JP2001288089A - Therapeutic agent or prophylactic agent for hepatic disease comprising diaminotrifluoromethylpyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent or a prophylactic agent for hepatic diseases comprising a diaminotrifluoromethylpyridine derivative or its salt extremely effective as the therapeutic agent or prophylactic agent for the hepatic diseases because the development of a more effective and safer therapeutic agent for the hepatic diseases has been desired in the clinical field. SOLUTION: This therapeutic agent or prophylactic agent comprises the diaminotrifluoromethylpyridine derivative represented by formula (I) [wherein, X is a group CW1R1, a group COCOR2, a group CW1NHCOR2, or the like; Y is an alkyl group, a group CW3R6, a group COCOR7, a group NHCOR7, a group C(=W3)W4R8, a group (NH)mSO2R9, a group (NH)mSO2OR10 or a group (NH)mSO2N(R11)R12; R1, R6 and R9 are each a chain hydrocarbon group, or the like; R2 and R7 are each an alkyl group, an alkoxy group, or the like; R3, R8 and R10 are each an alkyl group, an alkenyl group, or the like; R4, R5, R11 and R12 are each an alkyl group; W1, W2, W3 and W4 are each O or S; and (m) is 0 or 1].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a therapeutic or preventive agent for liver disease, comprising a diaminotrifluoromethylpyridine derivative or a salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Japanese Patent No. 2762323 and U.S. Pat. No. 5,229,403 disclose that diaminotrifluoromethylpyridine derivatives or salts thereof have a phospholipase A ₂ inhibitory action and are used as anti-inflammatory agents or anti-pancreatitis. It is described as being useful as an active ingredient of an agent. The publication also states that
(1) Hosuhoripa platelets and inflammatory cells - Ze A ₂ is secreted or activated by stimulation, platelet activating factor (PA
F) and contributes to the production of arachidonic acid metabolites,
(2) metabolites of arachidonic acid may have various pathologies, such as rheumatoid arthritis, osteoarthritis, tendinitis, bursitis, psoriasis and related inflammatory conditions such as skin inflammation;
Rhinitis, allergic-bronchial bronchial airway disorders such as bronchial asthma; closely related to immediate hypersensitivity reactions such as allergic conjunctivitis; (3) phospholipase A secreted from the pancreas ₂ is activated in the intestine and exerts a digestive action, but once activated in the pancreas, it is considered to be one of the factors that cause pancreatitis; (4) and the diaminotrifluoromethylpyridine derivative is by inhibiting Ze a _2, inflammatory conditions, nasal, bronchial airway disorder symptoms, immediate hypersensitivity reactions, Hosuhoripa such pancreatitis - is effective for the treatment of conditions associated with Ze a _2, anti-inflammatory agents, treatment of bronchial asthma It can be used as an agent, an anti-allergic agent, an anti-pancreatitis agent, an anti-nephritis agent, an anti-multi-organ disorder agent, and the like.

Further, US Pat. No. 5,492,908 discloses that these compounds can be used as a therapeutic agent for rheumatoid arthritis.
The publication describes that some of these compounds are effective as anticancer agents having a carcinogenesis-suppressing effect.

[0004]

The present invention relates to liver diseases such as acute hepatitis,
Fulminant hepatitis, chronic hepatitis, cirrhosis, fatty liver, alcoholic liver injury, drug-induced liver injury (drug-toxic hepatitis), congestive hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hepatic porphyria, or There are many cases such as pericholangitis, sclerosing cholangitis, hepatic fibrosis, chronic active hepatitis, etc., which are reported to frequently occur as complications of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. The disease is known. The causes are also diverse, and acute or chronic liver damage based on various factors such as hepatitis virus, drugs, alcohol, toxic substances, autoimmune function abnormalities, metabolic abnormalities, hepatic circulatory system abnormalities, bile duct obstruction, alone or in combination. Are involved. As a treatment method for liver disease, the principle is to prevent progression of hepatocellular necrosis, promote liver regeneration, correct metabolic abnormalities, deal with complications, and eliminate the cause of viruses and the like. In addition, since it has been revealed that most liver cancers develop on the basis of cirrhosis, in the treatment of acute hepatitis and chronic hepatitis, early treatment aimed at preventing fulminancy and progression to cirrhosis, respectively, is required. Considered clinically significant.

