MXPA00010694A - Compounds having glucuronic acid derivatives and glucosamine derivatives in the structure, process for producing the same and utilization thereof - Google Patents

Abstract

1) Compounds having glucuronic acid derivatives and glucosamine derivatives represented by general formula (1) in the structure, pharmacologically acceptable salts thereof and solvates of the compounds or solvates of the salts;2) a process for producing the compounds 1);3) medicinal compositions containing the compounds 1);4) polymers having at least one of the compounds 1) as a side chain structure;5) coatings containing as the active ingredient at least one of the compounds 1) or polymers thereof;and 6) molded articles, artificial organs, medical instruments and devices for cell culture produced by using the polymer 4) and/or the coatings 5).

Description

COMPOUNDS THAT HAVE A DERIVATIVE OF GLUCURONIC ACID AND A DERIVATIVE OF GLUCOSAMINE IN STRUCTURE OF THIS, METHOD TO PRODUCE THE COMPOUNDS AND UTILIZATIONS OF COMPOSITIONS TECHNICAL FIELD This invention relates to innovative compounds having a glucuronic acid derivative and a glucosamine derivative in its structure, a method for producing the compounds, a pharmaceutical composition containing the compounds and polymers having compounds in their structure. side chain, molded products that produce them and artificial organs, medical devices, and cell culture equipment produced through the use of molded products as components. BACKGROUND OF THE TECHNOLOGY Thrombosis has become one of the leading causes of death in Western countries and in Japan in recent years. It is the predominant cause of death that surpasses cancer, if the causes include arterial diseases such as myocardial infarction and cerebral infarction. Various factors are involved in thrombosis, and in vascular lesions such as arteriosclerosis often forms the basis for thrombosis. A normal blood vessel is made highly antithrombotic through vascular endothelial cells. However, platelets adhere to activated vascular endothelial cells at the site of a vascular lesion as a focus of arteriosclerosis, or to a subendothelial vascular tissue exposed through damage, so that the pathological thrombus tends to form. While drugs to suppress the formation of the pathological thrombus, drugs to suppress adhesion or aggregation of platelets, ie "antiplatelet agents", have attracted attention and have found widespread use. The history of antiplatelet agents is relatively recent and development is expected for better drugs of this type. As described above, the normal blood vessel is made highly antithrombotic through the vascular endothelial cells. The roles of vascular cells will be discussed more closely. Vascular endothelial cells are a group of single-layer cells that continuously cover systemic vascular lumens. Normal vascular endothelial cells play a wide variety of roles, such as F the suppression of vascular permeability, ® the antithrombotic action of the vascular lumen, Q) the regulation of relaxation and contraction of the vascular soft muscle, and ® the control of deviation or growth of vascular wall cells. This is how it is said that vascular endothelial cells are of central importance in making the blood vessels as such. It is said that humans age with blood vessels, and that vascular walls become damaged with age. When a vascular wall is damaged and broken, the blood vessel rhexis appears as a vascular disease, such as a myocardial infarction, an aortic aneurysm, a cerebral stroke or necrosis. Arteriosclerosis is the most prominent cause of rupture of the vascular wall. Current treatments or prophylaxis of arteriosclerosis, most are approaches from the aspect of improvement of lipid metabolism and anti-lipemic agents are generally used as drugs. Other drugs administered are antiplatelet agents or anticoagulants to prevent vascular blockage in the arteriosclerosis site. However, these drugs do not positively treat the rupture of the vascular wall. It is expected that these show an indirect action to avoid the progression of rupture by keeping low the hyperlipidemia that is a cause of rupture, or thrombus formation that is a cause of progression of rupture. Regarding the appearance or progression of arteriosclerosis, injuries or functional losses of vascular endothelial cells are considered important and indispensable. With conventional therapies, as mentioned above, it has only been dependent on the repair of the body's function for the elimination of the root cause of the vascular rupture, the most important measure for the treatment, that is, the regeneration and functional restoration of endothelial cells Vascular Therefore, "vascular endothelial regeneration therapy", a therapy to promote the regeneration and functional restoration of vascular endothelial cells that have suffered damage and loss of their intrinsic functions, is considered to be a very useful therapy capable of overcoming the relapses of conventional therapies. However, the drugs usable for the therapy of endothelial vascular regeneration have not been put to practical use, and the development of high-quality drugs is desirable. An example of endothelium regeneration therapy has been presented through a report (Asahara, T. et al., Circulation, 94, 3291, 1996) of a study in which a factor of a gene for vascular endothelial growth (VEGF) was introduced into the vascular endothelial lesion site of a rabbit experimentally injured to express VEGF, and its efficacy was investigated. Percutaneous transluminal coronary angioplasty (PTCA) is a method of inflating a balloon catheter into the blood vessel, (ie, the act of distending an organic cavity with air) to dilate the narrowing site formed as a result of the progression of the arteriosclerosis. This method is one of the established therapies of coronary arteriosclerosis. However, restenosis was noted in the order of 30 to 50% of the patients within 6 months after the operation, and thus this method has presented a major problem. It is said that restenosis is a type of arteriosclerosis that is caused by distending an organic cavity with air (ballooning) and progresses rapidly. In addition to the contraptions of the techniques to distend an organic cavity with air and the improvement in catheters, it has been tried to use treatments using several drugs up to now. They are still insufficient, and the development of better therapies and drugs is expected. Vascular endothelial regeneration therapy may have the ability to effectively prevent post-PTCA restenosis (see report by Asahara et al.), And the development of excellent drugs used for this therapy is expected. The prognosis for ischemic diseases, such as myocardial infarction, is affected by many factors, and it has been thought that the degree of development of collateral vessels is one of the most important determining factors for prognosis. In the presence of a sufficient development of the collateral vessels, even if stenosis or blockage (infarction) occurs, ischemia or tissue necrosis is suppressed, and a reduction in the infarct dimension and an improvement in the prognosis is achieved. . As mechanisms of collateral vessel formation, changes in intravascular pressure and blood flow are emphasized. However, there are reports of cell division images accompanied by the synthesis of DNA observed in vascular endothelial cells or vascular soft muscle cells during the formation of the collateral vessel. It is understood that the process of collateral vessel formation is not simply the dilatation of the blood vessels anastomosed by physical factors, but at least part of the procedure is a neovascularization procedure in which the growth of the cells constituting a wall of the glass. In recent years, there have been attempts to treat ischemic heart disease through a new therapy called "angiogenic therapy" (for example, in Yanagisa a-Miwa, A. et al., Science, 257, 1401, 1992). Angiogenic therapy is an attempt to promote angiogenesis around the ischemic tissue, thus positively assuring a collateral vessel and protecting the ischemic tissue. It is a new therapy that can be called "pharmacological referral therapy." Nevertheless, this therapy has not been put into practical use, and the development of excellent drugs and therapeutic methods used for this is expected. An attempt has also been made to use angiogenic growth factors (eg, fibroblast growth factor) for the treatment of wounds (see, for example, Hockel, M. et al., Arch. Surg., 128, 423, 1993). Artificial organs are designed to complement or replace the functions of various living tissues and organs, such as the heart, blood vessels, heart valve, lungs, pancreas, kidneys, liver, skin and mucosa, through of products molded using artificial materials, or devices using them as components. The artificial organ shows its functions when they are implanted in the valve or when they come into contact with blood withdrawn by cannula inside the blood vessel. Thus, a material used for this must have the nature of being used without harming the body, specifically, biocompatibility. The most important reaction in vivo that defines the biocompatibility of an artificial organ is a thrombus formation reaction. Adhesion and aggregation of platelets are among the important biological reactions that take part in the thrombus formation reaction, within the range with the activation of the blood coagulation proteins. These reactions are present for the hemostatic function indispensable for the normal defense system in vivo. There is also the possibility that when the blood comes into contact with an artificial organ, thrombus formation mediated by adhesion and aggregation of platelets is carried out. At the time of thrombus formation, the artificial organ can not perform its inherent function. To avoid disadvantages such as the formation of thrombi, it has been tried to develop materials that do not cause adhesion or aggregation of platelets, specifically, antithrombotic materials. Several studies have been conducted energetically, but the studies of the materials are still unsatisfactory. The development of better antithrombotic materials indispensable for the development of excellent artificial organs is expected. To prevent the formation of thrombi, it has been tried to develop materials that do not cause thrombus formation on contact with blood, specifically, antithrombotic materials. What directly touches the blood in the body are the vascular endothelial cells that make up the vascular endothelium and do not form thrombi in the normal vascular endothelial cell. As an ongoing material, the best antithrombotic material is a vascular endothelial cell, a natural antithrombotic material. If the surface of an artificial organ in contact with blood is coated with a vascular endothelial cell such as an intact organ, the reaction of thrombus formation is not carried out. As an attempt to develop an artificial organ in a positive way using the antithrombotic properties of the vascular endothelial cell, we have tried the clinical application of an intimate neogenetic healing that promotes the artificial blood vessel, etc., with some successful results (for example, Nioshiki, Y. et al., Trans Am. Soc. Artif. Intern. Organs., 27, 309, 1986). The approach has not been given, such as the use of highly cytophilic materials, and the increases in the porosity of molded products for the promotion of cell penetration. However, some attempts have been made to promote the coating with vascular endothelial cells through the use of a substance that promotes the growth of these cells. In addition to artificial organs, it is desirable that medical devices that have opportunity to make contact with blood use antithrombotic materials, because it is not advantageous if their contact with blood causes adhesion and platelet aggregation. For these reasons too, the development of better antithrombotic materials is expected. In addition, substances that have the action of promoting the growth of vascular endothelial cells can be used as materials for cell culture compositions or cell culture equipment.

