JPS60115519A - Promotor for blood clotting - Google Patents

Abstract

PURPOSE:The titled promotor having XII factor activating ability, shortening extremely time required for blood clotting, having stable promoting effect, comprising a cyclic organic compound wherein two neighboring carbonyl groups are in the sterically and substantially same plane. CONSTITUTION:A promotor for blood clotting comprising a cyclic organic compound [e.g., O-quinone ring-containing compound shown by the formula II (e.g., R<1>, R<2>, R<3>, and R<4> are H, hydrocarbon group, polar substituent group or polycyclic compound residue), homocyclic compound shown by the formula III, etc.]. A concentration of the compound in the blood is at least 1X10<-10>g/ml (blood). In more preferable administration, the compound is supported on a carrier having large specific surface area, and it is added to the blood in a container for testing blood.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood coagulation promoter, and more particularly to a blood coagulation promoter having the ability to activate factor XN.

In recent years, with the remarkable progress in testing technology, blood tests such as serum biochemical tests, serum immunology tests, and hematology tests have become widespread, and have greatly contributed to disease prevention and early diagnosis. Serum tests are the main body of blood tests, and the serum required for this test is usually collected into a blood test container, coagulated, and then centrifuged to obtain serum of different specific gravities. A blood clot, that is, a gel-like mass containing a mixture of fibrin and blood cells, is separated, and the serum portion is collected by sucking up with a pipette or by decantation.

However, blood generally takes a considerable amount of time to coagulate, making it difficult to conduct tests quickly. Even with glass blood test containers, which are said to have the shortest blood coagulation time, it takes 40 to 60 minutes for blood to coagulate after blood is injected. , it is necessary to leave the blood for 4 hours or more before the blood coagulates.

For this reason, glass, kaolin, bentonite, silica, ellagic acid, etc., which have the ability to activate factor X and promote blood coagulation, are used as blood coagulation promoters in serum tests.
Although it is in practical use as a component of a reagent for measuring activated partial thromboplasmin time, which is one of the blood coagulation function tests, there is a problem that its activation ability is unstable depending on its purity and composition.

The present invention has been made in order to solve the above-mentioned problems, and the present invention is made by activating the The purpose is to provide a coagulation accelerator.

The blood coagulation promoter of the present invention is represented by the general formula () (where A represents a residue of a cyclic compound),
Further, it is characterized in that it consists of a cyclic organic compound in which the two adjacent carbonyl groups are sterically located on substantially the same plane.

The above-mentioned cyclic organic compound as a blood coagulation promoter according to the present invention may be either a homocyclic or a heterocyclic compound formed by two adjacent carbonyl groups and a residue A,
In addition, such cyclic compounds may be monocyclic or polycyclic compounds, but they may be monocyclic or polycyclic compounds, but may include a ring in which the ring containing two carbonyl groups is a 6-membered ring or a 5-membered ring. Formula compounds are preferred.

Particularly preferred 6-membered cyclic compounds are the following formula 1 (+1) (wherein R1, R2, R3 and R are hydrogen, a hydrocarbon group,
Indicates a polar substituent or a residue in a polycyclic compound. ) It is a compound having an 0-quinone ring represented by:

In the above formula, the hydrocarbon group is not particularly limited, but is preferably an alkyl group, and the polar substituents are not particularly limited, but include, for example, a carboxyl group, a carboxylic acid ester group, and a hydroxyl group. , amine group,
Such as mercapto group. Therefore, as preferred specific examples of compounds having an 0-quinone ring, for example, 0-quinone,
Gallic acid alkyl ester oxide represented by the following general formula () (where R5 represents an alkyl group), ellagic acid partial oxide and complete oxide represented by the following formula () () (), respectively, Examples include 1,4-di(3,4-dihydroxydiphenyl)2,3-dimethylbutane partial oxide and complete oxide represented by the formula () ().

Further, as a preferable specific example of a homocyclic compound in which the ring containing two carbonyl carbon atoms is a 5-membered ring, R2,3-1-liketohydroindene represented by the following formula (] () can be mentioned. .

Further, the preferred heterocyclic compound as a blood coagulation promoter according to the present invention has the following general formula 1 (6 (IX) , R and R represent hydrogen, a hydrocarbon group, a polar substituent, or a residue in a polycyclic compound), where the above hydrocarbon group and polar substituent are the same as above. be.

Preferred specific examples of such compounds include, for example,
Isatin represented by the following formula can be mentioned.

(X) All of these compounds in this group have two carbonyl groups that are sterically identical or close to each other (that is, two adjacent carbonyl groups on the same plane), and the detailed mechanism of action is unknown. On the other hand, although it has adjacent carbonyl groups in its molecule, it also has a blood coagulation promoter function because they are not on the same plane. Examples of compounds that do not include 1,2-diketocyclohexane represented by the following formula.

