Peptide derivatives and application thereof

Abstract: A peptide derivative containing 1 to 20 units of peptide unit represented by the following general formula [I] or a pharmaceutically acceptable salt thereof; [Z]-Arg-X-Asp-[Y] [I] wherein Arg represents L- or D-arginine residue, Asp represents L-aspartic acid residue, X represents L- or D-leucine, D-isoleucine, L- or D-norleucine, L- or D-phenylalanine, D-phenylglycine or D-alanine residue, and [Z] and [Y] each represents an amino acid or a peptide residue, which may be present or absent, selected from glycine, L-serine, L-threonine, L- and D-aspartic acid, L-alanine, L- and D-glutamic acid, L-proline residues and a peptide residue constituted by the foregoing amino acid residues, and a pharmaceutical composition comprising the peptide derivative. The composition of the present invention is useful as an agent for inhibiting tumor metastasis.

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a peptide derivative comprising a tripeptide unit or a pharmaceutically acceptable salt thereof as an essential constituent unit as well as a composition for inhibiting metastasis of tumor. 2. Prior Art Fibronectin is a protein involved in the cell-extracellular substrate cohesion and is likewise thought to be involved in coagulation of blood platelets and the metastasis of tumor. These interactions are mediated by a series of receptors present in the cell surface region, it is confirmed that these receptors can specifically recognize an amino acid sequence: arginine-glycine-aspartic acid (hereinafter abbreviated as "Arg-Gly-Asp") of the fibronectin although the fibronectin is a macromolecule having a molecular weight of about 250,000, and there has been reported that the sequence plays an important role in the interaction between the receptors and the fibronectin (Nature, 309, 1984, p30). The above tripeptide sequence, Arg-Gly-Asp, is present in other cohesive proteins such vitronectin, and fibronectin associates with receptors of cells via the tripeptide sequence to transfer the information of fibronection to the adhered cells. Further, fibronectin is thought to have bonding ability to natural macromolecules such as heparin, collagen and fibrin and to be involved in adhesion of cells and interstitial connective tissue as well as differentiation and proliferation of cells. Since the proteins having the cell adhesion activity have various biological activities as described above, there have been conducted many studies on the applications of these proteins for pharmaceutical drugs and materials. For example, there has been reported a method for inhibiting the coagulation of blood platelets by the use of various linear and cyclic oligopeptides having an Arg-Gly-Asp sequence (Polymer Preprints, Japan, 38 , 1989, p. 3149; Japanese Unexamined Patent Publication (hereinafter referred to as "JP-A-") 2-174797); a method in which a peptide having an Arg-Gly-Asp sequence is used as a cell movement-inhibiting agent (JP-A- 2-4716); and a method using, as a cell-adhesive membrane, a PMMA film on which Arg-Gly-Asp sequences are immobilized (Polymer Preprints, Japan, 37 , 1988, p. 705). In addition, JP-A- 1-309682 and 1-305960 disclose a method which comprises covalently bonding peptides having Arg-Gly-Asp sequences as essential structural units to a polymer and in which the resulting product is used as a substrate for cultivating animal cells or for biological composite artificial organs and JP-A-64-6217 discloses a method in which a polypeptide having Arg-Gly-Asp-Ser sequences is used as a platelet protective agent for blood taken out of the body. Further, the cell-adhesive proteins have been paid attention as materials involved in metastasis of tumor. During the series of stages of the metastasis of tumor, tumor cells could contact with various host cells and biological macromolecules and, by the presence of the cell adhesive proteins such as fibronectin, the cells form cell coagulations to facilitate proliferation and survival of the tumor cells. In this regard, however, it is reported that if the adhesive core sequence of fibronectin, the tripeptide Arg-Gly-Asp, is present in such a circumstance, the tripeptide would associate with the receptors on the surface of the cells in a competitive manner with the cell adhesive proteins and thus may inhibit the metastasis of tumor (Science, 238 (1986) p467). Further, there has been known a method comprising inhibiting the metastasis of tumor by the use of an oligopeptide having Arg-Gly-Asp sequences or a polypeptide having the sequence as repeating units (Int. J. Biol. Macromol., 11, 1989, p23 ibid, 11, 1989, p. 226; and Jpn. J. Cancer Res., 60, 1989, p. 722). As described above, many studies on the applications of the activities of the cell adhesive proteins such as fibronectin or peptide fragments thereof for pharmaceutical drugs and related medical materials were actively conducted, and the applications of the adhesive core sequence, Arg-Gly-Asp-Ser, to tumor metastasis inhibiting agents are particularly intensively conducted. However, according to the studies so far, the core sequence was regarded as essential for the expression of the biological activity mediated by the receptor and the ligand and it was reported that any peptide analog having another amino acid residue instead of any of the constitiuent amino acid residues, particularly the Arg residue, could not exhibit the activity (Polymer Preprints, Japan, 38 (1989) p3149: J. Biol. Chem., 262 (1987) p17294). Proceedings National Academy of Science USA, Vol. 83, pages 5985-5988 (1984) discloses a tetrapeptide sequence, Arg-Gly-Asp-Ser, which is essential for the recognition of fibronectin by cells. Particularly the three amino acids Arg-Gly-Asp are essential for the interaction with the cell; a substitution of said amino acids by another amino acid leads to the loss of the interaction with the cell. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a novel peptide derivative or pharmaceutically acceptable salt thereof, which exhibits enhanced ability for inhibiting metastasis of tumor as compared with the adhesive core sequence of fibronectin, Arg-Gly-Asp-Ser, and is stable in blood. Another object of the present invention is to provide a composition for inhibiting metastasis of tumor comprising such a peptide derivative. To achieve the above objects, we have systematically investigated various sequences of the adhesive core sequence, particularly analogues having other various amino acid residues instead of a Gly and Ser residue of the adhesive core sequence Arg-Gly-Asp-Ser and determined the biological activities thereof to find novel peptide derivatives exhibiting sufficient tumor metastasis inhibiting property, being stable in the bloodstream for a long period of time, being easily synthesized and not exhibiting any serious side-effect, and finally achieved the present invention. According to an aspect of the present invention, there is provided a peptide derivative containing 1 to 20 units of a peptide unit represented by the following general formula [I] or a pharmaceutically acceptable salt thereof; [Z]-Arg-X-Asp-[Y] wherein Arg represents L- or D-arginine residue, Asp represents L-aspartic acid residue, X represents L- or D-leucine, D-isoleucine, L- or D-norleucine, D-phenylalanine, or D-phenylglycine, and [Z] and [Y] each represents an amino acid or a peptide residue, which may be present or absent, selected from glycine, L-serine, L-threonine, L- and D-aspartic acid, L-alanine, L- and D-glutamic acid, L-proline residues and a peptide residue constituted by the foregoing amino acid residues. According to another aspect of the invention, there is provided a composition for inhibiting tumor metastasis comprising, as an effective ingredient, the peptide derivatives defined above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will hereinafter be explained in more detail. The peptide derivatives of the present invention are those described above. The peptide derivatives of the present invention may be a peptide composed of one unit of the peptide sequence represented by the formula [I], but preferably they are either those composed of oligopeptide or polypeptide comprising two or more of the above peptide units represented by the general formula [I] or those composed of a compound consisting of one or more of the peptide unit represented by the general formula [I] and one or more of pharmaceutically acceptable organic groups bonded to the units, which maintain the water-solubility of the compound and do not reduce the biological activity of the compound. When the peptide derivatives of the present invention consist of oligopeptide or polypeptide, the carboxyl terminal of the peptides may be amidated. It has been known that stability of pharmaceutical drugs in living bodies after the administration thereof, such as represented by the period of staying in the bloodstream and the period before the drugs are excreted from the living bodies, would greatly infuluence on whether the drugs may be maintained at a therapeutically effective concentration in the living bodies. That is, not only the biological activity but also the stability of the drugs in living bodies are very important for the drugs to be sufficiently effective. This may be also applied to the peptide sequence of the present invention represented by the formula [I]. If the peptide sequences of the formula [I] are administered by themselves, the peptide sequences may be rapidly degraded and excreted and such rapid degradation and excretion are generally inherent to peptide compounds. Thus, it is not necessarily possible to expect sufficient biological activity of the peptide sequences of the formula [I] when the sequences are administered by themselves. This is the reason why we have investigated various peptide derivatives containing the peptide sequence of the formula [I], such as those composed of oligopeptide containing the sequence as a repeating unit, those containing the sequences bonded to other organic groups and those containing D-amino acids instead of the corresponding L-amino acids, and we finally achieved the present invention. As explained above, the important purposes of the modification of the peptide sequence with the organic groups are to protect the effective sequence from the degradation by the enzymes in body fluid by modifying the neighborhood of the sequence, to obviate or aim at accumulation of the derivatives in a specific organ by modifying the sequence e.g. with acidic groups or saccharide groups, to endow the derivatives with the slow release property by making the sequence contained in high molecular weight compounds. Therefore, as far as the organic groups to be bonded to the sequence are pharmaceutically acceptable, able to maintain the water-solubility of the compound and do not deteriorate the biological activity of the sequence, various organic groups may be used depending on the purposes. The organic groups are preferably selected from substituted and unsubstituted acyl, alkyl, alkylamino groups, which groups preferably have 1 to 15 carbon atoms and may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond, and groups derived from monosaccharides, oligosaccharides, preferably containing 2 to 7 monosaccharide units, polysaccharide derivatives, polycarboxylic acids, preferably having 2 to 12 carboxyl groups, polyamines, preferably having 2 to 12 amino groups, polymers formed from monomers having an ethylenically unsaturated bond such as acrylic acid, methacrylic acid, ethacrylic acid and allylamine, polyethylene glycol, preferably having an average molecular weight of 2,000 to 10,000 and carboxylic acid derivative of polyethylene oxide (PEO Acid). When the organic groups are selected from those derived from the saccharides, the peptide derivatives of the invention preferably contain one to ten units of the peptide sequence of the formula [I]. When the organic groups are selected from those derived from the polycarboxylic acids or polyamines, the peptide derivatives of the invention preferably contain one to five units of the peptide sequence of the formula [I]. The constituent saccharides of the monosaccharides, oligosaccharides and polysaccharides are preferably selected from e.g. glucose, galactose, N-acetylglucosamine, glucosamine, N-acetylgalactosamine, galactosamine, uronic acid, sialic acid, and these saccharides may be used in any combination. Examples of the polysaccharide include chitin, chitosan, carboxymethylated chitin, sulfated carboxymethylated chitin, chondroitin sulfate, curdlan sulfate, heparin sulfate, keratin sulfate and hyaluronic acid. The polysaccharides preferably have a molecular weight of from 10,000 to 30,000. Those organic groups may have anionic groups such as -SO 3 (X), -OSO 3 (X), -OPO 3 (X) and -CO 2 (X), wherein X represents a hydrogen atom or pharmaceutically acceptable counter anion, preferably it represents an alkali metal anion. The peptide sequence and the organic groups are bonded e.g. with an ester bond, amide bond, urethane bond, urea bond. In particular, when the organic groups are selected form those derived from e.g. monosaccharides, oligosaccharides, polysaccharides, polymers, the peptide sequence of the formula [I] and the organic group may be bonded through an alkylene group or an arylene group. In such cases, the alkyl group and arlylene group are preferably linear and substituted, preferably have 1 to 15 carbon atoms and may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond. The organic groups are preferably bonded to the peptide sequence of the formula [I] at the carboxyl terminal or the amino terminal of the peptide sequence. When the organic group is bonded to the peptide sequence at the amino terminal of the peptide sequence, the carboxyl terminal of the peptide sequence is preferably in the form of -OR a or -NR b R c , wherein each of R a , R b and R c represents a hydrogen atom or a linear or cyclic alkyl group and R b and R c may be bonded together to form a ring structure. Further, R a , R b and R c may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond. R a , R b and R c are preferably selected from a methyl, ethyl, iso-propyl and cyclohexyl group. When the organic group is bonded to the peptide sequence at the carboxyl terminal of the peptide sequence, the amino