DISCLOSURE OF THE INVENTION As is clear from the foregoing descriptions, it is an important challenge for medical practice to provide excellent antithrombotic material. Furthermore, it is an important challenge for medical practice and experiments in cell biology to provide an excellent substance promoting vascular endothelial cell growth and an excellent high molecular substance that has an activity that promotes vascular endothelial cell growth. To meet these challenges, the inventors of the present invention conducted extensive studies. As a result of this, they found that the compounds of the general formula (1), salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts have excellent adhesion / suppressive action of platelet aggregation. They also found that polymers having the compounds as a side chain structure have an excellent suppressive action of platelet adhesion. These findings led them to achieve the present invention. The inventors also found that the compounds of the general formula (1), salts and solvates of the pharmacologically acceptable compounds, or the solvates of the salts have an excellent vascular endothelial cell growth promoting action and an excellent promoter action of angiogenesis. They also found that the high molecular substances that the compounds have as a side chain structure have an excellent action promoting vascular endothelial cell growth. These findings led them to achieve the present invention. That is, this invention provides compounds for the general formula described below (1) having a glucuronic acid derivative and a glucosamine derivative in the structure thereof, salts and solvates of the pharmacologically acceptable compounds or solvates of the salts. The invention further provides a method for producing the compounds of the general formula (1), characterized in that it includes the step of depolymerizing the hyaluronan or its salt. The invention further provides a pharmaceutical composition containing at least one of the compounds of the general formula (1) as an active ingredient. The pharmaceutical composition is useful for drugs in the treatment and prevention of thrombosis, drugs for treatment and prevention of cardiovascular diseases, drugs and treatment for the prevention of cerebrovascular disorders and drugs for the treatment and prevention of peripheral vascular disorders. The invention further provides an antiplatelet agent that contains at least one of the compounds of the general formula (1) as an active ingredient. The invention further provides a vascular endothelial cell growth promoting agent of the general formula (1) as an active ingredient. The vascular endothelial cell growth promoting agent is useful as a therapeutic or preventive drug for the therapy of vascular endothelial regeneration, or a therapeutic or preventive drug for angiogenic therapy. The invention further provides polymers having at least one of the compounds of the general formula (1) as a side chain structure. The invention also provides coating agents containing at least one of the compounds of the general formula (1) or the above polymers as an active ingredient.

