MXPA01002324A

MXPA01002324A - Preventives/remedies for multiple organ failure

Info

Publication number: MXPA01002324A
Application number: MXPA/A/2001/002324A
Authority: MX
Inventors: Tsuyoshi Hara; Kazuko Fujiwara
Original assignee: Daiichi Pharmaceutical Co Ltd
Priority date: 1998-09-03
Filing date: 2001-03-02
Publication date: 2001-11-21

Abstract

Preventives/remedies for syndrome caused by the worsening of sepsis, hyperchemokinemia and hepatic diseases which contain as the active ingredient an antithrombin agent and/or a thrombin synthesis inhibitor. Because of being usable in preventing or treating diseases including sepsis, severe sepsis, septic shock and multiorgan failure, these drugs are useful in the treatment of trauma, burn, heat attack, severe infection, etc. caused by, in particular, traffic accidents in the field of emergency care. These drugs are also useful in preventing and treating hyperchemokinemia and hepatic diseases.

Description

REMEDIES / PREVENTIONS FOR THE INSUFFICIENCY OF MULTIPLE ORGANS BACKGROUND OF THE INVENTION 5 FIELD OF THE INVENTION The present invention relates to a pharmaceutical compound, and more particularly to a preventive and / or therapeutic drug for hypercytomacemia, liver diseases and syndromes caused by the aggravation of sepsis.

RELATED BACKGROUND TECHNIQUE Previously, sepsis was understood to refer to systemic aggravation resulting from the invasion of bacteria in the blood (bacteremia) and, for example, organ failure caused by it. At first it seemed that there was no effective remedy for sepsis, but since the 1980s sepsis has been treated positively. 20 Recently, sepsis has been defined as the onset of a systemic inflammatory response syndrome (SRIR) caused by an infectious disease, and it has become an objective of medical treatment (Igakunoayumi, Vol. 181, No 1, p 3-7, April 5, 1997). ^^^^ ^^ lfc ^ ^ It is known that sepsis increases the concentration of several cytokines in the blood, causing hypercyccinemia. In addition, the progress of sepsis can cause severe sepsis, septic shock, and multiple organ failure syndrome (MODS, by its acronym in English). The prevention and treatment of diseases that include sepsis and syndromes caused by the aggravation of sepsis, including the syndrome of multiple organ failure are very important for the emergency medical service, for the treatment of 10 injuries caused by accidents of traffic, burns, heat attack and various infectious diseases, and therefore, the development of effective drugs is desirable. Accordingly, the aim of the present invention is to provide a therapeutic or preventive drug for the diseases comprising sepsis and the syndromes caused by the aggravation of sepsis.

BRIEF DESCRIPTION OF THE INVENTION The inventors of the present have carried out studies extensively by using the model of intravenous injection of lipopolysaccharides (Nikkyukyuikaishi, 1994: 5: p1-14) known as an animal test model for sepsis and septic shock, and it has been found that an anti-thrombin agent and / or an inhibitor of thrombin production; plus Specifically, factor Xa, an inhibitor of blood coagulation, exhibits an excellent effect by allowing protection against sepsis and septic shock as well as by allowing the prevention and therapy of hypercytomemia and liver diseases. The present invention has been achieved based on these findings. In accordance with the foregoing, the present invention provides a preventive and / or therapeutic drug for the syndrome caused by the aggravation of sepsis, containing as an active ingredient an anti-thrombin agent and / or an inhibitor of thrombin production. The present invention also provides a preventive and / or therapeutic drug of hypercyncinemia, which contains as an active ingredient an anti-thrombin agent and / or an inhibitor of thrombin production. The present invention also provides a preventive and / or therapeutic drug for liver diseases, which contains as an active ingredient An anti-thrombin agent and / or an inhibitor of thrombin production. The present invention also provides the use of an antithrombin agent and / or an inhibitor of thrombin production for the manufacture of a drug with preventive and / or therapeutic capacity for the syndrome caused by the aggravation of sepsis. The present invention also provides the use of an anti-thrombin agent and / or an inhibitor of thrombin production for the production of a preventive and / or therapeutic drug for hypercytomacemia.

