WO2004004773A1 - Remedies for respiratory diseases - Google Patents

Abstract

A remedy for respiratory diseases which comprises an antagonistic compound to cysLT1 receptor and an antagonistic compound to cysLT2 receptor. A compound antagonistic to both of cysLT1 receptor and cysLT2 receptor or a preparation comprising the combined use of an antagonistic compound to cysLT1 receptor and an antagonistic compound to cysLT2 receptor is useful as a remedy for respiratory diseases. It is expected that such a remedy is highly useful as a remedy for respiratory diseases (for example, bronchial asthma, chronic obstructive pulmonary disease, etc.) which is superior in therapeutic effect to the existing cysLT1 receptor-selective antagonist.

Description

 Description Respiratory disease therapeutic agent Technical field

The present invention relates to a respiratory disease treatment agent comprising cys 1 \ antagonize the receptor compound and cys LT ₂ compounds拮pile receptor. Background art

Bronchial asthma is a disease in which the airways are narrowed due to airway constriction and inflammation, and exhibit paroxysmal cough, wheezing, and dyspnea. While bronchial asthma is known to involve a variety of chemical Medei d one coater, among which Shisuti sulfonyl Roy Coto Lien _{(cys LT s; LTC 4,} LTD 4, LTE 4) are approximately as compared to histamine It has 1000 times stronger airway constriction. In addition, cys LT s has an effect of inducing airway inflammation mainly in inflammatory cell infiltration in the airways, enhancing airway hypersensitivity and promoting mucus secretion in the airways, and is deeply involved in the basic pathology of bronchial asthma are doing.

Cys LT s is a metabolite of 5-lipoxygenase of arachidonic acid and is a biologically active substance in the organism. There are at least two types of receptors for cys LTs, and the cys 1 \ receptor and cys LT ₂ receptor have been cloned (Nature, 399, 789-793, 1999; J. Biol., Chem., 275, 30531-30536, 2000). The cys LT i receptor is mainly expressed on airway smooth muscle and inflammatory cells and is deeply involved in the development of bronchial asthma (Am. J. Respir. Crit. Care Med., 163, 226-233, 2001). In addition, leukotriene (LT) receptor antagonists significantly improve respiratory function in chronic obstructive pulmonary disease (COPD), suggesting that cys LT receptor plays an important role in COPD. (Eur. Respir. J., 16, 276s, 2000). The currently marketed LT receptor antagonists (pranlukast hydrate, montelukast sodium and zafirlukast) are selective cys LTi receptor antagonists (Nature, 399, 789-793, 1999). ) The bronchial asthma has acquired indication. These cys LT \ receptor antagonist in vitro (in vitro) by LTC ₄ and by LTD ₄ contractions human trachea muscle induced to completely inhibit (Am. Rev. Respir. Dis. , 146, 923-929, 1992), suppresses eosinophil infiltration into the respiratory tract (Eur. Respir. J., 14, 12-18, 1999) and airway hyperresponsiveness in patients with bronchial asthma (Respir. Med., ^ Z, 133-138, 1993), inhibiting mucus secretion in the respiratory tract (Am. J. Respir. Crit. Care Med., 165, 108-116, 2002), and in many clinical trials It has been recognized as a useful therapeutic agent for bronchial asthma that can improve respiratory function. Based on the above, the cys LT receptor plays an important role in bronchial asthma, and antagonizing the cys LT receptor has been considered as one of the drug treatments for bronchial asthma. 778-784, 2001).

- how, new black one Jung has been cys LT ₂ receptors are the cys 1 \ receptor as well as LTC _4, 1 ^ Ding 0 ₄ Oyobi Ding £ ₄ ligand, which represents originating in bronchial smooth muscle (J. Biol. Chem "275, 30531-30536, 2000, Am. J. Respir. Crit. Care Med .. 164. 2098-2101, 2001) However, cys LT ₂ reception in disease states Little is known about the functions and roles of the body.

Bay—U97733 developed as a therapeutic agent for bronchial asthma. 3 1 ^ Ding ₁ receptor and cys LT ₂ to the receptor antagonizing are known (Mol. Pharmacol., 1601-1608, 2000) Significance of antagonizing the cys LT ₂ receptors in force bronchial asthma The details have not been clarified. Also cys and 1 \ ぉ. antagonizing ys Ding ₂ receptor DUO- LT is been reported to develop a clinical targeting ischemic diseases and inflammatory diseases les, Ru (98th American Thoracic Society 2002, Atranta , Advance Program D38, F4) . From the above, cy in bronchial asthma up to now s the role of the LT ₂ receptor has not been completely proven.

 It is known that currently marketed LT receptor antagonists respond to mild and moderate bronchial asthma, and there are non-responders in mild and moderate cases that do not show the efficacy of the drug . Therefore, LT receptor antagonists that can be expected to be more effective than at present have been sought.