The invention further provides molded products using at least one of the polymers as a material. The invention also provides an artificial organ using at least one of the molded products as a component. The invention also provides a medical device that uses at least one of the molded products as a component. The invention further provides a composition for a cell culture containing a polymer as an active ingredient. The invention also provides equipment for the cell culture produced using the molded product and / or the coating agent. BEST MODE FOR CARRYING OUT THE INVENTION [Compounds of the invention] Formula (1) wherein R1 denotes a protecting group, or any of the following formulas of (2) to (5) wherein R10 denotes a hydrogen atom, a protective group, or any of the following formulas from (6) to (8) , and R11 denotes a hydrogen atom or a protecting group, whereas when R10 and Rll are each a hydrogen atom or a protecting group, R1 can be linked in a trans or cis form with respect to COOR4. Formula (2) -OR 10 Formula (3) -NHR11 Formula (4) - CH R, Formula (5) -SR 11 Formula (6) Formula (7) Formula (8) R11 or when R is any of the formulas (6) a (8), R12 to R28, except R13, R17 and R26, in the formulas (6) to (8) are the same or different, and each denotes a hydrogen atom or a protecting group, and R 13 R 17 and R each denote a group of asido or the following formula (9) Formula ( 9) -NR29R30 wherein R29 and R30 are the same or different, and each denotes a hydrogen atom or a protecting group, R2 to R8 are the same or different, and each denotes a hydrogen atom or a protective group R9 denotes a hydrogen atom, a protective group, or the following formula (19) or (11) Formula (10) Formula (11) where R31 to R37 are the same or different, and each denotes a hydrogen atom or a protective group and n denotes an integer from 0 to 25, whereas when n is 0, R1 is a group of the formula (2) , R10 is a group of the formula (8), and R9 is a group of the formula (10) or (11), with the proviso that in the formulas (1), (6) to (8), and ( 10) to (11), the protecting groups are the same or different, and each denotes an optionally substituted straight chain or a branched chain of alkyl having from 1 to 8 carbon atoms, and is optionally substituted with straight chains or branched chains of alkene having from 2 to 8 carbon atoms, an acyl having from 1 to 8 carbon atoms, an optionally substituted aromatic acyl, or an optionally substituted aromatic alkyl, either of the two protecting groups such as R to R > 37, except R, R and R 26, can together form an optionally substituted alkylidene having from 3 to 8 carbon atoms, an optionally substituted cyclic alkylidene having from 3 to 8 carbon atoms, an optionally substituted benzylidene, or a phthaloyl optionally substituted, and when n is 2 or more, R2 to R8 may be the same or different in each of the recurring units. That is, the compounds of the invention expressed by the formula (1) have a structure comprising a D-glucosamine derivative of the formula (12) and a D-glucuronic acid derivative of the formula (13) linked together. Formula (12) " where R38 to R43 each denotes a hydrogen atom or a protecting group. Formula (13) where R44 denotes a hydroxyl group or a protecting group, and R45 to R48 each denotes a hydrogen atom or a protecting group. In the formula (1), n denotes an integer from 0 to 25, and when n is 0, R1 is a group of the formula (2), R10 is a group of the formula (8), and R9 is a group of the formula (10) u (11). That is, the compounds of the formula (1) are expressed by the following formula (14) or (15). Formula (14) jOR11 Formula (15) The protective group in the present being refers to those that include various protective groups from those shown in Theodra W. Green "Protective Groups in the Organic Synthesis", 2nd Ed .; 1991. The protecting groups shown in formulas (1) to (11) are as follows: Examples of straight chain or branched chain of optionally substituted alkyl having from 1 to 8 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, octyl, methoxymethyl, tertiary butylthiomethyl, 1-ethoxyethyl, siloxymethyl, and 2-methoxyethoxymethyl. Examples of straight chain or branched chain of optionally substituted alkenyl having from 2 to 8 carbon atoms are ethenyl, 1-propenyl, 2-propenyl, butenyl, octenyl. Examples of the straight chain or the branched chain of alcyclic having 1 to 8 carbon atoms with formyl, acetyl, propionyl, butyryl, valeryl, or pivaloyl and haloacyl, examples of haloacyl are chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl. Examples of optionally substituted aromatic acyl are benzoyl and parachlorobenzoyl. Examples of the optionally substituted aromatic alkyl are an optionally substituted benzyl, an optionally substituted diphenylmethyl, or an optionally substituted triphenylmethyl, an example of the optionally substituted benzyl is 4-methoxybenzyl. In relation to the protective groups shown in formulas (1) to (11), either of the two protecting groups such as R2 to R, 37, except R, 13, R. 17 and R, can together form a protecting group, is say, an alkylidene optionally substituted with 3 to 8 carbon atoms, an optionally substituted cyclic alkylidene having from 3 to 8 carbon atoms, an optionally substituted benzylidene or an optionally substituted phthaloyl. Examples of the optionally substituted alkylidene having from 3 to 8 carbon atoms are propylidene, butylidene and octylidene. Examples of the optionally substituted cyclic alkylidene having from 3 to 8 carbon atoms are cyclopentylidene, cyclohexylidene and cycloheptylidene. Other examples are an optionally substituted benzylidene, an optionally substituted phthaloyl. The preferred protecting group for a hydroxyl group is an optionally substituted straight chain or branched chain acyl having from 1 to 8 carbon atoms, an optionally substituted aromatic alkyl, a straight chain alkenyl or optionally substituted branched chain having 2 to 5 carbon atoms. or more carbon atoms, or an optionally substituted benzylidene. More preferably they are acetyl, benzyl, 1-propenyl, or benzylidene. The protective group preferably for an amino group is an optionally substituted straight chain or branched chain acyl having 1 or more carbon atoms, or an optionally substituted phthaloyl. More preferably it is acetyl or fraloyl. The preferred protecting group for a carboxyl group is an optionally substituted straight chain or branched chain alkyl having from 1 to 8 carbon atoms, or an optionally substituted aromatic alkyl. More preferably it is methoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or diphenylmethyl. The protective groups described above can be the same or different in the same compound, and can be selected arbitrarily. In formula (1), n is an integer from 0 to 25, preferably from 0 to 10 and particularly preferably from 0 to 5. R9 may be consistent with the foregoing descriptions, and is preferably of formula (11). That is, the compounds of the formula (1) are preferably the following formula (16). Formula (16) At this time, it is further preferred that in the presence of the formula (11), R1 is any of the formulas (6) to (8), that is, the compounds of the formula (1) are any of the following formulas (17) to (19) Formula (17) Formula (18) Formula (19) In addition, in formulas (17) 19), it is particularly preferred that R, 113J, R17 and R26 are formula (9). The compounds of the invention have two different categories of actions, (A) a platelet adhesion / aggregation suppressive action, and (B) a vascular endothelial cell growth promoting action and an angiogenesis promoting action. When the compounds to be used for the purpose of (B) the compounds of the formula (16) are particularly preferred. The pharmacologically acceptable salt herein refers to the salt that does not exert an adverse influence on the body when the compound of the invention is administered at the therapeutically necessary dose, or a salt that does not impair the effective pharmacological nature of the compound of the invention when this compound becomes a salt form. Examples of this salt are alkali metal salts or alkaline earth metals, such as sodium salt, potassium salt and calcium salt; salts of hydrohalogenic acids, such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; low alkylsulfonates, such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonates, such as benzenesulfonate, and p-toluenesulfonate; salts of organic acid, such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and amino acid salts, such as glutamate and aspartate. Still further, the compounds of the invention and their salts include solvates with various pharmacologically acceptable solvents, such as water, organic solvents, and buffers, as well as those that are polymorphs. The compounds of the invention may have an asymmetric carbon atom, depending on the type of substituent, and may exist as optical isomers based on the presence of the asymmetric center. Thus, the compounds of the invention include all the respective isomers and their mixtures. For example, the compounds include mixtures of certain optical isomers and their enantiomers, especially racemic modifications that are mixtures of equal amounts of D and L isomers, or mixtures of certain optical isomers and their diastereomers. [METHOD FOR PRODUCING COMPOUNDS OF THE INVENTION] It goes without saying, that various methods are available to obtain the compounds of the invention. Examples of these methods are organic chemical methods, namely, the methods of synthesizing or modifying intermediates or desired compounds through organic chemical techniques using glucuronic acid derivatives and glucosamine derivatives as starting materials, or methods to obtain intermediates or desired compounds through the decomposition of polysaccharides with acids or alkalis; biochemical methods, specifically, methods of synthesizing or modifying the desired intermediates or compounds through the use of reverse transferase reactions or depolymerization of enzymes with the use of glucuronic acid and N-acetylglucosamine as starting materials, or methods for obtaining intermediates or the desired compounds through the depolymerization of polysaccharides with enzymes; and the method for involving genetic engineering technologies, specifically methods for obtaining starting materials, intermediates or desired compounds, or enzymes for use in synthesis or modification through the introduction of genes for enzymes within microorganisms or cells . These methods are used alone or in combination. It can be continued without saying that the compounds of the invention are not restricted by these production methods, and any of the methods can be employed while obtaining the desired compounds. Of the various manufacturing methods, the methods for the production using substances that occur naturally, especially the polysaccharides or oligosaccharides, as starting materials or intermediates that are the most efficient and preferred methods. Furthermore, it is more preferred to employ a method in which hyaluronan and its salts extracted from animal tissue or cultures of microorganisms, followed by purification if necessary, are used as starting materials, and hyaluronan is depolymerized to obtain products of depolymerization, and these products are used as intermediates or desired compounds. The methods for depolymerization can be, for example, physical methods using heat or ultrasound, chemical methods using acids or alkalis, or biochemical methods using enzymes. These methods can be used alone or in combination. Of these methods, methods using enzymes are preferred due to the specificity, efficiency or safety of the reaction. The enzymes used may be those which have the activity of catalyzing the depolymerization reaction of hyaluronan, and are not restricted. These enzymes can be used alone or as a combination of plural types, depending on the purpose. Examples of the enzymes are enzymes of animal tissue origin, such as a testicular hyaluronidase (EC 3.2.1.35), leech hyaluronidase (EC 3.2.1.36), venom hyaluronidase from Inimicus japonicus (EC 3.2.1), ß-glucuronidase (EC 3.2.1.31), and ß-N-acetylhexosaminidase (EC 3.2.1.52), and enzymes of microorganism origin, such as hyaluronidase from streptomyces hyaluroliticus (EC 4.2.2.1), hyaluronidase SD (EC 4.2.2.5), and chondroitinase AC II (EC 4.2.2.5). Of these enzymes, enzymes originating from microorganisms are preferred because of the advantage that they can be delivered stably with stable quality. Of these, the Streptomyces hyaluroliticus enzyme is particularly preferred. The reaction of the enzyme can be carried out, under various conditions, such as temperature, pH, which are adjusted according to the characteristics of the enzymes. To omit a desalting step that is highly similar to that required in carrying out the fractionation, purification or subsequent modification, the reaction is preferably carried out in a salt-free state, or in a substantially non-salt free state. Volatile and insoluble salts in organic solvents. The substantially salt-free state refers to a state that does not contain a salt in an amount exceeding this amount so as to make it possible to easily perform a fractionation, purification or modification step without performing a desalination step after the reaction of the enzyme. Preferably, the salt content in the reaction mixture is 10% (w / w) or less, more preferably 1% (w / w) or less of the desired compound. The salts in the reaction mixture herein, refer to the components of a buffer used for the adjustment of the strength and pH of the ion, for example, sodium acetate, sodium phosphate, potassium citrate, sodium acetate, sodium phosphate, potassium citrate, sodium chloride, potassium chloride and calcium chloride. The non-volatile salts mentioned herein refer to salts that are different from the volatile salts which can be relatively easily volatilizable through a pressure reduction step, such as ammonium acetate, and ammonium bicarbonate. The use of volatile salts makes it possible to remove salts at the stime that they remove the liquid components from the solutions of the intermediates or the desired compounds through the reduction of pressure or similarly. The insoluble salts in organic solvents herein refer to salts that are different from the salts which are not only soluble in water, but also in organic solvents, (for example, ethanol, methanol, and propanol), such as ammonium, sodium acetate, potassium acetate, and calcium acetate. When salts soluble in organic solvents are used, a mixture containing an intermediate or a desired compound, which is soluble in water incorporating the salts soluble in organic solvents but which is insoluble in organic solvents, is washed with a suitable organic solvent, where the Incorporated salts can be easily separated. The resulting depolymerization product can be separated and purified, where necessary, by a customary method, such as extraction, concentration, filtration, recrystallization, reprecipitation, or chromatography. It is preferred to include the step of separating and purifying by chromatography, more preferably, ion exchange chromatography, because of its high efficiency. It is even more preferred to use an anion exchanger as a carrier. The chromatograph is available as a batch type, a type of circulation, a type of moving bed, or a pseudo-mobile bed type, and the optimum can be selected according to the circumstances. An eluent for use in chromatography may be that of the optimum composition according to the method used. To omit a highly possible desalination step that is required in carrying out the purification or subsequent modification, it is preferred to use it in a substantially free eluent of non-volatile salts and salts insoluble in organic solvents. The "substantially free eluent of non-volatile salts and salts insoluble in organic solvents" refers to an eluent that does not contain non-volatile salts or salts insoluble in organic solvents, the salts will be in an amount exceeding this amount that would make it possible to perform easily a fractionation, purification or modification step without performing a desalting step after chromatography. Preferably, the content of each of the salts in the eluent is 0.5 M or less, more preferably 0.1 M or less. Normally, the eluent used in ion exchange chromatography contains salts to adjust the strength and pH of the ion. When the eluent containing salts is used, it is preferred to use the eluent which substantially contains only volatile salts as salts. As a volatile salt, the ammonium salt is preferred in view of ease of handling, safety, ease of acquisition, and price. The ammonium acetate is even more preferred. Alternatively, it is preferred to use the eluent which substantially contains only soluble salts in the organic solvents as salts. As the soluble salt in an organic solvent, acetate is preferred in view of ease of handling, safety and ease of acquisition and price. Still more preferred is ammonium acetate or sodium acetate. The resulting intermediate can be converted to the desired compound through purification or modification using various methods, for example, organic chemical methods or biochemical methods or a combination thereof. [Mode of administration, dose, dosage form of the compound of the invention] The compound of the invention, its pharmacologically acceptable salt or solvates, or a solvate of the salt are usually administered systemically or locally or orally or parenterally. Like the dose, the optimal dose should be determined according to the general judgment based on the conditions, such as the type of disease, the severity of the symptoms, the age, and the body weight of the subject receiving the treatment. The dose is not restricted, but in adults, the usual daily dose is 0.01 to 100 mg / kg orally, or 0.001 to 10 mg / kg parenterally. The dose is administered once a day or in divided doses when necessary. The compound of the invention, its pharmacologically acceptable salt or solvate or a solvate of the salt can be administered in any form, such as oral forms, including a solid composition, a liquid composition and another composition, or in parenteral forms including injection, externally used preparation, and suppository. The most suitable form is selected according to the need. A pharmaceutical composition containing at least one of the compounds of the invention, their pharmacologically acceptable salts and solvates, or solvates of the salts can be prepared through the use of carriers, excipients and other additives used for ordinary pharmaceutical manufacture. Examples of these carriers and excipients for the preparations are lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa cream, ethylene glycol, and other customary materials. As a solid composition for oral administration, tablets, pills, capsules, powder, and granules are used. In this solid composition, at least one of the active substances (active ingredient) is mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, crystallite cellulose, starch, polyvinylpyrrolidone, or metalsilicate / magnesium aluminate. . According to the customary method, the composition may contain additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrants such as calcium carboxymethylcellulose and adjuvant solutions such as glutamic acid or aspartic acid. The tablets or pills can, if desired, be coated with a sugar coating or a soluble gastric film or a soluble enteric film composed of sucrose, gelatin, hydroxypropyl phthalate methylcellulose or the like. Alternatively, tablets or pills can be coated with one or more layers. In addition, a capsule of a substance that can be absorbed, such as gelatin, is also included. The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, and may contain inert diluents generally used, such as purified water and ethanol. This composition may contain, in addition to the inert diluents, adjuvants such as wetting agents or suspending agents, sweetening agents, flavoring agents, flavors, and preservatives. Injection for parenteral administration contains sterile aqueous agents, or non-aqueous solubilizing agents, suspending agents, or emulsifying agents. Examples of aqueous solubilizing agents and suspending agents are injectable water, and physiological saline for injection. Examples of non-aqueous solubilizing agents and suspending agents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and POLYSORBATE. (registered trademark). As a composition it may further contain adjuvants, such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers (for example, lactose) and adjuvant solutions / for example, glutamic acid and aspartic acid). These agents can be sterilized through ordinary sterilization methods, such as sterilization by filtration with a microfiltration membrane, sterilization by heating as wet heat sterilization, or the incorporation of a bactericide. Alternatively, a sterile solid composition is produced, and can be used after dissolving in sterile water or a sterile solvent for injection before use.

Other pharmaceutical compositions for parenteral administration contain at least one of the compounds of the invention as an active ingredient. These include liquids for external use, ointments, liniments, suppositories, transdermal preparations, and ophthalmic solutions. [Polymer of the invention and method for its production] The polymer of the invention is a high molecular compound having the compound of the invention as a side chain structure, and can be used as a polymeric material having antithrombotic properties. A polymer as a main chain for use in the production of the polymer of the invention is preferably a biocompatible polymer. Examples of this polymer are polyethylene, polystyrene, polyurethane, polyvinyl chloride, ethylene vinyl acetate copolymer, polypropylene, polycarbonate, silicone, polymethyl methacrylate, polytetragluoroethylene, polyethylene terephthalate, polyamide, polysulfone, ABS resin, polyacetal, and derivatives of these polymers. A suitable spacer can be inserted between the main chain and the side chain, where flexibility can be imparted to the side chain that has antithrombotic properties. Alternatively, the polymer may be a block of copolymers of a plurality of polymeric compounds having the compound of the invention in the structure of the side chain. In addition, the polymer may have in addition to the compound of the invention, an antithrombotic substance bound thereto, an example of the antithrombotic substance which is a substance suppressing the formation of thrombi such as heparin, or a thrombolytic enzyme such as urokinase. As a matter in progress, the polymer of the invention is not restricted by the production method, and any of the methods can be adopted, while obtaining the desired product. Various methods are available to obtain the polymer of the invention, and these methods can be used alone or in combination. These production methods are publicly known among people skilled in technology. For example, after the compound of the invention is linked to a monomer for the polymer that will become a main chain, a polymerization reaction can be performed to form the main chain polymer. Alternatively, the compound of the invention can be linked to the main chain polymer.