[0005] As therapeutic agents for liver diseases based on this philosophy, there are two types of agents, which are directed to symptomatic treatments represented by liver function improving agents (liver protective agents) and agents directed to liver function improvement and causal treatment. Types of drugs are used. Examples of the former include nutritional supplements such as amino acid infusion and glucose solution with special composition, glycyrrhizin preparations, germanium preparations (such as propagermanium), Chinese medicine Sho-saiko-to preparations, glutathione, cysteine, liver extract, polyenphosphatidylcholine , Diisopropyramine-dichloroacetate,
Thiopronin, protoporphyrin, methyl-methionine-sulfonium-chloride, adenosine triphosphate, ursodeoxycholate and the like are known. On the other hand, examples of the latter include corticosteroids such as prednisolone, anti-inflammatory and immunosuppressive agents such as 6-mercaptopurine and D-penicillamine, antiviral agents such as vidarabine (Ara-A) and interferon preparations. Are known.
In parallel with these treatments, treatments using artificial liver assist devices such as plasma exchange, activated charcoal blood (plasma) perfusion, and highly permeable membrane hemodialysis aiming at correction of metabolic abnormalities are sometimes performed. Furthermore, in recent years, development of new therapeutic agents for liver diseases has been promoted. For example, recombinant human hepatocyte growth factor (JP-A-5-111383), 1,3-benzoxathiol-2-thione derivative (JP-A-6-23985)
No. 6), a cholestanone derivative (JP-A-7-69898) and a 3-hydroxy-2,3-dihydrobenzofuran derivative (JP-A-11-228563) are known to be useful as active ingredients for treating liver diseases. ing. However, although treatment with existing marketed drugs has achieved certain results in each of the indications, liver disease has a limited effective rate due to its various etiologies, underlying diseases, and complications, due to its diverse etiology. In addition, there are concerns about side effects and adverse events due to drug treatment. For example, a glycyrrhizin preparation is
Cases have been reported in which side effects associated with the onset of pseudoaldesterone action become problematic. In the treatment with a drug having an SH group such as glutathione or cysteine, the active SH group exerts a detoxification effect, but may reduce the efficacy of other drugs used in combination. In addition, treatment with corticosteroids may cause side effects such as concurrent infection and atrophy of the thymus and adrenal glands. In principle, careful medication under hospital management is required. In addition, side effects such as fever and leukopenia are frequently observed in interferon preparations,
In addition, severe side effects such as interstitial pneumonia (pulmonary fibrosis), autoimmune disease (thyroiditis), psychoneuropathy, and cardiomyopathy due to long-term administration develop. Under these circumstances, there is a demand for a more effective and safer therapeutic agent for liver disease in clinical settings.

The present inventors have conducted various studies on the pharmacological action of a diaminotrifluoromethylpyridine derivative or a salt thereof. As a result, they have found that these compounds are extremely effective as agents for treating or preventing liver diseases, and have completed the present invention.

The present invention relates to a compound of the formula (I):

Embedded image[Wherein X is -CW¹R¹Group, -COCOR^TwoGroup, -CW¹
NHCOR^TwoGroup, -C (= W¹) W^TwoR^ThreeGroup or -CW¹N
(R^Four) R^FiveY is an alkyl group, -CW^ThreeR⁶Group,
-COCOR⁷Group, -NHCOR⁷Group, -C (= W^Three) W^Four
R⁸Group,-(NH)_mSO_TwoR⁹Group,-(NH)_mSO_TwoOR
^TenGroup or-(NH)_mSO_TwoN (R¹¹) R^{1 Two}And R is
¹, R⁶And R⁹Are each independently a optionally substituted chain formula
Hydrocarbon group, monocyclic hydrocarbon group which may be substituted, substitution
Polycyclic hydrocarbon group which may be substituted, monocyclic ring which may be substituted
A heterocyclic group or a polycyclic heterocyclic group which may be substituted;
R ^TwoAnd R⁷Are each independently an optionally substituted
Kill group, optionally substituted alkoxy group, optionally substituted
A good phenyl group or an optionally substituted phenoxy group
R^Three, R⁸And R^TenMay be each independently substituted
Alkyl group, alkenyl group which may be substituted,
Alkynyl group, cycloalkyl which may be substituted
A kill group, an optionally substituted phenyl group or an optionally substituted
A good benzyl group,^Four, R^Five, R¹¹And R¹²Are each
Independently an optionally substituted alkyl group;¹,
W^Two, W^ThreeAnd W^FourAre each independently an oxygen atom or a sulfur atom
And m is 0 or 1. However, one of X and Y
Is -COCF_TwoX¹Group (X¹Is a hydrogen atom, a halogen atom,
An alkyl group or a haloalkyl group), and the other is
-COCF_TwoX^TwoGroup (X^TwoRepresents a hydrogen atom, a halogen atom,
Alkyl, haloalkyl or alkylcarbonyl groups
A) or -COOX^ThreeGroup (X^ThreeIs an optionally substituted al
Or a phenyl group which may be substituted) or-
COX^FourGroup (X^FourIs an alkyl group, haloalkyl group, alk
A nyl group, an alkynyl group, a phenyl group which may be substituted,
Furanyl group or naphthyl group)
Diaminotrifluoromethylpyridyl represented by
Treatment of liver disease containing an active ingredient or a salt thereof
To provide remedies.

