HK1077216B - Use of thiazole deirvatives for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease - Google Patents

Description

Use of thiazole derivatives for the treatment of chronic obstructive pulmonary disease

Technical Field

The invention relates to a medicament for treating chronic obstructive pulmonary disease.

Background

Chronic Obstructive Pulmonary Disease (COPD) is characterized by a progressive development of airflow limitation (airway obstruction) (Pauwell r.a., et al: am.j.respir.crit.care med., 2001 (163)), 1256-.

COPD is a major cause of morbidity and mortality in chronic diseases worldwide, and in asia-pacific regions, COPD patients are also expected to grow rapidly within twenty years from now on due to the increase in smokers and the aging population.

Smokers with these clinical symptoms and disorders should consider a possible diagnosis of COPD, such as progressive developing abnormal shortness of breath with airflow obstruction. For this reason, there is great interest in the diagnosis and treatment of COPD in every country in the world.

Currently, in the pharmacotherapy sector of COPD treatment, certain drugs (e.g. β) with bronchodilatory action₂Agonists, anticholinergics, etc.) are experimentally used to prevent or suppress symptoms. However, these drugs having a bronchodilating effect cannot show an improving effect on the deterioration of lung function for a long period of time, which is a characteristic and the most important clinical index of COPD.

Steroids have potent inhibitory effects on cytokine production and have been evaluated on a large scale as an inhalant in a number of clinical studies. However, most of them also show that steroids do not improve the deterioration of lung function for a long period of time (Pauwels R.A., Lodahl C.G., Laitinen L.A., Schouten J.P., Postma D.S., Pride N.B., et al: N.Engl.J.Med., 1999(340), 1948. 1953; Vestbo J.S., Sorensen T., Lange P., Brix A., Torre P., Viskum K., Lancet, 1999(353), 1819. 1823; Burge P.S., Calverley P.M., Jones P.W., Spencer S., Anderson J.A., Masson T.K., BMJ, 2000, 1297, 1303), etc.).

As for drugs having an inhibitory effect on the production of active oxygen, no reliable clinical studies have been conducted.

N-acetylcysteine is an antioxidant, and it has a similar action to a drug having an inhibitory action on the production of active oxygen. Clinical studies have shown that N-acetylcysteine decreases the acute exacerbation rate of COPD (c.stem, j.stem, s.bachmann, t.c.medici, m.r.tramer; eur.respir.j., 2000, (16), 253-. However, it has not been reported at all that N-acetylcysteine has been shown to improve the deterioration of lung function in COPD patients for a long period of time.

Further, clinical studies are being conducted to test whether drugs that inhibit phosphodiesterase IV activity can treat COPD. However, these drugs have been reported to have adverse side effects such as nausea, vomiting and increased gastric acid secretion (Peter J. Barnes: N.Engl. J. Med., 2000(343) No.4, 269-280).

As explained above, there are no drugs having an improving effect on the pulmonary function deterioration of COPD and no drugs having a sufficient ability to treat COPD, which have not been developed.

Disclosure of Invention

It is an object of the present invention to provide a drug for treating COPD which is effective and highly safe.

The present inventors have made an animal model having pathological characteristics very close to those of COPD in clinical practice, and have conducted extensive research work using the animal model. As ｃA result, the inventors have found the fact that some thiazole derivatives known as inhibitors of the production of active oxygen, production of cytokines and cell adhesion, which are disclosed in JP-A-5-51318, JP-A-10-152437, EP 513387 Al and W098/14191, have an effect of improving deterioration of lung function (e.g., airflow obstruction), and thus, these thiazole derivatives show extremely high effects and low side effects (e.g., nauseｃA, vomiting and gastric acid secretion) for the treatment of COPD, and have high safety. Finally, the present invention has been completed on the basis of these findings.

1) The present invention relates to a drug useful for treating COPD, characterized by comprising at least one compound selected from the group consisting of thiazole derivatives represented by the general formula (1) and salts thereof as an active ingredient,

wherein R is¹Is phenyl, which may have 1 to 3 lower alkoxy groups on the phenyl ring; r²Is a pyridyl group, which may have 1 to 3 carboxyl groups on the pyridine ring.