The compound of the invention has, in its structure, derivatives of the body components, such as a glucuronic acid derivative and a glucosamine derivative. As will be understood from this fact, the compound of the invention is highly biocompatible, and exerts a minimal adverse influence on the living body, and exerts a minimal adverse influence on the body even if the compound of the invention is decomposed from the polymer. [Coating agent and molded product of the invention and methods for its production] The invention also provides a coating agent containing at least one of the compounds of the invention as an active ingredient, and a coating agent containing at least one of the polymers of the invention as an active ingredient. These coating agents can be coated by dissolving or dispersing the compound or polymer of the invention in a suitable solvent, and apply the resulting solution or dispersion to an artificial organ or medical device through a method such as coating, impregnation or spray coating. The molded product of the invention is produced by using at least one of the compounds or polymers of the invention as a material, and is manufactured in accordance with the purpose of use. Therefore, the molded product can be prepared by any method, unless the essential nature of the material becomes incapacitated. To obtain the molded product of the invention, various methods are available, such as coating the compound or polymer in a molded product produced separately; the binding of the compound to a molded product produced separately, the binding of the compound to a molded product produced separately, a direct molding from a material containing the compound or polymer, these methods can be used alone or in combination. Since the molded product of the invention has high antithrombotic properties, it can be used as a component for an artificial organ or a medical device, or it can be used as an artificial organ or a medical device as such.The shape of the molded product depends on the nature of the material used, and may be one of the following: film, membrane, tube, plate, net, fiber, or cloth, according to the purpose of use.