The present invention also provides the use of an antithrombin agent and / or an inhibitor of thrombin production to produce a preventive and / or therapeutic drug for liver diseases. The present invention also provides a method of treating a syndrome caused by the aggravation of sepsis, wherein an anti-thrombin agent and / or an inhibitor of thrombin production is administered to a patient in need thereof. The present invention also provides a method of treating hypercytomacinemia, wherein an anti-thrombin agent and / or an inhibitor of thrombin production is administered to a patient in need thereof. The present invention also provides a method of treating liver diseases, wherein an anti-thrombin agent and / or an inhibitor of thrombin production is administered to a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effect of compound A against hypercytomacinemia.

DETAILED DESCRIPTION OF THE PREFERRED ASA MODALITIES In the drug of the present invention, no particular limitation has been imposed on anti-thrombin agents and / or thrombin production inhibitors that serve as active ingredients, while inhibiting thrombin activity. Examples of the inhibitors include thrombin inhibitors, inhibitors of blood coagulation factor Xa, and inhibitors of the blood coagulation factor Vlla. Examples of thrombin inhibitors include 10 synthesized anti-thrombin agents; specifically, the Argatroban. Examples of the blood coagulation factor Xa inhibitors include the compounds represented by the formula described below, DZ-4927 (product of the Zeneca company) and the compounds described in German Patent No. 19530996 and in European patent application No. 0842941 A1. Examples of inhibitors of blood clotting factor Vlla include Corsevein (product of the company Corvas). Of the inhibitors described above, inhibitors of thrombin production and inhibitors of blood coagulation factor Xa are preferred. Of the blood coagulation factor Xa inhibitors, the aromatic amidines derived from the formula (1), a salt of the derivative, a solvate of the derivative, and a solvate of the salt of the derivative are preferred. "~~ * > ^ - * ^ & ^^^^ A ^ á.,. .. .. ^ ^" Jfa ^ --- ^ -. . *? * éi ^ »** > .. ..Ai ^ BaMttU [wherein R 1 represents a hydrogen atom or a lower alkoxyl group. R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, or an alkoxycarbonylalkyl group. R3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group. R4 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group, or a lower alkoxy group, n represents an inclusive number between 0 and 4; and A represents a C 1 -C 4 alkylene group optionally substituted by one or two hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups, or alkoxycarbonylalkyl groups, or a group represented by the following formula; R5 - E-N- (wherein E represents a lower alkylene group or a carbonyl group and R5 represents a hydrogen atom or a group represented by the formula -D-W-R6, (wherein D is a group represented by Z - c- (where Z is an oxygen atom or a sulfur atom), a group represented by or a sulfonyl group; W represents an individual bond or a group represented by -NR7-, (wherein R7 represents a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-alkylaminocarbonyl group Lower, a lower alkylsulfonyl group, a lower mono- or di-alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent, or a lower alkanoyl group which may have a substituent); and R6 represents a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have an Substituent, or a heteroaryl group which may have a substituent)]; X represents a single bond, an oxygen atom, a sulfur atom, a carbonyl group; Y represents a 5 or 6 membered cyclic or heterocyclic hydrocarbon group either saturated or unsaturated which may have a substituent, an amino group which may have a substituent, or an aminoalkyl group which may have a substituent; the group represented by represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, or indanyl]. The Japanese patent application open to the public. { kokai) No. 208946/1993 and WO 96/16940 disclose that the above described aromatic amidines derived from the formula (1), salts of the derivatives, solvates of the derivatives, and solvates of the salts of the derivatives inhibit factor Xa of blood coagulation and are useful as depressants of blood coagulation and as therapeutic and preventive drugs against thrombi. In the formula (1) described above, examples of lower alkyl groups include linear, branched and cyclic C1-C6 alkyl groups. Specific examples of the foregoing include the methyl groups, an ethyl group, a propyl group, an isopropyl group, a butyl group, a secondary butyl group, a tertiary butyl group, a pentyl group, a hexyl group, an Ato. , - «., > "**». «» »A ^^^ & ^^^^^^^^^^^^^^^^^^^^^^^^^^ f ^ cyclopropyl group, a cyclobutyl group? ufi cyclopentyl group, and a cyclohexyl group. The lower alkyl group may contain a substituent, and examples of the substituents include the halogen atom, a carboxyl group, a carbamoyl group, an amino group, a grtfo cyano, a nitro group, a lower alkanoyl group, a lower alkoxy group , a lower alkoxycarbonyl group, a lower mono- or dialkylamino group, an aryl group, an aralkyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group, a lower alkylthiocarbonyl group, a hydroxyl group, a carbamoyl group, Y a lower mono- or di-alkylaminocarbonyl group. Examples of lower alkoxy groups include a C1-C6 alkoxy group, and specific examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a secondary butoxy group, and a tertiary butoxy group. Examples of alkoxycarbonyl groups include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and a butoxycarbonyl group. Examples of carboxyalkyl groups include a carboxymethyl group, a carboxyethyl group, and a carboxypropyl group. Examples of alkoxycarbonylalkyl groups include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a methoxycarbonylethyl group, a group - S * ¿^! ^ A-: '^ -, ~ - ^, .. í, - & ethoxycarbonylethyl, a methccarbonylpropyl group, and an ethoxycarbonylpropyl group. Examples of carboxyalkoxy groups include a carboxymethoxy group, a carboxyethoxy group, and a carboxypropoxy group. Examples of alkoxycarbonylalkoxy groups include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a propoxycarbonylmethoxy group, and an ethoxycarbonyletoxy group. Examples of hydroxyalkyl groups include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxybutyl group. Examples of C1-C4 alkylene groups include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group. Examples of lower mono- or di-alkylaminocarbonyl groups include lower monoalkylaminocarbonyl groups such as the methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a butylaminocarbonyl group, an isobutylaminocarbonyl group, a pentylaminocarbonyl group, an isopentylaminocarbonyl group, an Hexylaminocarbonyl group, and an isohexylaminocarbonyl group. Examples of di-alkylaminocarbonyl groups include symmetrical dialkylaminocarbonyl groups having two lower alkyl groups as well as substituents such as the dimethylaminocarbonyl group, the diethylaminocarbonyl group, the dipropylaminocarbonyl