terminal preferably has a hydrogen atom or substituted or unsubstituted acyl group. The acyl group preferably has 1 to 15 carbon atoms. Preferred examples of the substituent of the acyl group are the foregoing anionic groups such as a carboxyl group and sulfonic group. The acyl group may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond. The molecular weight of the peptide derivatives of the present invention is not particularly limited as far as the biological activity of the derivatives is maintained and the whole derivative is maintained as water-soluble, but the average molecular weight thereof preferably ranges from 1,000 to 100,000. As the salts of the peptide derivatives of the present invention, there may preferably be mentioned, salts with inorganic acids, for instance, hydrochlorides, sulfates, nitrates, phosphates and borates, and salts with organic acids, for instance, acetates, trifluoroacetates, trifluoromethanesulfonates, lactates and tartrates. Conversion of the derivatives into these salts may be carried out by a conventional manner. Preferred examples of the peptide derivative according to the present invention including those described in the Examples (Synthesis of the derivatives and investigation of the biological activities thereof) will be listed below, but the present invention is by no means limited to these specific examples. When the amino terminal of the peptide sequence has a hydrogen atom and when the carboxyl terminal of the peptide sequence has -OH, indications of the hydrogen atom and the -OH group are omitted in the formulae in accordance with the orthography in this field. Further, D-amino acids are shown with the indications of "D-", but the indications of "L-" of L-amino acids are omitted. Compounds 56 to 63 are those polymers formed from each of the following Monomers 56 to 63. Methods for synthesizing the peptide sequences are not particularly limited to any specific method and a suitable method may be selected from liquid phase methods, solid phase methods and methods utilizing an automatic synthesizer depending on the kind of the organic group to be bonded with the peptide sequences. In the solid phase methods, oligopeptides are synthesized using Boc groups, cleavage of the peptides from a resin carrier and elimination of the protection groups on the side chain are carried out using trifluoromethanesulfonic acid and the peptides or the derivatives thereof are purified by HPLC (high performance liquid chromatography) for fractionation and collected as fractions showing a single peak. For example, the peptide derivatives of the present invention, Compounds 36, 37 and 40 to 46 may be fractionated by using a YMC-Pack ODS column (length: 500 mm, inner diameter: 20 mm) and a suitable eluent such as 0.01N HCl/acetonitrile, 0.1% TFA/acetonitrile and 0.1% TFA/water. The eluent may have a suitable gradient. The peptides are then converted into e.g. hydrochloric acid salt, acetic acid salt by passing through an anion-exchange resin column such as Amberlite IRA-400; C1 form and IRA-93ZU; acetic acid salt form. Though thus obtained peptide may be directly reacted with the organic groups, they may be modified with the organic groups before the cleavage from the resin carrier. In the synthesis by the liquid phase methods, the peptides are generally synthesized in the properly protected form, optionally deprotected at a specific modification site or sites and modified, and then totally deprotected. Though only the representative examples of the synthesis of the protected peptides are described herein, the details of the synthesis methods of protected peptides are described in, for example, Lectures on Biochemical Experiments, "Chemistry of Proteins IV", p207 to 495, edited by the Biochemical Society of Japan, published by Tokyo Kagaku Dojin; Lectures on Biochemical Experiments, Second Series, "Chemistry of Proteins (the last volume)", edited by the Biochemical Society of Japan, published by Tokyo Kagaku Dojin and "Fundamental Knowledge and Experiments of Peptide Synthesis", edited by Izumiya et al., published by Maruzen. Alternatively, it is also possible to use commercially available synthetic peptides as intermediates. The peptides composed of repeating units may be easily synthesized by the continuous polymerization method by means of diphenylphosphoryl azide (DPPA) by N. Nishi et al., Int. J. Peptide Protein Res., 30 , p275 (1987). In addition, the peptides may be prepared by the methods of genetic engineering. Synthesis of the saccharide moiety may be carried out by using glycosylation reaction as a key reaction. Various methods of the glycosylation are known and the reaction conditions may be selected taking account of the kinds and availability of saccharides and the conditions of the deprotection. The synthesis of saccharide is carried out essentially by condensation reaction of a sugar donor and a sugar receptor of alcohol in the presence of a promoter. For example, when sugar chloride, sugar bromide and the like are used as the sugar donor, silver oxide, silver carbonate, silver perchlorate, silver trifluoromethanesulfonate, mercury (II) cyanide, mercury bromide and the like may be used as the promoter. When sugar fluoride and the like are used as the sugar donor, tin (II) chloride/silver perchlorate, zirconocene dichloride/silver perchlorate and the like may be used as the promoter. When alkylthio compounds of sugar are used as the sugar donor, dimethyl(methylthio)sulfonium triflate, methyl trifluoromethane sulfonate ester, phenylselenyltriflate and the like may be used as the promoter. When imidate compounds are used as the sugar donor, the reaction is carried out by using lewis acids such as boron trifluoride/diethyl ether complex. Dehydration desiccating agents such as molecular sieves and Drylite may be used in the glycosylation reactions explained above. When the sugar donor has a reducing terminal sugar of 2-acetoamido-2-deoxy sugar such as N-acetylglucosamine, the glycosylation reaction may be effectively carried out by the oxazoline method. Sugar residues of aryl glycoside may be synthesized by using a reaction of polyacetylated sugar and phenol which are heated in nonpolar solvent such as benzene and toluene as the key step. Further, as regards p-nitrophenyl glycoside compounds, many of such compounds are commercially available. S-glycosides may be synthesized by the Koenig-Knorr method wherein the sugar donors of sugar chloride, sugar bromide and the like are reacted with thiol compounds. Nucleophilic reactivity of thiol compounds is higher than that of alcohols, and therefore the reaction easily proceeds. When the peptide sequences and the pharmaceutically acceptable organic groups are bonded with amide bonds or ester bonds, the peptide derivatives of the present invention may be prepared e.g. by the active ester methods, the mixed acid anhydride method, the azide method, the acid chloride method, the symmetric acid anhydride method, the DCC method, the DCC-additive method, the carbonyldiimidazole method. The peptide derivatives composed of polymers such as propeneamide derivatives may prepared e.g. by a conventional radical polymerization method, ion polymerization method. Resulted polymers may be fractionated depending on the molecular weight thereof e.g. by conventional methods such as gel filtration, dialysis. The mechanism of the potent in vivo activity for inhibiting tumor metastasis of the peptide derivatives or the salts thereof according to the present invention is not completely elucidated. However, it was clearly shown that the cell-migration (infiltration) inhibitory activity in an in vitro system of the present peptide derivatives is superior to that of the peptide Arg-Gly-Asp-Ser, which is the minimum unit of the cell-adhesive proteins for exhibiting the adhesive function, though the cell-adhesion inhibitory activity and the platelet-coagulation inhibitory activity in an in vitro system of the present peptide derivatives are not necessarily superior to those of Arg-Gly-Asp-Ser. Therefore, the peptide derivatives or the salts thereof according to the present invention can be administered to patients optionally together with conventional carriers or pharmaceutical auxiliary agents, i.e., as a composition containing at least one of the peptide derivatives of the present invention, as tumor or cancer metastasis inhibiting agents. The administration dose thereof may vary depending on conditions like the disease to be treated, age and body weight of patients, but generally ranges from 0.2µ g/kg to 400 mg/kg a day. The peptide derivatives of the present invention may be administered through various routes which are generally used for the administration of peptide-containing medicines. For example, it is preferably administered parenterally, e.g., intravenously, intramuscularly and subcutaneously. In the preparation of injectable pharmaceutical preparations containing the peptide derivatives of the present invention, the derivatives are dissolved in, for example, PBS and physiological saline solution as described hereinbelow, or dissolved in about 0.1N aqueous solution of acetic acid and then lyophilized to give a lyophilized preparation. These pharmaceutical preparations may comprise a conventional stabilizer such as glycine and albumin. In addition, the peptide derivative of the present invention may be orally administered in the form of a microcapsule by encapsulating the derivatives in, for example, liposomes and microspheres or in the form of hydrogel. Further, if the derivatives are formulated in the form of , for example, a suppository, sublingual tablets and nasal sprays, they can be absorbed through mucous other than in the digestive tracts. The present invention will hereinafter be explained in more detail with reference to the following non-limitative examples , but the present invention is by no means limited to these specific Examples. The abbreviations used herein are listed below. In the descriptions hereinbelow, D-amino acid residues are described with the indications of "D-", but, as regards L-amino acid residues, the indications of "L-" are omitted. Boc t-butoxycarbonyl Bn benzyl Z benzyloxycarbonyl Ac acetyl Su succinyl Me methyl Et ethyl iPr isopropyl OSu N-hydroxysuccinimide ONb nitrobenzyl ester Mts mesitylenesulfonyl HOBt 1-hydroxybenzotriazole DCC dicyclohexylcarbodiimide iPr2NEt diisopropylethylamine AcOH acetic acid AcOEt ethyl acetate DMF dimethylformamide CDI carbonyldiimidazole TFA trifluoroacetic acid DC-urea dicyclohexylurea Thr threonine Arg arginine Gly glycine Asp aspartic acid Ser serine Pro proline Val valine Leu leucine Phe phenylalanine Phg phenylglycine Ile isoleucine Nle norleucine Glu glutamic acid Ala alanine Example 1: Synthesis of Compound 1 Compound 1 was synthesized by following Route 1 below. Synthesis of Compound (1a) To a DMF solution (150 ml) containing t-Boc-Ser(Bn) (14.8 g, 50 mmol) and NaHCO 3 (8.4 g, 0.1 mol), benzyl bromide (8.55 g, 50 mmol) was added dropwise, and the solution was stirred for 24 hours at room temperature. The reaction solution was extracted by adding 4% aqueous solution of Na 2 CO 3 and ethyl acetate and the organic and aqueous layers were separated. The ethyl acetate layer was washed with water and saline solution successively and dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to give 17.0 g (4.4 mol) of Compound (1a) as an oily product. Yield: 88%. Synthesis of Compound (1b) Compound (1a) (17.0 g, 44 mmol) was dissolved in methylene chloride (30 ml), added with TFA (30 ml) and dried over 3 hours at room temperature. After removing methylene chloride and TFA by means of a rotatory evaporator, the residue was extracted by adding ethyl acetate and 4% aqueous solution of Na 2 CO 3 and the organic layer was separated. The organic layer was washed with water and saline solution successively and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in a mixed solvent of methylene chloride (60 ml) and DMF (40 ml), added with t-Boc-Asp(OBn) (15 g, 46 mmol) and HOBt monohydrate (HOBt · H 2 O, 6.7 g, 44 mmol) and stirred with ice cooling. The reaction mixture was added with DCC (10.3 g) and stirred for 2 hours with ice cooling and overnight at room temperature. Then, the precipitated urea derivative was removed by filtration and the nitrate was concentrated under reduced pressure. The residue was extracted by adding ethyl acetate and 4% aqueous solution of Na 2 CO 3 and the organic layer was separated. The ethyl acetate layer was washed with water and saline solution successively and dried over sodium sulfate. After removing newly precipitated urea derivative by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 2/1) to give Compound (1b) (15.8 g, 26.7 mmol) as a white solid. Yield: 61%. Synthesis of Compound (1c) Compound (1c) (15.5 g, 26.2 mmol) was dissolved in methylene chloride (30 ml), added with TFA (30 ml) and stirred for 30 minutes at room temperature. After removing ethylene chloride and TFA by means of a rotatory evaporator, the residue was added with a mixed solvent of n-hexane and ether (5:1) and precipitated white solid of Compound (1c) (15.0 g, 24.8 mmol) was taken by filtration. Yield: 95%. Synthesis of Compound (1d) A reaction mixture containing Compound (1c) (1.5 g, 2.48 mmol), t-Boc-Leu· H 2 O (690 mg, 2.96 mmol), HOBt · H 2 O (380 mg, 2. 