In the formula (I), examples of the chain hydrocarbon group contained in R ¹ , R ⁶ and R ⁹ include an alkyl group, an alkenyl group and an alkynyl group, and the monocyclic hydrocarbon group includes Cycloalkyl group, cycloalkenyl group, phenyl group and the like.Examples of the polycyclic hydrocarbon group include naphthyl group, tetrahydronaphthyl group, condensed polycyclic hydrocarbon group such as indanyl group or adamantyl group, nor Adamantyl group, norbornanyl group, cross-linked polycyclic hydrocarbon groups such as norbornanonyl group, and the monocyclic heterocyclic group is a pyrrolyl group, a furanyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, Isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group, dihydrofuran Lanyl group, tetrahydrofuranyl group, dihydrothienyl group, tetrahydrothienyl group,
Pyrazolinyl group, hydantoinyl group, oxazolinyl group, isoxazolinyl group, isoxazolidinyl group,
Thiazolinyl group, thiazolidinyl group, dioxolanyl group, dithiolanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, dihydrooxopyridazinyl group, tetrahydrooxopyridazinyl group , A dihydrooxopyrimidinyl group, a tetrahydrooxopyrimidinyl group, a piperazinyl group, a dihydropyranyl group, a tetrahydropyranyl group, a dioxanyl group, a dihydrodithiynyl group, a dithianyl group, a morpholinyl group and the like, and the above-mentioned polycyclic heterocyclic group Include thienothienyl group, dihydrocyclopentathienyl group, indolyl group, benzofuranyl group, benzothienyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzimidazo Group, tetrahydrobenzo-thienyl group, dihydrobenzofuranyl group, tetrahydrofuryl benzisoxazolyl group, benzodioxolyl group, a quinolinyl group, isoquinolinyl group, benzodioxanyl group,
Examples include a condensed polycyclic heterocyclic group such as a quinoxalinyl group or a crosslinked polycyclic heterocyclic group such as a quinuclidinyl group.

An optionally substituted linear hydrocarbon group contained in R ¹ , R ⁶ and R ⁹ , an optionally substituted alkyl group and an optionally substituted alkoxy group contained in R ² and R ⁷ ,
The optionally substituted alkyl group, the optionally substituted alkenyl group and the optionally substituted alkynyl group contained in R ³ , R ⁸ and R ¹⁰ , and the substitution contained in R ⁴ , R ⁵ , R ¹¹ and R ¹² Examples of the alkyl group which may be substituted and the substituent of the alkyl group which may be substituted contained in X ³ include a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group, a cycloalkoxy group, a cycloalkenyl group and a cycloalkyl group. Alkenyloxy group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbonyloxy group, aryl group, aryloxy group, arylthio group, amino group, amino group substituted with alkyl group, and the like. The number of the substituents or the substituents attached to the substituents may be one, two or more, or two or more. In such a case, those substituents may be the same or different.

Also, an optionally substituted monocyclic hydrocarbon group, an optionally substituted polycyclic hydrocarbon group, an optionally substituted monocyclic heterocyclic ring contained in R ¹ , R ⁶ and R ⁹ Group and optionally substituted polycyclic heterocyclic group, optionally substituted phenyl group included in R ² and R ⁷ and optionally substituted phenoxy group, substitution included in R ³ , R ⁸ and R ¹⁰ A cycloalkyl group which may be substituted, a phenyl group which may be substituted and a benzyl group which may be substituted, and a substituent of the phenyl group which may be substituted contained in X ³ may be a halogen atom,
Alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, cycloalkyl group, cycloalkoxy group, cycloalkenyl group, cycloalkenyloxy group, alkoxycarbonyl group, alkylcarbonyl group, alkylcarbonyloxy group, aryl group , An aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, a cyano group, a nitro group, and the like. The number of the substituents or the substituents attached to the substituents is 1 Or two or more, and in the case of two or more, the substituents thereof may be the same or different.