[Artificial organ of the invention and method for its production] The artificial organ of the invention is produced by using at least one of the compounds or polymers of the invention as a material, or by using at least one of the molded products of the invention. the invention as a component. It is manufactured in accordance with the purpose of its use. It can also be produced by coating the coating agent of the invention on the artificial organ produced, or a conventional artificial organ produced by another method. Thus, the artificial organ can be produced through any method, unless the essential nature of the material or component becomes incapacitated. Examples of the artificial organ of the invention are an artificial blood vessel, an artificial heart, a cardiac pacemaker, a prosthetic heart valve, an artificial kidney, an artificial lung, a cardiac-pulmonary machine, an artificial pancreas, an artificial bone, a Artificial joint and an artificial ligament. [Medical device of the invention and method for its production. ] The medical device of the invention is produced by using at least one of the compounds or polymers of the invention as a material, or by using at least one of the molded products of the invention as a component. It is manufactured according to the purpose of its use. This is how the medical device can be produced through any method, unless the essential nature of the material or component becomes incapacitated. Examples of the medical device of the invention are a syringe for injection, a needle for injection, a resident needle for dialysis, a resident needle, an infusion set, an infusion / blood filter, a blood bag, a tube catheter (for nutrition, for stomach / esophagus, for bile duct, for breathing, for urology, for blood, for heart, for blood, for heart, for aspiration / injection / drainage, etc.), a hemodialyzer box, a hollow hemodialyzer wire, a membrane for hemodialysis, a blood circuit of extracorporeal circulation, an external derivation, an artificial pulmonary membrane, a material for covering wounds, and a "stent". [Composition for the cell culture of the invention] The composition for cell culture according to the invention can be produced by adding the compound of the invention or a polymer, having at least one of the compounds of the invention as a structure of side chain, to a conventional composition for cell culture. Examples of the culture medium for a cell culture, to which the compound of the invention is added or to the polymer having at least one of the compounds of the invention as a side chain structure are but are not restricted to the medium. , MEM (Eagle's minimum essential medium), BME (Eagle's basal medium) DMEM (Dulbecco's modified Eagle's medium), RPMI1640, Ham's F12 medium, MCDB104, and MCDB153. Cells that can be cultured using the composition for cell culture of the invention, include, but are not restricted to, vertebrate cells, such as fish cells, amphibian cells, bird cells, and mammalian cells. The compound of the invention has an endothelial cell growth promoting action, and a marked angiogenesis promoting action. Thus, the composition for culturing the cell of the invention can be used for the culture of mammalian cells, especially vascular endothelial cells, for the purpose of culture for testing and research. The composition can also be used for the production of a useful substance such as cell growth factor (for example VEGF), as well as for the production of therapeutic tissue, such as artificially cultivated skin to relieve burns. [Cell culture equipment of the invention] The cell culture equipment according to the invention is produced by using at least one of the compounds or polymers of the invention as a material, or through using at least one of the molded products of the invention as a component. It is manufactured according to the purpose of its use. It can also be produced by coating the coating agent of the invention on the equipment produced for cell culture, or for conventional equipment for cell culture produced by another method. Thus, equipment can be produced by any method, unless the essential nature of the material or component becomes incapacitated. Examples of the cell culture equipment of the invention is a petri dish, a flask, a microplate and a bottle. [Suppressive action of platelet aggregation and suppressive action of the platelet adhesion of the compound and of the polymer of the invention] The suppressive action of platelet aggregation of the compounds of the invention (Examples of compounds 1, 2, 3, 4, 6 , 8, 10) was measured according to the methods of Born and O'Brien (Born, G., V., R .: Nature (London), 194, 924 (1962)., O'Brien, JR: Clin Pathol., 15, 556 (1962)) using plasma rich in rabbit platelets. As a control for comparison, the same test was conducted on ticlopidine hydrochloride, an antiplatelet agent. As a result of this, the compounds of the invention exhibited a marked suppressive action of platelet aggregation at low concentrations. The platelet adhesion suppressing action of the polymeric compounds (Examples of polymers 2 to 4) having the compound of the invention as a side chain structure were evaluated by the microsphere column method (Kataoka, K., Maeda, M Nishimura, T. Nitadori, Y., Tsuruta, T., Akaike, T., Sakurai, Y .: J. Biomed, Mater.Res., 14, 817 (1980)) using rabbit platelet rich plasma. As a result of this, the polymers of the invention exhibited a marked suppressive action of platelet adhesion. In addition, a molded product having the compound of the invention fixed thereto was obtained by reacting the compound of the invention with an activated polyethylene polyethylene tube, and the ratio of the platelet adhesion of the molded product was measured. Platelet adhesion was not detected at all, compared to the untreated tube to which the compound of the invention was not fixed. It was found that the molded product showed excellent antithrombotic properties. [Promotional action of vascular endothelial cell growth of the compounds and polymers of the invention] The vascular endothelial cell growth promoting action of the compounds of the invention was measured using bovine aortic endothelial cells. As a result of this, the compounds of the invention used in the test showed an excellent growth promoting action in low concentrations. Also, the compounds of the invention acted synergistically with vascular endothelial growth factor (VEGF), a cytokine which is known to specifically act on vascular endothelial cells and promotes the growth of these cells, thus showing a better promoter action of vascular endothelial cell growth. This is a finding that the compounds of the invention act synergistically with the intrinsic VEGF originating in the body and the extrinsic VEGF, which has been administered or induced for therapeutic purposes, thus exhibiting a better vascular endothelial cell growth promoting action. Bovine aortic endothelial cells were cultured in microplates coated with the above polymers used in the invention and a vascular endothelial cell growth promoting action was measured. As a result of this, the polymers of the invention (molded products of the invention) showed an excellent growth promoting action. [Angiogenesis promoting action of the compounds of the invention] The angiogenesis-promoting action of the compounds of the invention was measured using bovine aortic endothelial cells. As a result, the compounds of the invention showed an excellent action promoting angiogenesis. EFFECTS OF THE INVENTION The compounds of the general formula (1), of pharmacologically acceptable salts and solvates or solvates of the compounds, or solvates of the salts having an excellent suppressive action of platelet adhesion / aggregation and are useful as therapeutic agents with based on this action, that is, as antiplatelet agents. Specifically, it can be used in the treatment for the inhibition of the progress of thrombosis, the prevention of recurrence, the secondary prevention of thrombosis in patients who have risk factors for thrombosis and primary prevention of thrombosis in healthy persons. More specifically, these are effective in the treatment and prophylaxis of cardiovascular diseases (acute myocardial infarction, unstable angina, chronic stable angina, myocardial infarction, thromboembolism due to atrial fibrillation, disseminated intravascular coagulation syndrome (DIC), obstruction of graft after coronary bypass surgery, coronary stenosis and obstruction after percutaneous transluminal coronary angioplasty (PTCA), thrombotic complications after prosthetic heart valve replacement (thromboembolism, thrombosed valve), pulmonary thromboembolism, activation of platelets in blood circulation extracorporeal), cerebrovascular disorders (transient cerebral ischemic attack (TIA), cerebral infarction), peripheral arterial obstruction (obstructive arteriosclerosis, obstructive thromboangiitis, obstruction after revascularization), glomerular nephritis, nephrotic syndrome, and otr as thrombosis (essential thrombocythemia, thrombotic thrombocytopenic purpura (TPP), hemolytic uraemic syndrome, antiphospholipid antibody syndrome, Kawasaki disease, eclampsia, Beh? et disease). The invention also provides a method for production that is useful in the production of these excellent compounds. The compounds of the general formula (1), especially the compounds of the formula (16), salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts, have an excellent action promoting vascular endothelial cell growth, and an excellent action Promoter of angiogenesis. These are useful as therapeutic agents based on these actions. Specifically, are useful as therapeutic agents and prophylactic agents used for vascular endothelial regeneration therapy or angiogenic therapy (vascular endothelial cell growth promoters, angiogenesis promoters). More specifically, these are effective for the treatment and prophylaxis of cardiovascular diseases (acute myocardial infarction, unstable angina, chronic stable angina, infarct to the old myocardium, thromboembolism due to atrial fibrillation, disseminated intravascular coagulation syndrome (DIC), obstruction of graft after coronary bypass surgery, coronary stenosis and obstruction after percutaneous transluminal coronary angioplasty (PTCA), thrombotic complications after prosthetic heart valve replacement (thromboembolism, thrombosed valve), pulmonary thromboembolism, cerebrovascular disorders (cerebral ischemic attack) passenger (TIA), cerebral infarction), peripheral arterial obstruction (obstructive arteriosclerosis, obstructive thromboangiitis, obstruction after revascularization), glomerular nephritis, nephrotic syndrome, and other thrombosis (essential thrombocythemia, thrombotic thrombocytopenic purpura (TPP) hemolytic uremic syndrome, antibody syndrome antiphospholipid, Kaeasaki disease, eclampsia, Beh? et disease); and the treatment of wounds (chronic dermal ulcers including decubitus, diabetic ulcer, burns, corneal wound, oral mucositis in cancer patients receiving chemotherapy or radiotherapy, wounds after various operations such as skin grafts, gastrointestinal tissue lesions, etc.) . The compounds and polymers of the invention have excellent antithrombotic properties. Thus, they are useful as coating materials or agents for preparing molded products that require antithrombotic properties. The compounds, polymers and molded products of the invention have excellent antithrombotic properties. This is how they are useful as components for artificial organs and medical devices that require antithrombotic properties, or as artificial organs and medical devices per se. Specifically, they are useful as materials and components for artificial organs such as an artificial blood vessel, an artificial heart, a cardiac pacemaker, a prosthetic heart valve, an artificial kidney, an artificial lung, an artificial cardiopulmonary machine, an artificial pancreas, a bone artificial, an artificial joint and an artificial ligament; and medical devices such as a syringe for injection, a needle for injection, a resident needle for dialysis, a resident needle, an infusion set, an infusion / blood filter, a blood bag, a tube catheter (for nutrition, for stomach / esophagus, for bile duct, for breathing, for urology, for blood, for heart, for blood, for heart, for aspiration / injection / drainage, etc.), a hemodialyzer box, a hollow hemodialyzer wire, a membrane for hemodialysis, a blood circuit of extracorporeal circulation, an external derivation, an artificial pulmonary membrane, a material for covering wounds, and a "stent". The compounds of the invention, and the polymers having them as a side chain structure have an excellent action promoting vascular endothelial cell growth, and promote the coating with vascular endothelial cells. Thus, they can be useful as coating materials or agents for preparing molded products that require antithrombotic properties. In addition, these compounds, polymers and molded products have an excellent action promoting vascular endothelial cell growth and promote the coating with vascular endothelial cells. This is how they are useful as components for artificial organs and medical devices that require antithrombotic properties, or as artificial organs and medical devices per se. In addition, the compounds of the invention, or polymers having at least one of the compounds as a side chain structure, are useful as ingredients for compositions for cell culture. The compounds of the invention and the polymers having the compounds as a side chain structure can be expected to be used as cell culture equipment. EXAMPLES In the Examples below, the present invention will be described in greater detail in the form of Examples of Production of Compound, Example of Production of Polymer, Example of Production of Molded Product, Test of Antithrombotic Action, and Example of Production of Preparation. It goes without saying that the invention is not restricted to the substances, formulations and methods described in the following examples, and includes all the substances, formulations and methods included in the scope of the claims. Example 1: Production Example of Compound 1 Production of 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1) >; 4) -3-O-ß-D-glucopyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl- > 3GlcNAc ßl-4GlcA ßl-3GlcNAc (Example of compound 1)], 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-ß-D- glucopyranosyl- (1-4) -3-0-β-D-glucopyranuronosyl (l-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1- ^ 4) -3- 0- ß-D-glucopyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl-3GlcNAc ßl-4GlcA ßl- »3GlcNAc ßl -» 4GlcA ßl- »3GlcNAc (Example of compound 2)], 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1 ~ ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> g. 4) -3-0-ß-D-glucopyranuronosyl- (1-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-β -D-glucopyranuronosyl- (1 ~ ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-β-D-glucopyranuronosyl- (1-3) ) - 0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl ~ 3GlcNAc ßl-4GlcA ßl-3GlcNAc ßl-4GlcA ßl-3GlcNAc ßl-4GlcA ßl-3GlcNAc (Example 3)], and 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1 ~ 3) -0-2-acetam ida-2-deoxy-β-D-glucopyranosyl- (1-> > 4) - 3-0-ß-D-glucopyranuronosyl- (1-3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-O-β-D -glucopyranuronosyl- (l-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1- ^ 4) -3-0-β-D-glucopyranuronosyl- (1-3) - 0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-ß-D-glucopyranuronosyl- (l-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl- 3GlcNAc ßl- > 4GlcA ßl- 3GlcNAc ßl ~ 4GlcA ßl- »3GlcNAc ßl" 4GlcA ßl- »3GlcNAc ßl-» 4GlcA ßl-> 3GlcNAc (Compound 4 example)] 30g of solid hyaluronate (a product of KIBUN FOOD CHEMIFA; trade name "Hyaluronic acid FCH") was dissolved in 3L of distilled water, and the solution was heated to 40 ° C. The pH of the solution was adjusted to 6.0 with an aqueous solution of 0.1M sodium hydroxide, then hyaluronidase of origin Streptomyces hyaluroliticus (a product of Amano Pharmaceutical, trade name "Hyaluronidase" Amano "") was added to a turbidity reduction unit of 0.5 per mg of sodium hyaluronate and the reaction was carried out for 100 hours at 40 ° C. the reaction, the enzyme was removed from the solution through an ultrafiltration membrane (a Millipore product) of hydrophilic polyethersulfone with a molecular cut-off of lOk.The solvent was removed through lyophilization to obtain a depolymerization product (27.4 g The depolymerization product was fractionated through anion exchange chromatography (column: YMC-Pack IEC-AX, eluent: A; water, B; 0.4M NaCl; linear gradient (30 min), detection: UV (232 n)) (examples of compounds 1, 2, 3, and 4 were eluted in that order) to obtain fractions containing the Examples of compounds 1 to 4. desalted the respective fractions through gel filtration (gel: Sephadex G-10, eluent: water), and then lyophilized to obtain Compounds 1 to 4 (white powder). Production was Compound Example 1: 1.7 g, Compound Example 2: 5.9 g, Compound Example 3: 3.4 g, and Compound Example 4: 2.2 g, respectively. The respective compounds were obtained as sodium salts. Examples of Compounds 1 to 4 are compounds expressed by the following formula (20) where n denotes an integer from 1 to 4. This formula represents the Example of Compound 1 where n is 1, the Example of Compound 2 when n is 2, the Example of Compound 3 where n is 3 and the Example of Compound 4 where n is 4. Formula (20) The purity of each of the compounds measured by high-performance liquid chromatography (column: TSKgel DEAE-5PW, eluent: A; water, B; 0.3 M NaCl; linear gradient (20 min), detection: UV (232 nm ), percentage area method) was 97% or more. The uronic acid content of each of the Examples of Compounds 1 to 4 was analyzed through the Bitter and Muir method (Bitter, T., Muir, H .: Anal. Biochem., 4, 330 (1962)) using glucuronolactone as a standard product. The hexosamine content of each of the Compound Examples 1 to 4 was analyzed through the Boas method (without resin treatment; Boas, N., F.: J. Biol. Chem., 204, 553 (1953 )) using glucosamine hydrochloride as a standard product after 16 hours of hydrolysis at 100 ° C in 3N hydrochloric acid. The values of the examples of the respective compound found through analysis were almost in accordance with the theoretical values. Example 2: Production Example of Compound 2 Production of 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1) -> 4) -3-O-ß-D-glucopyranuronosyl- (1"^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl- 3GlcNAc ßl ~> 4GlcA ßl - ^ 3GlcNAc (Compound Example 1)], and 4-deoxy-a-L-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamido-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-O-β-D-glucopyranuronosyl (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-4) -3-O- ß-D-glucopyranuronosyl- (l-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranose [? HexA ßl-> 3GlcNAc ßl- 4GlcA ßl- »3GlcNAc ßl-» 4GlcA ßl- »3GlcNAc (Example of Compound 2)] 60 g of sodium hyaluronate (a product of KIBUN FOOD CHEMIFA, trade name" Hyaluronic acid FCH ") was dissolved in 3 L of distilled water, and the solution was heated to 40 ° C. pH of the solution was adjusted to 6.0 with an aqueous solution of 0.1M sodium hydroxide. Luronidase of origin Steptomices hyaluroliticus (a product of Amano Pharmaceutical; trade name "Hyaluronidase" Amano "") was added to a turbidity decrease unit of 1 per mg of sodium hyaluronate, and the reaction was carried out for 100 hours at 40 ° C. After the reaction, the enzyme was removed from the solution through an ultrafiltration membrane (a Millipore product) of hydrophilic polyethersulfone with a nominal molecular cut-off of lOk. The solvent was removed by lyophilization to obtain a depolymerization product (53.7 g). The depolymerization product was fractionated through anion exchange chromatography (column: TSKgel DEAE-5P, eluent: A; water, B; aqueous solution of 0.5M sodium acetate; linear gradient (A / B / 90/10 ) - A / B (60/40), 40 min), UV detection (232 nm)) (Examples of Compounds 1 and 2 were discussed in this order) to obtain fractions containing Examples of Compounds 1 and 2. Fractions were lyophilized to remove the water. The lyophilized fractions were washed with ethanol to desalt, dissolved in water again, and then lyophilized to obtain the example of compound 1: 18.1 g, and Example of Compound 2: 29.5 g, respectively. The relative compounds were obtained as sodium salts. The purity of each of the compounds measured by high performance liquid chromatography (column: TSKgel Amida-80, eluent: acetonitrile / water / acetic acid / triethylamine (65/35/2/1, v / v), speed flow: 1.0 mL / min, column temperature: 80 ° C, detection: UV (232 nm), area percentage method) was 97% or more. The content of uronic acid and the hexosamine content of each of the Examples