(XI) In this case, the alicyclic ring without two adjacent carbonyl groups has considerable flexibility, and therefore these carbonyl/L/ groups have a tendency to sterically repel each other in the gauche position. and not on the same plane. This compound does not exhibit any specific effect on blood coagulation factors. These facts are probably due to the fact that two adjacent carbonyl groups located in special steric positions have a special steric relationship with a specific site of a blood coagulation factor, which is a protein.

In the use of the above-mentioned compound as a blood coagulation promoter of the present invention, for example, blood is collected into a 1111; ” 1. Blood test containers are not particularly limited to 1ti11, and can be made of glass or 4A, which have been commonly used in the past.
A container made of 4 fats is used as appropriate. In addition, the "-compound" may be added to the +iu solution in the form of a powder as it is, or after being dissolved or dispersed in an appropriate solvent,
Blood is collected instantly in a blood test container or BIX
If the protein components in the blood come into contact with a relatively high concentration of these compounds, the protein components in the blood may be denatured. Therefore, the above compounds are supported on a carrier with a large specific surface area, and this is added to the blood in the blood test container. is preferable. According to this method, the above-mentioned compounds are dispersed in the blood at a uniformly small concentration, and unlike the case where a solution or dispersion of these compounds is diluted and added to the blood, it dilutes the blood and interferes with the test. It never comes.

The above-mentioned carrier is not particularly limited as long as it does not have a harmful effect on blood tests and has a large specific surface area, and various carriers can be used, but for example,
Nonwoven fabrics, woven fabrics, resin beads, etc. can be suitably used. In order to support the above-mentioned compound on such a carrier, for example, the solution or dispersion may be applied or immersed therein, followed by drying and adhering to the carrier. Further, particles supporting the above compound can also be obtained by mixing with an appropriate auxiliary agent such as gum arabic to form an aqueous dispersion, and then rapidly freeze-drying the resulting aqueous dispersion.

The amount of the above-mentioned compound as a blood coagulation promoter in the blood is at least 1 x 10 g per ml of blood, and if it is less than this, the effect of promoting blood coagulation is poor. However, if it is present in too large a quantity, it may actually cause various problems in blood tests, so
It is preferable that it is less than g.

As described above, since the blood coagulation promoter of the present invention is a specific compound, it is easy to manufacture and purify, and has a stable blood coagulation promoting effect, and is suitable for various clinical tests. Can be used in the field. Thus, for example, when present in blood, factor x is rapidly activated and the time required for coagulation after blood is collected in a container is significantly reduced. Furthermore, it can also be used to stop bleeding on the bleeding side.

The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples in any way.

Example 1 n-propyl gallate, elladic acid oxide (formula (V
)), 1,4-di(3,4-dihydroxyphenyl)2,3-dimethylbutane oxide (formula (■) above), 1
．． 2.3-) Riketovidroindene, isatin and l.

A 0.05 weight percent physiological saline dispersion of 2-diketocyclohexane was prepared.

Add 1 ml of sodium citrate anticoagulated rabbit plasma to 1 ml of the test solution and 1 ml of 0.025M calcium chloride aqueous solution.
were mixed and kept at 25°C, and the time from immediately after mixing until blood coagulation (hereinafter referred to as calcium conversion time) was measured.

Comparative Example 1 A 0.05% by weight dispersion of glass powder in physiological saline was prepared, and in the same manner as in Example 1, 1 ml of this test solution and 1 ml of a 0.025 M calcium chloride aqueous solution were mixed with 1 ml of sodium citrate anticoagulated rabbit plasma. Calcium turnover time was measured at , 25°C.

Comparative Example 2 1 ml of sodium citrate anticoagulated rabbit plasma, 1 ml of physiological saline and 1 ml of 0.025M calcium chloride aqueous solution
were mixed and the calcium recovery time was measured at 25°C.

The above results are shown in the table. It is clear that the blood coagulation promoter of the present invention has an excellent blood coagulation promoting effect.

Patent Applicant Sekisui Chemical Co., Ltd. Representative Mototoshi Fujinuma J-Day Itoshi'5 Neichi -itmi ν10 (Voluntary)
1. Display of case 1982 Patent Application No. 225266 2, name of invention tin, “r*coagulation accelerator; 3. Relationship with case 11-” Patent applicant Zip code 530 Address Nishitenma, Kita-ku, Osaka Nichoshi 14th 4-'; 39,
'J Kobe Tokyo Torito Tl41. (f13) 434-
95525 Contents of amendment (1) In the first line of page 9 of the specification, the phrase "blood coagulation promoter function" is corrected to "blood coagulation promoting function."

(2) On page 12, line 9 It says "rugulovir gallate" "Gallic acid lupropyl oxide" I am corrected.

(3) In the second row of the left column of the table on page 13, [-n-probyl gallate] is corrected to "rugulovir gallate oxide."

that's all

Claims (1)

[Claims] +1+ Represented by the general formula (where A represents a residue of a cyclic compound),
The blood coagulation promoter is characterized in that it is composed of a cyclic organic compound in which the two adjacent carbonyl groups are sterically located on substantially the same plane.