WO2003089426A1

WO2003089426A1 - Medicine for prevention and/or therapy of disseminated intravascular coagulation syndrome

Info

Publication number: WO2003089426A1
Application number: PCT/JP2003/004985
Authority: WO
Inventors: Asako Hitomi; Yoshinori Toshima
Original assignee: Asahi Kasei Pharma Corporation
Priority date: 2002-04-19
Filing date: 2003-04-18
Publication date: 2003-10-30
Also published as: JP2005320247A; AU2003231369A1

Abstract

An medicine for prevention and/or therapy of disseminated intravascular coagulation syndrome which comprises, as an active component, a substance selected from the group consisting of a compound represented by the general formula (I), wherein R1 represents a hydrogen atom or a hydroxyl group and a pharmaceutically acceptable salt thereof, and a hydrate thereof and a solvate thereof.

Description

Description Pharmaceutical for prevention and / or treatment of disseminated intravascular coagulation

The present invention relates to an agent for preventing and treating disseminated intravascular coagulation. BACKGROUND ART-Disseminated intravascular coagulation syndrome (hereinafter, abbreviated as "DIC" in the present specification (Disseminated intravascular coagulation; jf, And many coagulation factors are consumed, their blood levels are reduced, and secondary fibrinolysis is also added, resulting in a marked tendency to bleeding. The principle of DIC treatment is to correct the hypercoagulable state together with the treatment of the underlying disease, and to treat heparin, low molecular weight heparin, gabexate mesylate. Anticoagulant therapies such as nafamostat mesilate and dry concentrated human antithrombin III are being used, but anticoagulants are also subject to side effects such as bleeding. There is an eager need for superior DIC treatments.

Tissue factor (hereinafter abbreviated as “TF” in the present specification (Tissue Factor)) is expressed on the surface of vascular endothelial cells by stimulation of endotoxin and cytokin, and is said to be involved in the development of intravascular coagulation. ing. In particular, in DIC, the extrinsic coagulation cascade is deeply involved in the formation of the initial disease state.However, since TF is the starting point of this extrinsic coagulation cascade, inhibiting TF production requires early treatment of DIC. It is thought to be possible. In addition, TF production inhibitors have no bleeding side effects compared to anticoagulants that act directly on clotting factors such as thrombin and plasmin in the treatment of DIC in which the coagulation and fibrinolytic system is compromised due to differences in the underlying disease It is expected as a new therapeutic agent [clinical blood, 35 (5), 461 (1994), History of medicine, 198 (1), 88 (2001)]. Further, the compound represented by the following general formula (I) and an anticoagulant such as heparin, low molecular weight heparin, gabexate mesylate, nafamostat mesilate, and dry concentrated human antithrombin III preparation have the mechanism of action. Are different, and additive or synergistic effects can be expected.

On the other hand, the compounds represented by the general formula (I) have kinase inhibitory activities such as rho kinase, myosin light chain phosphatase, and protein kinase C, and have a vascular smooth muscle relaxing action, a blood flow increasing action, a blood pressure lowering action, It is already known that it has a brain and cardioprotective effect, and is an effective substance in vasodilators (especially therapeutic agents for angina pectoris), brain and cardioprotectors, and the like. No. 152658, JP-A-61-22

No. 7581, Japanese Unexamined Patent Publication No. 2-256617, Japanese Unexamined Patent Publication No. 4-1264030, Japanese Unexamined Patent Application Publication No. 6-056668, Japanese Unexamined Patent Application Publication No. 6-080569, Japanese Unexamined Patent Application Publication No. 06433, WO 00/03746, Br. J. Pharmacol., 98, 1091 (1989), J. Pharmacol.Exp.Ther., 259, 738 (1991), Circulation, 96, 4357 (1997), Cardiovasc. Res. , 43, 1029 (1999)].

Until the present invention described in the present specification, the compound represented by the general formula (I) is a compound represented by the formula:

Being useful for the prevention or treatment of IC, and a compound represented by the general formula (I), and heparin, low-molecular-weight heparin, gabexate mesylate, nafamostat mesilate, and dry concentrated human antithrombin There are no reports suggesting that a composition in combination with at least one or more therapeutic agents selected from the group consisting of III, and thrombomodulin preparations is effective for DIC. Disclosure of the invention

An object of the present invention is to provide a medicament for preventing or treating DIC.