5 mmol) and diisopropyl ether (0.470 µl, 2.7 mmol) in methylene chloride (15 ml) and DMF (7 ml) was stirred with ice cooling. This reaction mixture was added with DCC (570 mg) and stirred for 2 hours with ice cooling and overnight at room temperature. After removing precipitated urea derivative by filtration, the.filtrate was concentrated under reduced pressure. The residue was added with ethyl acetate and washed with 10% aqueous solution of citric acid, 4% aqueous solution of Na 2 CO 3 , water and saline solution successively. After removing newly precipitated urea derivative by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 10/1) to give Compound (1d) (1.39 g, 2 mmol) as a white solid. Yield: 80%. Synthesis of Compound (1e) Compound (1d) (1.15 g, 1.6 mmol) was dissolved in methylene chloride (6 ml), added with TFA (6 ml) and stirred for 1 hour at room temperature. After evaporating methylene chloride and TFA by means of a rotatory evaporator, the residue was extracted by adding ethyl acetate and 4% aqueous solution of Na 2 CO 3 and the organic layer was separated. The ethyl acetate layer was washed with water and saline solution successively and dried over sodium sulfate. After evaporating the ethyl acetate under reduced pressure, the residue was dissolved in a mixed solvent of methylene chloride (15 ml) and DMF (8 ml), added with t-Boc-Arg(Z 2 ) (970 mg, 1.8 mmol) and HOBt · H 2 O (220 mg, 1.4 mmol) and stirred with ice cooling. The reaction mixture was added with DCC (420 mg) and stirred for 2 hours with ice cooling and overnight at room temperature. Then, the precipitated urea derivative was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was extracted by adding ethyl acetate and 4% aqueous solution of Na 2 CO 3 and the organic layer was separated. The ethyl acetate layer was washed with water and saline solution successively and dried over sodium sulfate. After removing newly precipitated urea derivative by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 10/1) and recrystallized from a mixed solvent of n-hexane and ethyl acetate (2/1) to give Compound (1e) (690 mg, 0.61 mmol) as a white solid. Yield: 38%, M.P.: 100-104°C. Synthesis of Compound 1 Compound (1e) (590 mg, 0.53 mmol) was dissolved in methylene chloride (6 ml), added with TFA (6 ml) and stirred for 30 minutes at room temperature. After removing ethylene chloride and ethyl acetate by means of a rotatory evaporator, the residue was added with acetic acid (10 ml) and 10% palladium/carbon (Pd/C, 60 mg) and hydrogenolysis was carried out overnight at room temperature. After removing the catalyst by filtration and evaporating acetic acid under reduced pressure, the residue was added with ether and precipitate was taken by filtration. Thus obtained crude peptide was dissolved in a small amount of water (pH 1 - 2) and developed in a column of Amberlite IRA93ZU (acetic acid form) with pure water. Positive fractions in the ninhydrin reaction (pH 4 - 5) were combined, concentrated and finally lyophilized to give Compound 1 (240 mg) as a white amorphous product. In the proton NMR, a peak of methyl group of acetic acid was observed at 2.02 ppm, of which integral intensity showed that Compound 1 was obtained as a monosalt of acetic acid. Yield: 82%. FAB Mass: 490 (M+H) + Example 2: Synthesis of Compound 8 Condensation reaction was carried out in the same manner as in the synthesis of Compound (1e) by using t-Boc-D-Arg(Z 2 ) in stead of t-Boc-Arg(Z 2 ) to obtain Compound 8 in the totally protected form. Yield: 40%, M.P.: 136 - 139°C. Hydrogenolysis and purification of the totally protected Compound 8 (620 mg, 0.55 mmol) were carried out in the same manner as in the synthesis of Compound 1 to obtain Compound 8 as a monosalt of acetic acid (280 mg). Yield: 84%. FAB Mass: 490 (M+H) + Example 3: Synthesis of Compound 23 The fully protected Compound 8 (4.02 g, 3.56 mmol) was dissolved in methylene chloride (30 ml), added with TFA (30 ml) and stirred for 1 hour at room temperature. After removing methylene chloride and TFA by means of a rotatory evaporator, the residue was extracted by adding chloroform and 4% aqueous solution of Na 2 CO 3 and the organic was separated. The organic layer was washed with water and saline solution successively and dried over sodium sulfate. By evaporating chloroform under reduced pressure, Compound (1e) of which t-Boc was eliminated (3.56 g, 3.46 mmol) was obtained. Yield: 97%. Thus obtained t-Boc-eliminated Compound (1e) (1.36 g, 1.32 mmol) was dissolved in methylene chloride (15 ml), added with acetic anhydride (0.15 ml) and stirred for 2 hours at room temperature. Formed precipitate was taken by filtration and recrystallized from acetonitrile to give Compound 23 in the totally protected form (930 mg, 0.87 mmol). Yield 66%, M.P.: 163 - 166°C. The totally protected product (930 mg) was dissolved in acetic acid (15 ml) and 10% palladium/carbon (90 mg) and hydrogenolysis was carried out for 1 hour at 40 °C and overnight at room temperature. After removing the catalyst by filtration and evaporating acetic acid under reduced pressure, the residue was added with ether and resulted precipitate was taken by filtration. Thus obtained crude peptide was dissolved in pure water, added with activated carbon and stirred for 15 minutes at room temperature. After removing the activated carbon by filtration and evaporating water, the residue was lyophilized to give Compound 23 (290 mg). Yield 61%. FAB Mass: 532 (M+H) + , 554 (M+Na) + Example 4: Synthesis of Compound 20 t-Boc-eliminated Compound (1e) (1.1 g, 1.07 mmol) obtained in the same manner as in Example 3 was dissolved in methylene chloride (15 ml), added with succinic anhydride (130 mg) and stirred for 2 hours at room temperature. After evaporating the solvent under reduced pressure, the residue was recrystallized from acetonitrile to give Compound 20 in the totally protected form (1.18 g, 1.05 mmol). Yield 98%, M.P.: 167 - 169 °C. The totally protected product (1.0 g, 0.886 mmol) was dissolved in acetic acid (15 ml) and 10% palladium/carbon (90 mg) and hydrogenolysis was carried out for 1 hour at 40°C and overnight at room temperature. After removing the catalyst by filtration and evaporating acetic acid under reduced pressure, the residue was added with ether and resulted precipitate was taken by filtration. Thus obtained crude peptide was dissolved in pure water, added with activated carbon and stirred for 15 minutes at room temperature. After removing the activated carbon by filtration and evaporating water, the residue was lyophilized to give Compound 20 (480 mg). Yield 92%. FAB Mass: 590 (M+H) + Example 5: Synthesis of Compound 17 A methylene chloride solution (60 ml) containing t-Boc-Ser(Bn) (8.86 g, 30 mmol), N,N-dimethylaminopyridine (360 mg) and methanol (1.4 ml) was stirred with ice cooling and added with DCC (6.2 g). After stirring the solution overnight, methylene chloride was evaporated and the residue was added with ethyl acetate (40 ml). After removing formed urea derivative by filtration, the ethyl acetate filtrate was washed with an aqueous solution of citric acid, aqueous solution of NaHCO 3 and saline solution successively and dried over magnesium sulfate. After evaporating ethyl acetate under reduced pressure, crude t-Boc-Ser(Bn)-OCH 3 (9.3 g) was obtained as a colorless oily product. Compounds (17b) to (17e) were prepared by following the above described Route 1 and using the above obtained crude t-Boc-Ser(Bn)-OCH 3 instead of Compound (1a). Compounds (17b) to (17e) have a methyl ester group at the serine residue instead of the benzyl ester group of Compounds (1b) to (1e). Yields of the preparation steps are as follows. (17b) 79%, (17c) 86%, (17d) 75%, (17e) 62%, M.P. 130 - 132°C Compound 17 was prepared as a monosalt of acetic acid in the same manner as in Example 4 by using Compound (17e) instead of Compound (1e). FAB Mass: 604 (M+H) + Example 6: Amidation of carboxyl terminal The amidation at the carboxyl terminal of the peptide according to the invention may be carried out by either of the active esterification method and the DCC method. A typical example of the conversion into an amide compound is given below. Synthesis of Boc-Ser(Bn)-NHMe Boc-Ser(Bn)-OH (29.5 g, 0.1 mol) and p-nitrophenol (13.9 g, 0.1 mol) were dissolved in a mixed solvent of methylene chloride (20 ml) and DMF (20 ml) and added with DCC (20.6 g, 0.1 mol) with ice cooling. The reaction mixture was stirred for 1 hour with ice cooling and overnight while allowing the mixture to warm up to room temperature. The mixture was filtered through a Celite layer to remove the precipitate, and the Celite layer was washed with ethyl acetate. The filtrate and the washing liquor were combined and concentrated under reduced pressure to obtain crude p-nitrophenyl ester compound. This product was dissolved in THF (150 ml) and added with 40% methylamine solution. The reaction mixture was stirred for 20 hours at room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain the desired methylamide compound as colorless powder (29.6 g). Yield 96%. Other amide compounds may be obtained in a similar manner. Example 7: Synthesis of Compound 16 Compound (1e) (4.2 g, 3.7 mmol) was dissolved in methylene chloride (20 ml), added with TFA (20 ml) and stirred for 1 hour at room temperature. After removing the methylene chloride and the TFA by means of a rotatory evaporator, the residue was extracted by adding chloroform and 4% aqueous solution of Na 2 CO 3 and the organic was separated. The chloroform layer was washed with water and saline solution successively and dried over sodium sulfate. After evaporating the chloroform under reduced pressure, the residue was dissolved in a mixed solvent of methylene chloride (30 ml) and DMF (30 ml), added with t-Boc-Asp (OBn) (1.3 g, 45 mmol) and HOBt · H 2 O (610 mg, 4.0 mmol) and stirred with ice cooling. The reaction mixture was added with DCC (850 mg) and stirred for 2 hours with ice cooling and overnight at room temperature. After removing precipitated urea derivative by filtration, the filtrate was concentrated under reduced pressure. The residue was extracted by adding chloroform and 4% Na 2 CO 3 aqueous solution and the organic layer was separated. The ethyl acetate layer was washed with water and saline solution successively, and newly precipitated urea derivative was removed by filtration. The filtrate was concentrated under reduced pressure and dried over magnesium sulfate. After evaporating the ethyl acetate under reduced pressure, the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane (3:1) and then from acetonitrile to give t-Boc-Asp(OBn)-Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-OBn (3.2 g, 2.4 mmol) as a colorless solid product. Yield: 65%. Compound 16 was prepared through t-Boc eliminating reaction, acetylation reaction, hydrogenolysis and purification similar to those of Example 4 by using above-obtained totally protected product instead of Compound (1e). FAB Mass: 647 (M+H) + , 669 (M+Na) + Example 8: Synthesis of Compound 18 In the same manner as used in the synthesis of Compound 16, Compound 18 was prepared by using t-Boc-Glu(OBn) instead of t-Boc-Asp(OBn). FAB Mass: 661 (M+H) + Example 9: Synthesis of Compounds 2 to 7 Compounds (2d), (3d), (4d), (5d), and (7d) were prepared in the same manner as used in the synthesis of the intermediate compound for the synthesis of Compound 1, Compound (1d), by using t-Boc-D-Leu, t-Boc-Nle, t-Boc-D-Nle, t-Boc-D-Phg, and t-Boc-D-Phe instead of t-Boc-Leu respectively. Then, Compounds (2e), (3e), (4e), (5e), and (7e) were prepared in the same manner as used in the synthesis of Compound (1e) by using Compounds (2d), (3d), (4d), (5d), and (7d) respectively instead of Compound (1d). Finally, deprotection and purification of Compounds (2e), (3e), (4e), (5e), and (7e) were carried out in the same manner as used in Example 1 to obtain Compounds 2 to 7 in the form of monosalt of acetic acid. Yields of the reactions, melting points and mass spectrum data of the above-obtained compounds according to the present invention are listed below. Yield (%) Compound (2d) 87 Compound (2e) 76 Compound 2 88 Compound (3d) 86 Compound (3e) 84 Compound 3 87 Compound (4d) 69 Compound (4e) 69 Compound 4 86 Compound (5d) 86 Compound (5e) 81 Compound 5 92 Compound (7d) 66 Compound (7e) 78 Compound 7 80 Melting point (°C) Compound (2e) 126 - 127 Compound (3e) 139 - 141 Compound (4e) 131 - 134 Compound (5e) 147 - 151 Compound (7e) 141 FAB Mass Compound 2 490 (M+H) + , 512 (M+Na) + Compound 3 490 (M+H) + Compound 4 490 (M+H) + Compound 5 510 (M+H) + Compound 7 524 (M+H) + , 546 (M+Na) + Example 10: Synthesis of Compound 56 (a) An aqueous solution of sodium hydroxide containing β-alanine (17.8g, 0.2 mol) was added with methacryloyl chloride (20.9 g, 0.2 mol) with ice cooling, stirred for 4 hours and neutralized with hydrochloric acid. After concentrating the reaction mixture under reduced pressure, precipitated sodium chloride was removed by filtration. The concentrate was extracted with chloroform and dried. After evaporating the chloroform, the concentrate was washed with ether to obtain carboxymethylmethacrylamide as a white solid product (17.6 g). Yield: 56%. CH 2 =CCH 3 -CONHCH 2 CH 2 -COOH In the same manner as described above, various propenoic acid derivatives may be prepared, for example, from combinations of methacryloyl chloride and 4-aminobutyric acid, ethacryloyl chloride and 5-aminovaleric acid, methacrylic acid and 6-aminocaproic acid, acrylic acid and 12-aminolauric acid, acrylic acid and leucine, methacrylic acid and glutamine, acrylic acid and 2-(2-aminoethoxy)propyonic acid, methacrylic acid and 2-(2-aminoethoxy)acetic acid, methacrylic acid and glycylglycine and the like. (b) Synthesis of Boc-Arg(Mts)-Leu-Asp(OBn)-ser(Bn)-OBn Boc-Lue-Asp(OBn)-Ser(Bn)-OBn (Compound (1d)) (28 g, 39 mmol) was added with a mixed solvent (200 ml) of TFA and CH 2 Cl 2 (1:1) and stirred for 1 hour at room temperature, and then the TFA and CH 2 Cl 2 were evaporated under reduced pressure. The residue was dissolved in ethyl acetate, neutralized with NaHCO 3 aqueous solution and washed with NaCl aqueous solution. The mixture was dried over sodium sulfate, and the ethyl acetate was evaporated under reduced pressure. Thus obtained product and Boc-Arg(Mts) (17.8 g, 39 mmol) were dissolved in DMF (400 ml), added with DCC (8.0 g, 39 mmol) and HOBt (6.8 g, 45 mmol) with ice cooling and stirred for 3 hours with ice cooling and overnight at room temperature. After removing DC-urea by filtration, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with NaHCO, aqueous solution, 1M citric acid aqueous solution and NaCl aqueous solution successively, dried over sodium sultate and evaporated to dryness under reduced pressure to obtain the desired compound as white powder (19.5 g). Yield: 48%. (c) Synthesis of Monomer 56 Boc-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-OBn (15.6 g, 15 mmol) was added with a mixed solvent (100 ml) of TFA and CH 2 Cl 2 (1:1) and stirred for 1 hour at room temperature, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, neutralized with NaHCO 3 aqueous solution and washed with NaCl aqueous solution. The mixture was dried over sodium sulfate, and the ethyl acetate was evaporated under reduced pressure. Thus obtained product and carboxyethylmethacrylamide (2.4 g, 15 