(2) The present invention relates to a medicament for the treatment of COPD as mentioned in 1) above, wherein the thiazole derivative is 6- [2- (3, 4-diethoxyphenyl) thiazol-4-yl ] pyridine-2-carboxylic acid.

Best Mode for Carrying Out The Invention

The thiazole derivative represented by the general formulｃA (1) of the present invention is ｃA known compound and can be prepared by the method disclosed in JP-A-5-51318 as an example.

Each of the groups in the above-mentioned general formula (1) is explained below one by one.

As the phenyl group which may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring, there may be mentioned, for example, phenyl groups which may have 1 to 3 straight-chain or branched alkoxy groups (having 1 to 6 carbon atoms) as substituents on the phenyl ring, such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 3-ethoxy-4-methoxyphenyl, 4-hexyloxyphenyl, 3, 4-dimethoxyphenyl, 3, 4-diethoxyphenyl, 2, 3-dimethoxyphenyl, 2, 6-dimethoxyphenyl, 3-propoxy-4-methoxyphenyl, 3, 5-dimethoxyphenyl, 3, 4-dipentyloxyphenyl, 3, 4, 5-trimethoxyphenyl, 3-methoxy-4-ethoxyphenyl and the like.

As the pyridyl group which may have 1 to 3 carboxyl groups as substituents on the pyridine ring, there may be mentioned, for example, a pyridyl group which may have 1 to 3 carboxyl groups as substituents on the pyridine ring, such as a pyridyl group, a 2-carboxypyridyl group, a 3-carboxypyridyl group, a 4-carboxypyridyl group, a 2, 3-dicarboxylpyridyl group, a 3, 4-dicarboxylpyridyl group, a 2, 4-dicarboxylpyridyl group, a 3, 5-dicarboxylpyridyl group, a 3, 6-dicarboxylpyridyl group, a 2, 4, 6-tricarboxypyridyl group and the like.

In the thiazole derivative represented by the general formula (1) of the present invention, a compound having a basic group may form a salt thereof with a pharmaceutically acceptable acid. As such an acid, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid or the like; and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, succinic acid, benzoic acid, and the like.

In the thiazole derivative represented by the general formula (1) of the present invention, a compound having an acidic group may form a salt thereof with a pharmaceutically acceptable basic compound. As such a basic compound, there may be mentioned, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogencarbonate and the like.

The thiazole derivatives of the present invention include their optical isomers.

Generally, the compounds represented by the general formula (1) are used in the form of ordinary pharmaceutical preparations.

Pharmaceutical formulations are prepared with conventional diluents or excipients, such as fillers, diluents, binders, wetting agents, disintegrants, surfactants, lubricants and the like.

As for the pharmaceutical preparation, the desired unit dosage form may be selected according to the therapeutic purpose. Typical unit dosage forms include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), inhalants, and the like.

For the purpose of preparing a formulation in the form of a tablet, any carrier widely used in the art may be used. Examples of the carrier include excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup (simple syrup), glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone; disintegrants, for example, dry starch, sodium alginate, agar-agar powder, laminarin powder (laminaran), sodium bicarbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, glycerol monostearate, starch and lactose; disintegration inhibitors such as white sugar, stearin, cacao oil and hydrogenated oil; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; humectants, such as glycerol and starch; absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; lubricants, such as refined talc, stearate, boric acid powder and polyethylene glycol. If necessary, the tablets may be further coated with a conventional coating material to give sugar-coated tablets, gelatin film-coated tablets, enteric coating-coated tablets, film-coated tablets, double-layered tablets and multi-layered tablets.

For forming the pharmaceutical composition in the form of a pill, any excipient known and widely used in the art can be used, for example, carriers such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and the like; binders such as acacia powder, powdered tragacanth, gelatin, ethanol and the like; disintegrating agents, such as kelp (laminaria), agar-agar, and the like.