The present inventors have conducted intensive studies on the compound represented by the general formula (I), and as a result, it has been found that the compound has the above-mentioned vascular smooth muscle relaxing action, blood flow increasing action, blood pressure lowering action, brain and heart protecting action. For example, the prevention and prevention of DIC, which is completely unexpected from And Z or have a therapeutic effect. Further, a compound represented by the general formula (I), heparin, low molecular weight heparin, gabexate mesylate, nafamostat mesylate, dried and concentrated human antithrombin III, and thrompomodulin preparation Surprisingly, the composition containing at least one or more drugs selected from the group consisting of the above can exert extremely high effects on the prevention and / or treatment of DIC as compared with the use alone. And completed the present invention.

That is, according to the present invention, the following general formula (I):

(Wherein R 1 represents a hydrogen atom or a hydroxyl group) and a pharmaceutically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof. A medicament for preventing and / or treating DIC, which is contained as a component, is provided.

Further, from another viewpoint, the above substance and a group consisting of heparin, low molecular weight heparin, gabexate mesylate, nafamostat mesylate, dried concentrated human antithrombin III, and thrompomodulin preparations A pharmaceutical composition for preventing and / or treating DIC comprising at least one selected drug is provided. From still another viewpoint, a compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof for the production of the above-mentioned medicament or for the production of the above-mentioned pharmaceutical composition; Use of a substance selected from the group consisting of hydrates and solvates thereof, and a method for the prevention and / or treatment of DIC, comprising the steps of: A method comprising the step of administering; and a method for preventing and / or treating DIC, wherein said substance is combined with heparin, low molecular weight heparin, and mesyl. A method comprising the step of administering at least one therapeutic drug selected from the group consisting of gabexate acid, nafamostat mesilate, dry concentrated human antithrombin III, and thrombomodulin preparations simultaneously or at different times. Is done. BEST MODE FOR CARRYING OUT THE INVENTION

The compound represented by the general formula (I) can be prepared by a known method, for example, Chem. Pharam. Bull., 40, (3) 770-773 (1992), and JP-A-61-152658 Can be synthesized according to the method described in, for example. Further, as the salt, an acid addition salt can be used, and for example, a pharmaceutically acceptable non-toxic salt is preferable. Examples include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, and salts of organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, and methanesulfonic acid. Can be. As the active ingredient of the medicament of the present invention, a hydrate or solvate of the compound represented by the above general formula (I) or a salt thereof may be used. Examples of the hydrate include / hydrate and the like (see US Pat. No. 5,924,505).

The medicament of the present invention can be administered orally or parenterally and can be prepared as a pharmaceutical composition in a form suitable for the administration route. When preparing the pharmaceutical composition, an effective compound selected from the group consisting of the compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof is provided. What is necessary is just to mix the substance which is a component and a well-known pharmaceutically acceptable carrier. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice, and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; Alcohols such as stearin alcohol and benzyl alcohol; gums; polyalkylenedaricols and the like. Examples of the liquid carrier include water, physiological saline, dextrose or a similar saccharide solution, and Darcols such as ethylene daricol, propylene glycolone, polyethylene glycolone, and polypropylene glycolone. When a capsule is prepared, it is usually preferable to prepare the capsule using gelatin. The pharmaceutical composition of the present invention can contain the above-mentioned substance which is an active ingredient in an amount of usually 0.01% by weight or more and 80% by weight or less, preferably 60% by weight or less. Pharmaceutical compositions suitable for oral administration include tablets, capsules, powders, granules, liquids, elixirs and the like, and pharmaceutical compositions suitable for parenteral administration include liquids. When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, it is administered as a sterile solution containing other solutes such as salt or glucose to make the above active substance isotonic. You can also. When administered by injection, it is also preferable to dissolve in sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, dextrose, intravenous injection solution, electrolyte solution (for intravenous injection), etc. . When dissolved in this way, it can be prepared so as to contain usually 0.01 to 20% by weight, preferably 0.1 to 10% by weight of the active ingredient. In the case of liquid for oral administration,

0.01 to 20 weight. Suspensions or syrups containing the / ₀ active ingredient are mentioned as preferred examples. In this case, the carrier includes aqueous excipients such as flavors, syrups, and pharmaceutical micelles.

The dosage of the medicament of the present invention may be, for example, the age, health condition, body weight, degree of symptoms, type of concurrent treatment, if any, treatment frequency, nature of desired effect, or administration route or administration schedule, etc. In general, parenteral administration is 0.01 to 20 mg / kgday, and oral administration is 0.02 to 4 mg / kgday.