mmol) were dissolved in CH 2 Cl 2 (200 ml), added with DCC (3.1 g, 15 mmol) and stirred for 3 hours with ice cooling and further stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and added with acetone, and formed DC-urea was removed by filtration. The mixture was concentrated under reduced pressure, washed with ether and dried under reduced pressure to obtain white powder (10.0 g). Yield: 62%. The above obtained product (10.0 g, 9.3 mmol) was dissolved in TFA, added with a solution of 1M-trifluoromethanesulfonic acid/thioanisole/m-cresol in TFA with ice cooling and allowed to react for 1 hour to eliminate the protection groups present on the side chain and the terminal of the peptide. The reaction solution was poured into ether, resulted oily precipitate was dissolved in distilled water, then washed with ethyl acetate, passed through an anion-exchange resin column (Amberlite IRA-400;C1 form) to convert into a hydrochloride and lyophilized to give the desired monomer as a white solid product (4.4 g). Yield: 76%. Amino Acid Analysis (nmol/50µl) Arg 0.9877 Leu 0.9916 Asp 0.9899 Ser 0.8891 β - Ala 1.0115 Mass Spectra (MS) M + 573 (d) Synthesis of Compound 56 (Polymerization of Monomer 56) Monomer 56 (500 mg) was dissolved in water (5 ml), the pH value adjusted at 7.4 with 1N NaOH and added with potassium persulfate (2.5 mg) and sodium hydrogensulfite (1.0 mg) as initiators and allowed to cause polymerization reaction under nitrogen flow at 20 °C for 20 hours. After the reaction, the reaction mixture was dialyzed against pure water using Spectrapore 7 (MWCO: 3000) to eliminate low molecular weight compounds and lyophilized to obtain the desired Compound 56 (240 mg). The obtained Compound 56 was fractionated according to the molecular weight thereof by gel permeation chromatography, which was carried out by using TSK Gel G3000SW column available from Toso Co.,Ltd., and 0.2 M phosphate buffer (pH 7.4) as a mobile phase at a flow rate of 1.0 ml/min. The determined molecular weight of the fractions of Compound 56 are as follows (Standard: PEG). Fraction 1 Molecular weight about 48,000 (Compound 56-1) Fraction 2 Molecular weight about 21,000 (Compound 56-2) Fraction 3 Molecular weight about 12,000 (Compound 56-3) Example 11: Synthesis of Compound 56-4 (Synthesis of low molecular weight polymer by altering the amount of initiator) Compound 56-4 was prepared in the same manner as used in Example 10 by using the following initiators. Initiator Potassium persulfate 10 mg Sodium hydrogensulfite 4 mg Yield 180 mg Molecular weight about 5,000 Example 12: Synthesis of Reference Polymer A The above-synthesized carboxyethylmethacrylamide was polymerized through radical polymerization reaction as follows. Carboxyethylmethacrylamide (2 g) was dissolved in DMF (20 ml), added with a radical initiator V65 (2,2-azobis(2,4-dimethylvaleronitrile, Wako Junyaku Co.,Ltd., 10 mg) and allowed to cause polymerization under nitrogen flow at 65 °C for 4 hours. The resulted polymer was precipitated with ethyl acetate, dialyzed against pure water using Spectrapore (MWCO: 3000) to eliminate low molecular weight fraction and lyophilized to obtain Reference Polymer A (1.24 g). Reference Polymer A H-(CH 2 -CHCH 3 (CONHCH 2 CH 2 COOH)) n Molecular weight (Standard: PEG): about 30,000 Example 13: Synthesis of Monomer 57 Monomer 57 was prepared in the same manner as used in Example 10 by using the following reagents and the amounts thereof. (a) Synthesis of Boc-Asp(OBn)-Ser(Bn)-NHCH 3 Boc-Asp(OBn) 32.3 g (0.1 mol) Ser(Bn)NHCH 3 HCl 24.4 g (0.1 mol) N-methylmorpholine 10.1 g (0.1 mol) CH 2 Cl 2 500 ml DCC 20.6 g (0.1 mol) Yield 44.2 g (Mw 513.6) (b) Synthesis of Boc-Leu-Asp(OBn)-Ser(Bn)-NHCH 3 Product of (a) 25.6 g (0.05 mol) TFA/CH 2 Cl 2 150 ml/150 ml Boc-Leu 11.5 g (0.05 mol) CH 2 Cl 2 300 ml DCC 10.3 g (0.05 mol) Yield 20.1 g (Mw 614.7) (c) Synthesis of Boc-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NHCH 3 Product of (b) 20.7 g (0.03 mol) TFA/CH 2 Cl 2 100 ml/100ml Boc-Arg(Mts) 13.7 g (0.03 mol) DMF 250 ml DCC 6.18 g (0.03 mol) HOBt 4.0 g (0.03 mol) Yield 17.5 g (Mw 953.1) (d) Synthesis of Boc-Gly-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NHCH 3 Product of (c) 9.53 g (0.01 mol) TFA/CH 2 Cl 2 100 ml/100ml Boc-Gly 1.75 g (0.01 mol) DMF 80 ml DCC 2.06 g (0.01 mol) HOBt 1.36 g (0.01 mol) Yield 6.53 g (Mw 1009.9) (e) Synthesis of Boc-Gly-Gly-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NHCH 3 Product of (d) 5.04 g (0.005 mol) TFA/CH 2 Cl 2 50 ml/50 ml Boc-Gly 0.88 g (0.005 mol) DMF 200 ml DCC 1.03 g (0.005 mol) HOBt 0.68 g (0.005 mol) Yield 3.84 g (Mw 1066.7) (f) Synthesis of Monomer 57 Product of (e) 3.20 g (0.003 mol) TFA/CH 2 Cl 2 40 ml/40 ml Methacrylic acid 0.22 g (0.003 mol) DMF 60 ml DCC 0.62 g (0.003 mol) HOBt 0.41 g (0.003 mol) TFA solution of 1M-Trifluoromethanesulfonic acid/thioanisole/m-cresol 25 ml (Amberlite IRA-400;Cl form treatment) Amino Acid Analysis (nmol/50µl) Arg 0.9845 Gly 2.1361 Asp 0.9554 Ser 0.8879 Leu 0.9472 MS M + 656 Example 14: Synthesis of Monomer 59 Monomer 59 was prepared in the same manner as used in Example 10. CH 2 =CHCONHCH 2 CH 2 CO-Asp-Arg-D-Leu-Asp-Ser Yield: 35% Amino Acid Analysis (nmol/50µl) Arg 0.9982 Ser 1.0319 Asp 1.9971 D-Leu 1.0063 β -Ala 1.024 MS M + 729 (729.75) Example 15: Synthesis of Monomer 62 Monomer 62 was prepared in the same manner as used in Example 10. CH 2 =CCH 3 CONHCH 2 CH 2 CH 2 CO-Arg-Phg-Asp-Ser Yield: 24% Amino Acid Analysis (nmol/50µl) Arg 1.0028 Phg 1.0014 Asp 1.0043 Ser 0.9963 4-aminobutyric acid 1.0257 MS M + 662 (662.67) Example 16: Synthesis of Monomer 61 Monomer 61 was prepared in the same manner as used in Example 10. CH 2 =CCH 3 CONHCH 2 CH 2 CH 2 CH 2 CO-Gly-D-Arg-Leu-Asp-Ser Yield: 17% Amino Acid Analysis (nmol/50µl) D-Arg 1.0056 Gly 1.0012 Asp 0.9645 Leu 1.0177 Ser 1.0090 MS M + 713, 713.8 Example 17: Synthesis of Monomer 63 Monomer 63 was prepared in the same manner as used in Example 10. CH 2 =CCH 3 CONHCH 2 CH 2 CO-(Asp-Arg-D-Leu-Ser) 2 Yield: 10% Amino Acid Analysis (nmol/50µl) Arg 2.0484 D-Leu 2.0965 Asp 2.0333 Ser 2.1032 β -Ala 1.0449 MS M + 1100 (1100.21) Example 18: Synthesis of Compounds 57 to 63 (Polymerization of Monomers 57 to 63) Polymerization of Monomers 57 to 63 was carried out in the same manner as used in Example 10 (d). Compound No. Yield (mg) Molecular weight 57 230 9,500 58 180 13,000 59 190 9,000 61 240 16,000 62 150 11,000 63 170 10,000 Example 19: Synthesis of succinylated polyallylamine Polyallylamine (5.2 g, Nitto Boseki Co.,Ltd.) and triethylamine (15.2 g) were dissolved in water (100 ml), added with 4-dimethylaminopyridine (1.7 g) and succinic anhydride (15.0 g) and stirred overnight at room temperature. The desired compound, succinylated polyallylamine, was precipitated with acetone, washed with ether and dried. Yield: 1.26 g, Molecular weight 11,000. Example 20: Synthesis of Compound 102 Succinylated polyallylamine carrying -Arg-D-Leu-Asp-Ser The succinylated polyallylamine (0.39 g) obtained in Example 19 was dissolved in phosphate buffer (25 ml, pH 7.4), added with a solution of 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (0.26 g) in phosphate buffer (5.0 ml) at 0°C and allowed to react for 1.5 hours. Then, the reaction solution was added with a solution of Arg-D-Leu-Asp-Ser (0.71 g) dissolved in phosphate buffer (10 ml) and allowed to react overnight at 4 °C . The reaction solution was dialyzed against ion-exchanged water and then against pure water using Extrapore 7 (MWCO: 8000) to eliminate low molecular weight compounds, purified and lyophilized. Yield: 0.71 g. The structure of the product was confirmed by IR and elemental analysis. As a result of the elemental analysis, the introduction rate of the peptide fragment was found to be about 15 %. The introduction rate was calculated as described in Example 44. Elemental Analysis: N; 19.80% IR: Stretching vibration of amidocarbonyl (C=O) 1648 cm -1 Example 22: Synthesis of Compound 104 Arg-D-Leu-Asp-Ser-Gly- carrying polyallylamine The protected peptide having a free carboxyl group described in Example 31 (6) (4.04 g, 4 mmol) was dissolved in DMF (40 ml), added with DCC (0.83 g, 4 mmol) and HOBt (0.54 g, 4 mmol) with ice cooling and stirred for 1 hour. The reaction mixture was added with polyallylamine hydrochloride (0.78 g) dissolved in DMF (20 ml) and stirred for 3 hours with ice cooling and overnight at room temperature. Then, after removing formed DC-urea, the reaction mixture was concentrated under reduced pressure. Deprotection of the product was carried out in the same manner as Used in the synthesis of Monomer 56 (Example 10 (c)). Yield: 0.82 g. TFA solution of 1M-Trifluoromethanesulfonic acid/ thioanisole/m-cresol : 150 ml (Amberlite IRA-400;Cl form treatment) The structure of the product was confirmed by IR and elemental analysis. As a result of the elemental analysis, the introduction rate of the peptide fragment was found to be about 11%. Elemental Analysis: N; 24.93% IR: Stretching vibration of amidocarbonyl (C=O) 1652 cm -1 Example 23: Synthesis of Compound 65 Compound 65 was prepared by following Route 2 below. (a) Synthesis of Intermediate Compound 1 Sodium 4-hydroxybutyrate (25 g, 0.2 mol) and benzyl bromide (37 g, 0.22 mol) were dissolved in a mixed solvent of DMF (40 ml) and ethyl acetate (50 ml), and the reaction mixture was heated and refluxed for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, diluted with a proper amount of ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product. The resulted product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1) to give 34.9 g of benzyl 4-hydroxybutyrate. Yield: 90%. Thus obtained benzyl 4-hydroxybutyrate (19.4 g, 0.1 mol) and imidazole (10.2 g, 0.15 mol) were dissolved in DMF (100 ml), added with t-butyldimethylsilyl chloride (16 g, 0.11 mol) and stirred overnight at room temperature. After evaporating a major part of the solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product. The resulted product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 10/1) to give 29. 8 g of benzyl 4-t-butyldimethylsilyloxybutyrate as a colorless oily product. Yield: 97%. Thus obtained benzyl 4-t-butyldimethylsilyloxybutyrate (29 g, 94 mmol) was dissolved in ethyl acetate (400 ml), added with 10% palladium/carbon (1.5 g) and stirred for 18 hours under hydrogen atmosphere at room temperature. The catalyst was removed by filtration through a Celite layer, and the Celite layer was washed with ethyl acetate. The filtrate and the washing liquor were combined and concentrated under reduced pressure to give 20 g of the objective Intermediate Compound 1 as a colorless oily product. Yield: 98%. (b) Synthesis of Intermediate Compound 2 Intermediate Compound 1 (440 g, 2 mmol) was dissolved in dry DMF (10 ml) and added with a solution of CDI (330 mg, 2 mmol) in dry DMF (10 ml). The reaction mixture was stirred for 1 hour with ice cooling and added with a solution of H-Arg(Z 2 )-Leu-Asp(Bn)-Ser(Bn)-OBn (2.06 g, 2 mmol) in DMF (25 ml). The reaction mixture was stirred for 4 hours with ice cooling and overnight while allowing to warm up to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with chloroform, washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with ether to give 2.13 g of the objective Intermediate Compound 2. Yield: 87%, FAB-MS: (M+H) + 1228. (c) Synthesis of Intermediate Compound 3 Intermediate Compound 2 (2.1 g, 1.7 mmol) was dissolved in acetonitrile (30 ml), added with 5 drops of 46% hydrofluoric acid and stirred for 2 hours at room temperature. After confirming the completion of the reaction by TLC, the reaction mixture was poured into a saturated solution of sodium hydrogencarbonate and extracted with chloroform. The combined chloroform layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with ether to give 1.8 g of the objective Intermediate Compound 3 as colorless powder. Yield: 95%, FAB-MS: (M+H) + 1114. (d) Synthesis of Compound 65 Intermediate Compound 3 (1.8 g, 1.6 mmol) was dissolved in dry DMF (15 ml), added with sulfur trioxide/trimethylamine complex (500 mg, 3.6 mmol) and stirred for 20 hours at room temperature. After confirming the disappearance of the starting compounds, the reaction was stopped by adding a proper amount of saturated aqueous solution of sodium hydrogencarbonate, and the major part of the solvent was evaporated under reduced pressure. The residue was crystallized with ether, and the obtained crystals were washed and dried to obtain a sulfuric acid ester compound. This ester compound was dissolved in acetic acid (20 ml), added with 10% palladium/carbon (100 mg) and stirred for 40 hours under hydrogen atmosphere. The catalyst was removed by filtration through a Celite layer, and the Celite layer was washed with water. The filtrate and washing water were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of water, purified by gel permeation chromatography using Sephadex G-10 and lyophilized to obtain 610 mg of the objective Compound 65 as colorless powder. Yield: 59%, FAB-MS: (M-H) - 654. Example 24: Synthesis of Compound 47 Monomer 56 (620 mg, 1 mmol) was dissolved in water (20 ml), added with sodium hydrogensulfite (300 mg, 3 mmol), and the reaction mixture was heated and stirred for 23 hours at 70 °C . After allowing the reaction mixture to cool down to room temperature, a major portion of the water was evaporated under reduced pressure. The residue was dissolved in a small amount of water, purified by gel permeation chromatography using Sephadex G-10 and lyophilized to obtain 580 mg of the objective Compound 47 as colorless powder. Yield: 80%, FAB-MS: (M-H) - 709. Example 25: Synthesis of Compound 73 Tetrahydrofuran-2,3,4,5-tetracarboxylic acid(Arg-Leu-Asp-Ser) 4 Tetrahydrofurantetracarboxylic acid (0.13 g, 0.5 mmol) was dissolved in DMF (10 ml), added with CDI (0.35 g, 2.2 mmol) with cooling at 0 °C and allowed to react for 2 hours. The reaction mixture was added with trifluoroacetic acid salt of Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-OBn (2.40 g, 2.1 mmol) and diisopropylethylamine (0.28 g, 2.2 mmol) and allowed to react for 2 hours at 0 °C and for 24 hours at room temperature. After evaporating DMP, the residue was recrystallized from ethyl acetate to obtain 0.60 g (0.14 mmol) of the objective compound in the protected form. The protected compound (0.60 g) was dissolved in acetic acid (10 