group, the diisopropylaminocarbonyl group, the dibutylaminocarbonyl group, and the dipentylaminocarbonyl group; and groups * Jt? >; ~ ». .V * ?. $ ^ && amp; Asymmetric dialkylaminocarbonyl having two lower alkyl groups as substituents such as the ethylmethylaminocarbonyl group, a methylpropylaminocarbonyl group, an ethylpropylaminocarbonyl group, a butylmethylaminocarbonyl group, a butylethylaminocarbonyl group, and a 5-butylpropylaminocarbonyl group. Examples of lower alkylsulfonyl groups include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a pentylsulfonyl group, an isopentylsulfonyl group, a hexylpropyl group, and a group isohexylpropyl. With respect to the lower mono- or di-alkylaminothiocarbonyl groups, examples of lower monoalkylaminthiocarbonyl groups include a methylaminothiocarbonyl group, an ethylaminothiocarbonyl group, a propylaminthiocarbonyl group, a isopropylaminothiocarbonyl group, a group Butylaminothiocarbonyl, an isobutylaminothiocarbonyl group, a pentylaminothiocarbonyl group, an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group. Examples of dialkylaminothiocarbonyl groups include symmetrical dialkylaminothiocarbonyl groups having two lower alkyl groups at the same level as substituents such as diethylaminothiocarbonyl groups, a diethylaminothiocarbonyl group, a dipropylaminothiocarbonyl group, a diisopropylaminothiocarbonyl group, a dibutylaminothiocarbonyl group, or a dipentylaminothiocarbonyl group; and asymmetric dialkylaminothiocarbonyl groups that they have two different lower alkyl groups as substituents such as the ethylmethylaminothiocarbonyl group, a methylpropylaminothiocarbonyl group, an ethylpropylaminothiocarbonyl group, a butylmethylaminothiocarbonyl group, a butylethylaminothiocarbonyl group, or a butylpropylaminothiocarbonyl group. Examples of lower afnanoyl groups include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a isvaleryl group, a pivaloyl group, and a hexanoyl group. Of these, an acetyl group, a propionyl group, and a butyryl group are preferred, with acetyl and propionyl groups being even more suitable. The lower alkanoyl group may have a substituent. Examples of groups that can serve as substituents of the lower alkanoyl group include the halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl group, a lower alkoxyl group , a lower alkoxycarbonyl group, a lower mono- or di-alkylamino group, an aryl group, an aralkyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group, a lower alkylthiocarbonyl group, a hydroxyl group, a carbamoyl group, and a lower mono- or di-alkylaminocarbonyl group. Examples of aryl groups include a phenyl group, a naphthyl group, a biphenyl group, and an anthryl group. The aryl group may contain a substituent. Examples of heteroaryl groups include a furyl group, a thienyl group, a pyrolyl group, an imidazolyl group, a pyrozolyl group, a ^^^^ ^. ^. á ^^^^, ... ..... ^^^.,., ^ ^. tf, ^^^^. ^^^: ^^^^^^ and ^ to the isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group, a lsoquinolyl group, a quinazolinyl group, a quinolidinyl group, a quinoxalinyl group, a cinolinyl group, a benzimidazolyl group, an imidazopyridyl group, a benzofuranyl group, a naphilidinyl group, a 1, 2-benzoisoxazolyl group, a benzoxazolyl group, a benzothiazolyl group, an oxazolipyridyl group, a group isothiazolopyridyl, and a benzothienyl group. Of these, a furyl group, a thienyl group, a pyrolyl group, an imidazolyl group, and a pyridyl group are preferred. The aryl group may have a substituent. Examples of groups that can serve as substituents of these aryl or heteroaryl groups include the halogen atom, a carboxyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group , a lower mono- or di-alkylamino group, a lower alkanoyl group, and a lower alkyl group which may optionally have a substituent. Preferably, the saturated or unsaturated 5- or 6-membered heterocyclic group is a heterocyclic group having from 1 to 2 nitrogens or oxygen atoms. Specific examples of heterocycles include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazidine, pyrrolidinone, piperidinone, and morpholine. Examples of saturated or unsaturated cyclic hydrocarbon groups include a cyclopentinyl group, and a cyclohexyl group. Examples of aminoalkyl groups include an aminomethyl group, an aminoethyl group, and an aminopropyl group. Heterocyclic groups and cyclic hydrocarbon groups may have substituents. Examples of groups that can serve as substituents of the heterocyclic groups or the cyclic hydrocarbon groups include a lower alkyl group, a lower alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl group, an alkanoimidyl group, a benzimidoyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino group, an alkanoylaminoalkyl group, a minimum group, and an alkoxycarbonylimino group. Examples of groups that can replace the amino moiety of the group and the aminoalkyl group include a lower alkyl group, a pyrrolidinyl group, a pyrazyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a lower alkanoyl group, a group formimidoyl, an alkanoimidoyl group, a benzimidoyl group, and an alkoxycarbonyl group. The groups described above such as the alkyl group, the alkoxy group, and the alkanoyl group, as well as the alkyl moiety, the alkoxy moiety, and the alkanoyl moiety, of these groups preferably have from 1 to 6 carbon atoms. The group represented by ^^^ ft ^^ O ^ t ^^^^^^^^^ j gA ^^^^^^^^^^^^ S ^^ it is preferably selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl, or tetrahydronaphthyl. The aromatic amidine derivatives represented by the formula (1) according to the present invention, the salts of the derivatives, the solvates of the derivatives, and the solvates of the salts of the derivatives may have a symmetrical carbon atom. In this case, optical isomers, stereoisomers, and mixtures thereof attributed to the asymmetric carbon atom are all within the scope of the present invention. In the present invention, among the aromatic amidine derivatives described above represented by the formula (1), the salts of the derivatives, the following compounds and the salts or solvates of the above are particularly preferred: 2- [4- [((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] pheny] -3- (7-amidin-2-naphthyl) propionic acid (+) - 2- [4 - [((3S ) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid (2S) -2- [4 - [((3S) -1-acetimidoyl-3) pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic, (2R) -2- [4 - [((3R) -1-Acetylimido-3-pyrrolidinyl) oxy]] phenyl] -3- (7-amidino-2-naphthyl) propionic acid 2- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+) - 2- [4 - [(1- acetimidoyl-4-p-pyridyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, 2- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3 - (5- amidinobenzo [b] thien-2-yl) propionic, 2- [4 - [((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-10-amidinobenzoic acid [b] thien-2-yl) propionic acid, (+) - 2- [4 - [((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenl] -3- (5-amidinobenzo) acid [b] thien-2-yl) propionic acid, 3- [4 - [((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5-amidinobenzo [b] thien-2) -yl) butyric, 2- [4 - [((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidin-1-ethyl-2-indolyl) propionic acid, acid 2- [4 - [((3R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phen l] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4- [(1-acetylimido-4-piperidnol) oxy] phenol] -3- (6-amidino- 1- 20 ethyl-2-indolyl) propionic, N- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amidin-2-naphthyl) methyl] -N'-methylsulfamide, N- [N-4 - [(1-Acetylamide-4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate ethyl, 4- [N-] 4 - [(1-Acetimidoyl-4-piperidl) oxy] phenyl] -N - [(7-aminon-2-naphthyl) methyl] sulfamoyl] benzoic acid, N- [ 4 - [(1-Acetimidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid, N- [4 - [(1-acetylamidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] ethyl glycinate, N- [N-4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] - N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine, and N- [N-4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N - [(7 -amidino-2-naphthyl) methyl] sulfamoyl] glycine. Particularly preferred are: (2S) -2- [4 - [((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7- 15 amidino-2-naphthyl) propionic, acid (+ ) -2- [4 - [(1-acetimidoyl-4-piperidyl) oxy] pheny] -3- (7-amidino-2-naphthyl) propionic acid (+) - 2- [4- [((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3 (5-amido-benzo [b] thien-2-yl) propionic, 20 N- [N- [4- [(1-Acetymidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amino-2-naphthyl) methyl] sulfamoyl] ethyl glycinate, N- [N-4 - [(1-acetimidoyl- 4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine, and N- [4 - [(1-Acetimido * ÍK4-piperidyl) oxy] phen l] - N - [(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid. In addition, the following compounds are also preferred as follows: (2S) -2- [4 - [((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2) hydrochloride -naphthyl) propionate pentahydrate, (+) - 2- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid co, (+) - 2- [4 - [((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amido-benzo [b] thien-2-acid dihydrochloride] -l) propionic, N [N- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride ethyl, N- [N-4 [(1-acetylamidoyl-4-piperidyl) oxy] phenyl] -N - [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride; N- [4 - [(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N- [(7-amidino-2-naphthyl) methyl] sulfamoyl acetic acid dihydrochloride. As described below, the compounds described above from formula (1), which is an inhibitor of blood coagulation factor Xa (a type of anti-thrombin agent and / or an inhibitor of thrombin production), they exhibit an excellent effect against the sepsis model using the intravenous injection of a lipopolysaccharide that counteracts the syndrome of multiple organ failure caused by sepsis. Therefore, an anti-thrombin agent and / or a production inhibitor of thrombin are useful as therapeutic agents and preventive of the syndrome caused by the aggravation dec ^ epsis. The drug of the invention is directed to the prevention or treatment against sepsis; for example, the systemic inflammatory response syndrome (SIRS) that accompanies an infectious disease. Examples of the syndromes caused by the aggravation of sepsis include severe sepsis, septic shock, and multiple organ failure syndrome. The animal model of intravenous injection of the lipopolysaccharide described above is also known as the hypercytomacine model (Nikkyukyuigakukaishi, 1994: 5: p 1-14). In this model, an anti-thrombin agent and / or an inhibitor of thrombin production exhibit an effect in hypercyncycinemia therapy; particularly, in the decrease of IL-6. This effect against hypercytomacinemia is considered as a mechanism of an anti-thrombin agent and / or an inhibitor of thrombin production against the syndrome caused by the aggravation of sepsis. The inventors of the present study studied the changes in the parameters of liver functions in the previously described animal model of intravenous injection of lipopolysaccharide. Subsequently, they found that this model can be used as a model for liver diseases, since, as compared to the control, this model exhibits significant increases in GOT, GPT, LDH (lactic acid dehydrogenase), and T-BIL (total bilirubin ). In addition, researchers studied the action of the anti-thrombin agent and / or the inhibitor of thrombin production against this model. Based on the significant improvement of liver function parameters (GOT, GPT, LDH and T-BIL), they found that these agents are useful as preventive and therapeutic agents of the 5 hepatic diseases. The drug of the present invention can be administered orally and parenterally. The dose of the drug of the present invention may be increased or appropriately reduced according to the symptoms, age, and weight of the patient. For example, when the compound of Formula (1) is administered orally, the appropriate dose thereof being 5-1000 mg / day, preferably, 10-500 mg / day for an adult. The compound can be administered in tablets, capsules, powder, or in the form of granules. By mixing it with common additives, such as excipients, lubricants and other binders, the compound can be processed to pharmaceutical products by the known methods. When the compound of the formula (1) is administered subcutaneously by intravenous injection or by intravenous infusion by drip, the appropriate dose is 0.1-100 mg / day, preferably 0.5-30 mg / day, for an adult. In addition, the compound of the formula (1) can be administered percutaneously. When an agent of Percutaneous administration is produced from the compound, as a percutaneous absorption promoter, preferably one or more ingredients selected from the group consisting of higher alcohols, major alkanes, higher fatty acids, fatty acid esters of the polyhydric alcohol, terpenes, sulfates, phenyls, acid oxides, carboxybidines, polyoxyalkylene alkyl ethers, sulfoxides, and amides. EXAMPLES The present invention will be described in greater detail by means of examples, which will not be considered as limiting the invention. 5 EXAMPLE 1 Sepsis, septic shock, and multiple organ failure syndrome (1) Method rats (Sic: Wistar, male, 10 weeks old, n = 15) were anesthetized with halothane. Subsequently, lipopolysaccharide (LPS) (E. Coli, 055: B5) (20 mg / 2 ml / kg) was administered to each rat through the femoral vein. Immediately after administration, acid chlorhydrate (2S) -2- [4 - ([(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy) phenyl] -3- (7-amidino-2-naphthyl) propionic pentahydrate (hereinafter referred to as " compound A ") was subcutaneously administered to each rat at a dose of 0.3, 1 or 3 mg / kg. The mortality of the rats was observed 24 hours after the administration of LPS. 20 (2) Results As shown in Table 1, where the mortality of the rats in the control group was 100%, the groups that were administered compound A with doses of 0.3, 1, and 3 mg / kg exhibited a mortality of 80, 40, and 7%, respectively, demonstrating that compound A decreases the mortality of rats in a dose-dependent manner (X2 test: p < 0.001).

