JP2000355551A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition having synergistically high prophylactic and therapeutic effects on various kinds of inflammatory diseases, reduced in adverse effects and useful as a prophylactic or a therapeutic agent by including two specific enzyme inhibitors in combination. SOLUTION: This composition is obtained by including (A) a leukotriene converting enzyme inhibitor and (B) a thromboxane converting enzyme inhibitor. The ingredient A is preferably at least one kind such as 6- [3-fluoro-5-(4- methoxytetraphydropyran-4-yl)phenoxy]methyl}-1-methylquinolin-2(1H)-one or 4-[(6-hydroxy-4,5,7-trimethyl-2-benzothiazolyl)aminomethyl]benzenesulf onamide hydrochloride. The ingredient B is preferably at least one kind such as ozagrel or isbogrel. The administration ratio of the ingredients A to B is usually within the range of (1:50) to (50:1) expressed in terms of weight ratio.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition comprising a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor.

[0002]

2. Description of the Related Art The role of chemical mediators in allergic inflammatory diseases such as asthma has been rapidly elucidated, and platelet activating factor (PAF), leukotrienes, thromboxane A _{2 and the} like have become known in addition to histamine ( "Allergy Area" Makino Souhei; 3 (1), 67-72 (199
6), Hiroi Nagai et al .; 3 (1), 51-58 (1996); Masaki Fujimura; 3 (1), 6
0-65 (1996)). Among them, it is elucidated that leukotrienes are produced from arachidonic acid by the action of 5-lipoxygenase, and that thromboxane A ₂ is produced by thiaraboxane synthase from arachidonic acid after the action of cyclooxygenase. (Masaki Fujimura, “Allergy Area” 3 (1), 60-65 (1996)).

Leukotrienes and thromboxane A ₂
Are various inflammation and allergic diseases, for example, joint inflammation such as rheumatoid arthritis, osteoarthritis, and gout; inflammatory bowel disease, inflammation of the gastrointestinal system such as gastritis; skin diseases such as psoriasis, eczema, and dermatitis; Respiratory diseases such as asthma, bronchitis, and allergic rhinitis; are known to be involved in ischemic disease, cerebral ischemic disease, and cardiac ischemic disease (Shozo Yamamoto et al., "Prostaglandin Research Method" Tokyo Chemical Industry) Doujin (1987)
etc). Therefore, studies on converting enzyme inhibitors and receptor antagonists have been conducted in order to suppress the pharmacological activity of these mediators.

[0004]

[SUMMARY OF THE INVENTION However, suppressing the pharmacological activity of the therapeutic methods and thromboxane A ₂ to suppress the pharmacological activity of the leukotrienes are mediators of inflammatory diseases by leukotriene converting enzyme inhibitors thromboxane converting enzyme inhibitors There is no sufficient therapeutic effect for such treatment.

[0005]

Means for Solving the Problems As a result of repeated studies on the prevention and treatment of various inflammatory diseases, the present inventor has found that by using a combination of a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor, various types of inflammatory diseases can be obtained. A method has been found that can significantly enhance the effect of preventing or treating diseases. That is, the gist of the present invention resides in a pharmaceutical composition comprising a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor.

According to a preferred embodiment of the present invention, zileuton, 6-[[3-fluoro-5- (4-methoxytetrahydropyran-4-yl) phenoxy] methyl]-.
1-methylquinolin-2 (1H) -one (ZD-213
8), 4-[(6-hydroxy-4,5,7-trimethyl-2-benzothiazolyl) aminomethyl] benzenesulfonamide hydrochloride (E-6080), (+)-(S)
-2- [6- (2-quinolinylmethoxy) -2-naphthyl] propionic acid (Wy-50295), N- (6-
Phenoxy-2H-1-benzopyran-3-ylmethyl) -N-hydroxyurea (CGS-23885), N
-[3- [5- (4-Fluorophenoxy) -2-furyl] -1-methyl-2-propynyl] -N-hydroxyurea (A-78773), (R) -2-cyclopentyl-2- [4 -(Quinolin-2-ylmethoxy) phenyl] acetic acid (Bay-x-1005), a leukotriene converting enzyme inhibitor selected from the group consisting of ozagrel, nafagrel, lidogrel, imidrodust, isbogrel,
(E) -2- (4-methoxy-3,6-dimethyl-2,
5-dioxo-2,5-dihydrobenzylidene) -7-
(3-pyridyl) heptanoic acid (E-6700), 4-
It consists of a thromboxane converting enzyme inhibitor selected from [hydroxy- [5- (1H-imidazol-1-yl) -2-methylphenyl] methyl] -3,5-dimethylbenzoic acid sodium salt (Y-20811). The present invention provides a pharmaceutical composition as an agent for preventing or treating inflammation, specifically, an antiallergic agent, an antiasthmatic agent, and a therapeutic agent for dermatitis.

