Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-10-30
2003-09-02
Barts, Samuel (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S004100, C536S119000, C536S018700, C514S025000, C514S822000, C514S054000, C435S101000
Reexamination Certificate
active
06613897
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel compounds having a glucuronic acid derivative and a glucosamine derivative in their structure, a method for producing the compounds, a pharmaceutical composition containing the compounds and polymers having the compounds in their side chain structure, molded products produced using them, and artificial organs, medical devices, and cell culture equipment produced by use of the molded products as components.
BACKGROUND ART
Thrombosis has become one of the major causes of it deaths in Western countries and in Japan in recent years. It is the predominant cause of death surpassing cancer, if the causes include arterial diseases such as myocardial infarction and cerebral infarction. Various factors are involved in thrombosis, and vascular lesions such as arteriosclerosis often form the basis for thrombosis. A normal blood vessel is made highly antithrombotic by vascular endothelial cells. However, platelets adhere to activated vascular endothelial cells at the site of a vascular lesion, such as a focus of arteriosclerosis, or to vascular subendothelial tissue exposed by damage, so that pathological thrombus tends to form. As drugs for suppressing pathological thrombus formation, drugs for suppressing adhesion or aggregation of platelets, i.e., “antiplatelet agents”, have attracted attention, and have found wide clinical use. The history of antiplatelet agents is relatively recent, and the development of better drugs of this type is expected.
As described above, the normal blood vessel is made highly antithrombotic by vascular endothelial cells. The roles of the vascular endothelial cells will be discussed more closely. The vascular endothelial cells are a group of single-layered cells which continuously cover the systemic vascular lumina. Normal vascular endothelial cells play a wide variety of roles, such as {circle around (1)} suppression vascular permeability, {circle around (2)} anti-thrombosing of vascular lumen, {circle around (3)} regulation of relaxation and contraction of vascular smooth muscle, and {circle around (4)} control of wandering or growth of vascular mural cells. Thus, vascular endothelial cells are said to be of central importance in making blood vessels as such.
Humans are said to age with blood vessels, and vascular walls are damaged with age. When a vascular wall is damaged and ruptured, the rhexis of the blood vessel appears as cardiovascular disease, such as myocardial infarction, aortic aneurysm, cerebral apoplexy, or necrosis. The most prominent cause of vascular wall rupture is arteriosclerosis.
The-current treatments or prophylaxes of arteriosclerosis are mostly approaches from the aspect of improvement of lipid metabolism, and antilipemic agents are generally used as drugs. Other drugs administered are antiplatelet agents or anticoagulants for preventing vascular blockage at the site of arteriosclerosis. However, these drugs do not positively treat the rupture of the vascular wall. They are expected to show the indirect action of preventing progression of rupture by holding down hyperlipidemia which is a cause of rupture, or thrombus formation which is a cause of progression of rupture.
For the occurrence or progression of arteriosclerosis, injury or functional loss of vascular endothelial cells is considered important and indispensable. With conventional therapies, as stated earlier, only the repairing function of the body has been relied on for elimination of the radical cause of vascular rupture, the most important measure for treatment, i.e., the regeneration and functional restoration of vascular endothelial cells. Hence, “vascular endothelium regeneration therapy”, a therapy for promoting the regeneration and functional restoration of vascular endothelial cells which have undergone damage and lost their intrinsic functions, is believed to be a very useful therapy capable of overcoming the drawbacks of conventional therapies. However, drugs usable for the vascular endothelium regeneration therapy have not been put to practical use, and the development of high quality drugs is desired. An example of the vascular endothelium regeneration therapy was presented by a report (Asahara, T. et al., Circulation, 94, 3291, 1996) of a study in which a gene for vascular endothelial growth factor (VEGF) was introduced at the vascular endothelial injury site of an experimentally injured rabbit to express VEGF, and its efficacy was investigated.
Percutaneous transluminal coronary angioplasty (PTCA) is a method for inflating a balloon catheter inserted into the blood vessel (i.e., ballooning) to dilate the site of narrowing formed as a result of progression of arteriosclerosis. This method is one of the established therapies of coronary arteriosclerosis. However, restenosis was noted in 30 to 50% of patients within 6 months after operation, and so this method has posed a major problem. Restenosis is said to be a kind of arteriosclerosis which is caused by ballooning, and progresses rapidly. In addition to contrivances for ballooning techniques and improvements on catheters, treatments using various drugs have so far been tried. They are still insufficient, and the development of better therapies and drugs is expected. The vascular endothelium regeneration therapy may be able to prevent post-PTCA restenosis effectively (see the report by Asahara et al.), and the development of excellent drugs used for this therapy is expected.
Prognoses of ischemic diseases, such as myocardial infarction, are affected by many factors, and the degree of collateral vessels development has been thought to be one of the most important determinant factors for prognosis. In the presence of a sufficient development of collateral vessels, even if stenosis or blockage (infarction) occurs, ischemia or necrosis of tissue is suppressed, and reduction of an infarct size and improvement of prognosis are achieved. As mechanisms of collateral vessel formation, changes in intravascular pressure and bloodstream have been emphasized. However, there have been reports of images of cell division accompanied by DNA synthesis observed in vascular endothelial cells or vascular smooth muscle cells during collateral vessel formation. It is understood that the process of collateral vessel formation is not simply the dilatation of the existing anastomosed blood vessels by physical factors, but at least part of the process is a neovascularization process which the growth of cells constituting a vessel wall is involved in. In recent years, there have been attempts to treat ischemic heart disease by a new therapy called “angiogenic therapy” (e.g., Yanagisawa-Miwa, A. et al., Science, 257, 1401, 1992). Angiogenic therapy is an attempt to promote angiogenesis around ischemic tissue, thereby positively securing a collateral vessel and protecting the ischemic tissue. It is a new therapy which can be called “pharmacological bypass therapy”. However, this therapy has not been put to practical use, and the development of excellent drugs and therapeutic methods usable for it is expected. The attempt to utilize angiogenic growth factors (e.g., fibroblast growth factor) for the treatment of wounds has also been made (see, for example, Hockel, M. et al., Arch. Surg., 128, 423, 1993).
Artificial organs are designed to supplement or replace the functions of various living tissues and organs, such as heart, blood vessel, cardiac valve, lung, pancreas, kidney, liver, skin, and mucosa, by molded products using artificial materials, or devices using them as components. The artificial organ shows its function when implanted in vivo or when contacted with blood withdrawn by cannulation into the blood vessel. Thus, a material used for it must have the nature of being usable without doing harm to the body, namely, biocompatibility. The most important in vivo reaction that defines the biocompatibility of an artificial organ is a thrombus formation reaction.
Platelet adhesion and aggregation are among important biological reactions which take part in the thrombus formation reaction, rank
Moriyama Shigeru
Nishikawa Masazumi
Sato Nobuyuki
Tamai Tadakazu
Yatsuka Nobuaki
Barts Samuel
Birch & Stewart Kolasch & Birch, LLP
Khare Devesh
Maruha Corporation
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