TABLE 1 Decrease in mortality in the choaue model by intravenous administration of LPS Dosage (mg / kg) Mortality Mortality in terms of percentage (%) Control 0.3 15/15 100 Compound A 1 12/15 80 3 6/15 40 1/15 7 * M - ^^^^ »A? StíSa &JBA * ,, Hgg ¡JCSC ^ -A * .. m EXAMPLE 2 Hypercycinemaemia (1) Method Rats (Sic: Wistar, male, 10 weeks old, n = 7) were anesthetized with halothane. Subsequently, the LPS (E. Coli, 055: B5) (20 mg / 2 ml / kg) was administered to each rat through the femoral vein. Immediately after the administration, compound A was administered subcutaneously to each rat at a dose of 1 or 3 mg / kg. Six hours after the administration of LPS, a blood sample was taken from the abdominal aorta in the presence of citric acid, and plasma IL-6 was measured by ELISA. (2) Results Figure 1 shows the concentration of plasma IL-6 six hours after the administration of LPS. As seen in Figure 1, compound A suppresses in a dose-dependent manner the increase in the concentration of IL-6 after administration of LPS (#p < 0.1) 8 * ^ ~ £ * * * x EXAMPLE 3 Liver disease (1) Method Rats (Sic: Wistar, male, 10 weeks old, n = 7) were anesthetized by halothane. Subsequently, the LPS (£ .coli, 055: B5) (20 mg / 2ml / kg) was administered to each rat through the femoral vein. Immediately after the administration, compound A was administered subcutaneously to each rat at doses of 0.3, 1, or 3 mg / kg. Six hours after the administration of LPS, a blood sample was taken from the abdominal aorta in the presence of citric acid, and the blood was collected to measure liver function parameters (GOT, GPT, LDH, and T-BILL) . (2) Results Table 2 shows the concentrations of GOT, GPT, LDH, and T-BIL measured six hours after the administration of LPS. As seen in table 2, compound A suppresses in a dose-dependent manner the increase of each liver function parameter after administration of LPS.