Therefore, if the cys otocho ₂ receptor is involved in bronchial smooth muscle contraction, airway inflammation, airway hyperreactivity, and mucus secretion in the airway, as in the case of the 0: ys1 \ receptor, and cys LT ₂ receptors by simultaneously antagonizing believed respiratory diseases therapeutic agent useful than existing L T receptor antagonists can be created. For example, simultaneous antagonism of the cys LT \ and cys LT ₂ receptors can be effective in patients with more severe bronchial asthma and non-responders of existing LT receptor antagonists Can be expected. Disclosure of the invention

The present inventors have conducted intensive studies in view of the above-mentioned problems of the prior art, and as a result, by simultaneously antagonizing the cys LT \ receptor and the cys LT ₂ receptor, a more useful respiratory receptor than existing leukotriene receptor antagonists was obtained. The present inventors have found that it can be used as a therapeutic agent for organ diseases and completed the present invention.

 That is, the present invention

(1) cys 1 \ compounds that antagonize the receptor cys Ding ₂ receptor respiratory diseases containing a compound that antagonizes,

(2) cys 1 preceding compounds that antagonize the receptor cys LT ₂ compounds that antagonize the receptor is the same compound (1), wherein the therapeutic agent,

 (3) The therapeutic agent according to the above (1), which is a respiratory function improving agent,

(4) The therapeutic agent according to (4), wherein the respiratory function is spirometric capacity, respiratory resistance, or oxygen exchange capacity. (5) The therapeutic agent according to the above (1), wherein the compound that inhibits cys and 1 \ receptor is Bay—u 9773 or D UO—LT.

 (6) The therapeutic agent according to the above (1), wherein the compound that antagonizes the cys LT2 receptor is Bay-u 9773, or DUO-LT.

 (7) c y s! ^ Compounds that antagonize the receptor include pranlukast hydrate, montelcast sodium, zafirlukast, MK-571, LY-2036

47, WY-46016, WY-48422, WY-49353, WY-49451, RG-12553, MDL-43291, CGP-44044A, RG-14524, LY-2877192, LY-290324, L-695 499 , RPR_ 105735B, WAY-125007, OT—4003, LM-1376, LY—290154, SR—2566, L—74051 5, LM—1453, CP_195494, LM-1484, CR—3465, Abrucast, Pobil force St, Sulcast, L—648051, RG-12

525, RG_7 152, SK & F—106203, SR—2640, WY—50295, sodium ilarkast, benolenorecast, MCC—847,

B AY- X-7195, Lithorenocast, Sinalcast, CGP_44826, FK-011, YM-158, MEN-91507, KCA- 757, RS

— 601, RS—635, S—36496, ZD—3523, DS-4574, piromast, AS—35, YM-57158, MC1826, NZ_107, 4414—CERM, YM—16638, Wy — 48252, Wy

— 44329, Wy—48090, VUF—4679, Tomenolecast, SM—1 1044, SC—39070, OT—3473, N—2401, LY—243364, L—649923, Doklast, DP—1934, YM—1755 1, Wy—47 1 20, VUF—K—8707, SK & F—880 46, SK & F—101 1 32, SK & F—102922, LY—1 376 17, LY—163443, LY—302905, L-647438, L- 708738, KY-234, FPL-55712, CP-288886, S-36527, CS-615, MD L-1 9301 D, SCH-401 20 and ZD-3705 The therapeutic agent according to the above 1

(8) The therapeutic agent according to the above (1), wherein the compound that antagonizes the cys-1 receptor is pranlukast hydrate, montelukast sodium, or zafirlukast;

 (9) The therapeutic agent according to (1), wherein the respiratory disease is bronchial asthma, chronic obstructive pulmonary disease, interstitial pneumonia, severe acute respiratory syndrome, acute respiratory distress syndrome, rhinitis, or sinusitis.

 (10) The therapeutic agent according to the above (1), which is an expectorant or an antitussive.

 (1 1) The therapeutic agent according to the above (1), which is for administration to a non-responsive patient.

 (1 2) The therapeutic agent according to (1), which is combined with one or two agents selected from steroids and sympathomimetics,

(13) cys LT \ receptor antagonism and cys LT ₂ receptor antagonism 0.1 mu Micromax following IC _5. The therapeutic agent according to the above (1), which shows a value,

(14) The therapeutic agent according to the above (1), wherein the cys LT ₂ receptor antagonism exhibits an IC ₅₀ value of 0.1 // M or less.