of Compounds 1 and 2 were analyzed by the methods shown in Example 1. It was found that the values were almost in accordance with the theoretical values. Example 3: Production Example of Compound 3 Production of 4-deoxy-L-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- ( 1- ^ 4) -3-0-ß-D-glucopyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranitol [? HexA ßl- > 3GlcNAc ßl- > 4GlcA ßl- > 3GlcNAc OH (Example of Compound 5) 1, and 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1"> 4) -3-0-β-D-glucopyranuronosyl- (1-> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-4) -3-0- ß-D-glucopyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranitol [? HexA ßl- 3GlcNAc ßl »4GlcA ßl-» 3GlcNAc ßl-4GlcA ßl- 3GlcNAc OH (Example Compound 6)] 50 mg of the Example of Compound 1 was dissolved in 50 mL of an aqueous solution of 3 mg / mL sodium borohydrate, and the solution was treated for 1 hour at room temperature 5 mL of acetic acid 6 was added. M to finish the reaction, then 50 mL of methanol was added, the mixture was evaporated to dry by means of an evaporator, addition of 50 mL of methanol and evaporation to dry was repeated twice. After evaporation to dryness it was dissolved in 5 mL of water. gel filtration in the same manner as in Example 1, and then lyophilized to obtain Example 5 of compound 5 (white powder: 44.7 mg). In the same way, the Example of Compound 6 was obtained using the Example of compound 2 as a starting material. The Example of Compound 5 and the example of Compound 6 are compounds expressed by the formula (21) wherein n denotes an integer from 1 to 2. This formula represents Compound 5 when n is 1, and Compound 6 when n is 2 Formula (21) The purity of each of Compounds 5 and 6 was measured by the method shown in Example 2, and found to be 98% or higher. The uronic acid content and the hexosamine content of these compounds was analyzed by the methods shown in Example 1. The values found through the analysis are almost in accordance with the theoretical values. Example 4: Production Example of Compound 4. Production of 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- ( 1- ^ 4) -3-O-ß-D-glucopyranuronic acid [? HexA ßl- 3GlcNAc ßl- ^ 4GlcA (Compound Example 7)], and 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1 ~> 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-β-D-glucopyranuronosyl (1-> 3) -0-2 -acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-β-D- glucopyranuronic acid [α HexA ßl- ^ 3GlcNAc ßl- 4GlcA ßl- > 3GlcNAc ßl- »4GlcA (Compound Example 8)] The Example of Compound 1 was heated in a borate buffer with a pH of 9 according to the method of Reissig et al. (Reissig, J., L., Strominger, J.L., Leloir, L., F.: J. Biol. Chem., 217, 959 (1953)). The boric acid was removed in the reaction mixture as methyl borate in the same manner as in Example 3. The remaining mixture was desalted through gel filtration in the same manner as in Example 1, and then freeze-dried to obtain the example of Compound 7 (white powder). When the 50 mg of the Example of Compound 1 was used as the starting material, 43.1 mg of the Example of Compound 7 was obtained. Similarly, when 50 mg of the example of Compound 2 was used as the starting material, 44.8 mg were obtained. of the Example of Compound 8 (white powder). The Example of Compound 7 and the Example of Compound 8 are compounds expressed by the formula (22) when n denotes an integer from 0 to 1. This formula represents Compound 7 when n is 0, and Compound 8 when n is 1 Formula (22) The purity of each of the Examples of the Compounds 7 and 8 were measured by the method shown in Example 2, and found to be 98% or higher. The content of uronic acid and the hexosamine content of these compounds was analyzed by the methods shown in Example 1. The values found through analysis were almost in accordance with the theoretical values. Example 5: Production Example of Compound 5 Production of 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-) > 4) -3-0-ß-D-glucopyranuronitol [? HexA ßl- ^ 3GlcNAc ßl- »4GlcA OH (Compound Example 9)], and 4-deoxy-aL-threo-hexa-4-enepyranuronosyl- (1 - ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-O-β-D-glucopyranuronosyl- (1"> 3) -0-2 -acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-O-ß-D-glucopyranuronitol [? HexA ßl- 3GlcNAc ßl- 4GlcA ßl-> 3GlcNAc ßl- 4GlcA OH (Example Compound 10)] The Example of compound 7 was treated in the same manner as in Example 3 to obtain the example Compound 9 (white powder) When 20 mg of the Example of Compound 7 was used as starting material, 15.0 mg was obtained of the Example of Compound 9. Similarly, when 20 mg of the Example of Compound 8 was used as the starting material, 17.8 mg of the Example of Compound 10 (polv. or white) The Example of Compound 9 and the Example of Compound 10 are compounds expressed by the formula (23) where n denotes an integer from 0 to 1. This formula represents Compound 9 when n is 0 and Compound 10 when n is 1. Formula (23) H The purity of each of Compounds 9 and 10 was measured by the method shown in Example 2, and found to be 98% or higher. The content of uronic acid and the hexosamine content of these compounds was analyzed by the methods shown in Example 1. The values found by the analysis were almost in accordance with the theoretical values. Example 6: Production Example of a Polymer Compound Production of poly (Np-vinylbenzyl- [0-4-deoxy-aL '-treo-hexa-4-enepyranuronosyl- (l-3) -0-2-acetamide-2- deoxy-β-D-glucopyranosyl- (1 ~ ^ 4) -3-0-β-D-glucopyranuronosyl (l-3) -0-2-acetamide-2-deoxy-β-D-gluconamide]) (Example of Polymer 1), poly (Np-vinylbenzyl) - [0-4-deoxy-L-threo-hexa-4-enepyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl - (1- ^ 4) -3-0-ß-D-glucopyranuronosyl- (l- >; 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-ß-D-glucopyranuronosyl- (1 ~ ^ 3) -0-2-acetamide -2-deoxy-β-D-gluconamide]) (Example of Polymer 2), poly (N-p-vinylbenzyl- [0-4-deoxy-L-threo-hexa-4-enepyranuronosyl- (1- ^ 3) - 0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1- ^ 4) -3-0-β-D-glucopyranuronosyl- (l-3) -0-2-acetamide-2-deoxy-β -D-glucopyranosyl- (1- ^ 4) -3-0-β-D-glucopyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1 ~ > 4) -3-0-β-D-glucopyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-gluconamide]) (Example Polymer 3), and poly (N-vinylbenzyl) [0-4-deoxy-aL-threo-hexa-4-enepyranuronosyl (l-3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-4) -3-0-β- D-glucopyranosuronyl- (1-3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-> 4) -3-0-β-D-glucopyranuronosyl- (1- ^ 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1- ^ 4) -3-0-β-D-glucopyranuronosyl- (l-3) -0-2-acetamide-2-deoxy- β-D-glucopyranosyl- (1-> 4) -3-0-β-D-glucopyranur onosyl- (1-> 3) -0-2-acetamide-2-deoxy-β-D-gluconamide]) (Example Polymer 4) 10 g of Compound 1 Example were dissolved in 5 L of distilled water, and they added 45 mL of methanol, followed by mixing. The mixture was added to the methanol solution of iodine (17.1 g / 200 L) heated to 40 ° C, and the resulting mixture was allowed to stand for 30 minutes at 40 ° C. A 4% methanol solution of potassium hydroxide was added gradually until the color of the iodine disappeared. The reaction mixture was cooled with ice, and the precipitated form was collected through filtration. The precipitate was washed with cold ethanol and cold ether in this order, and recrystallized from ethanol-water (90/10, w / w) to obtain a potassium salt. The potassium salt was dissolved in 50 mL of distilled water, and the solution was passed through a column packed with an ion exchange resin (Amberlite IR-12B (type H +), and then lyophilized. lyophilized product and the mixture was concentrated under reduced pressure to obtain crystals.A small amount of methanol was added to the crystals to dissolve them, and additionally ethanol was added, followed by dehydration and concentration.This procedure was repeated 5 times, and then the residue was evaporated to dryness under reduced pressure to obtain the Example of lactonized Compound 1 (7.4 g), 7 g of the example of lactonized Compound 1 were dissolved in 50 mL of methanol, and a methanol solution of p-aminomethylstyrene (2.5 g. /0.5 L) was added under reflux with heating.After 120 minutes of reflux by heating, 200 mL of acetone was added for crystallization.The crystals were recrystallized. hoisted twice from methanol to obtain purified crystals (N-p-vinylbenzyl- [0-4-deoxy-L-threo-hexa-4-enepyranuronosyl- (1->). 3) -0-2-acetamide-2-deoxy-β-D-glucopyranosyl- (1-4) -3-0-β-D-glucopyranuronosyl- (1- ^ 3) -0-2-acetamide-2- deoxy-β-D-gluconamide]; 3.3 g). 2 g of purified crystals were dissolved in 2 mL of water, and potassium peroxodisulfate (0.2 mol%) was added as a polymerization initiator. The mixture was heated for 24 hours at 60 ° C in a flow of nitrogen to perform a polymerization reaction. After polymerization, the liquid was emptied into the methanol to precipitate the resulting polymer. The methanol was removed by decanting to remove the polymer. The polymer was subjected to a reprecipitation method in which the polymer was dissolved in water, and crystallized from the methanol. As a result of this, the polymer was purified to obtain Polymer Example 1 (1.4 g). In the same way, Example of Polymer 2 was obtained using the Example of Compound 2 as a starting material, Polymer Example 3 was obtained using the Example of Compound 3 as the starting material, and Polymer 4 Example was obtained using the example of Compound 4 as the starting material. The Examples of Polymers 1 to 4 are compounds expressed by the formula (24) where n denotes an integer from 1 to 4. This formula represents the Example of Polymer 1 when n is 1, and the Example of Polymer 2 when n is 2, the Example of Polymer 3 when n is 3, and the example of Polymer 4 when n is 4. The average weight of the molecular weights of the examples of Polymers 1 to 4 were measured by the light scattering method, and it was found to be in the order of 40,000. Formula (24) Example 7: Example of Production of a Molded Product The production of polyethylene tubes has Examples of Compounds 1 to 4 fixed thereto (Examples 1 to 4 of Molded Products). The production is carried out according to the method of Lar et al. (Larm, O., Lasson, R., Olsson, P .: Biomat, Med. Dev. Art. Org., 11, 161 (1983)). The example of Compound 1 and a polyethylene tube activated with polyethylenimine (1.8 mm ID x 100 cm L) were reacted with NaB (CN) H3 in 0.15 M NaCl for 2 hours at 50 ° C and a pH of 3.5 to obtain an example of Compound 1 - fixed polyethylene tube (Example of Molded Product 1). In the same way, the Example of the Molded Product 2 was obtained using the example of Compound 2 as the starting material, the Example of the Molded Product 3 was obtained using the example of Compound 3 as starting material, and the Example of the Molded Product 4 was obtained using the example of Compound 4 as the starting material. Example 8: Action to suppress platelet aggregation of the compounds of the invention Blood was taken from the aorta of a rabbit in an amount of 9 volumes of blood per volume of an aqueous solution of 3.8% sodium citrate. The blood sample was centrifuged immediately (50 x g, 10 min, room temperature) to obtain platelet-rich plasma (RPR) as a superfluoride. For 100 μL of PRP, 10 μL of a solution of each of Compounds 1 to 7 of the invention in each of the concentrations. The mixture was kept for 1 minute at 37 ° C, and then 10 μL of 10 μg / mL of collagen (bovine tendon collagen: a product of Meiji Yakuhin) was added as an aggregation inducer. An aggregation curve was recorded for 7 minutes after the addition. Measurement of platelet aggregation was performed according to the methods of Born and O'Brien (Born, G., V., R .: Nature (London), 194, 924 (1962), O'Brien, J., R .: J. Clin, Patho., 15, 556 (1962)) using an aggregometer (produced by: MC Medical). As a control for comparison, the same test was conducted on ticlopidine hydrochloride as a representative antithrombotic agent. The results are shown in Table 1. Table 1 As shown in Table 1, the compounds of the invention exhibit an excellent platelet aggregation-suppressing action. Example 9: Acute toxicity of the compounds of the invention. Representative examples of the compounds of the invention (ie, Examples of compounds 1 to 10) were tested for their acute toxicity using rats (weighing 300 to 400 g, instar, males). Their LD50 values were 500 mg / kg or more. Example 109: Suppressive action of the platelet adhesion of the polymers of the invention The suppressive action of the platelet adhesion of Polymer Examples 2 to 4 was evaluated through the microsphere column method (Kataoka, K., Maeda, M. , Nishimura, T. Nitadori, Y., Tsuruta, T. Akaike, T., Sakarai, Y.,: J. Biomed, Mater.Res., 14, 817 (1980)). The PRP was obtained in the same manner as in Example 8 it was washed with Dubecco PBS through centrifugation performed twice for 7 minutes at 1,200 G to prepare a platelet suspension with a final concentration of 1 x 10 5 platelets / μL. An aqueous solution of each of the polymers was emptied in a varying concentration into a microsphere column (Teflon column (3 ID mm x 50 mm L) filled with polystyrene beads (diameter 150 μm, 20% crosslinked divinylbenzene, non-porous ), and adsorbed.After adsorption, the column was thoroughly rinsed with distilled water.The platelet suspension was passed through this column (flow velocity 0.5 mL / minute, room temperature). platelets in the suspension after passage, and the platelet adhesion rate was calculated.The results are shown in Tables 2 to 4. Table 2 E in Polymer 2 Table 3 Example of Polymer 3 As shown in Tables 2 to 4, the compounds of the invention exhibited an excellent suppressive action of antiplatelet adhesion. Example 11: Antithrombotic properties of the molded products of the invention. The antithrombotic properties of the Examples of the Molded Products 2 to 4 were evaluated. In the same manner as in Example 10, a platelet suspension was prepared with a final concentration of 1 x 105 platelets / μL. The platelet suspension was passed and circulated through the Product examples Molded 2 to 4 and the untreated polyethylene tube) (flow rate 0.5 mL / min, 1 hour, room temperature). The count and concentration of platelets in the solution were measured after passing, and the platelet adhesion rates of the untreated tube and the examples of Molded Product 2 to 4 were calculated. The results are shown in Table 5. 5 As shown in Table 5, the Examples of the Molded Product 2 to 4 were clearly inferior to the untreated tube as a function of the rate of platelet adhesion. This result verifies that the molded products of the invention have excellent antithrombotic properties. Example 12: Vascular endothelial cell growth promoting action 1 of the compounds of the invention This test used bovine aortic vascular endothelial cells (step number 3) as cells, and MEM containing 10% FCS (fetal calf serum), 100 units / mL of penicillin G, and 100 μg / mL of streptomycin as a culture medium. 96 well microplates were seeded with the cells in an amount of 4 x 10 3 cells / well (4 x 10 4 / ml, 100 μL), and the compounds of the formula (1) (examples of Compounds 1 to 10) (10 μL, dissolved in the culture medium) were added in a predetermined final concentration (or, 0.1, 0.5, 1, 5, 10 μg / mL). The culture was carried out for 20 hours at 37 ° C and 5% C02, and then the effect of the compounds on vascular endothelial cell growth was measured using "the BrdU Color Development Kit for Cell Growth ELISA" (Boehringer Mannheim) (the intake of 6-bromodeoxyuridine (BrdU) was adopted as indicator). As controls, Comparative Compounds 1 and 2 were subjected to the same test. The comparative compounds are compounds expressed by the formula (25) where n denotes an integer of 1 or 2. This formula represents Comparative Compound 1 (Comp.1 in the following table) where n is 1, and Comparative Compound 2 ( Comp.2 in the table) where n is 2. Comparative Compounds 1 and 2 were prepared according to Example 2. However, hyaluronidase was of bovine testicular origin, and detection was performed at 206 nm. The purity of each of the compounds was 97% or higher. The content of uronic acid and the hexosamine content of these compounds is almost in accordance with the theoretical values. Formula (25) The promoter action of vascular endothelial cell growth of each of the compounds was evaluated from the following equation: Promoter rate (%) =. { (Increase in the BrdU intake in the compound addition test) / (Increase in the BrdU intake in the control test)} x 100 The results are shown in Table 6. Table 6 As shown in Table 6, the examples of compounds 1 to 10 all showed excellent vascular endothelial cell growth promoting action. Example 13: The vascular endothelial cell growth promoting action 2 of the compounds of the invention A test was conducted to investigate the interaction of the compounds of the invention with vascular endothelial growth factor (VEGF). Like VEGF, a recombination of human VEGF (Vascular Endothelial Growth Factor, Human, Recombination, for biochemical use: a product of Wako Pure Chemical Industries) was used. The test was conducted in the same manner as in Example 12, but the VEGF (final concentration of 10 ng / mL) was added simultaneously with the addition of the compound. As comparative tests, a simple addition test of VEGF (a test in which only VEGF was added) and a negative control test (a test in which neither the compound nor VEGF was added) were performed. The effect on vascular endothelial cell growth was measured in the same manner as in Example 12. The promoter action of vascular endothelial cell growth of each of the compounds was evaluated from the following equation: Rate of promotion (%) = . { (Increase in BrdU intake in the compound addition test) / (Increase in BrdU intake in the negative control test)] x 100 The results are shown in Table 7. Table 7 In Table 7, the promotion rates shown in the column for the compound concentration of 0 represent the promotion rates obtained when VEGF was added alone. Based on Table 6 and Table 7 showing the results of the simple addition test of the compounds of the invention, the test compounds all acted synergistically with VEGF, and showed an excellent action promoting vascular endothelial cell growth. Example 14: Angiogenesis 1 promoting action of the compounds of the invention. One volume of reconstitution buffer (500 mM NaOH, 260 mM NaHCO3, 200 mM HEPES) was mixed with a volume of free 1/10-concentrated NaHC03-MEM with cooling in a freezing water bath. Then 8 volumes of a 0.3% solution of collagen hydrochloric acid (pH 3.0) were added, followed by an intense mixture, to prepare a collagen solution. The collagen solution (0.5 L) was dispensed into 24 well microplates, and incubated for 30 minutes at 37 ° C for gelation. In the collagen gel, bovine aortic vascular endothelial cells were seeded (step number 3 to 8) in an amount of 5 x 10 4 cells / well. The culture was carried out for 3 hours at 37 ° C to cause adhesion of the cells. Then, the culture medium was removed, and 0.5 mL of a collagen solution was overlaid, followed by incubation for 30 minutes at 37 ° C, to the system gel. Then, 1 mL / well of a 2% medium of FBS-MEM containing each of the Examples of compounds 1 to 4 in a varied concentration was added. The mixture was cultured in a CO 2 incubator for 3 days at 37 ° C. After 3 days of culture, blood vessel-like luminosities (neogenetic blood vessels) were formed at a magnification of 100x under the phase contrast microscope. The photographs were tracked and the image analyzed uses the Microcomputer Imaging Device (a product of Neuroscience) to measure the length of the blood vessel similar to light per unit area. As a control test, the cells were cultured in the free medium of the compound by measuring them for the length of the blood vessel similar to light in the same manner. The promoter action of angiogenesis of each of the compounds was evaluated from the following equation: Rate of promotion (%) =. { [(Length of alumina in each of the tests) - (Lumia length in the control test)] / (Lumina length in the control test)} x 100 The results are shown in Table 8 Table 8 As shown in Table 8, Compounds 1 to 4 all showed excellent angiogenesis promoting action. Example 15: Angiogenesis-promoting action 2 of the compounds of the invention The angiogenesis-promoting action of the Examples of Compounds 1 and 2 was evaluated by the method of the diffusion chamber in rats. That is, a diffusion chamber (membrane with pore diameter of 0.45 μm, a Millipore product) was assembled, and 200 μL of physiological saline from each of compounds 1 and 2 varying in concentration (0.10-8, 10 ~ 7, 10"6, 10-5 M) were sealed therein The Winstar rats (male, body weight 200 to 250 g) were anesthetized by intraperitoneal administration of pentobarbital (10 mg / animal).