To form the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art can be used, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.

To form the pharmaceutical composition in the form of a capsule, it is prepared according to a conventional method by mixing the active ingredient with the above-mentioned various carriers, and then filling it into a hard gelatin capsule shell or a soft gelatin capsule shell.

To form a pharmaceutical composition in the form of an injection, solutions, emulsions and suspensions may be sterilized and preferably made isotonic with blood. In the manufacture of injections, any diluent commonly used in the art may be used, for example, water, ethanol, polyethylene glycol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In these cases, appropriate amounts of sodium chloride, glucose or glycerol may be added to the desired injection to make them isotonic with blood. Further, conventional dissolution aids, buffers, analgesics may also be added. Further, if necessary, coloring agents, preservatives, flavors, seasonings, sweetening agents and other medicaments may also be added to the desired pharmaceutical preparation.

The inhalant composition can be prepared by a conventional method. That is, the active ingredient is prepared in powder or liquid form and mixed with an inhalation propellant and/or carrier and then filled into a suitable inhalation container. Further, when the active ingredient is in powder form, a conventionally used mechanical powder inhaler may be employed; when the active ingredient is in liquid form, an inhaler like a nebulizer may be used. As the inhalation propellant, any known in the art may be used, for example, fluorocarbon type compounds such as flon-11, flon-12, flon-21, flon-22, flon-113, flon-114, flon-123, flon-142C, flon-134a, flon-227, flon-C318, 1, 1, 1, 2-tetrafluoroethane, etc.; hydrocarbons such as propane, isobutane, n-butane, etc.; ethers such as diethers and the like; compressed gases such as nitrogen, carbon dioxide, and the like.

If necessary, the inhalant of the present invention can be prepared by adding a surfactant, oil, flavoring agent, cyclodextrin or its derivative, etc., accordingly. As the surfactant, there may be mentioned, for example, oleic acid, lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glycerol trioleate, glycerol laurate, glycerol monooleate, glycerol monostearate, glyceryl monolaurate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetylpyridinium chloride, sorbitan trioleate (trade name: Span 85), sorbitan monooleate (trade name: Span 80), sorbitan monolaurate (trade name: Span 20), polyoxyethylated hardened castor oil (trade name: HCO-60), polyoxyethylene (20) sorbitan monolaurate (trade name: Tween 20), polyoxyethylene (20) sorbitan monolaurate (trade name: Tween 80), lecithin derived from natural sources (trade name: Epikuron), oleyl polyoxyethylene (2) ether (trade name: Brij 92), stearyl polyoxyethylene (2) ether (trade name: Brij 72), lauryl polyoxyethylene (4) ether (trade name: Brij30), oleyl polyoxyethylene (2) ether (trade name: Genapol 0-020), a block copolymer of oxyethylene and oxypropylene (trade name: Synperonic), and the like. As the oils, there may be exemplified corn oil, olive oil, cottonseed oil, castor oil and the like.

In the case of preparing the active ingredient of the present invention into a liquid form preparation, the active ingredient may be dissolved in a carrier in a liquid form. As the carrier in liquid form, water, an aqueous solution of sodium chloride, an organic solvent and the like can be exemplified. Among these carriers, water is preferred. Further, in the case of dissolution, a surfactant such as polyoxyethylene glycol having a molecular weight of 200-; sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc. may also be added thereto.

In the case of preparing the effective ingredient of the present invention into powder, the ingredient may be ground into powder according to a conventional method, for example, the ingredient is ground into fine powder, and a uniform mixture is prepared by mixing with lactose, starch, etc.

The amount of the active ingredient contained in the therapeutic agent of the present invention is not particularly limited. Can be selected from a wide range and will generally comprise from about 1 to about 70% by weight of the pharmaceutical composition of interest.

The mode of administration of the therapeutic agent of the present invention is not particularly limited. The therapeutic agent of the present invention can be selectively administered depending on the method of use, age, sex, other conditions of the patient, condition of symptoms, and the like. For example, tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally. The injection is injected intravenously alone or in mixture with an injection transfusion (e.g., glucose solution, amino acid solution, etc.); the injection can be singly injected intramuscularly, intracutaneously, subcutaneously or intraperitoneally, if necessary. Suppositories are administered intrarectally. The inhalant is administered orally.