A compound selected from the group consisting of the compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof, and a compound already used as a therapeutic agent for DIC. When used in combination with a therapeutic agent, the compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof The daily dose varies depending on the administration route and administration schedule, but generally, may be smaller than the single dose. For example, the parenteral dose is 0.005 to 2 OmgZkg 'day, and the oral dose is 0.01 to 40 mg / kg'day.

Drugs that should be used in combination include, for example, heparin, low molecular weight heparin, Examples include at least one drug selected from the group consisting of bexate, nafamostat mesilate, dry concentrated human antithrombin III, and oral tonbomodulin preparations. These drugs can be administered primarily by intravenous or intravenous infusion. Other administration methods may be used as long as the effective concentration can be reached in the blood, specifically, intramuscular injection, subcutaneous administration, oral, nasal, lung, enteral And transmucosal administration methods as described above. Administration *: 1 to 100,000 units / day for heparin, 1 to 10,000 units / day for low molecular weight heparin, 1-10000 units for anticiprombin III, Z day, 1 to 10 Omg / day for gabexate mesylate For acid nafamostat, 0.01 to 10 mg Z days is exemplified. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like of the administration subject.

A substance selected from the group consisting of the compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof, and a hydrate and a solvate thereof; and heparin and low-molecular-weight heparin. When used in combination with at least one therapeutic agent selected from the group consisting of gabexate mesilate, nafamostat mesilate, dry concentrated human antithrombin III, and thrombomodulin, the order of administration of these active ingredients is restricted. There is no limitation, and they may be administered at the same time or individually at different times, but it is also possible to prepare a composition (a so-called combination drug) containing two or more active ingredients in combination and administer them simultaneously. Example

Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1

Effect on TF production in human umbilical vein vascular endothelial cells (HUVEC) HUVEC was dispensed into a 96-well plate with 10% FBS-supplemented DF-12 medium. After culturing for an hour, the medium was removed, and LPS was added to a final concentration of 100 OngZml or TN Fa to a final concentration of 100 UZm1 in F-12 medium supplemented with 10% FBS. The compound represented by the general formula (I) (wherein R 1 is a hydrogen atom or a hydroxyl group) was dissolved in physiological saline and added simultaneously with the addition of LPS and TNF o! To a final concentration of 10 / xM. After incubation at 37 ° C and 5% C% ² for 6 hours, the plate was washed twice with PBS and the TF on the HUVEC surface was measured by the following two-step amidolytic assay. FactorVII, was added assay buffer containing clotting factor and Shioi匕calcium and the synthetic substrate S ²² 22 comprising X in 2 5 0 μ 1 / well, the 0D405 value of 3 7 ° C, 3 0 minutes after heating It was measured with an absorbance meter. With the value of the buffer alone being 0% and the addition of LPS or TNFa being 100%, the inhibition rate of the compound represented by the general formula (I) (R 1 is a hydrogen atom or a hydroxyl group) on TF production was determined.

As shown in Table 1, the compound represented by the general formula (I) (wherein R 1 is a hydrogen atom or a hydroxyl group) suppressed the production of TF on the HUVEC surface by LPS and TNFa stimulation. -

Example 2

The acute toxicity test of the compound of the present invention was performed using rats (Jcl: Wistar, 5 weeks old) and mice (Slc: ddY, 5 weeks old), and as a result, low toxicity was confirmed. The results are shown in Table 2. Table 2

Example 3

Formulation example (sterile injection)

The components shown in Table 3 below were dissolved in distilled water for injection, and then distilled water for injection was added to obtain the required final weight. 2 ml of this solution was sealed in an ampoule and heat-sterilized.

Table 3

Example 4

Formulation example (tablet)

Tablets containing the components shown in Table 4 below were prepared by a conventional method. Table 4

Industrial applicability

According to the present invention, there is provided a medicament for Dc prevention and Z or treatment.

Claims

Scope of request General formula (I) below

(Wherein R 1 represents a hydrogen atom or a hydroxyl group) and a pharmaceutically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof, as an active ingredient. For preventing and / or treating disseminated intravascular coagulation syndrome.

2. The substance according to claim 1 and heparin, low molecular weight heparin, gabexate mesylate, nafamostat mesylate, and dried concentrated anti-antithrombin II.

A pharmaceutical composition for the prevention and / or treatment of DIC, comprising: I, and at least one drug selected from the group consisting of thrombomodulin preparations.