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The leukotriene converting enzyme inhibitors used in the present invention include, for example, JP-A-63-264456, JP-A-2-268157, U.S. Pat. No. 4,929,
No. 623, U.S. Pat. No. 5,208,344,
JP-A-3-83979, JP-T-5-508861
And the compound groups described in Japanese Patent Application Laid-Open No. Hei. When these compounds have an asymmetric carbon, their optical isomers and mixtures of these isomers can also be used in the present invention. Furthermore, when a pharmacologically acceptable salt or hydrate is formed, salts and hydrates of those compounds can also be used in the present invention.

[0008] Preferred leukotriene converting enzyme inhibitors include the following compounds. JP-A-63-264
No. 456, etc. (Chemical name:
N- (1-benzo [b] thiophen-2-ylethyl)
-N-hydroxyurea). Zyleuton has an asymmetric carbon, and its optical isomers and mixtures of these isomers can be used. When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used.

6-[[3-Fluoro-5- (4-methoxytetrahydropyran-4-yl) phenoxy] methyl] -1- described in JP-A-2-268157 and the like.
Methylquinolin-2 (1H) -one (hereinafter referred to as ZD-21)
38). When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used. 4-[(6-hydroxy-4,5,7-trimethyl-2-benzothiazolyl) aminomethyl] benzenesulfonamide hydrochloride described in U.S. Pat. No. 4,929,623 and the like and a free base of this compound. When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used.

(+)-(S) -2- [6- (2-quinolinylmethoxy) -2-naphthyl] propionic acid described in US Pat. No. 5,208,344. This compound has an asymmetric carbon, and its optical isomers and mixtures of these isomers can be used. When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used. JP-A-3-839
No. 79, etc., the N- (6-phenoxy-2H
-1-benzopyran-3-ylmethyl) -N-hydroxyurea. When the compound forms a pharmacologically acceptable salt or hydrate, the salt and the hydrate of the compound are also included.

[0011] N- [3- [5- (4-fluorophenoxy) -2 described in JP-T-5-508861 and the like
-Furyl] -1-methyl-2-propynyl] -N-hydroxyurea. This compound has an asymmetric carbon, and its optical isomers and mixtures of these isomers can be used.
Further, when the compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of these compounds can also be used. (R) described in, for example, JP-T-Hei 2-19359.
-2-cyclopentyl-2- [4- (quinolin-2-ylmethoxy) phenyl] acetic acid. This compound has an asymmetric carbon, and its optical isomers and mixtures of these isomers can be used. When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used.

The thromboxane converting enzyme inhibitors used in the present invention include, for example, JP-A-57-131969, JP-A-1-316318, and JP-A-62-1.
No. 61759, JP-A-62-252784,
JP-A-58-219162, JP-A-5-7832
No. 1, JP-A-61-277670 and the like. When these compounds have an asymmetric carbon, their optical isomers and mixtures of these isomers can also be used in the present invention. Furthermore, when a pharmacologically acceptable salt or hydrate is formed, salts and hydrates of those compounds can also be used in the present invention. When the carboxylic acid moiety of the thromboxane converting enzyme inhibitor forms a pharmacologically acceptable ester or amide, the ester and amide can also be used.

Preferred thromboxane converting enzyme inhibitors include the following compounds. JP-A-57-131
No. 769, etc. (chemical name:
(E) -3- [4- (1H-Imidazol-1-ylmethyl) phenyl] -2-propenoic acid). When ozacrel forms a pharmacologically acceptable salt or hydrate, salts and hydrates such as ozagrel hydrochloride can also be used. JP-A-1-31
Nafagrel (chemical name:
6- (1H-Imidazol-1-ylmethyl) -5
6,7,8-tetrahydronaphthalene-2-carboxylic acid). When nafagrel forms a pharmacologically acceptable salt or hydrate, salts and hydrates such as nafagrel hydrochloride can also be used.