^ | ¡Gj ^^ TABLE 2 GOT GPT LDH TBIL (IU / L) (IU / L) (IU / L) (mg / dL) Without administration of 73 ± 3 55 ± 3 67 ± 13 0.05 * 0.002 LPS Control 3404 * 406 3716 + 496 23847 * 3225 0.046 * 0.15 Compound A (0.3 mg / kg) 1939 * 442 19861467 11560 * 2983 0.4810.22 * (1 mg / kg) 1183 * 281 1216 ± 352 6297 2291 0.2010.10 *** *** *** ** (3 mg / kg) 364 ± 42 189 ± 22 9721186 0.1010.01 *** *** *** *** Mean ± E.E. (n = 7); * refers to p < 0.05, ** refers to p < 0.01, and *** refers to P < 0.001 with respect to control (Multiple Comparison of Turkey). * * * * * The present invention is applicable to the prevention or therapy of diseases such as sepsis, severe sepsis, septic shock, and multiple organ failure syndrome. More particularly, the present invention is useful for emergency medical services, for the treatment of wounds caused by traffic accidents, burns, heat shock, or severe infectious diseases. In addition, the present invention is useful for the prevention and therapy of hypercytokinemia and liver diseases.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A preventive and / or therapeutic drug of a syndrome caused by the aggravation of sepsis, containing an antithrombin agent and / or an inhibitor of the production of thrombin as an active ingredient.