(15) cys LT \ receptor antagonism and cys LT ₂ receptor antagonism preceding show K i values below _0.1 μ Μ (1), wherein the therapeutic agent,

(16) cys Ding ₂ receptor antagonism preceding showing the following K i values of 0.1 // M (1) wherein the therapeutic agent,

 (17) The therapeutic agent according to (14), wherein the activity ratio represented by the following formula (1) is 0.01 to 100:

, 'IC ₅ tongue ratios cysLT ₁ receptor antagonism. Value ( ₁ )

IC for cysLT ₂ receptor antagonism. value (18) The therapeutic agent according to the above (16), wherein the activity ratio represented by the following formula (2) is 0.01 to 100:

^ ,. ^ cysL "^ の value of receptor antagonism

Sex ratio = ^! (2)

Ki value of cysl_T ₂ receptor antagonism

(1 9) a method of treating respiratory disorders which comprises administering a compound which antagonizes the compound cys LT ₂ receptor antagonizing cys 1 \ receptor effective amount to a mammal,

(20) use of a compound that antagonizes cys- ₁ receptor and a compound that antagonizes cys-1 receptor for the manufacture of a therapeutic agent for respiratory disease, and

(21) A therapeutic agent for a respiratory disease comprising a compound that antagonizes cys- ₂ receptor.

In the present invention, cys and 1 \ a compound which antagonizes the receptor and cys LT ₂ compounds that antagonize the receptor may be the same or different.

Since the therapeutic agent of the present invention antagonizes the cys LT \ receptor and the cys LT ₂ receptor, for example, an airway constriction inhibitor, an inflammatory cell (eg, eosinophil, neutrophil, lymphocyte, basophil, etc.) ) Are useful as infiltration inhibitors, mucus secretion inhibitors, and airway hypersensitivity inhibitors. Further, the therapeutic agent is cys LT \ receptors and cys to Ding ₂ disease receptor is involved in the present invention, for example, respiratory diseases (e.g., bronchial asthma, chronic obstructive pulmonary disease, interstitial pneumonia, severe acute It is useful as a preventive and therapeutic agent for respiratory syndrome (SARS), acute respiratory distress syndrome (ARDS), rhinitis, sinusitis, etc., expectorants and antitussives. The therapeutic agent of the present invention is also useful as a respiratory function improving agent. Respiratory functions include, for example, the ability to move air into and out of the lungs (virtual capacity), the ability to pump oxygen from the lungs into the blood, and to transport carbon dioxide out of the blood (oxygen exchange capacity) and respiratory resistance. Say.

In the present invention, the respiratory organ is, for example, an airway, an oral cavity, a nasal cavity, a sinus, a trachea, It refers to the body part involved in breathing, such as bronchi, bronchioles, and lungs.

 In the present invention, a non-responder is a patient who does not achieve a sufficient or no effect even when an existing LT receptor antagonist is administered. Since the therapeutic agent of the present invention is a more useful therapeutic agent for respiratory diseases than existing LT receptor antagonists, it does not respond to patients or patients with severe impairment in respiratory function (for example, patients with severe bronchial asthma) Is preferably administered.

 In the present invention, the activity ratio represented by the above formula (1) is preferably from 0.01 to 100, and more preferably from 0.1 to 10.

 In the present invention, the activity ratio represented by the above formula (2) is preferably from 0.01 to 100, and more preferably from 0.1 to 10.

In the present invention, cys 1 \ receptor antagonism and cys LT ₂ receptor拮IC ₅ anti action. The method for measuring the value or K i value is not particularly limited, and can be measured according to a known method. For example, it can be carried out according to the method described in Nature, 399, 789-793, 1999 or J. Biol. Chem., 275, 30531-30536, 2000.

In the present invention, as the compound antagonize both cys LT \ receptors and cys LT ₂ receptors, e.g., B ay- u 9773, DUO- LT is Ru mentioned.

In the present invention, examples of compounds that antagonize cys and 1 \ receptor include plan ^ / cast hydrate, montanolecast sodium, zafinolenocast, MK-571, LY-203647, WY-46016, WY — 48422, WY-49353, WY-49451, RG—12553, MDL—43291, CGP-44044 A, RG—14524, LY—287192, L Υ—290324, L—6995499, R PR-105735 B , WAY-1 25007, OT-4003, LM-1376, LY-290154, SR-2566, L-174051 5, LM-1453, CP-195494, LM-1484, CR-3465, Abrucast, Povircus G, Surkas , L-648051, RG-12525, RG-71 52, SK & F-106203, SR-2640, WY-50295, Iralkast sodium, Berlukast, MCC-847, BAY-X-7195, Littlecus G, sinal cast, CGP_44826, FK-011, YM-158, MEN-91 507, KC A-757, RS-601, RS-635, S-36649, ZD-3523, DS-4574, Piro Domast, AS—35, YM—57158, MC I 826, NZ—107, 4414—CERM, YM—1 6638, Wy—48252, Wy—44329, Wy-48090, VU F—4679, Tomercast, SM—1 1044, SC—39070, OT—3473, N—2401, LY—243364, L—649923, Doctor, DP—1934, YM-17551, Wy—47 120, VUF—K—8707, SK & F_88046 , SK & F— 1 01 132, SK & F— 102922, LY— 1 3761 7, LY— 163443, LY— 30 2905, L— 647438, L_708738, KY_234, FPL— 5571 2, CP— 288886, S— 36527, CGP— 35949, CS-6 15, MDL-1 9301 D, SCH- 401 20 Or ZD- 3705, and the like.