Lidogrel (chemical name: (E) -5-[[3-pyridyl- (3-trifluoromethylphenyl) methylene]) described in JP-A-62-161759 and the like
Amino] oxypentanoic acid). Lidogrel has an asymmetric carbon, and its optical isomers and mixtures of these isomers can also be used. Furthermore, when litogrel forms a pharmacologically acceptable salt or hydrate, the salt and hydrate of those compounds are also included. Imitrodust (chemical name: 2- (1H-imidazol-1-ylmethyl) -4,5-dihydrobenzo [b] thiophene-6-carboxylic acid) described in JP-A-62-252784 and the like. When imitrodast forms a pharmacologically acceptable salt or hydrate, salts and hydrates such as imidrodast sodium can also be used.

Isvogrel (chemical name: (E) -7-phenyl-) described in JP-A-58-219162 and the like
7- (3-pyridyl) -6-heptenoic acid). When isbogrel forms pharmacologically acceptable salts and hydrates, salts and hydrates of those compounds are also included. JP-A-5-78
(E) -2- (4-methoxy-3,6-dimethyl-2,5-dioxo-2,5-dihydrobenzylidene) -7- (3-pyridyl) heptanoic acid described in JP-A-321 and the like. When this compound forms a pharmacologically acceptable salt or hydrate, the salt or hydrate of the compound is also included.

4- [hydroxy- [5- (1H-imidazol-1-yl) -2-methylphenyl] methyl] -3,5 described in JP-A-61-277670 and the like.
-Dimethylbenzoic acid sodium salt. This compound has an asymmetric carbon, and its optical isomers and a mixture of these isomers can be used, and the free acid of this compound can also be used.
When this compound forms a pharmacologically acceptable salt or hydrate, salts and hydrates of those compounds can also be used.

In the present invention, one or more leukotriene converting enzyme inhibitors are selected, and thromboxane converting enzyme inhibitors are also selected from one or two or more types. One of the inhibitors is selected, and one of the thromboxane converting enzyme inhibitors is selected and used in combination. Pharmaceutical compositions comprising a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor of the present invention have excellent inhibitory effects on various inflammatory diseases, and therefore, include antiallergic agents, antiasthmatic agents, dermatitis therapeutic agents and the like. It is useful as an agent for preventing or treating various inflammations.

According to the present invention, the use of a combination of a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor results in superior inflammation of various types as compared with the case where each agent is used alone. Shows preventive or therapeutic effects. Such effects can be obtained even if the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor are not present in the body at the same time. In other words, even after one drug has acted and metabolized first, the effect of the other drug is superior to that of a single drug.

However, it is convenient to simultaneously administer the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor, and it is possible to administer the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor in the form of a combination. desirable. However, when it is not preferable to physically mix the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor due to the formulation technique, each single agent can be administered simultaneously. In addition, since the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor show excellent effects without simultaneous administration, the respective enzyme inhibitors can be administered at appropriate intervals.
In this case, the administration interval between the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor can be confirmed clinically or by animal experiments.

The route of administration of the pharmaceutical composition comprising the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor of the present invention is generally oral. Therefore, leukotriene converting enzyme inhibitor and thromboxane converting enzyme inhibitor are each powder alone, granules, tablets, capsules,
Although separate unit dosage forms such as syrups, emulsions and suspensions can be used, they can also be mixed and prepared into one unit dosage form. Other administration routes include injections such as subcutaneous injections, intravenous injections, intramuscular injections, and intraperitoneal injections; instillations; external preparations such as nasal administration preparations, transdermal preparations, and ointments; Suppositories such as rectal suppositories and vaginal suppositories can be given.

These preparations can be produced by a generally known method. Oral preparations include active ingredients of leukotriene converting enzyme inhibitor and thromboxane converting enzyme inhibitor, such as lactose, sucrose, starch,
Excipients such as mannitol, erythritol, and crystallized cellulose; disintegrants such as calcium carbonate and carboxymethylcellulose calcium; pregelatinized starch, gum arabic;
Binders such as carboxymethylcellulose and polyvinylpyrrolidone; or talc, magnesium stearate,
It is manufactured by adding a lubricant such as polyethylene glycol 6000 and compression-molding, and then coating by a known method for taste masking, enteric coating or persistence as required.

The injectable composition contains active ingredients of a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor, for example, Tween 80 (manufactured by Atlas Powder), HCO 60
(Manufactured by Nikko Chemicals), dispersants such as polyethylene glycol, carboxymethylcellulose, sodium alginate; preservatives such as methylparaben, propylparaben, and benzyl alcohol; distilled water together with isotonic agents such as sodium chloride, glycerin, sorbitol, and glucose;
It is manufactured by dissolving, suspending or emulsifying in an aqueous solvent such as physiological saline and Ringer's solution or an oily solvent such as olive oil, sesame oil and propylene glycol.