In the formula (I), the alkyl group and the alkyl moiety contained in X and Y include those having 1 to 18 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, Examples include a heptyl group, an octyl group, a decyl group, a nonadecyl group, and the like, including those having a linear or branched fatty chain structural isomer. The alkenyl group and alkenyl moiety contained in X and Y include those having 2 to 18 carbon atoms, for example, a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group,
Examples thereof include a decenyl group and a nonadecenyl group, and they also include those having a structural isomer of a linear or branched aliphatic chain. X
And the alkynyl group and the alkynyl moiety contained in Y are those having 2 to 18 carbon atoms, such as an ethynyl group,
Examples include a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group, a nonadecynyl group, and the like, including those having a linear or branched aliphatic chain with structural isomerism. As the cycloalkyl group and the cycloalkyl moiety contained in X and Y, those having 3 to 8 carbon atoms, for example,
Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. The cycloalkenyl group and the cycloalkenyl moiety contained in X and Y include those having 5 to 8 carbon atoms, for example, a cyclopentenyl group, a cyclohexenyl group, a cyclooctenyl group and the like. Further, examples of the halogen atom contained in X and Y include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Ants contained in X and Y
Examples of the phenyl group and aryl group include a phenyl group, a thienyl group, a furanyl group, a pyridyl group, a naphthyl group, a benzothienyl group, a benzofuranyl group, and a quinolinyl group.

Preferred embodiments of the compound of the present invention are described below. In the formula (I), X represents a —CW ¹ R ¹ group or —C
(= W ¹ ) It is preferable that the group is a W ² R ³ group and Y is a —SO ₂ R ⁹ group. R ¹ and R ⁶ are an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted phenyl group, An optionally substituted tetrahydronaphthyl group, an optionally substituted indanyl group, an optionally substituted furanyl group or an optionally substituted thienyl group; an alkyl group, a haloalkyl group,
An alkoxycarbonylalkyl group, an alkenyl group, a haloalkenyl group, an alkenyl group substituted with a thienyl group,
Cycloalkyl group, cycloalkyl group substituted with halogen atom, phenyl group, phenyl group substituted with halogen atom, phenyl group substituted with alkyl group or haloalkyl group, phenyl group substituted with alkoxy group or haloalkoxy group , A tetrahydronaphthyl group, an indanyl group, a furanyl group or a thienyl group are more desirable. R ² and R ⁷ are preferably an optionally substituted alkoxy group or an optionally substituted phenyl group; more preferably an alkoxy group, a haloalkoxy group, a phenyl group or a phenyl group substituted with a halogen atom. R ³ , R ⁸ and R ¹⁰ are preferably an optionally substituted alkyl group; more preferably an alkyl group or a haloalkyl group. R ⁴ ,
R ⁵ , R ¹¹ and R ¹² are preferably alkyl groups. R ⁹ is
Desirably, an alkyl group which may be substituted, an alkenyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted or a phenyl group which may be substituted; an alkyl group, a haloalkyl group, A phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group or a haloalkyl group, and a phenyl group substituted with an alkoxy group or a haloalkoxy group are more desirable.

Preferred compounds among the compounds of the present invention include, in the above formula (I), an alkenylcarbonyl group in which X is substituted with an alkoxycarbonylalkylcarbonyl group, an alkenylcarbonyl group, a thienyl group, a cycloalkylcarbonyl group, an indanyl group. A carbonyl group, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl group or a benzoyl group which may be substituted with a halogen atom or a haloalkyl group, and a compound wherein Y is an alkylsulfonyl group; specifically, N- (2- Methylsulfonylamino-5-trifluoromethyl-3-pyridyl) acrylamide, N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) crotonamide, N- (2-ethylsulfonylamino-5-
Trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5)
-Trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-
5-trifluoromethyl-3-pyridyl) cyclopentanecarboxamide, N- (2-n-propylsulfonylamino-5-trifluoromethyl-3-pyridyl) -6
-(1,2,3,4-tetrahydronaphthalene) carboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -5-indanecarboxamide, N- (2-methylsulfonylamino-5 -Trifluoromethyl-3-pyridyl) acetoxyacetamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) crotonamide, N- (2
-Methylsulfonylamino-5-trifluoromethyl-
3-pyridyl) -2-thiophenecarboxamide, N-
(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3-trifluoromethylbenzamide, N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) -3-fluorobenzamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) -6- (1,2,3,4
-Tetrahydronaphthalene) carboxamide, N- (2
-Methylsulfonylamino-5-trifluoromethyl-
3-pyridyl) -3- (2-thienyl) acrylamide or a salt thereof.

More desirable compounds include those in the above formula (I) wherein X is a cycloalkylcarbonyl group, an alkenylcarbonyl group or a tetrahydronaphthylcarbonyl group, and Y is an alkylsulfonyl group. N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) acrylamide, N- (2-methyl Sulfonylamino-5
-Trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-
5-trifluoromethyl-3-pyridyl) cyclopentanecarboxamide, N- (2-n-propylsulfonylamino-5-trifluoromethyl-3-pyridyl) -6
-(1,2,3,4-tetrahydronaphthalene) carboxamide or a salt thereof.