ml), and hydrogenolysis was carried out in a conventional manner using Pd/C as a catalyst to obtain the objective Compound 73, tetrahydrofuran-2,3,4,5-tetracarboxylic acid(Arg-Leu-Asp-Ser) 4 (0.28 g, 0.13 mmol) Amino Acid Analysis (nmol/50µl) Arg 3.7352 Leu 3.6256 Asp 3.7157 Ser 3.2917 MS M+H + 2133 Example 26: Synthesis of Compound 74 Citric acid(Arg-Leu-Asp-Ser-NHCH 3 ) 3 Citric acid (0.19 g, 1.0 mmol) and trifluoroacetic acid salt of Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-NHCH 3 (3.19 g, 3.0 mmol) were dissolved in DMF (40 ml) and added with HOBt (0.40 g), DCC (0.62 g, 3.0 mmol) and diisopropylethylamine (0.39 g, 3.0 mmol) with cooling at 0°C. After 2 hours, the mixture was allowed to warm up to room temperature and to react overnight. After the completion of the reaction, urea was removed and DMF was evaporated. The residue was recrystallized from ethyl acetate to obtain the objective compound in the protected form (0.79 g, 0.26 mmol). Hydrogenolysis of this product was carried out in the same manner as used in Example 73 to obtain the objective citric acid(Arg-Leu-Asp-Ser-NHCH 3 ) 3 (0.39 g, 0.24 mmol). Amino Acid Analysis (nmol/50µl) Arg 3.4512 Leu 3.3499 Asp 3.4332 Ser 3.0414 MS (M + H + ) 1645 Example 27: Synthesis of Compound 75 Aconitic acid(β-Ala-Arg-Leu-Asp-Ser-NH-iPr) 3 Trans-aconitic acid (0.17 g, 1.0 mmol) and trifluoroacetic acid salt of β-Ala-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NH-iPr (3.23g, 3.0 mmol) were condensed with CDI in DMF. The product was treated as in Example 73 to obtain the objective compound in the protected form (0.67 g, 0.22 mmol). The protected compound was dissolved in trifluoroacetic acid (10 ml), added with a trifuluoroacetic acid solution of 1M-trifluoromethanesulfonic acid/thioanisole/m-cresol with ice cooling at 0 °C and allowed to react for 1 hour to eliminate the protective group on the side chains and at the terminal of the peptide. The reaction mixture was poured into ether, and resulted oily precipitate was dissolved in distilled water, washed with ethyl acetate, passed through an anion-exchange resin column (Amberlite IRA400; C1 form) to convert the product into hydrochloride and lyophilized to obtain the objective aconitic acid(β-Ala-Arg-Leu-Asp-Ser-NH-iPr) 3 (0.29 g, 0.15 mmol). Amino Acid Analysis (nmol/50µl) β -Ala 3.1009 Arg 3.0881 Leu 2.9975 Asp 3.0720 Ser 2.7214 MS (M + H + ) 1924 Example 28: Synthesis of Compound 76 Iminodiacetic acid-tetracraboxylic acid derivative (β -Ala-Arg-Leu-Asp-Ser) 4 Diethyliminodiacetic acid (1.89 g, 0.010 mol) were dissolved in DMF (30 ml) and added with triethylamine (1.5 g, 0.015 mol) and (Boc) 2 O (2.4 g, 0.011 mol) while stirred with ice cooling. The reaction mixture was stirred for 30 minutes at room temperature, concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and dried. The residue was concentrated and crystallized to obtain Boc-diethyliminodiaceti c acid (2.60 g). Yield: 90%. Boc-dietyliminodiacetic acid (2.60 g) was dissolved in methanol (100 ml), added with 1M NaOH (1.1 eq.) and stirred for 1 hour. After the completion of the reaction, methanol was evaporated and the reaction mixture was added with 10% citric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, concentrated and crystallized to give Boc-iminodiacetic acid (1.86 g). Yield: 89%. Boc-iminodiacetic acid (1.89 g, 0.008 mol) and diethyliminodiacetic acid (3.0 g, 0.016 mol) were condensed with CDI (2.60 g, 0.016 mol) in DMF. After evaporating DMF, the residue was dissolved in ethyl acetate, washed with an aqueous solution of NaHCO 3 and water, dried, concentrated and recrystallized from ethyl acetate/hexane. The resultant was again saponified to give the objective tetracarboxylic acid (2.85 g). Yield: 77%. The obtained tetracarboxylic acid (0.23 g, 0.5 mmol) and trifluoroacetic acid salt of β-Ala-Arg(Mts)-Lell-Asp(OBn)-Ser(Bn)-OBn (2.25 g, 2.0 mmol) were condensed with CDI (0.32 g, 2.0 mmol) in DMF. After evaporating DMF, the residue was crystallized from ethyl acetate to obtain a protective compound (0.67 g, 0.15mmol). The protected compound (0.67 g) was treated with TFA to eliminate the Boc group, dissolved in DMAc (20 ml) and added with triethylamine (40 mg). The mixture was further added with a solution of methacryloyl chloride (21 mg) in DMAc (2 ml) and allowed to react for 1 hour. The reaction mixture was poured into water, and resulted precipitates were recovered, washed with water and then with ether and recrystallized from ethyl acetate to give a methacrylamide derivative (0.53 g, 0.12 mmol). Deprotection of this methacrylamide derivative (0.53 g) was carried out in the same manner as used in Example 75 to obtain methacrylamide of iminodiacetic acid-tetracraboxylic acid derivative(β-Ala-Arg-Leu-Asp-Ser) 4 (0.29 g, 0.11 mmol). This methacrylamide derivative was treated with sodium hydrogensulfite in the same manner as used in Example 24 to obtain the objective compound quantitively (0.29 g, 0.11 mol). Amino Acid Analysis (nmol/50µl) β -Ala 3.6405 Arg 3.7707 Leu 3.7271 Asp 3.8197 Ser 3.3838 MS (M + H + ) 2682 Example 29: Synthesis of Compound 77 Succinylated pantaethylenehexaamine (β-Ala-Arg-Leu-Asp-Ser-NH-iPr) 6 Pentaethylenehexaamine (3.56 g, 0.015 mol) was dissolved in ethanol (80 ml), added with succinic anhydride (20.0 g, 0.20 mol) and a solution of triethylamine (20.0 g) in methanol (20 ml) and allowed to react overnight. After the completion of the reaction, methanol and triethylamine were evaporated under reduced pressure, and the residue was dissolved in water and treated with a cation-exchange resin (Amberlite IRA-120B (H + )). The eluate was lyophilized to obtain succinylated pantaethylenehexaamine (1.04 g, 0.004 mol). Succinylated pentaethylenehexaamine (0.23 g, 1.0 mmol) and trifluoroacetic acid salt of β-Ala-Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NH-iPr (6.45 g, 6.0 mmol) were condensed with CDI in DMF, and the resulted product was treated as in Example 73 to obtain the objective compound in the protected form (1.17 g, 0.18 mmol). Deprotection of the protected compound was carried out in the same manner as used in Example 75 to obtain the objective succinylated pentaethylenehexaamine(β-Ala-Arg-Leu-Asp-Ser-NH-iPr) 6 (0.54 g, 0.13 mmol) Amino Acid Analysis (nmol/50µl) β - Ala 4.8209 Arg 4.6912 Leu 4.5448 Asp 4.4577 Ser 4.1263 MS (M + H + ) 4163 Example 30: Synthesis of Compound 78 Aconitic acid triaspartylamide (Arg-D-Leu-Asp-Ser-NH-cycloC 6 H 11 ) 6 Trans-aconitic acid (1.83 g, 0.0105 mol) and Asp(OBn) 2 (13.5 g) were dissolved in DMF (40 ml), added with DCC (6.60 g, 0.032 mol) and HOBt (4.32 g, 0.032 mol) at 0°C, allowed to react for 2 hours, warmed up to room temperature and allowed to react overnight at room temperature. After removing urea and evaporating DMF under reduced pressure, the residue was crystallized from ethanol/hexane, washed with ether and dried under reduced pressure to give aconitic acid triaspartylamide (8.71 g, 8.2 mmol). This product was dissolved in acetic acid (40 ml) and subjected to hydrogenolysis using palladium/carbon catalyst to obtain hexacarboxylic acid (3.89 g, 7.5 mmol). The hexacarboxylic acid (0.52 g, 1.0 mmol) and trifluoroacetic acid salt of Arg(Mts)-Leu-Asp(OBn)-Ser(Bn)-NH-cycloC 6 H 11 (6.26 g, 6.0 mmol) were condensed with CDI in DMF, and the product was treated as in Example 73 to obtain the objective compound in the protected form (0.91 g, 0.15 mmol). Deprotection of this protected compound was carried out in the same manner as used in Example 75 to obtain the objective Aconitic acid triaspartylamide (Arg-D-Leu-Asp-Ser-NH-cycloC 6 H 11 ) 6 (0.46 g, 0.12 mmol). Amino Acid Analysis (nmol/50µl) Arg 5.2567 Leu 5.1025 Asp 5.2293 Ser 4.6328 MS (M + H + ) 3832 Example 31: Synthesis of Compound 79 (Arg-D-Leu-Asp-Ser-Gly) 4 triethylenetetramide 1. Synthesis of peptide fragment Boc-Arg(Mst)-D-Leu-Asp(OBn)-Ser(Bn)-Gly The above protected peptide was synthesized in a liquid phase by a sequential-extension method. (1) Synthesis of Boc-Gly-ONb Boc-Gly (35 g, 0.2 mol), triethylamine (28 ml, 0.2 mol) and p-nitrobenzyl bromide (43.2 g, 0.2 mol) were dissolved in ethyl acetate (400 ml), refluxed for 5 hours and left overnight at room temperature. The resulted salt was taken by filtration, washed with an aqueous solution of NaHCO 3 and water, dried over sodium sulfate, concentrated under reduced pressure and recrystallized from ethyl acetate/hexane to obtain the objective compound (52.7 g, 0.17 mol). (2) Synthesis of Boc-Ser(Bn)-Gly-ONb Boc-Gly-ONb (46.5 g, 0.15 ml) was added with TFA/CH 2 Cl 2 (1: 1, 400 ml) and stirred for 1 hour at room temperature. After evaporating TFA/CH 2 Cl 2 under reduced pressure, the residue was dissolved in ethyl acetate, neutralized with an aqueous solution of NaHCO 3 , washed with an aqueous solution of NaCl and dried over sodium sulfate. Then the ethyl acetate was evaporated under reduced pressure. This product and Boc-Ser(Bn) (41.7 g, 0.15 mol) were dissolved in CH 2 Cl 2 (750 ml), added with DCC (30.9 g, 0.15 mol), stirred with ice cooling for 3 hours and further stirred at room temperature. After evaporating CH 2 Cl 2 under reduced pressure, the residue was dissolved in ethyl acetate, washed with an aqueous solution of NaHCO 3 , 1M aqueous solution of citric acid and an aqueous solution of NaCl successively and dried over sodium sulfate. Then, the reaction mixture was evaporated to dryness to give white powder (58.4 g, 0.12 mol). The peptide was further elongated sequentially in the same manner as described above. Reagents used, amounts thereof and the like are shown below. (3) Synthesis of Boc-Asp(OBn)-Ser(Bn)-Gly-ONb Product of (2) 58.4 g (0.12 mol) TFA/CH 2 Cl 2 200 ml/200 ml Boc-Asp(OBn) 36.7 g (0.12 mol) CH 2 Cl 2 750 ml DCC 24.7 g (0.12 mol) Yield 67.2 g (0.10 mol) (4) Synthesis of Boc-D-Leu-Asp(OBn)-Ser(Bn)-Gly-ONb Product of (3) 67.2 g (0.10 mol) TFA/CH 2 Cl 2 200 ml/200 ml Boc-D-Leu 21.4 g (0.10 mol) CH 2 Cl 2 750 ml DCC 20.6 g (0.10 mol) Yield 63.6 g (79 mmol) (5) Synthesis of Boc-Arg(Mts)-D-Leu-Asp(OBn)-Ser(Bn)-Gly-ONb Product of (4) 63.6 g (79 mmol) TFA/CH 2 Cl 2 200 ml/200 ml Boc-Arg(Mts) 36.0 g (79 mmol) DMF 800 ml DCC 16.3 g (79 mmol) HOBt 10.8 g (80 mmol) Yield 49.7 g (43 mmol) (6) Synthesis of Boc-Arg(Mts)-D-Leu-Asp(OBn)-Ser(Bn)-Gly The product of (5) (11.44 g, 10 mmol) was dissolved in 90% acetic acid (300 ml), added with Zn powder (32.7 g, 0.5 mol) and stirred for 3 hours at 0 °C. After removing the Zn powder by filtration, the filtrate was concentrated under reduced pressure, made acidic with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated under reduced pressure and added with ether to give white powder (6.86 g, 6.8 mmol). Amino Acid Analysis (nmol/50µl) Arg 2.3055 D-Leu 2.2380 Asp 2.1065 Ser 2.0314 Gly 2.4707 MS (M + H + ) 1010 2. Condensation of Triethylenetetramine and Peptide fragment Boc-Arg(Mts)-D-Leu-Asp(OBn)-Ser(Bn)-Gly (4.04 g, 4.0 mmol) was dissolved in DMF (20 ml), added with DCC (0.83 g, 4.0 mmol) and HOBt (0.54 g, 4.0 mmol) with ice cooling and stirred for 1 hour. The reaction mixture was added with triethylenetetramine (0.14 g, 0.96 mmol) dissolved in DMF (20 ml), stirred for 3 hours with ice cooling and further stirred overnight at room temperature. After removing urea, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the objective compound in the protected form (1.13 g) Deprotection of the protected compound was carried out in the same manner as used in Example 74 to obtain (Arg-D-Leu-Asp-Ser-Gly) 4 triethylenetetramide (0.47 g, 0.21 mmol). Amino Acid Analysis (nmol/50µl) Arg 4.1419 D-Leu 4.0203 Asp 4.1202 Ser 3.6501 Gly 4.2725 MS (M + H + ) 2259 Example 32: Synthesis of Compound 80 Compound 80 was synthesized by following Route 3 below. (a) Synthesis of Arg(Z 2 )-Leu-Asp(OBn)-Ser(OBn 2 ). Compound (le) of Example 1 (7.0 g, 6.2 mmol) dissolved in methylene chloride (30 ml) was added with trifluoroacetic acid (30 ml) and stirred for 1 hour at room temperature. After the completion of the reaction, the solvent was evaporated and the residue was dissolved in chloroform. The chloroform layer was washed with saturated aqueous solution of NaHCO 3 and saturated saline solution successively, dried on anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ether to obtain the Boc-eliminated compound (6.3 g, quantitative). FAB-MS: (M+H) + 1028. (b) Synthesis of Intermediate Compound 2 A mixture comprising 2-(2-N-benzyloxycarbonylaminoethoxy)-ethanol (7.2 g, 30 mmol), silver carbonate (12 g), Drylite (40 g) and dry chloroform not containing alcohol (100 ml) was stirred for 1 hour while shielded from light to eliminate moisture in the mixture. The mixture was added with iodine (4 g), then added with a solution of (2,3,4-tri-O-acetyl-a -D-glucopyranosyl bromide)-uronate methyl ester (8 g, 20 mmol, prepared according to the method of Y.A. Hassan, J. Carbohydrates Nucreosides Nucreotides, 4 , p77 (1977) in chloroform (50 ml) over more than 30 minutes and stirred for 30 hours at room temperature. The reaction mixture was filtered through a Celite layer to eliminate insoluble components, and the Celite layer was washed with chloroform. The filtrate and the washing liquor were combined and washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oily product. This product was purified by silica gel column chromatography (eluent: chloroform) to give 8.9 g of the desired Intermediate Compound 2 as a colorless oil. Yield: 80%, FAB-MS: (M+H) + 556, (M+Na) + 578. (c) Synthesis of Intermediate Compound 3 Intermediate Compound 2 (5.4 g, 9.7 mmol) was dissolved in methanol (100 ml), added with 10% palladium/carbon (300 mg) and stirred for 13 hours at room temperature under hydrogen atmosphere. After the completion of the reaction, the catalyst was removed by filtration thorough a Celite layer and the Celite layer was washed with methanol. The filtrate and the washing liquor were combined and concentrated under reduced pressure to give an amine compound (4.1 g) as a colorless oily product. The amine compound was dissolved in methylene chloride (50 ml), added with triethylamine (1.02 g, 10 mmol), and added with succinic anhydride (980 mg, 9.8 mmol) with ice cooling. After stirring the reaction mixture at room temperature for 1 hour, the reaction was stopped by adding a proper amount of water. The water layer was separated from the organic layer and extracted with chloroform. The combined chloroform was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.0 g of the objective Intermediate Compound 3 quantitatively. FAB-MS: (M+H) + 552. (d) Synthesis of Intermediate Compound 4 Intermediate Compound 3 (1.04 g, 2 mmol) was dissolved in dry DMF (1 ml) and added with a solution of CDI (330 mg, 2 mmol) in dry DMF (10 ml) with ice cooling. The reaction mixture was stirred for 1 hour with ice cooling and added with a solution of the Boc-eliminated compound of (a) (2.06 g, 2 mmol) in DMF (25 ml). The reaction mixture was stirred for 2 hours with ice cooling and further 20 hours while allowed to warm up to room temperature, and then the solvent was evaporated under reduced pressure. The residue was recrystallized from ether to give 2.3 g of the objective Intermediate Compound 4 as colorless powder. Yield: 75%, FAB-MS: (M+H) + 1531. (e) Synthesis of Intermediate Compound 5 Intermediate Compound 4 (1.1 g, 0.7 mmol) was dissolved in acetic acid (30 ml), added with 10% palladium/carbon (100 mg) and stirred for 18 hours at room, temperature under hydrogen atmosphere. The catalyst was removed by filtration through a Celite layer and the Celite layer was washed with acetic acid. The filtrate and the washing liquor were combined and concentrated under reduced pressure. the residue was dissolved in a small amount of water and lyophilized to give 690 mg of Intermediate Compound 5 as colorless powder. Yield: 96.7%, FAB-MS: (M+H) + 993. (f) Synthesis of Compound 80 Intermediate Compound 5 (650 mg, 0.65 mmol) was dissolved in water (20 ml), added with sodium methoxide powder (180 mg, 3. 