The external preparation comprises solid components of the active ingredients of the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor,
It is manufactured by preparing a semi-solid or liquid composition.
For example, a solid composition is prepared by adding the active ingredient as it is or adding excipients such as lactose, mannitol, erythritol and starch; thickeners such as natural gums, cellulose derivatives and acrylic acid polymers, etc. It is manufactured by making it into a shape. Liquid compositions are prepared in much the same way as for injections. The semi-solid composition is preferably an aqueous or oily gel or cartilage. Any of these compositions may contain a pH adjuster, a preservative, and the like.

Suppositories are prepared by converting the active ingredients of the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor into oily or aqueous solid, semi-solid or liquid compositions. Examples of the oil base used include glycerides of higher fatty acids, intermediate fatty acids, and vegetable oils. Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.

The dose and the dose ratio of the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor used in the present invention may be determined by referring to the dose of each drug. It is prepared according to the symptoms, age, sex, body weight, administration time, dosage form, administration method, combination of other drugs, and the like. For example, taking leukotriene converting enzyme inhibitor as an example, zileuton and 6-[[3-fluoro-5- (4-methoxytetrahydropyran-4-yl) phenoxy] methyl] -1-methylquinoline-2
(1H) -on refers to an in-vivo model using a diseased animal model.
Due to the different activities of the vivo, the doses of these two agents can vary by an order of magnitude or more. Similarly, the dosage of a thromboxane converting enzyme inhibitor may vary.

The pharmaceutical composition comprising the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor of the present invention has an additive or synergistic effect on various inflammatory diseases as compared with the case where each drug is used alone. And expressed. Therefore, since the dose of each inhibitor of the pharmaceutical composition of the present invention is lower than the dose of each enzyme inhibitor used alone, the side effects of each enzyme inhibitor can be reduced.

The dose ratio of the leukotriene converting enzyme inhibitor to the thromboxane converting enzyme inhibitor is adjusted depending on the combination of the selected inhibitors and the degree of pharmacological activity. The administration ratio of the agent to the thromboxane converting enzyme inhibitor is in the range of 1:50 to 50: 1 by weight. The dose is
The patient's pathological symptoms, age, gender, weight, administration time, dosage form,
It is necessary to prepare by the administration method, the combination of other drugs, and the like. In the case of oral drugs, the dose per adult is generally 0.1 to 1000 (mg / mg) in terms of a pharmaceutical composition.
Days). In the present invention, the leukotriene converting enzyme inhibitor and the thromboxane converting enzyme inhibitor are each administered once or several times in the above-mentioned doses.

[0028]

[Formulation Example 1]

 Preparation of tablets Leukotriene converting enzyme inhibitor (ZD-2138) 12.5 g Thromboxane converting enzyme inhibitor (Isbogrel) 12.5 g Lactose 62.0 g Corn starch 40.0 g Hydroxypropyl cellulose 2.0 g Magnesium stearate 1.0 g

After the above leukotriene converting enzyme inhibitor, thromboxane converting enzyme inhibitor, lactose and corn starch are mixed until uniform, a 5 W / V% ethanol solution of hydroxypropylcellulose is added and kneaded and granulated. After passing through a 16-mesh sieve and sieving, the tablets were compressed in a conventional manner, and the weight per tablet was 130 mg, the diameter was 7 mm,
A tablet having a drug content of 25 mg was obtained.

[Preparation Example 2] Preparation of capsule preparation Leukotriene converting enzyme inhibitor (ZD-2138) 12.5 g Thromboxane converting enzyme inhibitor (Isbogrel) 12.5 g Lactose 62.0 g Avicel 62.0 g Magnesium stearate 0g

The above-mentioned compound of the present invention, lactose, Avicel PH
After thoroughly mixing -101 (manufactured by Asahi Kasei) and magnesium stearate until uniform, the capsules were filled into No. 3 capsules to give capsules having a content of 150 mg per capsule and a weight of the main drug of 25 mg.