In the compound represented by the formula (I), Y is -S
In the case of an O ₂ R ⁹ group (R ⁹ is as described above), salts may be formed, and those salts may be pharmaceutically acceptable, for example, potassium salt, sodium salt And alkaline earth metal salts such as calcium salts, and organic amine salts such as triethanolamine salts and tris (hydroxymethyl) aminomethane salts. Some of these salts have water of crystallization.

The compound represented by the formula (I) can be produced, for example, by the method described in Japanese Patent No. 2762323. Further, these compounds have geometric isomers depending on the type of the substituent, and the present invention includes each isomer (cis isomer, trans isomer) and a mixture of isomers.

The compound of the present invention represented by the above formula (I) is useful as an active ingredient of an agent for treating or preventing liver disease. Among various liver diseases, acute hepatitis, fulminant hepatitis,
Liver diseases such as chronic hepatitis, cirrhosis, fatty liver, alcoholic liver injury, drug-induced liver injury (drug-toxic hepatitis), congestive hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hepatic porphyria, etc. Disability, liver failure), or ulcerative colitis or black
As an active ingredient of a therapeutic or preventive agent for pericholangitis, sclerosing cholangitis, hepatic fibrosis, chronic active hepatitis, etc., which are reported to frequently occur as a complication of inflammatory bowel disease such as Useful, especially acute hepatitis, fulminant hepatitis,
Liver diseases such as chronic hepatitis, cirrhosis, fatty liver, alcoholic liver injury, drug-induced liver injury (drug-toxic hepatitis), congestive hepatitis, autoimmune hepatitis, primary biliary cirrhosis, hepatic porphyria, etc. It is useful as an active ingredient of a therapeutic or prophylactic agent for disorders, liver failure). Among them, the compound of the present invention is
It is useful as an agent for treating or preventing liver injury (drug-induced liver injury, drug-induced hepatitis) due to drugs such as acetaminophen and liver injury caused by ischemia-reperfusion. In addition, it can be expected to be more effective when used in combination with other drugs such as Chinese herbal medicines.

When the compound of the present invention is administered as an active ingredient of a therapeutic agent for liver disease, a pharmaceutical composition suitable for oral or parenteral use alone or in combination with a pharmacologically acceptable carrier. For example, they are administered in the form of tablets, powder packaging, capsules, granules, injections, ointments, inhalants, enemas, suppositories and the like.

Formulations suitable for oral use include, for example, solid compositions such as tablets, capsules, powders, granules and troches; liquid compositions such as syrup suspensions. Solid compositions such as tablets, capsules, powders, granules and troches include binders such as microcrystalline cellulose, acacia, tragacanth, gelatin, polyvinylpyrrolidone; starch, lactose, carboxymethyl. Excipients such as cellulose; alginic acid, constar
Disintegrants such as carboxymethyl cellulose; lubricating agents such as magnesium stearate, light anhydrous silicic acid and colloidal silicon dioxide; sweetening agents such as sucrose; flavoring agents such as peppermint and methyl salicylate. Bar agent;
And the like. Liquid compositions such as syrups, suspensions include sorbitol, gelatin, vegetable oils such as methylcellulose, carboxymethylcellulose, peanut oil,
It can contain emulsifiers such as lecithin, and if necessary, sweetening agents, preservatives, coloring agents and flavoring agents, and these can also be provided as a dry preparation. These preparations preferably contain 1 to 95% by weight of the active ingredient compound.

Preparations suitable for parenteral use include, for example, injections. The injection may be in the form of a salt, for example, dissolved in ordinary water for injection, or in the form of a suspension or emulsion (in a mixture of a pharmaceutically acceptable oil or liquid) for injection. . in this case,
It may contain a pharmaceutically acceptable buffer or a reagent for adjusting osmotic pressure, such as antibacterial agent benzyl alcohol and antioxidant ascorbic acid. This injection preferably contains 0.1 to 8% by weight of the active ingredient compound. Formulations suitable for topical or rectal use include, for example, inhalants, ointments, enemas, suppositories and the like. As an inhalant, the compound of the present invention itself or a pharmaceutically acceptable inert carrier can be dissolved in a solution for aerosol or nebulizer, or can be administered to the respiratory tract as a fine powder for inhalation. In the case of fine powder for inhalation, the particles should be 50 microns or less, preferably 1 micron.
0 microns or less. When used as these inhalants, if necessary, they can be used in combination with other anti-asthmatics or bronchodilators.