Afterwards, the animal's back was shaved, disinfected with diluted iodine tincture. The skin was cut without injuring the muscles, and the sealed diffusion chamber of the previous solution was grafted between a subcutaneous area and the fascia. The site of the incision was sutured, and the animal was left in breeding for 1 week. Then, an incision was made in the back of the anesthetized rat to expose the camera. After observing the presence of angiogenesis, the camera was cut along with the muscle and fixed in formalin. The results are shown in Table 4. In the table, +, + _ and - represent that the induction of angiogenesis was positive, false positive, and negative res ectively.

As shown in the table, Compounds 1 and 2 both showed excellent angiogenesis promoting action. Example 16: The vascular endothelial cell growth promoting action of the molded products produced by the polymeric compounds. 0.01 w / v% of an aqueous solution of each of Polymer Examples 1 to 4 was prepared, and dispensed in 96 well polystyrene microplates in an amount of 0.5 mL / well. The microplates were allowed to stand overnight at room temperature, and then the solution was removed to coat the plates. The coated plates were used to culture the bovine aortic vascular endothelial cells in the same manner as in Example 8. As a control test, a culture was performed using the uncoated plates. The growth promoter action was measured in the same manner as in Example 12, and the vascular endothelial cell growth promoting action of the Polymer Examples (Molded Products) was evaluated using the following equation: Rate of promotion (%) =. { (Increase in BrdU intake in each of the tests) / (Increase in BrdU intake in the control test)} x 100. The results are shown in Table 10. Table 10 As shown in Table 10, examples of Polymer 1 to 4 all showed excellent vascular endothelial cell growth promotion.