[Experimental Example 1] Drug action of guinea pig on antigen-induced airway contraction model Using a guinea pig sensitized with ovalbumin, a test compound suspended in 5% gum arabic was orally administered, and antigen induction 2 hours after administration The inhibitory effect on airway constriction was measured by the Konzett-Rossler method. Sensitized guinea pigs (5 to 7 animals per group) were anesthetized with 35 mg / kg pentobarbital by inserting a cannula into the respiratory tract and connected to a ventilator, inserting a cannula into the carotid artery and 5 mg / kg suxamethonium and 5 mg / kg mepyramine treatment was performed. Next, the nebulizer causes the guinea pig to inhale atomized ovalbumin from the nebulizer to cause airway contraction, and the ratio of the outflow to the detector to the amount of air supplied from the ventilator is used as the airway contraction rate to determine the airway contraction inhibitory activity. Was.
ZD-2138 as a leukotriene converting enzyme inhibitor
Are shown below when Isbogrel is used in combination as a thromboxane converting enzyme inhibitor and when each enzyme inhibitor is used alone.

[0033]

[Table 1]

The pharmaceutical composition of the present invention has a synergistic reduction in airway contraction rate in a guinea pig antigen-induced airway contraction model as compared to the case where a leukotriene converting enzyme inhibitor or a thromboxane converting enzyme inhibitor is used alone. It is growing and is useful as a medicine.

[0035]

Industrial Applicability The pharmaceutical composition of the present invention has a synergistically higher effect of preventing and treating various inflammatory diseases as compared with the case where a leukotriene converting enzyme inhibitor or a thromboxane converting enzyme inhibitor is used alone. It has reduced side effects and is useful as a pharmaceutical.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/38 601 A61K 31/38 601 31/415 606 31/415 606 31/425 603 31/425 603 31 / 44 606 31/44 606 31/47 604 31/47 604 605 605 F F-term (Reference) 4C084 AA20 AA24 NA05 ZA591 ZA592 ZA891 ZA892 ZB111 ZB112 ZB131 ZB132 ZC021 ZC022 ZC121 ZC122 ZC201 ZC2020ABC03 ABC013A BC38 BC84 GA02 GA04 GA07 MA02 MA03 MA04 NA05 ZA59 ZA89 ZB11 ZB13 ZC02 ZC12 ZC20 ZC75

Claims (10)

[Claims] 1. A pharmaceutical composition comprising a leukotriene converting enzyme inhibitor and a thromboxane converting enzyme inhibitor. 2. The method according to claim 1, wherein the leukotriene converting enzyme inhibitor is zileuton, 6-[[3-fluoro-5- (4-methoxytetrahydropyran-4-yl) phenoxy] methyl].
-1-methylquinolin-2 (1H) -one (ZD-21
38), 4-[(6-hydroxy-4,5,7-trimethyl-2-benzothiazolyl) aminomethyl] benzenesulfonamide hydrochloride (E-6080), (+)-
(S) -2- [6- (2-quinolinylmethoxy) -2
-Naphthyl] propionic acid (Wy-50295), N-
(6-phenoxy-2H-1-benzopyran-3-ylmethyl) -N-hydroxyurea (CGS-2388)
5), N- [3- [5- (4-fluorophenoxy)-
2-furyl] -1-methyl-2-propynyl] -N-hydroxyurea (A-78773) and (R) -2-cyclopentyl-2- [4- (quinolin-2-ylmethoxy) phenyl] acetic acid (Bay- 2. The pharmaceutical composition according to claim 1, which is at least one of x-1005). 3. The method of claim 1, wherein the thromboxane converting enzyme inhibitor is ozagrel, nafagrel, lidogrel, imitrodast,
Isvogrel, (E) -2- (4-methoxy-3,6-
Dimethyl-2,5-dioxo-2,5-dihydrobenzylidene) -7- (3-pyridyl) heptanoic acid (E-67
00) and 4- [hydroxy- [5- (1H-imidazol-1-yl) -2-methylphenyl] methyl]-
3,5-dimethylbenzoic acid sodium salt (Y-2081
2. The pharmaceutical composition according to claim 1, which is at least one of 1). 4. A preventive or therapeutic agent for a disease associated with arachidonic acid metabolite, comprising the pharmaceutical composition according to claim 1. 5. A consisting claims 1 to 3 Pharmaceutical composition according, prophylactic or therapeutic agent for diseases thromboxane A ₂ and leukotrienes are involved. 6. A preventive or therapeutic agent for a disease ameliorated by prostaglandins, comprising the pharmaceutical composition according to claim 1. 7. A prophylactic or therapeutic agent for inflammation comprising the pharmaceutical composition according to claim 1. 8. An antiallergic agent comprising the pharmaceutical composition according to claim 1. 9. An anti-asthmatic drug comprising the pharmaceutical composition according to claim 1. 10. A therapeutic agent for dermatitis comprising the pharmaceutical composition according to claim 1.