 Preferred compounds that antagonize the cys 1 \ receptor include pranlukast hydrate, montelukas sodium, zafirlukast and MK-571, and more preferably pranlukast hydrate, montelukast sodium, zafirlukast Is mentioned.

Compounds that antagonize both cys 1 \ receptor cys LT ₂ receptor used in the present invention, the compound antagonizes cys 1 receptor, and the cys LT ₂ compounds to antagonize the receptor, to date This includes not only what has been discovered but also what will be discovered in the future.

Compounds that antagonize both cys 1 \ and cys LT ₂ receptors, cys was compound antagonizes 1 \ receptors, and cys LT ₂ compounds that antagonize the receptors also include those made with a pharmaceutically acceptable salt form or prodrug form.

In the present invention, a compound which antagonizes the compound cys LT ₂ receptor antagonizing cys 1 receptor, in a form which is formulated in one formulation may be administered, administered in separate preparations, namely It may take the form of combined administration. This combined administration includes simultaneous administration and administration with a time difference. In the case of administrations with time difference, the administration of the compounds to antagonize the cys 1 \ receptors may be firstly administered after the compounds to antagonize cys LT ₂ receptor, antagonize the cys LT ₂ receptor The compound may be administered first and the compound that antagonizes the cys 1 ^ 1 \ receptor may be administered later, and the respective administration methods may be the same or different.

compounding ratio of cys 1 antagonizing receptor compounds and cys LT ₂ compounds that antagonize the receptor, age and body weight of the administration subject, administration route, administration time, target disease, condition, be appropriately selected by a combination it can. For example, the compound 1 part by weight of antagonizing cys LT \ receptors, a compound that antagonizes cys LT ₂ receptor may be used in an amount of 0.01 to 1 0 0 parts by weight.

 In addition, the therapeutic agent of the present invention comprises (1) a supplement and / or enhancement of the preventive and / or therapeutic effect of the therapeutic agent of the present invention, (2) improvement in kinetics and absorption of the therapeutic agent of the present invention, and a reduction in dosage. , And Z or (3) In order to reduce the side effects of the therapeutic agent of the present invention, it may be administered in combination with another agent in combination.

The combination preparation of the therapeutic agent of the present invention and another drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or may be in the form of separate preparations for administration. . The administration in the form of separate preparations includes simultaneous administration and administration with a time lag. In addition, the administration at a time difference may be performed by administering the therapeutic agent of the present invention first and then administering the other agent later, or administering the other agent first and then administering the therapeutic agent of the present invention later. Regardless, each administration method is the same but different May be.

 The other drug may be a low molecular compound, a high molecular protein, a polypeptide, a polynucleotide (DNA, RNA, gene), an antisense, a decoy, an antibody, or a vaccine. Is also good. The dose of the other drug can be appropriately selected based on the clinically used dose. Further, the compounding ratio of the therapeutic agent of the present invention to other agents can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination, and the like. For example, 0.01 to 100 parts by mass of another agent may be used for 1 part by mass of the therapeutic agent of the present invention. Other drugs may be administered in any combination of two or more at an appropriate ratio. Further, other drugs that supplement and / or enhance the prophylactic and / or therapeutic effects of the therapeutic agent of the present invention are based on the above-mentioned mechanism, and are to be found not only to date but also to date. Things are included.

 Diseases in which a prophylactic and / or therapeutic effect is exhibited by the above concomitant drug are not particularly limited, and may be any disease that complements and / or enhances the preventive and / or therapeutic effects of the therapeutic agent of the present invention.

For example, other drugs for supplementing and / or enhancing the preventive and / or therapeutic effects of the therapeutic agent of the present invention on respiratory diseases include, for example, antihistamines, antiallergic agents (chemical mediator release inhibitors) , Histamine antagonist, thromboxane synthase inhibitor, thromboxane antagonist, Th2 site force-in inhibitor), steroid, bronchodilator (xanthine derivative, sympathetic stimulant, parasympathetic blocker), Vaccine therapeutics, gold preparations, Kampo preparations, basic non-steroid anti-inflammatory drugs, 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, leukotriene synthesis inhibitors, prostaglandins, cannapinoids 1 2 Receptor stimulants, antitussives, expectorants, vaccinia virus-grafted rabbit inflamed skin extracts and the like. Examples of antihistamines include diphenhydramine, diphenylpyrazine hydrochloride, dipheniruraline diocleate, clemastine fumarate, dimen hydrinate, d1—chronorefenylamine maleate, d-chlorpheniramine maleate, triprolidine hydrochloride. , Promethazine hydrochloride, Alimezine tartrate, Isotipendyl hydrochloride, Homochlorcyclidine hydrochloride, Hydroxidine, Cyproheptadine hydrochloride, Levocabastine hydrochloride, Astemizizolu, Bepotastine, Destoratazine, TAK_427, ZCR-260 , NIP-530, mometasoneof mouth, mizolastine, BP-294, andlast, ortholanifin, acrivastin and the like.