The ointment is prepared by adding a commonly used base or the like and by a conventional method. The ointment preferably contains the active ingredient compound in an amount of 0.1 to 30% by weight.

Suppositories may contain pharmaceutical carriers well known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides and the like. Suppositories preferably contain 1 to 95% by weight of the active ingredient compound.

Pharmaceutical compositions suitable for oral, parenteral, topical or rectal use may be prepared in a known manner so that the active ingredient is rapidly released after administration to the patient. It can be formulated to be released in a timely manner or to be released in a delayed manner.

The dosage of the compound of the present invention may, of course, vary depending on the type of the compound, the method of administration, the conditions of the patient or the animal to be treated, etc. The appropriate amount and the number of administration under certain conditions may be determined by a specialist. Although to be determined, it will usually be that about 0.1 mg to about 10 g, preferably about 1 mg to about 1 g, per adult daily.
The dose of the compound of the present invention per dose in the inhalation method is desirably about 0.01 mg to about 1 g.

Next, specific examples of the preparation of the therapeutic agent for liver disease according to the present invention will be described, but the preparation of the present invention is not limited thereto.

Formulation Example 1 (tablet) (1) Active ingredient 20 mg (2) Lactose 150 mg (3) Starch 30 mg (4) Magnesium stearate 6 mg More than one component (1) to (4) is molded into a tablet. I do.

Formulation Example 2 (powder, fine granule, granule) (1) Active ingredient 20 mg (2) Sugar-ester (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., trade name: DK Ester F-160) 180 mg (3) Interface Activator (manufactured by Nikko Chemicals Co., Ltd., trade name: Decaglin 1-L) 15 mg (4) Light anhydrous silicic acid 25 mg The above (1) to (4) are mixed, powdered, and further granulated or granulated by granulation. And These can be encapsulated in a capsule to form a capsule.

Formulation Example 3 (Hard Gelatin Capsule) (1) Active ingredient 25 mg (2) Starch 200 mg (3) Magnesium stearate 10 mg More than one component (1) to (3) is packed in a hard gelatin capsule as one tablet. And hard gelatin capsules.

Formulation Example 4 (Injection) (1) Active ingredient 1 mg (2) Glucose 10 mg (3) Tris (hydroxymethyl) aminomethane 2.16 mg Tris buffer containing at least components (1) to (3) Lyophilize to make an injection.

Formulation Example 5 (External ointment for skin) (1) Active ingredient 0.5 g (2) White petrolatum 25 g (3) Stearyl alcohol 22 g (4) Propylene glycol 12 g (5) Sodium laurin sulfate 1 0.5g (6) Ethyl paraoxybenzoate 0.025g (7) Propyl paraoxybenzoate 0.015g (8) Purified water 100g At least the components (1) to (8) were prepared by a general preparation method of an ointment, and then applied to the skin. Obtain topical ointment.

Formulation Example 6 (Enema formulation) (1) Active ingredient 50 mg (2) Macrogol 400 2 g (3) Dipotassium phosphate 141 mg (4) Potassium dihydrogen phosphate 44 mg (5) Methyl paraoxybenzoate 20 mg (6) Purified water 50 g An active ingredient and methyl parahydroxybenzoate were added to Macrogol 400, and the mixture was stirred and mixed, and then a mixture of purified water and dipotassium phosphate and potassium dihydrogen phosphate was gradually added. To obtain an enema formulation.

Formulation Example 7 (suppository) (1) Active ingredient 50 mg (2) Higher fatty acid glyceride 1650 mg (1) is dispersed or dissolved in (2), and filled in a plastic container having a suitable size as a suppository. After cooling, the mixture is cooled and solidified to give a suppository.

Formulation Example 8 (rectal retention suppositories / controlled release suppositories) (1) Active ingredient 1 g (2) 19 g of Witepsol W35 19 g of suppository after mixing (1) with (2) previously heated and dissolved Filling into plastic container of appropriate size-
After sealing, the mixture is cooled and solidified to give a suppository.

[0034]

Example <Test Example 1> Hepatic disorder of mouse acetaminophen
Therapeutic effect on injury model N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide monosodium salt monohydrate against acetaminophen (APAP) -induced mouse liver injury model Compound 1 below
) Was examined.