Example 16: Production Example of Preparation Production of Tablet 1 Example of Compound 1 10 g Polyethylene glycol 6000 10 g Sodium lauryl sulfate 1.5 g Corn starch 3 g Lactose 25 g Magnesium stearate 0.5 g The above ingredients were weighed. The polyethylene glycol 6000 was heated to 70 to 80 ° C, and mixed with the example of Compound 1, sodium lauryl sulfate, corn starch and lactose, followed by cooling. The solidified mixture is granulated by means of a mill to obtain granules.

The granules are mixed with the magnesium stearate, and then tabletted to form tablets with a weight of 250 mg. Production of Tablet 2 Example of Compound 2 30 mg Lactose 55 mg Potato Starch 12 mg Polyvinyl Alcohol 1.5 g Magnesium Stearate 1.5 g The above ingredients were weighed. He Example of Compound 2, lactose, and potato starch were mixed uniformly. An aqueous solution of polyvinyl alcohol was added to the mixture, and the resulting mixture was converted to granules through wet granulation. The granules were dried, and mixed with magnesium stearate. Then, the mixture is compressed to form tablets with a weight of 200 mg. Production of capsules Example of Compound 3 10 g Lactose 25 g Corn starch 5 g Microcrystalline cellulose 9.5 g Magnesium stearate 0.5 g The above ingredients were weighed. The four ingredients, except magnesium stearate, were mixed uniformly. Magnesium stearate was added, and then the ingredients were mixed further for several minutes. The mixture is used to fill the hard capsules No. 1 in an amount of 200 mg / capsule, to form capsules. Production of powder Example of Compound 4 20 g Lactose 79 g Magnesium stearate 1 g The above ingredients were weighed. All the ingredients were uniformly mixed to form 20% powder. Production of suppository Example of Compound 2 10 g Polyethylene glycol 1500 18 g Polyethylene glycol 4000 72 g The Example of Compound 2 is thoroughly ground in a mortar to form a fine powder, and formed in a rectal suppository of 1 g through the melted method. Injection Production Example of Compound 6 0.1 g Sodium Chloride 0.9 g Sodium Hydroxide Adequate amount Water for injection 100 mL The above ingredients were weighed. The three ingredients were dissolved in water for injection and the solution was sterilized through filtration. Then, the solution was dispensed in 10 mL ampules in an amount of 5 mL per ampule. The vial is sealed with heat to form an injection.

Claims (38)

1. CLAIMS 1. Compounds of the following general formula (1) having a glucuronic acid derivative and a glucosamine derivative in a structure thereof, salts and solvates of the pharmacologically acceptable compounds, or solvates of salts. Formula 1) wherein R1 denotes a protecting group, or any of the following formulas of (2) to (5) wherein R10 denotes a hydrogen atom, a protecting group, or any of the following formulas from (6) to (8) ), and R11 denotes a hydrogen atom or a protecting group, whereas when R10 and Rll are each a hydrogen atom or a protective group, R1 can be linked in a trans or cis form with respect to COOR4. Formula (2) -OR10 Formula (3) Formula (4) Formula (5) Formula (6) Formula (7) Formula (8) 0R " or when R is any of the formulas (6) (8) Rx to R > 2¿8 except R 13 R, 17 and R 26 in the formulas (6) to (8) are the same or different, and each denotes a hydrogen atom or a protecting group, and R 13 R, 17 and R each denotes a group of azides or of the following formula (9) Formula (9) -NR 29 R 30 where R 29 and R 30 are the same or different, and each denotes a hydrogen atom or a protective group , R 2 to R 8 are the same or different, and each denotes a hydrogen atom or a protecting group R 9 denotes a hydrogen atom, a protective group, or the following formula (19) or (11) Formula (10) Formula (11) where R31 to R37 are the same or different, and each denotes a hydrogen atom or a protective group and n denotes an integer from 0 to 25, whereas when n is 0, R1 is a group of the formula (2) , R10 is a group of the formula (8), and R is a group of the formula (10) or (11), with the proviso that in the formulas (1), (6) to (8), and (10) to (11), the protecting groups are the same or different, and each denotes an optionally substituted straight chain or a branched alkyl chain having from 1 to 8 carbon atoms. carbon, and is optionally substituted with straight chains or branched chains of alkenino having from 2 to 8 carbon atoms, an acyl having from 1 to 8 carbon atoms, an optionally substituted aromatic acyl, or an optionally substituted aromatic alkyl, any of the two protecting groups such as R2 to R37, except R13, R17 and R26, can together form an optionally substituted alkylidene having from 3 to 8 carbon atoms, an optionally substituted cyclic alkylidene having from 3 to 8 carbon atoms, a optionally substituted benzylidene, or an optionally substituted phthaloyl, and when n is 2 or more, R2 to R8 may be the same or different in each of the recurring units.
2. 2. The compounds having a glucuronic acid derivative and a glucosamine derivative, salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts according to Claim 1, wherein n is 0 to 10.
3. 3. The compounds which have a glucuronic acid derivative and a glucosamine derivative, pharmacologically acceptable salts and solvates of the compound, or solvates of the salts according to Claim 2, wherein R9 is formula (11).
4. 4. The compounds having a glucuronic acid derivative and a glucosamine derivative, salts and solvates of the pharmacologically acceptable compounds or solvates of the salts according to Claim 3, wherein R1 is the formula (2), and R10 is the formula (6).
5. 5. The compounds having glucuronic acid derivatives and a glucosamine derivative, salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts according to Claim 3, wherein R1 is the formula (2), and R10 is the formula (7).
6. 6. Compounds having a glucuronic acid derivative and a glucosamine derivative, salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts according to Claim 3, wherein R1 is the formula (2) and R10 is the formula (8).
7. 7. Compounds having a glucuronic acid derivative and a glucosamine derivativepharmacologically acceptable salts and solvates or solvates of the salts according to Claim 4, wherein R13 is the formula (9).
8. 8. The compounds having a glucuronic acid derivative and a glucosamine derivative, pharmacologically acceptable salts and solvates or solvates of the salts according to Claim 5, wherein R17 is the formula (9).
9. 9. The compounds having a glucuronic acid derivative and a glucosamine derivative, salts and solvates of the pharmacologically acceptable compounds, or solvates of the salts according to Claim 6, wherein R26 is the formula (9).
10. A method for producing the compounds of Claim 1, characterized in that it includes the step of depolymerizing hyaluronan or its salt.
11. 11. The method of Claim 10, characterized in that an enzyme is used for depolymerization.
12. 12. The method of Claim 11, characterized in that the enzyme is derived from a microorganism.
13. 13. The method of Claim 12, characterized in that the microorganism is Steptomyces Hyaluroliticus.
14. The method of any of Claims 10 to 13, characterized in that the depolymerization is carried out in a solution substantially free of salts, a solution substantially free of non-volatile salts, or a solution substantially free of salts insoluble in organic solvents.
15. The method of any of Claims 10 to 14, characterized in that it includes the step of fractionating and purifying a depolymerized substance by anion exchange chromatography.
16. 16. The method of Claim 15, characterized in that an eluent is used which substantially contains only one volatile salt as salt.
17. 17. The method of Claim 16, characterized in that the salt is an ammonium salt.
18. 18. The method of Claim 17, characterized in that the ammonium salt is an ammonium acetate.
19. 19. The method of claim 15, characterized in that it uses an eluent that substantially contains only one salt soluble in an organic solvent as a salt.
20. 20. The method of Claim 19, characterized in that the salt is an acetate.
21. 21. The method of Claim 20, characterized in that the acetate is ammonium acetate or sodium acetate.
22. 22. A pharmaceutical composition containing at least one of the compounds of Claim 1 as an active ingredient.
23. 23. An antiplatelet agent containing at least one of the compounds of Claim 1 as an active ingredient.
24. The pharmaceutical composition of Claim 22 for use as drugs for treatment and prevention containing at least one of the compounds of Claim 1, and these drugs have been selected from the group consisting of drugs for the treatment and prevention of thrombosis, drugs for the treatment and prevention of cardiovascular diseases, drugs for the treatment and prevention of cerebrovascular diseases, drugs for the treatment and prevention of peripheral vascular diseases.
25. 25. A vascular endothelial cell growth promoting agent containing the compound of Claim 1 as an active ingredient.
26. 26. The vascular endothelial cell growth promoting agent of Claim 25, which contains a compound of the following formula (16) as an active ingredient.
27. 27. The vascular endothelial cell growth promoting agent of Claim 25, for use as a therapeutic or preventive drug for vascular endothelial regeneration therapy.
28. 28. The vascular endothelial cell growth promoting agent of Claim 25, for use as a therapeutic or preventive drug for angiogenic therapy.
29. 29. Polymers having at least one of the compounds of Claim 1 as a side chain structure.
30. 30. Coating agents containing at least one of the compounds of Claim 1 or the polymers of Claim 29 as an active ingredient.
31. 31. Molded products that use at least one of the polymers of Claim 29 as a material.
32. 32. The molded products produced using at least one of the coating agents of Claim 30.
33. 33. An artificial organ utilizing at least one of the molded products of Claim 31 or Claim 32 as a component.
34. 34. The artificial organ of Claim 32, which is an artificial organ of the extracorporeal circulation type, or an artificial and plantable organ.
35. 35. A medical device that uses at least one of the molded products of Claim 31 or Claim 32 as a component.
36. 36. The medical device of Claim 35, which is an extracorporeal medical device, an extracorporeal medical device connected to the interior of a body, or an implantable medical device.
37. 37. A composition for cell culture, which contains the polymer of Claim 29 as an active ingredient.
38. 38. Cell culture equipment, produced using the molded product of Claim 31 and / or the coating agent of Claim 30.