3 mmol) and stirred for 4 hours at room temperature. After the completion of the reaction, the reaction mixture was neutralized with diluted acetic acid and concentrated under reduced pressure. The residue was dissolved in a small amount of water, purified by gel permeation chromatography using Sephadex G-10 and lyophilized to give 440 mg of Compound 80 as colorless amorphous solid. Yield: 80%, FAB-MS: (M+H) + 854. Example 33: Synthesis of 6-O-carboxymethyl-N-acetylchitooligosaccharide. 6-O-carboxymethylchitin (CM-chitin, carboxymethylation degree: 0.8, deacetylation degree: 0, 6 g) was dissolved in pure water (600 ml) by stirring for a day, added with egg lysozyme (EC 3. 2. 1. 17, 1 g) and shaken for 2 days at 37°C. The reaction mixture was concentrated under reduced pressure and dialyzed against pure water using Spectrapore 6 (MWCO 2000). The outer liquor was lyophilized to give 3 g of 6-O-carboxymethyl-N-acetylchitooligosaccharide mixture. The obtained mixture was fractionated by ion-exchange chromatography (DEAE cellulose) to give 6-O-carboxymethyl-N-acetylchitohexaose (0.35 g), 6-O-carboxymethyl-N-acetylchitopentaose (0.3 g) and 6-O-carboxymethyl-N-acetylchitotetraose (0.3 g) Example 34: Synthesis of Compounds 87 to 91 Compounds 87 to 91 were prepared by using, as starting materials, 4-nitrophenyl-N-acetyl-β-glucosaminide, 4-nitrophenyl-di-N-acetyl-β-chitobiose, 4-nitrophenyl-di-N-acetyl-β-chitotriose, 4-nitrophenyl-a -D-glucopyranoside and 4-nitrophenyl-a -D-maltotrioside, which are commercially available from Seikagaku Kogyo Co.,Ltd. and Boeringer Mannheim & Yamanouchi Co.,Ltd. As the representative examples of the synthesis of Compounds 87 to 91, syntheses of Compounds 87 and 90 are described below. (a) Synthesis of Compound 87 Compound 87 was synthesized by following Route 4 below. 4-nitrophenyl-N-acetyl-β-glucosaminide (3.4 g, 0.01 mol) was added to acetic anhydride (50 ml) and pyridine (100 ml), stirred for 16 hours at room temperature and treated in a conventional manner to give white powder. This was repeatedly precipitated in ether/hexane to give 3.8 g of Intermediate Compound 1. Intermediate Compound 1 (3.0 g, 0.0064mol) was dissolved in ethyl acetate (100 ml) and added with 10% palladium/carbon (0.3 g) and hydrogenolysis was carried out for 6 hours under hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated to give 2.7 g of the objective Intermediate Compound 2 as an amorphous product. Because of unstability of this product, it was used in the next step without purification. Intermediate Compound 2 (2.5 g, 0.0057mol) was dissolved in pyridine (50 ml), added with glutaric anhydride (684 mg, 0.006mol) and catalytic amount of dimethylaminopyridine and warmed for 14 hours in a water bath at 50 °C. After a conventional post-treatment, the resulted residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 30/1) to give 2.1 g of the objective Intermediate Compound 3 as powder. Intermediate Compound 3 (2.0 g, 0.0036 mol) and carbonyldiimidazole (640 mg, 0.004 mol) were dissolved in dry tetrahydrofuran (40 ml) and cooled at 0°C. Boc-eliminated Compound 2 described in Example 2 (4.1 g, 0.004 mol), which has a free amino group, was dissolved in dry DMF (10 ml), cooled and added to the solution of Intermediate Compound 3 dropwise. The reaction mixture was stirred for 16 hours at room temperature and treated in a conventional manner. The resulted residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 20/1) to give 4.8 g of the objective Intermediate Compound 4. Intermediate Compound 4 (2.0 g, 0.0013mol) was dissolved in ethanol (20 ml), added with 1N NaOH aqueous solution (10 ml) and stirred for 8 hours at room temperature. After neutralization with 1N HCl, the solvent was evaporated and the residue was dried intensively. The residue was dissolved in dry DMF (15 ml), added with sulfur trioxide/trimethylamine complex (500 mg, 0.0036 mol) and stirred for 20 hours at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction mixture was added with a proper amount of saturated NaHCO 3 aqueous solution to stop the reaction and neutralized. After evaporating a major part of the solvent, the residue was crystallized with ether, washed with water and dried to give a sulfate ester compound. This product was dissolved in acetic acid (20 ml), added with 10% Pd/C (100 mg) and stirred for 40 hours at room temperature under hydrogen atmosphere. The catalyst was removed by filtration through a Celite layer, the Celite layer was washed with water. The filtrate and the washing water were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of water, purified by gel permeation chromatography using Sephadex G-10 and lyophilized to give 710 mg of Compound 87 as colorless powder. FAB-MS: (M-H) + 998 Compound 88 was prepared in the same manner as described above. FAB-MS data of this compound are shown below. Compound 88 (M-H) - 1387 (b) Synthesis of Compound 90 Compound 90 was prepared by following Route 5 below Commercially available 4-nitrophenyl-α-D-glucopyranoside (20g, 0.066 mol) and dimethoxypropane (24 ml) were dissolved in DMF (400 ml), added with catalytic amount of camphorsulfonic acid and stirred for 16 hours. This reaction mixture was added with acetic anhydride (50 ml) and pyridine (100 ml) and stirred for 24 hours. After removing the excess reagents and the solvent under reduced pressure, the residue was distributed between saturated saline solution and ethyl acetate and repeatedly extracted with ethyl acetate. The organic layer was washed with 5% aqueous hydrochloric acid and saturated saline solution and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane = 1/1) to give 14 g of the objective Intermediate Compound 1. Intermediate Compound 1 (10 g, 0.023 mol) was dissolved in ethyl acetate (400 mi) and added with 10% Pd/C (0.3 g) to carry out hydorogenolysis for 24 hours. Then, the reaction mixture was filtered and the solvent was evaporated from the filtrate to give the objective Intermediate Compound 2 (9.1 g) as an amorphous product. After confirming the absorbance of amino acids by IR spectra (KBr) (υ 3300 - 2950 cm -1 ), Intermediate Compound was used in the next step without purification because of its instability. Intermediate Compound 2 (7.0 g, 0.018 mol) was dissolved in a mixed solvent of chloroform (50 ml) and pyridine (8 ml), added with succinic anhydride (2.2 g, 0.02 mol) and stirred for 2 hours at room temperature. The reaction mixture was treated in a conventional manner, and resulted residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 6:1) to give 5.9 g of the objective Intermediate Compound 3 as a slightly yellow amorphous product. The totally protected t-Boc-Gly-Arg-D-Leu-Asp-Ser was prepared by bonding the Boc-eliminated Compound 2 (1.36 g, 1.32 mmol) obtained by the method described in Example 3 with t-Boc-Gly (0.23 g, 1.32 mmol) by a conventional method (DCC/HOBt method). Intermediate Compound 3 (1.03g, 0.002mol) and carbonyldiimidazole (400 mg, 0.0025 mol) were dissolved in dry tetrahydrofuran (40 ml) and cooled at 0 °C . The above-obtained protected peptide of which t-Boc group had been preliminarily eliminated to have a free amino group (2.0 g, 0.002 mol) were dissolved in dry DMF (10 ml) and added to the solution of Intermediate compound 3 dropwise with cooling. Then, the reaction mixture was stirred for 16 hours at room temperature and treated in a conventional manner. The resulted residue was purified by silica gel column chromatography (eluent: chloroform/methanol = 20/1) to give 1.8 g of the objective Intermediate Compound 4. Intermediate Compound 4 (0.78 g, 0.0005 mol) was added to acetic acid containing 85% water (20 ml) and stirred for 5 hours at room temperature. After the completion of the reaction, the solvent was evaporated under reduced pressure to give 0.73 g of the objective Intermediate Compound 5. The structure of this compound was confirmed by the disappearance of the peaks of methyl groups in the acetonide moiety, δ 1.38 (3H, singlet), 1. 61 (3H, singlet) in 1H-NMR (solvent: CDCl 3 ) and the mass spectra. FAB MS (M+H) + 1523. Intermediate Compound 5 (0.7 g, 0.00046 mol) was dissolved in dry DMF (15 ml), added with sulfur trioxide/trimethylamine complex (417 mg, 0.003 mmol) and stirred for 20 hours at room temperature. After confirming the disappearance of the starting materials by TLC, the reaction mixture was added with a proper amount cf saturated NaHCO 3 aqueous solution to stop the reaction, neutralized, added with 1N NaOH aqueous solution (5 ml) and further stirred for 2 hours. After evaporating a major part of the solvent, the residue was crystallized with ether and the crystals ware washed with water and dried to give a sulfate ester compound. This ester compound was dissolved in acetic acid (20 ml), added with 10% Pd/C (100 mg) and stirred for 40 hours at room temperature under hydrogen atmosphere. The catalyst was removed by filtration through a Celite layer and the Celite layer was washed with water. The filtrate and the washing water were combined and concentrated under reduced pressure. The residue was dissolved in a small amount of water and purified by silica gel permeation chromatography using Sephadex G-10 and lyophilized to give 280 mg of the objective Compound 90 as colorless powder. FAB-MS: (M-H) - 1103 Compound 91 was prepared in the same manner as described above. FAB MS: (M-H) - 1399 Example 35: Synthesis of Compound 94 6-O-carboxymethyl-N-acetylchitohexaose carrying -Asp-Arg-Leu-Asp-Ser 6-O-carboxymethyl-N-acetylchitohexaose (0.5 g) was dissolved in pure water, added with WSC (0.37 g) and stirred for 1 hour. Then, the reaction mixture was added with Asp-Arg-Leu-Asp-Ser (1.0 g) and stirred for a day. After concentrating the reaction mixture under reduced pressure, the residue was washed with ether and purified with an ion-exchange resin, Amberlite IRA-93 and Sephadex G-50 to give 0.6 g of the objective compound. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 0.98 Leu 0.95 Ser 0.78 Example 36: Synthesis of Compound 95 6-O-carboxymethyl-N-acetylchitopantaose carrying -Asp-Arg-D-Leu-Asp-Ser Compound 95 was prepared in the same manner as in Example 35 by using 6-O-carboxymethyl-N-acetylchitopantaose and Asp-Arg-D-Leu-Asp-Ser. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 0.87 D-Leu 0.86 Ser 0.72 Example 38: Synthesis of Compound 97 6-O-carboxymethyl-N-acetylchitotetraose carrying -Asp-Arg-D-Phe-Asp-Ser Compound 97 was prepared in the same manner as in Example 35 by using 6-O-carboxymethyl-N-acetylchitotetraose and Asp-Arg-D-Phe-Asp-Ser. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 1.02 D-Phe 0.99 Ser 0.83 Example 39: Synthesis of 6-O-sulfated-carboxymethyl-N-acetyl-chitooligosaccharide mixture 6-O-sulfated carboxymethylchitin (SCM-chitin, sulfated degree: 0.6, carboxymethylation degree: 0.4, 5.3 g) was prepared according to the method of Tokura et al., Jpn. J. Cancer Res., 80 , p866 (1989). The obtained 6-O-sulfated-carboxymethylchitin (5 g) was dissolved in pure water (500 ml) by stirring for a day, added with egg lysozyme (EC 3. 2. 1. 17, 1 g) and shaken for 2 days at 37°C. The reaction mixture was concentrated under reduced pressure and dialyzed against pure water using Spectrapore 6 (MWCO 2000). The outer liquor was lyophilized to give 3.5 g of 6-O-sulfated-carboxymethyl-N-acetylchitooligosaccharide mixture. Example 40: Synthesis of Compound 98 6-O-sulfated-carboxymethy-N-acetylchitooligosaccharide carrying -Asp-Arg-Leu-Asp-Ser 6-O-sulfated-carboxymethyl-N-acetylchitooligosaccharide (0.5 g) was dissolved in pure water, added with WSC (0.2 g) and stirred for 1 hour. Then, the reaction mixture was added with Asp-Arg-Leu-Asp-Ser (1.0 g) and stirred for a day. After concentrating the reaction mixture under reduced pressure, the residue was washed with ether and purified with an ion-exchange resin, Amberlite IRA-93 and Sephadex G-50 to give 0.3 g of the objective compound. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 0.96 Leu 0.96 Ser 0.81 Example 41: Synthesis of Compound 99 6-O-sulfated-carboxymethyl-N-acetylchitooligosaccharide carrying -Asp-Arg-D-Leu-Asp-Ser Compound 99 was prepared in the same manner as in Example 40 by using Asp-Arg-D-Leu-Asp-Ser. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 0.92 D-Leu 0.95 Ser 0.73 Example 42: Synthesis of Compound 100 6-O-sulfated carboxymethyl-N-acetylchitooligosaccharide carrying -Gly-Arg-Phe-Asp-Ser Compound 99 was prepared in the same manner as in Example 40 by using Gly-Arg-Phe-Asp-Ser. Amino Acid Analysis (nmol/50µl) Gly 1.04 Arg 1.12 Phe 0.94 Asp 1.00 Ser 0.84 Example 43: Synthesis of Compound 101 6-O-sulfated-carboxymethyl-N-acetylchitooligosaccharide carrying -Asp-Arg-D-Phe-Asp-Ser Compound 101 was prepared in the same manner as in Example 40 by using Asp-Arg-D-Phe-Asp-Ser. Amino Acid Analysis (nmol/50µl) Asp 2.00 Arg 1.11 Leu 0.98 Ser 0.69 Example 44: Synthesis of Compound 105 CM-chitin carrying -Arg-Leu-Asp-Ser CM-chitin (Viscosity: 9 cps (1% solution, 20 °C ), etherification degree: 0.78, deacetylation degree: 0.5, available from Yaizu Suisan Kagaku Kogyo Co.,Ltd., 0.30 g) was dissolved in phosphate buffer (pH 7.4), added with a solution of water-soluble DCC (1-ethyl-3-(dimethylaminopropyl)-carbodiimide 128 mg) in phosphate buffer (2.6 ml) while maintained at 0°C and allowed to react for 1.5 hours. Then, the reaction mixture was added with the peptide, Arg-Leu-Asp-Ser (400 mg), dissolved in phosphate buffer (8 ml) and allowed to react overnight at 4 °C . The reaction solution was packed in a Visking tube, purified by dialysis against deionized water and then pure water to eliminate low molecular weight compounds and lyophilized. Yield: 0.24 g. The structure of the product was confirmed by IR and amino acid analysis. Amino Acid Analysis (nmol/50µl) Glucosamine 20.5558 Arg 2.0556 Leu 2.1352 Asp 1.9854 Ser 1.8792 Introduction rate of peptide fragment was determined from the ratio of the concentration of arginine residue to that of glucosamine according to the following relation and found to be about 10%. Introduction rate = [Arg] / [Glucosamine] × 100 IR: Stretching vibration of amidocarbonyl (C=O) 1652 cm -1 Example 45: Synthesis of Compound 106 Succinylated CM-chitin carrying -Gly-Arg-D-Leu-Asp-Ser CM-chitin (20.0 g), the same as used in Example 44, was dissolved in 1% triethylamine solution (100 ml), added with succinic anhydride (34.0 g) and 4-dimethylaminopyridine (2.00 g) and stirred for 24 hours. After the completion of the reaction, the reaction solution was poured into a large excess of acetone to precipitate the succinylated CM-chitin. The recovered precipitates were washed with a large amount of methanol and then with ether and dried in vacuo. Yield: 22.40 g. The succinylated CM-chitin (0.30 g) was dissolved in phosphate buffer (pH 7.4) and added with a solution of water-soluble DCC (1-ethyl-3-(dimethylaminopropyl)-carbodiimide, 128 mg) in phosphate buffer (2.6 ml) while maintained at 0°C and allowed to react for 1.5 hours. Then, the reaction mixture was added with the peptide, Gly-Arg-D-Leu-Asp-Ser (400 mg), dissolved in phosphate buffer (8 ml) and allowed to react overnight at 4 °C . The reaction solution was packed in a Visking tube, purified by dialysis against deionized water and then pure water to eliminate low molecular weight compounds and lyophilized. Yield: 0.26 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 10%. Amino Acid Analysis (nmol/50µl) Glucosamine 23.6218 Arg 2.3622 D-Leu 2.1253 Asp 2.2391 Ser 2.0031 IR Stretching vibration of amidocarbonyl (C=O) 1652 cm -1 Example 46: Synthesis of Compound 107 Maleyl derivative of CM-chitin carrying -Asp-Arg-D-Ile-Asp-Ser-NHCH 3 CM-chitin (20.0 g) and maleic anhydride (36.6 g) were reacted in the same manner as used in Example 45 to obtain maleyl derivative of CM-chitin (21.60 g). The maleyl derivative of CM-chitin was dissolved in phosphate buffer (pH 7.4) and covalently bonded with the peptide fragment in the same manner as used in Example 45. Yield: 0.33 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 11%. Amino Acid Analysis (nmol/50µl) Glucosamine 28.4956 Arg 3.1345 Thr 2.7751 Asp 5.4426 Ser 2.5694 D-Ile 2.6120 IR Stretching vibration of amidocarbonyl (C=O) 1648 cm -1 Example 47: Synthesis of Compound 108 Phthaloyl derivative of CM-chitin carrying -Asp-D-Arg-Nle-Asp-Ser CM-chitin (20.0 g) and phthalic anhydride (50.0 g) were reacted in the same manner as used in Example 45 to obtain phthaloyl derivative of CM-chitin (22.31 g). The phthaloyl derivative of CM-chitin (0.30 g) was dissolved in phosphate buffer (pH 7.4) and covalently bonded with Asp-D-Arg-Nle-Asp-Ser in the same manner as used in Example 45. Yield: 0.44 g. The structure of the product was confirmed by IR and amino acid analysis. By amino acid analysis, the introduction rate of the peptide fragment was found to be about 12%. Amino Acid Analysis (nmol/50µl) Glucosamine 19.1856 D-Arg 1.1023 Nle 1.2231 Asp 1.0937 Ser 1.0632 IR Stretching vibration of amidocarbonyl (C=O) 1652 cm -1 Example 48: Synthesis of Compound 109 Itaconyl derivative of CM-chitin carrying -Arg-Leu-Asp-Ser CM-chitin (20.0 g) and Itaconic anhydride (38.0 g) were reacted in the same manner as used in Example 45 to obtain Itaconyl derivative of CM-chitin (21.45 g). The Itaconyl derivative of CM-chitin (0.30 g) was dissolved in phosphate buffer (pH 7.4) and covalently bonded with Arg-Leu-Asp-Ser in the same manner as used in Example 45. Yield: 0. 36 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 9%. Amino Acid Analysis (nmol/50µl) Glucosamine 35.2316 Arg 3.1708 Leu 3.2511 Asp 3.1005 Ser 2.8862 IR Stretching vibration of amidocarbonyl (C=O) 1650 cm -1 Example 49: Synthesis of Compound 110 CM-chitin carrying -Gly-Arg-D-Phe-Asp-Ser-Pro Compound 110 was prepared in the same manner as in Example 44 by using Gly-Arg-D-Phe-Asp-Ser-Pro (460 mg) as the peptide fragment. Yield: 0.36 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 10%. Amino Acid Analysis (nmol/50µl) Glucosamine 15.3319 Arg 1.5332 Gly 1.4132 Asp 1.3468 Ser 1.1132 Pro 1.3078 D-Phe 1.5810 IR Stretching vibration of amidocarbonyl (C=O) 1654 cm -1 Example 50: Synthesis of Compound 111 CM-chitin carrying -Gly-Asp-D-Phg-Asp-Thr-NH 2 Compound 111 was prepared in the same manner as in Example 44 by using Gly-Asp-D-Phg-Asp-Thr-NH 2 (460 mg) as the peptide fragment. Yield: 0.36 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 10%. Amino Acid Analysis (nmol/50µl) Glucosamine 17.6368 Arg 1.8166 Gly 1.8243 Asp 3.7468 Ser 1.6112 D-Phg 1.7134 IR Stretching vibration of amidocarbonyl (C=O) 1658 cm -1 Example 51: Synthesis of Compound 112 Succinylated CM-chitin carrying -(Arg-D-Leu-Asp-Ser) 2 Compound 112 was prepared in the same manner as in Example 45 by using (Arg-D-Leu-Asp-Ser) 2 (460 mg) as the peptide fragment. Yield: 0.31 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 12%. Amino Acid Analysis (nmol/50µl) Glucosamine 25.1913 Arg 6.0459 D-Leu 5.9883 Asp 5.8996 Ser 5.7398 IR Stretching vibration of amidocarbonyl (C=O) 1654 cm -1 Example 52: Synthesis of Compound 113 Sulfated CM-chitin carrying -Gly-Arg-Nle-Asp-Ser-NHCH 3 CM-chitin (etherification degree: 0.50, deacetylation degree: 0.05) was sulfated according to the method of Tokura et al., Jpn. J. Cancer Res., 80, p866-872 (1989) and Cancer Res., 50 , p3631-3637 (1990) and covalently bonded to Gly-Arg-Nle-Asp-Ser-NHCH 3 fragment in the same manner as used in Example 44. Yield: 0.36 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 12%. Amino Acid Analysis (nmol/50µl) Glucosamine 33.1569 Arg 3.9780 Gly 3.9251 Asp 3.6053 Ser 3.4921 Nle 3.5548 IR Stretching vibration of amidocarbonyl (C=O) 1650 cm -1 Example 53: Synthesis of Compound 114 Sulfated CM-chitin carrying -Gly-D-Arg-Leu-Asp-Ser The peptide fragment Gly-D-Arg-Leu-Asp-Ser (460 mg) and the sulfated CM-chitin as described in Example 52 were covalently bonded in the same manner as used in Example 44 to give Compound 114. Yield: 0.35 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 10%. Amino Acid Analysis (nmol/50µl) Glucosamine 25.1515 D-Arg 2.5152 Gly 2.4134 Asp 2.4251 Ser 2.1111 Leu 2.5631 IR Stretching vibration of amidocarbonyl (C=O) 1655 cm -1 Example 55: Synthesis of Compound 116 Sulfated succinylated CM-chitin carrying -Arg-D-Leu-Asp-Ser-Pro-NHC 2 H 5 Succinylated CM-chitin was sulfated in the same manner as used in Example 52 and covalently bonded with the peptide fragment Arg-D-Leu-Asp-Ser-Pro-NHC 2 H 5 to give Compound 116. Yield: 0.37 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 14%. Amino Acid Analysis (nmol/50µl) Glucosamine 18.6932 Arg 2.6170 D-Leu 2.7739 Asp 2.5931 Ser 2.2168 Pro 2.2916 IR Stretching vibration of amidocarbonyl (C=O) 1654 cm -1 Example 56: Synthesis of Compound 117 Chondroitin sulfate carrying -Gly-D-Arg-Leu-Asp-Ser-NH-isoC 3 H 7 Chondroitin sulfate (viscosity: 9 cps (1% solution, 20°C ), etherification degree: 0.78, available from Yaizu Suisan Kagaku Kogyo Co.,Ltd., 0.30 g) was dissolved in phosphate buffer (pH 7 4), added with a solution of 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (128 mg) in phosphate buffer (2.6 ml) and allowed to react 1.5 hours. Then, the reaction mixture was added with the peptide Gly-D-Arg-Leu-Asp-Ser-NHisoC 3 H 7 (400 mg) dissolved in phosphate buffer (8 ml) and allowed to react overnight at 4 °C . The reaction solution was packed in a Visking tube, purified by dialysis against deionized water and then pure water to eliminate low molecular weight compounds and lyophilized. Yield: 0.24 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 10%. Amino Acid Analysis (nmol/50µl) Glucosamine 20.5558 D-Arg 2.0556 Gly 2.1352 Asp 1.9854 Ser 1.8792 Leu 1.9790 IR Stretching vibration of amidocarbonyl (C=O) 1652 cm -1 Example 58: Synthesis of Compound 119 Maleyl derivative of chondroitin sulfate carrying -Arg-D-Leu-Asp-Ser Chondroitin sulfate (20.00 g) the same as used in Example 56 was reacted with maleic anhydride (36.6 g) in the same manner as used in Example 57 to obtain maleyl derivative of chondroitin sulfate (21.60 g). This maleyl derivative of chondroitin sulfate (0.30 g) was dissolved in phosphate buffer (pH 7.4) and covalently bonded with the peptide fragment, Arg-D-Leu-Asp-Ser, in the same manner as used in Example 45. Yield: 0. 33 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 11%. Amino Acid Analysis (nmol/50µl) Glucosamine 28.4956 Arg 3.1345 D-Leu 2.7751 Asp 2.7213 Ser 2.5694 IR Stretching vibration of amidocarbonyl (C=O) 1648 cm -1 Example 59: Synthesis of Compound 120 Trimellityl derivative of chondroitin sulfate carrying -Glu-Arg-Phg-Asp-Ser Chondroitin sulfate (20.00 g) the same as used in Example 56 was reacted with trimellitic anhydride (64.9 g) in the same manner as used in Example 57 to obtain trimellityl derivative of chondroitin sulfate (23.74 g). This trimellityl derivative of chondroitin sulfate (0.30 g) was dissolved in phosphate buffer (pH 7.4) and covalently bonded with the peptide fragment, Glu-Arg-Phg-Asp-Ser, in the same manner as used in Example 45. Yield: 0.37 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 14%. Amino Acid Analysis (nmol/50µl) Glucosamine 18.7612 Arg 2.6266 Glu 2.7899 Asp 2.5532 Ser 2.2689 Phg 2.2449 IR Stretching vibration of amidocarbonyl (C=O) 1656 cm -1 Example 60: Synthesis of Compound 121 Succinyl derivative of chondroitin sulfate carrying -(Arg-D-Leu-Asp-Ser) 2 By using (Arg-D-Leu-Asp-Ser) 2 (460 mg) as the peptide fragment, Compound 121 was prepared in the same manner as used in Example 57. Yield: 0.31 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 12%. Amino Acid Analysis (nmol/50µl) Glucosamine 25.1913 Arg 6.0459 D-Leu 5.9883 Asp 5.8996 Ser 5.8798 IR Stretching vibration of amidocarbonyl (C=O) 1654 cm -1 Example 61: Synthesis of Compound 122 Succinyl derivative of chondroitin sulfate carrying -(Arg-D-Leu-Asp-Ser) 5 By using (Arg-D-Leu-Asp-Ser) 5 (460 mg) as the peptide fragment, Compound 122 was prepared in the same manner as used in Example 57. Yield: 0.28 g. The structure of the product was confirmed by IR and amino acid analysis. By the amino acid analysis, the introduction rate of the peptide fragment was found to be about 15%. Amino Acid Analysis (nmol/50µl) Glucosamine 23.6811 Arg 23.0108 D-Leu 21.0993 Asp 20.3332 Ser 21.0728 IR Stretching vibration of amidocarbonyl (C=O) 1656 cm -1 Example 62: Synthesis of Compound 123 Cyanurate derivative of polyethylene glycol (Arg-Leu-Asp-Ser) 2 Compound 123 was prepared by following Route 6 below. (1) Synthesis of cyanurate derivative of polyethylene glycol (Cyanurate PEG 1 ) Polyethylene glycol monomethyl ether having an average molecular weight of 5000 (10 g, 2 mmol) was sufficiently dried, added with toluene (100 ml), sodium carbonate (5 g) and cyanuric chloride (1.1 g, 6 mmol) and stirred at 80 °C for 120 hours. After allowing the reaction solution to cool down to room temperature, the solution was filtered and the filtrate was added with hexane to be crystallized. The crystals were further purified by recrystallization from a solvent system of toluene/acetone/hexane to give white powder of Cyanyrate PEG 1 (7 g). (2) Synthesis of Cyanurate PEG 1 (Arg-Leu-Asp-Ser) 2 Boc-Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-OBn (1.14 g, 1 mmol) was dissolved in methylene chloride (10 ml), added with trifluoroacetic acid (10 ml) and stirred for 30 minutes at room temperature. After evaporating the solvent under reduced pressure, the residue was added with chloroform (100 ml), washed several times with 1N NaHCO 3 aqueous solution (100 ml) and saturated saline solution (100 ml) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give white powder. This white powder was mixed with Cyanurate PEG 1 (2.5 g), triethylamine (0.1 g) and chloroform (50 ml) and stirred for 24 hours at room temperature. Then, the mixture was purified by gel filtration (Sephadex LH-60 ) to give 3.1 g of Cyanurate PEG 1 (Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-OBn) 2 . This protected peptide derivative (3.1 g) was dissolved in acetic acid (50 ml) and added with 10% Pd/C (1.0 g) and hydrogenolysis was carried out for 24 hours at room temperature under hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtration through a Celite layer and evaporating the solvent under reduced pressure, the residue was purified by gel filtration (Sephadex LH-60) to give 2.5 g of Cyanurate PEG 1 (Arg-Leu-Asp-Ser) 2 . Amino Acid Analysis (nmol/50µl) Arg 1.0326 Leu 0.9574 Asp 0.9811 Ser 0.9209 Number Average Molecular Weight 6000 Example 63: Synthesis of Compound 124 Cyanurate derivative of polyethylene glycol-(Arg-D-Leu-Asp-Ser) Compound 124 was prepared by following Route 7 below. Boc-Arg(z 2 )-D-Leu-Asp(OBn)-Ser(Bn)-OBn (1.14 g, 1 mmol) was dissolved in methylene chloride (10 ml), added with trifluoroacetic acid (10 ml) and stirred for 30 minutes at room temperature. After evaporating the solvent under reduced pressure, the residue was added with chloroform (100 ml), washed several times with 1N NaHCO 3 aqueous solution (100 ml) and saturated saline solution (100 ml) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give white powder. This white