Crj: CD-1 (ICR) mouse, male, 6 weeks old
(Nippon Charles River Co., Ltd.), APAP (Sigma; Lot. No. 107H0332) dissolved in physiological saline (Fuso Pharmaceutical Co., Ltd .; Lot No. 80909D) was used as an active ingredient.
It was administered intraperitoneally at a dose of 0 mg / kg to induce liver damage. A
Three hours after the administration of PAP, Compound 1 dissolved in physiological saline was single-dose subcutaneously at a dose of 10 mg / kg of the active ingredient. The untreated group was similarly administered with saline. Blood was collected 6 hours after the APAP administration, and the glutamic acid oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in the serum were measured. The results are shown in Table 1. In this test, mice were bred under fasting from 20 hours before administration of APAP to the end of the test.

[0036]

[Table 1] Table 1 Biochemical test values (mean ± standard deviation)
N = 5

In the non-treatment group, acetaminophen increased the biochemical test value as an index of liver damage, but in the compound 1 treatment group, the increase in the test value was suppressed, and the compound was treated in an acetaminophen-induced mouse liver injury model. In contrast, it was shown to reduce the liver damage.

<Test Example 2> Rat liver ischemia / reperfusion liver injury
Therapeutic Effect on Dell The therapeutic effect of Compound 1 on a rat liver injury model induced by partially ischemia-reperfusion of the liver was examined.

(1) Compound 1 was used as a pharmaceutical product.
The formulation (content per vial) was as follows. (a) Compound 1 (in terms of anhydride) 100 mg (b) Mannitol (manufactured by Kyowa Hakko Kogyo) 100 mg (c) Tris (hydroxymethyl) aminomethane (manufactured by Junsei Chemical) 21.6 mg (d) Hydrochloric acid (manufactured by Sankyo Chemical) ) Suitable amount (e) Sodium hydroxide (manufactured by Nippon Rika) Suitable amount (f) Distilled water 10ml pH 8.7 ± 0.5

(2) Crj: SD (IGS) rat, male, 7 weeks old (Charles River Japan Co., Ltd.), anesthesia was induced with ether, anesthesia was maintained with halothane laughter, and compound 1 was converted to anhydrous. The above compound 1 was adjusted to a dosage of 10 mg / kg / hr.
5% glucose (Otsuka Pharmaceutical Factory Lot. 9I78)
The solution diluted in N) was administered once subcutaneously. Thereafter, the compound 1 was administered at a dose of 0.3 mg / kg / hr in terms of anhydride,
5% glucose (Otsuka Pharmaceutical Factory)
An osmotic pump (ALZA CORPORATION, USA, alzet osmotic pump 2001D) containing the product diluted with Lot. 9I78N was implanted under the dorsal neck subcutaneously. The untreated group also received only 5% glucose. Then make an incision in the ventral midline,
Hemostatic clamp completely blocked the square lobe of the liver and the hepatic portal vein branching of the medial and lateral left lobes (approximately 70% of the entire liver ischemia). The abdomen was closed and awakened, and after 90 minutes the abdomen was reopened under the above anesthesia,
The hemostatic clamp was removed and reperfusion was performed. The sham-induced group underwent surgery other than ischemia-reperfusion treatment. After abdominal closure and awakening, blood was collected 6 hours after reperfusion, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH)
And total bilirubin values were measured. The results are shown in Table 2.

[0041]

[Table 2] (Table 2) Biochemical tests (mean ± standard deviation)
N = 10

Compared with the sham-induced group, in the non-treated group, the ischemic reperfusion of the liver increased the biochemical test value as an index of liver injury, whereas the compound 1 treatment group suppressed the increase in the test value. In addition, it was shown to reduce the liver injury in a rat liver ischemia-reperfusion liver injury model.

Claims (8)