2. The preventive and / or therapeutic drug according to claim 1, further characterized in that the syndrome caused by the aggravation of sepsis is the syndrome of multiple organ failure.

3. A preventive and / or therapeutic drug of hypercytomacinemia, which contains an antithrombin agent and / or an inhibitor of the production of thrombin as an active ingredient.

4. A preventive and / or therapeutic drug of liver diseases, containing an antithrombin agent and / or an inhibitor of the production of thrombin as an active ingredient.

5. The preventive and / or therapeutic drug according to any of claims 1 to 4, further characterized in that the inhibitor of the production of thrombin is an inhibitor of blood coagulation factor Xa.

6. The preventive and / or therapeutic drug according to claim 5, further characterized in that the inhibitor of blood coagulation factor Xa is an aromatic amidine derived from the formula (1),

-_, ^^^^^ _ b ^ _ ^^^^^^^^^ and ^^^^ k ^^ - '' ^ -A ^^ a salt of the derivative, a solvate of the derivative, or a solvate of the salt of the derivative:

[wherein R1 represents a hydrogen atom or a lower alkoxy group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, or an alkoxycarbonylalkyl group; R3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group, or an alkoxycarbonylalkoxy group; R4 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group, or a lower alkoxy group; n represents an inclusive number between 0 and 4; and A represents a C1-C4 alkylene group optionally substituted by one or two hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups, or alkoxycarbonylalkyl groups, or a group represented by the following formula;

R5 - E-N-

. { wherein E represents a lower alkylene group or a carbonyl group and R5 represents a hydrogen atom or a group represented by the formula -D-W-R6 (wherein D is a group represented by