 Among the antiallergic agents, examples of the chemical mediator release inhibitor include sodium cromoglycate, tranilast, amlexanox, revinast, ibudilast, ぺ milorast potassium, dazanolast, nedocromil, chromoglycart, and israpaphant. .

 Among the antiallergic agents, histamine antagonists include, for example, ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, terfenadine, hemedastine fumarate, epinastine hydrochloride, ebastine, cetilidine hydrochloride, olopatadine hydrochloride, fulatatadine And sofenadine. Among the antiallergic agents, the thromboxane synthase inhibitor includes, for example, ozadarrel hydrochloride, imitrodastane sodium and the like.

 Among the antiallergic agents, the thromboxane antagonist includes, for example, cerato mouth dust, ramatroban, domitroban calcium hydrate, KT-2-962, and the like.

 Among the antiallergic agents, examples of the Th2 site force-in inhibitor include suplatast tosilate and the like.

Topical steroids include, for example, clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furoate, Betamethasone dipropionate, betamethasone butyrate, betamethasone valerate, difluprednate, pudesonide, diflucortron valerate, famcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone valerate, dexamethasone valerate Hydrocortisone butyrate, Hydrocortisone butyrate propionate, Deprodone propionate, Prednisolone valerate acetate, Fluocinolone acetonide, Beclomethasone propionate, Triamcinolone acetonide, Flumethasone pivalate, Alclomethasone propionate, Butycrosone butyrate , Prednisolone, ぺ clomethasone propionate, fludroxycortide, and the like. Examples of oral medicines and injections include vinegar. Cortisone, hydrocortisone, sodium hydrocortisone phosphate, sodium hydrocortisone sodium succinate, fludroconoretisone sodium acetate, pred-zolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium halopredomone , Methylprednisolone, methinoleprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, betamethasone acetate Inhalants include, for example, betamethasone propionate, flutipropionate propionate Dzone, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone paromithionate, mometasone furan carbonate, plasterone sulfonate, deflazacort, methylprednisolone reptanate, methyl prednisolone sodium And succinate.

Among the bronchodilators, the xanthine derivatives include, for example, aminophylline, theophylline, doxophylline, sipamphylline, diprofylline, proxifylline, and choline theophylline. Among the bronchodilators, the sympathetic stimulants include, for example, epinephrine, ephedrine hydrochloride, d1-methylefedrine hydrochloride, methoxyphenamine hydrochloride, isoproterenol sulfate, isoproterenol hydrochloride, orciprenaline hydrochloride, and cupreline hydrochloride Mouth luprenaline, trimethoquinol hydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, llobuterol hydrochloride, proforcerol hydrochloride, phenoterol hydrobromide, formoterol fumarate, clenbuterol hydrochloride, mabuterol hydrochloride, salmeterol xinafolate, R, -R Mouth, Mouth Bute, Pirbute Hydrochloride, Lithodrine Hydrochloride, Bumpterol, Doxamine Hydrochloride, Meradrine Tartrate, AR-C 68397, Levosalbutamonole, KUR- 1 246, KUL -72 11 1, AR—C89855, S_ 1319, etc.

 Among the bronchodilators, the parasympathomimetics include, for example, iprat poutium bromide, furpout poutium bromide, oxitropium bromide, shimetropium bromide, temiverine, tiotropium bromide, revatropate (UK-1 1 21 6 6).

 Vaccine therapeutics include, for example, Passpart, Astremedin, Bron Kasuma. Berna, CS-560 and the like.

 Examples of the gold preparation include gold sodium thiomalate. Examples of the basic non-steroid anti-inflammatory drug include tiaramid hydrochloride, tinolidine hydrochloride, epirizonole, emomonorefazone and the like.

Examples of 5-lipoxygenase inhibitors include Zyleuton, Docebenone, Piripost, SCH-40120, WY-50295, E-6700, ML-3000, TMK-688, ZD-2138, Darbuferon mesylate, R—68 151, E—6080, Du P—654, SC—45662, CV-6504, NE—1 1740, CM 1—977, NC—2000, E—3040, PD—1 36095, CM 392, TZ I—41 078, Or f — 20485, I DB — 18024, BF — 389, A — 78773, TA — 270, FLM-5011, CGS — 23885, A-79 175, ETH-615, and the like.

 Examples of the 5-lipoxygenase activating protein antagonist include MK-591 and MK-886.

 Examples of leukotriene synthesis inhibitors include auranofin, progamatasin maleate, L-674636, A-81834, UP A-780, A-93178, MK-886, REV-5901A, SCH-40 120, MK-591, Bay-x-1005, Bay-y-1015, DTI-0226, Amlexanox, E-6700 and the like.