The dose of the therapeutic agent of the present invention is selected depending on the method of use, age, sex, other conditions of the patient, condition of symptoms, etc., and the effective ingredient is usually administered daily at about 0.2 to 200mg/kg body weight.

The drug for treating COPD of the present invention has an excellent effect of ameliorating deterioration of lung function (e.g., airflow obstruction) and shows an extremely high effect of curing COPD.

The drug for treating COPD of the present invention is a drug with high safety and low side effects (e.g., nausea, vomiting, gastric acid secretion).

Examples

The present invention is explained in detail by the following pharmaceutical preparation examples and pharmacological test examples. However, the present invention is not limited to these examples.

In the examples that follow, "Compound A" refers to 6- [2- (3, 4-diethoxyphenyl) thiazol-4-yl ] pyridine-2-carboxylic acid.

Pharmaceutical preparation example 1

Compound A150 g

Avicel (trade name, manufactured by Asahi chemical industries, Ltd.) 40g

Corn starch 30g

Magnesium stearate 2g

Hydroxypropyl methylcellulose 10g

Polyethylene glycol-60003 g

Castor oil 40g

Ethanol 40g

Compound a, Avicel, corn starch and magnesium stearate were mixed together and ground to a powder. The resulting mixture was tabletted with a tabletting machine having a punch with a diameter of 10 mm. The film-coated tablet is prepared by coating with a film-coating agent comprising hydroxypropylmethylcellulose, polyethylene glycol 6000, castor oil and ethanol.

Pharmaceutical preparation example 2

Compound A150 g

Citric acid 1.0g

Lactose 33.5g

Dicalcium phosphate 70.0g

Pluronic F-68 30.0g

Sodium lauryl sulfate 15.0g

Polyvinylpyrrolidone 15.0g

Polyethylene glycol (Carbowax 1500) 4.5g

Polyethylene glycol (Carbowax 6000) 45.0g

Corn starch 30.0g

3.0g of dry sodium stearate

3.0g of dry magnesium stearate

And (3) ethanol q.s.

Compound A, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate were combined. The resulting mixture was screened through a No. 60 sieve and then wet granulated with an alcohol solution containing polyvinylpyrrolidone, polyethylene glycol 1500 and 6000. If desired, ethanol is added to the mixture to enable the mixture in paste form to agglomerate. Corn starch is then added thereto and the mixing operation is continued until uniform granules are obtained. The resulting mixture was screened through a No. 10 screen, and the screened mixture was then placed in a tray and baked in an oven at 100 ℃ for 12-14 hours. The resulting granules were sieved through a No. 16 sieve and dry sodium stearate and magnesium stearate were added with stirring. The product is compressed into a desired shape using a tablet press.

The core portion of the resulting tablet was treated with a varnish (varnish) and talc was applied to the surface of the tablet to prevent it from absorbing moisture. An inner coating is wrapped around the core. The varnish coating is carried out for a sufficient time to allow the tablets to be taken orally. To form the tablets into a perfect sphere with a smooth surface, a further coating operation may be performed to coat the inner coating layer and the smooth surface coating layer. The colored coating is applied until the resulting tablet has the desired top color. After drying, the coated tablets were polished to a uniform gloss.

Pharmaceutical composition example 3

Compound A5.0 g

Polyethylene glycol (molecular weight: 4000) 0.3g

Sodium chloride 0.9g

Polyoxyethylene sorbitan monooleate 0.4g

Sodium metabisulfite 0.1g

0.18g of methylparaben

Propyl p-hydroxybenzoate 0.02g

10.0ml of distilled water for injection

The above-mentioned parabens, sodium metabisulfite and sodium chloride were dissolved in half volume of distilled water at 80 ℃ with stirring. The resulting solution was cooled to 40 ℃, and then compound a, polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved in the above solution.