[Claims] 1. A compound of the formula (I)[Wherein X is -CW¹R¹Group, -COCOR^TwoGroup, -CW¹
NHCOR^TwoGroup, -C (= W¹) W^TwoR^ThreeGroup or -CW¹N
(R^Four) R^FiveY is an alkyl group, -CW^ThreeR⁶Group,
-COCOR⁷Group, -NHCOR⁷Group, -C (= W^Three) W^Four
R⁸Group,-(NH)_mSO_TwoR⁹Group,-(NH)_mSO_TwoOR
^TenGroup or-(NH)_mSO_TwoN (R¹¹) R^{1 Two}And R is
¹, R⁶And R⁹Are each independently a optionally substituted chain formula
Hydrocarbon group, monocyclic hydrocarbon group which may be substituted, substitution
Polycyclic hydrocarbon group which may be substituted, monocyclic ring which may be substituted
A heterocyclic group or a polycyclic heterocyclic group which may be substituted;
R ^TwoAnd R⁷Are each independently an optionally substituted
Kill group, optionally substituted alkoxy group, optionally substituted
A good phenyl group or an optionally substituted phenoxy group
R^Three, R⁸And R^TenMay be each independently substituted
Alkyl group, alkenyl group which may be substituted,
Alkynyl group, cycloalkyl which may be substituted
A kill group, an optionally substituted phenyl group or an optionally substituted
A good benzyl group,^Four, R^Five, R¹¹And R¹²Are each
Independently an optionally substituted alkyl group;¹,
W^Two, W^ThreeAnd W^FourAre each independently an oxygen atom or a sulfur atom
And m is 0 or 1. However, one of X and Y
Is -COCF_TwoX¹Group (X¹Is a hydrogen atom, a halogen atom,
An alkyl group or a haloalkyl group), and the other is
-COCF_TwoX^TwoGroup (X^TwoRepresents a hydrogen atom, a halogen atom,
Alkyl, haloalkyl or alkylcarbonyl groups
A) or -COOX^ThreeGroup (X^ThreeIs an optionally substituted al
Or a phenyl group which may be substituted) or-
COX^FourGroup (X^FourIs an alkyl group, haloalkyl group, alk
A nyl group, an alkynyl group, a phenyl group which may be substituted,
Furanyl group or naphthyl group)
Diaminotrifluoromethylpyridyl represented by
Of liver disease containing an active ingredient or its salt as an active ingredient
A therapeutic or prophylactic agent. 2. The method according to claim 1, wherein X is -CW ¹ R ¹
A group or a ^{-C (= W 1) W 2} R 3 group, Y is SO ₂ R ⁹ group, a therapeutic agent or prophylactic agent for a liver disease according to claim 1. 3. The method according to claim 1, wherein X is -CW ¹ R ^1.
Group or —C (又 は W ¹ ) W ² R ³ group, wherein R ¹ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, or an optionally substituted A cycloalkenyl group, an optionally substituted phenyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted indanyl group, an optionally substituted furanyl group or an optionally substituted thienyl group, wherein R ³ is An alkyl group which may be substituted, Y is a -SO ₂ R ⁹ group, and R ⁹ is an alkyl group which may be substituted, an alkenyl group which may be substituted, a cycloalkyl group which may be substituted, The therapeutic or preventive agent for liver disease according to claim 1, which is an optionally substituted cycloalkenyl group or an optionally substituted phenyl group. 4. The method according to claim 1, wherein X is -CW ¹ R ¹
Or an —C (＝ W ¹ ) W ² R ³ group, wherein R ¹ is an alkyl group, a haloalkyl group, an alkoxycarbonylalkyl group, an alkenyl group, a haloalkenyl group, an alkenyl group substituted with a thienyl group, or a cycloalkyl group , A cycloalkyl group substituted with a halogen atom, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group or a haloalkyl group, a phenyl group substituted with an alkoxy group or a haloalkoxy group, tetrahydronaphthyl A group, an indanyl group, a furanyl group or a thienyl group, R ³ is an alkyl group or a haloalkyl group, Y is a —SO ₂ R ⁹ group, R ⁹ is an alkyl group,
The liver disease according to claim 1, which is a haloalkyl group, a phenyl group, a phenyl group substituted with a halogen atom, a phenyl group substituted with an alkyl group or a haloalkyl group, or a phenyl group substituted with an alkoxy group or a haloalkoxy group. A therapeutic or prophylactic agent. 5. The method according to claim 1, wherein X is an alkoxycarbonylalkylcarbonyl group, an alkenylcarbonyl group, an alkenylcarbonyl group substituted by a thienyl group, a cycloalkylcarbonyl group, an indanylcarbonyl group, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl. The therapeutic or preventive agent for liver disease according to claim 1, wherein the agent is a benzoyl group optionally substituted with a halogen atom or a haloalkyl group, and Y is an alkylsulfonyl group. 6. The therapeutic or preventive agent for liver disease according to claim 1, wherein X is a cycloalkylcarbonyl group, an alkenylcarbonyl group or a tetrahydronaphthylcarbonyl group, and Y is an alkylsulfonyl group. . 7. The method of claim 1, wherein the diaminotrifluoromethylpyridine derivative is N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)
Cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclohexanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) cyclopentanecarboxamide, N- (2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl) acrylamide or N- (2-N-propylsulfonylamino-5-trifluoromethyl-3-pyridyl)-
The therapeutic or preventive agent for liver disease according to claim 1, which is 6- (1,2,3,4-tetrahydronaphthalene) carboxamide. 8. The method according to claim 1, wherein the diaminotrifluoromethylpyridine derivative is N- (2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)
The therapeutic or preventive agent for liver disease according to claim 1, which is cyclohexanecarboxamide.