 Examples of prostaglandins (hereinafter abbreviated as PG) include PG receptor agonists, PG receptor antagonists and the like.

 Examples of PG receptors include PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TX Receptor (TP) and the like.

 Examples of antitussives include codine phosphate, dihydrocodine phosphate, oxymethebanol, dextromethorphan hydrobromide, pentoxiberin citrate, dimemonolephane phosphate, oxerasin quenate, cloperastine, benproperin phosphate, clofedanol hydrochloride, Examples include hominoben hydrochloride, noscapine, thymidine hibenzate, eprazinone hydrochloride, and shazensou extract.

Examples of expectorants include ammonia whiskey, sodium hydrogen carbonate, potassium iodide, bromhexine hydrochloride, cherry bark extract, carbocistine, fudostin, ambroxol hydrochloride, ambroxol hydrochloride sustained-release agent, methyl cysteine Hydrochloride, acetyl cysteine, L-ethyl cysteine hydrochloride, tyloxapol and the like. The other drug is preferably a steroid drug or a sympathomimetic. Formulations for carrying out the present invention, compounds that antagonize both cys 1 \ receptor cys LT ₂ receptors, and cys! ^ 7 \ compounds to antagonize the receptor, the cys and Ding ₂ receptor It may be a formulation in which an antagonistic compound and another agent that complements and / or enhances the therapeutic effect of the compound are combined in one formulation, or may be a formulation in which each component is separately formulated. These formulations can be prepared by known methods.

 For use in the present invention, it is usually administered systemically or locally, in an oral or parenteral form.

 The dosage varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 1 mg to 100 mg per day per adult, once to several times a day. Orally or parenterally (preferably intravenously) once or several times daily, in the range of 1 mg to 100 mg per adult per dose; or It is continuously administered intravenously for 1 to 24 hours a day.

 Of course, as described above, the dose varies depending on various conditions, so a smaller dose than the above-mentioned dose may be sufficient, or may be required beyond the range.

 When administering a compound for the purpose of the present invention, a solid preparation for oral administration, a liquid preparation for oral administration, an injection for parenteral administration, an external preparation, a suppository, an eye drop, an inhalant, etc. Used as

 Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.

 Capsules include hard capsules and soft capsules.

In such solid dosage forms, one or more active substances may be intact or excipients (lactose, mannitol, glucose, micro- Crystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (calcium fiber glycolate, etc.), lubricants (magnesium stearate, etc.), It is mixed with stabilizers and solubilizers (glutamic acid, aspartic acid, etc.), etc., and used in the form of a formulation according to the usual methods. If necessary, it may be coated with a coating agent (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.), or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin.

 Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, Includes L, syrup, elixir, etc. In such solutions, one or more active substances are dissolved, suspended, or emulsified in a commonly used diluent (such as purified water, ethanol, or a mixture thereof). Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used. Further, this injection contains a stabilizer, a solubilizing agent (daltamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Is also good. These are prepared by sterilizing or aseptic processing in the final step. In addition, a sterile solid preparation, for example, a lyophilized product, can be manufactured and then used after dissolving in sterile or sterile distilled water for injection or other solvents before use. Dosage forms of eye drops for parenteral administration include eye drops, suspension-type eye drops, emulsion-type eye drops, dissolvable-type eye drops and eye ointments.

 These eye drops are produced according to a known method. For example, in the case of eye drops, isotonic agents (sodium chloride, concentrated glycerin, etc.), buffering agents (sodium phosphate, sodium acetate, etc.), surfactants (polysorbate 80 (trade name), stearic acid) Polyoxyl 40, polyoxyethylene hydrogenated castor oil, etc.), stabilizing agents (sodium citrate, sodium edetate, etc.), preservatives (benzanolone chloride, paraben, etc.), etc. are appropriately selected and manufactured as required. You. These are produced by sterilization or aseptic processing in the final step.

 Inhalants for parenteral administration include aerosols, powders for inhalation, and liquids for inhalation, which are used by dissolving or suspending in water or other appropriate medium at the time of use. It may be in a form to perform.

 These inhalants are manufactured according to a known method.

 For example, in the case of liquids for inhalation, preservatives (benzalkonium chloride, paraben, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), tonicity agents (sodium chloride, concentrated glycerin, etc.) It is manufactured by appropriately selecting a thickening agent (such as a cariboxyvul polymer), an absorption promoter and the like as needed.

 In the case of powders for inhalation, lubricants (stearic acid and its salts, etc.), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), coloring agents, preservatives (benzalkonium chloride, paraben) Etc.) and an absorption enhancer, etc., are appropriately selected as necessary and produced.

 A nebulizer (atomizer, nebulizer) is usually used to administer inhaled liquids, and a powdered inhaler is usually used to administer inhaled powders.

Other preparations for parenteral administration include topical solutions, ointments, salves, sprays, containing one or more active substances and prescribed in a conventional manner. And suppositories and pessaries for vaginal administration.

