 2 is dissolved in propylene glycol. Inject the sterilized water for injection to a total volume of 1, OOOmL, sterilize by filtration, dispense 5mL each into lOmL ampules, and seal to obtain injections.

 Formulation example 8 m ^ m m

 5 g of the compound of Example 7

 Ratatoose 95g

 After pulverizing the compound of Example 7 to a particle size of 10 m or less by a conventional method and uniformly mixing with ratatose, the mixture is added to a dry powder inhaler.

 Industrial applicability

[0045] The compound used in the present invention showed an excellent inhibitory effect in the guinea pig cough model induced by citric acid, and no abnormality was observed in the toxicity test. In addition, unlike existing drugs, it has good pharmacokinetic properties, not only excellent antitussive effect, but also excellent safety, because it has no inhibitory effect on HERG channels It can be used as a drug with few side effects.

 The pharmaceutical composition of the present invention has the following respiratory diseases for the purpose of an antitussive effect, for example, lung cancer, carcinomatous lymphangiosis, rib fracture, spontaneous pneumothorax, Kazusa syndrome, pulmonary tuberculosis, interstitial pneumonia pleurisy, pneumonia, Can be used for acute bronchitis, chronic bronchitis, emphysema, pneumoconiosis, bronchiectasis, diffuse panbronchiolitis, bronchial asthma, pulmonary embolism, pulmonary infarction, etc.Excellent prevention and Z or treatment of respiratory diseases Useful as an agent.

Claims

Claims Prevention and / or treatment of a respiratory disease characterized by containing a compound represented by the following formula (I) or an optically active form thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.  [Chemical 1]

 (Wherein, Z represents —C (CH 2) — or —CH (CH 2 (CH 2)) —;  3 2 3 2  n represents an integer of 0-2; R ¹ represents a C ¹⁴ alkyl group, a hydroxyl group, a trifluoromethyl group or an acetyloxy group, and when n is 2, R ¹ may be the same or different; R ² represents a hydrogen atom or a C14 alkyl group. ) [2] The compound represented by the formula (I)  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 Palin;  N— [4- (trifluoromethyl) benzoyl] -2-methylalanine;  N-benzoyl-2-methylalanine;  N- (p-toluoyl) -2-methylalanine; and  N— [3,5-bis (trifluoromethyl) benzoyl] parin;  2. The preventive and / or therapeutic agent for respiratory disease according to claim 1, which is a compound selected from the group consisting of: [3] An antitussive comprising the compound represented by the 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 for a cough suppressant, which comprises using a guinea pig to which thiolphan is administered before inhaling citrate, in a guinea pig-induced guinea pig cough model.