The remaining amount of distilled water for injection is added to the obtained solution so as to adjust to the final volume, and filtered and sterilized using an appropriate filter paper, thereby preparing the objective injection.

Pharmacological test examples

The subsequent pharmacological tests were carried out according to the method of Jun-ichi Fuchikami, et al (Japanese journal of Pharmacology, 2000, (82), p.247).

Hartley strain guinea pigs (5 weeks old, body weight: 300 to 379.5g) were exposed to cigarette smoke (trade name: Hi-Light, manufactured by Nicotiana Nippon Co., Ltd.) for 1 hour per day, 5 days per week, for four weeks by using a flow-through nose-only inhalation chamber (manufactured by Muenster Co., Ltd.). The control group was exposed to air instead of cigarette smoke as the normal group.

Compound a was suspended in a 0.5% aqueous solution of tragacanth and this suspension was forcedly orally administered to guinea pigs (compound a administration group) at a dose of 10mg/kg once a day for the day of exposure to smoke one hour before the smoke exposure and the morning of non-exposure.

Guinea pigs in the vehicle administration group were orally administered a 0.5% aqueous solution of tragacanth gum without compound a, instead of a suspension of compound a.

The guinea pigs of the control group were given neither 0.5% aqueous tragacanth solution nor a suspension of compound a.

Its respiratory function (specific airway resistance and peak expiratory flux) was measured non-invasively using a two-chamber plethysmography using a respiratory function measuring instrument (Pulmos-I, manufactured by m.i.p.s.co.) in guinea pigs consciously every week before and during four weeks of exposure to cigarette smoke.

Respiratory function (i.e., specific airway resistance and peak expiratory flow values) is expressed as the average of 100 measurements of function and is displayed as a percentage of the change in the corresponding value of respiratory function measured prior to exposure to cigarette smoke.

The results are shown in tables 1 and 2 below.

TABLE 1 specific airway resistance value variation

Experimental group	1 week after Exposure (%)	2 weeks after Exposure (%)	3 weeks after Exposure (%)	4 weeks after Exposure (%)
					Control group vehicle administration group Compound A	-3.23±16.20202.35±65.10*12.75±7.45#	-10.60±17.94188.64±58.07*41.82±26.91#	-4.35±17.82231.34±67.33**61.08±29.27#	7.61±21.57216.57±55.91**51.26±24.28#

Administration set

*: p < 0.05, x: p is less than 0.01: significant difference from control group (Student's test)

#: p is less than 0.05: has significant difference with the vector administration group (Student's test)

TABLE 2 Peak expiratory flux Change

Experimental group	1 week after Exposure (%)	2 weeks after Exposure (%)	3 weeks after Exposure (%)	4 weeks after Exposure (%)
					Control group vehicle administration group Compound A	10.31±5.63-22.57±4.83**9.67±8.48##	8.26±10.15-10.44±6.9015.67±14.98#	17.33±12.99-2.09±4.4814.08±8.48	53.57±21.3226.26±5.5437.06±11.33

Administration set

**: p is less than 0.01: significant difference from control group (Student's test)

# #: p is less than 0.01: has significant difference with the vector administration group (Student's test)

Tables 1 and 2 mentioned above have clearly demonstrated that compound a shows excellent improvement in both specific airway resistance and peak expiratory flux parameters (compared to those obtained for the vehicle-administered group). Therefore, it is apparent that compound a has an improving effect on the deterioration of lung function.

Claims (2)

1. Use of a compound for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease, which comprises as an active ingredient at least one compound selected from the group consisting of thiazole derivatives represented by the general formula (1) and salts thereof,

wherein R1 is a phenyl group which may have, as a substituent, 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms in the phenyl ring; r2 is a pyridyl group which may have 1 to 3 carboxyl groups as substituents on the pyridine ring.

2. Use according to claim 1, wherein the thiazole derivative is 6- [2- (3, 4-diethoxyphenyl) thiazol-4-yl ] pyridine-2-carboxylic acid.