 Sprays may contain, besides commonly used diluents, buffers that provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate or citric acid. It may be contained. Methods for producing spray agents are described in detail, for example, in U.S. Pat. Nos. 2,868,691 and 3,095,355. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the inhibitory effects of Montenorecastonatrime and Bay-u 9773 on monoremot tracheal muscle contraction. BEST MODE FOR CARRYING OUT THE INVENTION

cys was 1 ^ receptor cys LT ₂ receptors simultaneously respiratory function improving agent which antagonizes may be the existing more effective highly respiratory function improving agent than Roikotoryen antagonists (e.g., bronchial asthma agent) Was proved by the following experiment.

 The measurement method of the present invention shown below is an improvement of measurement accuracy and measurement sensitivity in order to evaluate compounds as described below.

In the following experiments, as cys 1 \ receptor cys LT ₂ receptors simultaneously拮against test compound, 5 (S) - human Dorokishi one 6 (R) -S- (4, - Karubokishifue two thio) _ 7 (E), 9 (E), 11 (Z), 14 (Z) —Eicosatetraenoic acid (Bay—U 9773) was used. The compound is described in Example 6 of the published specification EP410244.

In addition, as a test compound which selectively antagonizes cys LT \ receptor, 1-((((1 (R) 1 (3- (2- (7-chloro-1-2_quinolinyl) ethynyl) phenyl) -3) (2— (1—hydroxy 1-methylethyl) feninole) propinole) Zio) Methyl) Cyclopropaneacetic acid sodium salt (Montelukastnadium) was used. Said compound is described in Example 8 of the published specification WO95 / 18107.

(1) Evaluation of antagonism to cys LT \ receptor and cys LT ₂ receptor (Nature, 399, 789-793, 1999, J. Biol. Chem., 275, 30531-30536, 2000) Te were measured cys LT \ receptor and cys antagonize activity against Ding ₂ receptors of various compounds.

 (2) Evaluation of inhibitory effect on guinea pig tracheal muscle contraction

This experiment consisted of 6 cases per group, using Hartley male guinea pigs (Japan SLC Co., Ltd.). Active sensitization was administered guinea pig ovalbumin (OVA, Sigma) intraperitoneally saline 0.5 m L containing 1 mg and killed Bordetella pertussis (Chemo-Sero-Therapeutic Research Institute) 5 X 1 0 ^9. After 14 to 20 days of active sensitization, guinea pigs were killed by exsanguination using the carotid artery and their trachea was immediately removed. The extracted trachea was zigzag cut with a force razor to prepare a 3 mm wide tracheal muscle specimen. The specimen was kept at 37 ° C and a mixture of gas (95% oxygen + 5% carbon dioxide) was aerated with Krebs, solution (sodium hydroxide 119 mM, potassium chloride 4.6 mM, chloride). The suspension was suspended in a Magnus tube (containing 10 mL) containing 1.8 mM calcium, 0.5 mM magnesium sulfate, 24.9 mM sodium bicarbonate, 1.0 mM potassium dihydrogen phosphate, and 11. ImM glucose. The tracheal muscle was subjected to a 1 g tension load and washed with Creps nutrient solution every 60 minutes for 60 minutes. After tension specimen was stabilized, to enhance the production of cys LT s antigen-induced 6 0 minutes ago to inhibit histamine Ya cycloalkyl O key Shige kinase metabolite, either like a final concentration of 1 0- ⁴ M Were treated with pyrilamine (Sigma) and indomethacin (Sigma). The tracheal muscle contraction response is induced by an OVA solution at 10 ng Zm1, and the change in isometric tension is controlled by a strain pressure amplifier (Nihon Kohden Kogyo Co., Ltd.) via an isometric transducer (Nihon Kohden Corporation). ) And the average output was recorded on the recorder. Suffered The test compound was treated to a final concentration of 10 to ¹⁶ M 30 minutes before the antigen induction, and the time-dependent change in the tension due to OVA was observed. The efficacy was evaluated when the contractile response by OVA became a plateau, and the tracheal muscle contraction rate was calculated from the maximum contractile response obtained with acetylcholine (Sigma) at a final concentration of 1 mM. The values in each group are shown as the average soil standard error of six cases. The significance test was performed using the student's t-test, and a significance level of 5% or less was considered significant compared to the control.

 The results are shown in Figure 1.

From the results of FIG. 1, compound simultaneously antagonize the cys 1 \ receptors and cys LT ₂ receptors in bronchial asthma model suppresses significantly tracheal muscle contraction than compounds you selectively antagonize cys LT receptor It became clear.