Z - C-

(where Z is an oxygen atom or a sulfur atom), a group represented by

or a sulfonyl group; W represents an individual bond or a group represented by -NR7- (wherein R7 represents a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a lower monoalkylaminocarbonyl group, a lower alkylsulfonyl group, a lower mono- or di-alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent, or a lower alkanoyl group which may have a substituent); and R6 represents a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent)}; X represents an individual bond, an oxygen atom, a sulfur atom, or a carbonyl group; Y represents a saturated or unsaturated 5 or 6 membered cyclic or heterocyclic hydrocarbon group which may have a substituent, a

"- - • - - - ^ ~ -.- ~ .-. -i ~ - -A.- .- ^ aá ^ te ^. ^ A .A., ^ L ^ te. ^^ amino group that can have a substituent, an aminoalkyl group which may have a substituent, and the group represented by

represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, or the indanilo].

7. A preventive and / or therapeutic drug according to claim 5, wherein the inhibitor of blood coagulation factor Xa is the hydrochloride of the acid (2S) -2- [4 - ([((3S) -1 -acetylimido-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic pentahydrate 8.- The use of an antithrombin agent and / or of an inhibitor of thrombin production to produce a preventive and / or therapeutic drug 15 of the syndrome caused by the aggravation of sepsis 9.

The use according to claim 8, wherein the syndrome caused by the aggravation of sepsis is the syndrome of multiple organ failure.

The use of an antithrombin agent and / or of an inhibitor of thrombin production to produce a preventive and / or therapeutic drug of hypercytomacinemia.

^ • «- -" - ~ ^ - i¿ ^ ... y, ^,,, ...... ",,. -., ^^^^^ - ^ Á., ^ .. ^ ^ É ^ ^ ^^ ,, ^^^

11. The use of an anti-thrombin agent and / or of an inhibitor of thrombin production to produce a preventive and / or therapeutic drug for liver diseases.

12. The use according to any of claims 8 to 11, wherein the inhibitor of thrombin production is an inhibitor of blood coagulation factor Xa.

13. The use according to claim 12, wherein the inhibitor of blood coagulation factor Xa is an aromatic amidine derived from the formula (1), a salt of the derivative, a solvate of the derivative, or a solvate of the salt of the derivative:

[wherein R1 represents a hydrogen atom or a lower alkoxy group; R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a carboxyl group, a lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, or an alkoxycarbonylalkyl group; R3 represents a hydrogen atom, a carbonyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group, or an alkoxycarbonylalkoxy group; R4 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group,

a lower alkyl group, or a lower alkoxy group; n represents an inclusive number between 0 and 4; and A represents an optionally substituted C1-C4 alkylene group or by one or two hydroxyalkyl groups, carboxyl groups, groups

alkoxycarbonyl, carboxyalkyl groups, or alkoxycarbonylalkyl groups, or a group represented by the following formula;

R5 I - E-N-

. { wherein E represents a lower alkylene group or a carbonyl group and R5 represents a hydrogen atom or a group represented by the formula -D-W-R6 (wherein D is a group represented by Z

- c- (where Z is an oxygen atom or a sulfur atom), a group

15 represented by O O

II II - c- c-

or a sulfonyl group; W represents an individual bond or a group represented by -NR7- (wherein R7 represents a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a lower mono- or di-alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di lower alkylaminothiocarbonyl, a lower alkyl group which may have a substituent, or a lower alkanoyl group which may have a substituent); Y

g | gg • - 'i,. ^ w - > ¿. & amp; dk k ^ > * t- £ i & amp; R6 represents a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent or a heteroaryl group which may have an substituent)}; X represents an individual bond, an oxygen atom, a sulfur atom, or a carbonyl group; Y represents a saturated or unsaturated cyclic or heterocyclic 5 or 6 membered hydrocarbon group which may have a substituent, an amino group which may have a substituent, or an aminoalkyl group which may have a substituent; and the group represented by

represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, or indanyl. The use according to claim 12, wherein the inhibitor of the Blood coagulation factor Xa is the hydrochloride of the acid (2s) -2- [4 - ([((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic pentahydrate.

^ | £ * ^ »j * g * - ~ M¿¿ ^, *