Claims

The scope of the claims 1. cys 1 respiratory disease therapeutic agent comprising a compound which antagonizes the receptor compounds that antagonize body and cys LT ₂ receptor. 2. The therapeutic agent according to claim 1, wherein the compound that antagonizes the cys 1 receptor and the compound that antagonizes the cys LT ₂ receptor are the same compound. 3. The therapeutic agent according to claim 1, which is a respiratory function improving agent. 4. The therapeutic agent according to claim 4, wherein the respiratory function is spirometric capacity, respiratory resistance capacity, or oxygen exchange capacity. 5. The therapeutic agent according to claim 1, wherein the compound that antagonizes cys and 1 \ receptors is Bay—u9773 or DUO—LT. 6. The therapeutic agent according to claim 1, wherein the compound that antagonizes the cys Otocho ₂ receptor is Bay_u 9773, or D UO-LT. 7. Compounds that antagonize cys 1 \ receptor are pranlukast hydrate, sodium montelkast, zafirlukast, MK—571, LY-2036 4 7, WY- 4 6 0 16, WY- 4 8 4 2 2, WY- 4 9 3 5 3, WY- 4 94 5 1, RG- 1 2 5 5 3, MDL-4 3 29 1, CG P—44044 A, RG—1 524 24, LY—2 8 7 1 9 2, LY—2 9 0 3 24, L—6 9 5 4 9 9, RPR-1 0 5 7 3 5 B, WAY — 1 2 500 7, OT— 400 3, LM-1 3 7 6, LY— 2 90 1 54, SR— 2 5 6 6, L— 74 0 5 1 5, LM- 1453, CP- 1 95494, LM- 1484, CR- 3465, Able-force, Povinole-force, Snorre-force, L- 648051, RG-12525, RG- 71 52, SK & F- 106203, SR_2640, WY -50295, Sodium lanolecast, Benolenorecast, MCC-847, BAY-X-7195, Littlecast, Sinalukast, CGP-44826, FK-011, YM-158, MEN-911507, KCA-757, RS 601, RS—635, S—36496, ZD—3523, DS—4574, pirodast, AS—35, YM-5715.8, MC1826, NZ—107, 4414—CERM, YM_16638, Wy— 48252, Wy — 44329, Wy—48090, VUF—4679, Tomerkast, SM—1 1044, SC—39070, OT—3473, N—2401, LY—243364, L—649923, Doklast, DP—934, YM—1551 , Wy—471 20, VUF—K—8707, SK & F—880 46, SK & F—101 1 32, SK & F—102922, LY—1 376 17, LY-1 63443, LY—302905, L—647438, L_ 708738, Claim 1 which is one selected from KY_234, FPL-55721, CP-288886, S-36527, CS-615, MD L-1 9301 D, S CH-401 20 and ZD-3705. Therapeutic agent. 8. The therapeutic agent according to claim 1, wherein the compound that antagonizes the cytosine 1 \ receptor is pranlukast hydrate, montelukas sodium, or zafirlukast. 9. Claims wherein the respiratory disease is bronchial asthma, chronic obstructive pulmonary disease, interstitial pneumonia, severe acute respiratory syndrome, acute respiratory distress syndrome, rhinitis, or sinusitis The therapeutic agent according to box 1. 10. The therapeutic agent according to claim 1, which is an expectorant or an antitussive. 1 1. The therapeutic agent according to claim 1, which is for administration to a non-responder patient. 1 2. The therapeutic agent according to claim 1, which is combined with one or two agents selected from a steroid agent and a sympathomimetic agent. 1 3. cys 1 \ receptor antagonism and cys LT ₂ receptor antagonism 0.1 beta Micromax following IC _5. 2. The therapeutic agent according to claim 1, which shows a value. 14. cys and Ding ₂ receptor antagonism is below 0.1 μΜ IC _5. 2. The therapeutic agent according to claim 1, which shows a value. 1 5. The therapeutic agent according to claim 1, wherein the cys LTi receptor antagonism and the cys LT ₂ receptor antagonism exhibit a K i value of 0.1 βΜ or less. 1 6. The therapeutic agent according to claim 1, wherein the cys Otocho ₂ receptor antagonism exhibits a Ki value of Ο.ΙμΜ or less. 1 7. The therapeutic agent according to claim 14, wherein the activity ratio represented by the following formula (1) is 0.01 to 100. _¾tt ratio—cysLT ^ receptor antagonism ₍₁₎ cysLT ₂ receptor IC ₅ of antagonism. value 1 8. The therapeutic agent according to claim 16, wherein the activity ratio represented by the following formula (2) is 0.01 to 100. , 'Tongue ratio Κί value of cysLT ₁ receptor antagonism ₍₂₎ Ki value of cysl_T ₂ receptor antagonism 1 9. A method for treating a respiratory disease, comprising administering to a mammal an effective amount of a compound that antagonizes the cys 11 1 \ receptor and a compound that antagonizes the cys LT ₂ receptor. 20. Use of respiratory diseases agent cys for producing 1 \ of compounds that antagonize the receptor cys 1 chome ₂ compounds to antagonize the receptor. 2 1. A therapeutic agent for respiratory diseases consisting of a compound that antagonizes the cys ₂ receptor.