powder was mixed with cyanurate derivative of polyethylene glycol (Cyanurate PEG 2 , available from Seikagaku Kogyo Co.,Ltd., 1.25 g), triethylamine (0.1 g) and chloroform (50 ml) and stirred for 24 hours at room temperature. Then, the mixture was purified by gel filtration (Sephadex LH-60) to give 1.79 g of Cyanurate PEG 2 -(Arg(Z 2 )-D-Leu-Asp(OBn)-Ser(Bn)-OBn). This protected peptide derivative (1.79 g) was dissolved in acetic acid (50 ml) and added with 10% Pd/C (1.0 g) and hydrogenolysis was carried out for 24 hours at room temperature under hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtration through a Celite layer and evaporating the solvent under reduced pressure, the residue was purified by gel filtration (Sephadex LH-60) to give 1.34 g of Cyanurate PEG 2 -(Arg-D-Leu-Asp-Ser). Amino Acid Analysis (nmol/50µl) Arg 1.1408 D-Leu 0.9357 Asp 0.9412 Ser 0.9166 Number Average Molecular Weight 10000 Example 64: Synthesis of Compound 125 Polyethylene oxide carboxylic acid derivative carrying -Gly-Arg-Leu-Asp-Ser Boc-Gly-Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-OBn (0.63 g, 0.5 mmol) was dissolved in methylene chloride (10 ml), added with trifluoroacetic acid (10 ml) and stirred for 30 minutes at room temperature. After evaporating the solvent under reduced pressure, the residue was added with chloroform (100 ml), washed several times with 1N NaHCO 3 aqueous solution (100 ml) and saturated saline solution (100 ml) and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure to give white powder. This white powder was mixed with polyethylene oxide carboxylic acid derivative (PEO Acid #4000, available from Kawaken Fine Chemicals Co.,Ltd., 1.0 g), dicyclohexylcarbodiimide (0.12 g, 0.55 mmol) and chloroform (50 ml) and stirred for 24 hours at room temperature. Then, the mixture was purified by gel filtration (Sephadex LH-20, eluent: chloroform/methanol = 9/1) to eliminate peptide fragments which were not bonded to the polyethylene glycol derivative. The introduction rate of the peptide fragment to the carboxyl group in the product was determined from the ratio of the intensities of the methylene proton and the aromatic proton in 1 H NMR and found to be about 65 %. This protected-peptide-introduced polyethylene glycol derivative (1 g) was dissolved in ethanol (100 ml) and water (10 ml) and added with 10% Pd/C (1.0 g) and hydrogenolysis was carried out for 24 hours at room temperature under hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtration through a Celite layer and evaporating the solvent under reduced pressure, the residue was subjected to gel filtration (Sephadex LH-20, eluent: ethanol) to remove the released protective groups and purified by ion-exchange chromatography (DEAE-Sephadex A-25) to give 250 mg of carboxyl derivative of polyethylene glycol-(Gly-Arg-Leu-Asp-Ser). Amino Acid Analysis (nmol/50µl) Gly 1.0151 Arg 1.0045 Leu 0.9897 Asp 0.9564 Ser 0.9106 Number Average Molecular Weight 4900 Example 65: Synthesis of Compound 126 Polyethylene oxide carboxylic acid derivative carrying -Gly-Arg-Leu-Asp-Ser-Pro-NH 2 Protected peptide, Boc-Gly-Arg(Z 2 )-Leu-Asp(OBn)-Ser(Bn)-Pro-NH 2 was prepared by starting with Boc-Pro-NH 2 and sequentially extending each of corresponding amino acids at the N-terminal of the peptide. In the same manner as used in Example 64, PEO Acid #4000 (1.0 g) and the protected peptide (0. 6 g, 0.50 mmol) were condensed and subjected to hydrogenolysis to give 310 mg of the objective carboxyl derivative of polyethylene glycol-(Gly-Arg-Leu-Asp-Ser-Pro-NH 2 ) Amino Acid Analysis (nmol/50µl) Gly 0.9841 Arg 1.0193 Leu 0.9417 Asp 0.9924 Ser 0.8846 Pro 0.9511 Number Average Molecular Weight 5200 Pharmacological Test: Experimental tumor metastasis in lungs, liver and spleen The tumor metastasis inhibitory activities of the peptide derivatives of the present invention were examined as follows. Each of the following peptide derivatives according to the present invention, Compounds 1 to 13, 15, 19 to 22, 25, 32, 36, 37, 44, 47, 50, 56-1, 56-4, 59, 65, 68, 70, 73, 76, 77, 80, 84, 87, 89, 90, 94, 96, 99, 101, 103, 106, 112, 114, 118 and 121 was mixed with B16-BL6 melanoma cells having a potent metastatic tendency in PBS so that 0.2 ml of the mixture contained 3000, 1000 or 500 µg of the peptide derivative and 5 × 10 4 of B16-BL6 melanoma cells. Then, 0.2 ml of each mixture was intravenously administered to each individual of a group of C57BL/6 female mice consisting of 5 mice. Fourteen days after the administration, the number of melanoma cell colony in lungs was determined and compared with that of the control mice, which were administered with PBS. The results are shown in Table 4 below. Separately, each of the following peptide derivatives of the present invention, Compound 1, 2, 8, 12, 20, 47, 56, 59, 67, 73 and 85, was mixed with L5178Y ML25 T-lymphoma cells in PBS so that 0.2 ml of the mixture contained 3000 or 1000 µg of the peptide derivative and 4 × 10 4 of the T-lymphoma cells. Then, 0.2 ml of each mixture was intravenously administered to each individual of a group of CDF 1 (BALB/c× DBA/2) female mice consisting of 5 mice. Fourteen days after the administration, the weights of the livers and the spleens of the mice were determined and compared with those of the control mice. The results are shown in Table 5 below. For comparison, the peptide fragments known to have tumor metastasis inhibition activity, Arg-Gly-Asp-Ser (Comparison A), Gly-Arg-Gly-Asp-Ser (Comparison B) and (Arg-Gly-Asp)n (n=5) as well as Reference Polymer A were also administered to the mice in the same manner as above. As seen from the results shown in Tables 4 and 5, the peptide derivatives according to the invention more effectively inhibited the metastases of the tumor cells to the lungs as compared with the conventional adhesive peptide sequences. This clearly shows that the peptide derivatives of the present invention have higher tumor metastasis inhibitory activity than the conventional peptide compounds. In particular, the peptide derivatives of the present invention comprising the peptide sequences modified with the organic groups show high inhibitory activity with a small administration dose, and it means that the enhancement of the activity by the modification with organic groups, which is one of the important object of the present invention, has been successfully achieved. Further, it was also found that the peptide derivatives of the present invention can exhibit high tumor metastasis inhibitory activity even though the derivatives were administered 5 minutes after the administration of B16-BL6 cells without mixing the derivatives and tumor cells (Table 4, Experiment 2, Compounds 20 and 22). This means that the peptide derivatives of the present invention can exhibit the tumor metastasis inhibitory effect in patients having cancer, when the derivatives are administered to the patients by a proper way such as intravenous injection. Inhibitory Effect on Experimental Melanoma Metastasis in Lungs Caused by Injection of B16-BL6 Melanoma Cell Compound Dose (µg) Number of Colony Average ± SD (Range) Experiment 1 Control(PBS) --- 116 ± 27 (84 - 160) 1 3000 35 ± 3 (30 - 36) 2 3000 41 ± 8 (29 - 49) 3 3000 39 ± 18 (23 - 58) 4 3000 35 ± 11 (23 - 47) 5 3000 51 ± 6 (44 - 57) 7 3000 25 ± 6 (17 - 32) 8 3000 37 ± 9 (28 - 43) 9 3000 22 ± 10 (11 - 29) 11 3000 19 ± 10 (9 - 31) 12 3000 23 ± 4 (18 - 26) 13 3000 42 ± 8 (35 - 51) 15 3000 43 ± 12 (19 - 57) Comparison A 3000 70 ± 8 (59 - 78) Comparison B 3000 50 ± 10 (35 - 63) Comparison C 1000 40 ± 15 (26 - 59) Experiment 2 Control (PBS) --- 84 ± 11 (48 - 85) 19 1000 21 ± 8 (12 - 24) 20 1000 20 ± 9 (18 - 27) 21 1000 16 ± 13 (2 - 33) 22 1000 19 ± 8 (13 - 29) 25 1000 30 ± 6 (23 - 38) 32 1000 24 ± 5 (18 - 30) Comparison A 1000 62 ± 9 (54 - 73) Comparison B 1000 40 ± 10 (29 - 51) Comparison C 1000 23 ± 9 (13 - 29) Experiment 3 Control (PBS) --- 145 ± 30 (114 - 180) 36 500 46 ± 6 (39 - 57) 37 500 27 ± 11 (13 - 39) 44 500 66 ± 15 (49 - 79) Comparison A 3000 92 ± 14 (76 - 129) Comparison B 1000 89 ± 18 (71 - 98) Comparison C 500 68 ± 9 (58 - 79) Experiment 4 Control (PBS) --- 116 ± 19 (98 - 142) 73 500 38 ± 7 (30 - 44) 76 500 48 ± 5 (42 - 52) 77 500 41 ± 6 (34 - 48) 56-1 500 11 ± 10 (0 - 21) 56-4 500 19 ± 5 (13 - 23) 59 500 32 ± 9 (23 - 43) Reference Polymer A 1000 98 ± 26 (68 - 126) Comparison A 3000 74 ± 11 (66 - 87) Comparison B 1000 78 ± 8 (69 - 88) Experiment 5 Control (PBS) --- 91 ± 33 (65 - 136) 47 1000 25 ± 4 (20 - 28) 50 1000 19 ± 10 (4 - 30) 65 1000 10 ± 4 (4 - 14) 68 1000 16 ± 5 (10 - 23) 70 1000 23 ± 5 (14 - 30) Comparison A 3000 60 ± 4 (55 - 67) Comparison B 1000 49 ± 7 (33 - 56) Comparison C 1000 39 ± 11 (18 - 55) Experiment 6 Control (PBS) --- 128 ± 24 (100 - 156) 80 500 36 ± 7 (27 - 44) 84 500 13 ± 6 (5 - 20) 87 500 20 ± 9 (9 - 28) 90 500 44 ± 9 (32 - 51) Comparison A 3000 88 ± 20 (65 - 112) Comparison B 1000 76 ± 6 (65 - 87) Comparison C 500 57 ± 12 (44 - 71) Experiment 7 Control (PBS) --- 85 ± 20 (64 - 107) 94 500 14 ± 3 (8 - 16) 99 500 3 ± 3 (0 - 6) 101 500 13 ± 6 (2 - 22) 106 500 1 ± 1 (0 - 3) 112 500 14 ± 7 (6 - 23) 114 500 21 ± 11 (10 - 33) 118 500 43 ± 8 (33 - 49) 121 500 45 ± 11 (33 - 59) Comparison A 3000 51 ± 6 (45 - 59) Comparison B 1000 50 ± 8 (40 - 56) Comparison C 500 44 ± 16 (28 - 63) Inhibitory Effect on Experimental T-lymphoma Metastasis in Liver and Spleen Caused by Injection of L5178Y ML25 T-lymphoma cell Compound Dose (µg) Weight(g): Average± SD (Range) Liver Spleen Control (PBS) --- 4.21 ± 0.49 0.28 ± 0.03 1 3000 1.29 ± 0.32 0.10 ± 0.02 2 3000 2.01 ± 0.20 0.11 ± 0.02 8 3000 1.92 ± 0.20 0.11 ± 0.02 12 3000 2.67 ± 0.78 0.17 ± 0.05 20 1000 2.66 ± 0.67 0.16 ± 0.06 47 1000 2.28 ± 0.54 0.14 ± 0.04 56 1000 1.88 ± 0.28 0.13 ± 0.03 59 1000 1.80 ± 0.77 0.14 ± 0.04 67 1000 1.62 ± 0.52 0.12 ± 0.02 73 1000 1.95 ± 1.00 0.15 ± 0.05 85 1000 1.11 ± 0.09 0.10 ± 0.02 Comparison A 1000 3.67 ± 1.04 0.22 ± 0.03 Comparison B 1000 2.24 ± 0.46 0.17 ± 0.03 Reference 1.09 ± 0.11 0.08 ± 0 Toxicity In the above in vivo tests, it was confirmed that the peptide derivatives of the present invention have no cytotoxicity against the erythrocyte cells, the spleen cells and the thymus cells of the host mice and no undesirable serum protein coagulation activity. As described above, the peptide derivatives of the present invention have higher tumor metastasis inhibitory activities as compared with the core sequences of the cell adhesive proteins and suffer almost no problem of toxicity. The structures of the compounds are rather simple and, therefore, the peptide derivatives of the present invention are extremely valuable as pharmaceutical drugs.

Claims: A peptide derivative containing 1 to 20 units of the peptide unit represented by the following general formula [I] or a pharmaceutically acceptable salt thereof; [Z]-Arg-X-Asp-[Y] wherein Arg represents L- or D-arginine residue, Asp represents L-aspartic acid residue, X represents L- or D-leucine, D-isoleucine, L- or D-norleucine, D-phenylalanine or D-phenylglycine residue, and [Z] and [Y] each represents an amino acid or a peptide residue, which may be present or absent, selected from glycine, L-serine, L-threonine, L- and D-aspartic acid, L-alanine, L- and D-glutamic acid, L-proline residues and a peptide residue constituted by the foregoing amino acid residues. The peptide derivative of claim 1 which has an average molecular weight of from 1,000 to 100,000. The peptide derivative of claim 1 which is an oligopeptide or polypeptide composed of one or more of the peptide sequences of the formula [I] or pharmaceutically acceptable salts thereof, of which carboxyl terminal may be amidated. The peptide derivative of claim 3 which comprises 2 to 20 units of the peptide sequence of the formula [I] or pharmaceutically acceptable salt thereof. The peptide derivative of claim 1 which is a compound consisting of one or more of the peptide units represented by the general formula (I) and one or more of pharmaceutically acceptable organic groups bonded to the units selected from substituted and unsubstituted acyl, alkyl, alkylamino groups, which groups preferably have 1 to 15 carbon atoms and may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond, and groups derived from monosaccharides, oligosaccharides, preferably containing 2 to 7 monosaccharide units, polysaccharide derivatives, polycarboxylic acids, preferably having 2 to 12 carboxyl groups, polyamines, preferably having 2 to 12 amino groups, polymers formed from monomers having an ethylenically unsaturated bond such as acrylic acid, methacrylic acid, ethacrylic acid and allylamine, polyethylene glycol, preferably having an average molecular weight of 2,000 to 10,000 and carboxylic acid derivative of polyethylene oxide (PEO Acid). The peptide derivative of claim 5 wherein the organic group is selected from; i) acyl, alkyl and alkylamino groups, which groups may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond, and ii) groups derived from monosaccharides, oligosaccharides, polysaccharaide derivatives, polycarboxylic acids, polyamines, polymers formed from monomers having an ethylenically unsaturated bond, polyethylene glycol, and carboxylic acid derivative of polyethylene oxide, which groups may be bonded to the peptide sequences through an alkylene group or an arylene group, which alkylene and arlylene groups may contain -O-, -NH-, -S-, ester bond, amide bond, urethane bond or urea bond. The peptide derivative of claim 6 wherein the organic group is bonded to the peptide sequences at the amino terminals of the peptide sequences and the carboxyl terminals of the peptide sequences are represented by -OR a or -NR b R c , where each of R a , R b and R c represents a hydrogen atom or a linear or cyclic alkyl group and R b and R c may be bonded together to form a ring structure. The peptide derivative of claim 6 wherein the organic group is bonded to the peptide sequences at the carboxyl terminals of the peptide sequences and the amino terminals have a hydrogen atom or substituted or unsubstituted acyl group. The peptide derivative of claim 6 which is a polypeptide comprising 2 to 20 units of the peptide sequence of the formula [I] or pharmaceutically acceptable salt thereof, the amino terminal of the polypeptide having a substituted or unsubstituted acyl group and the carboxyl terminal of the polypeptide having a substituted or unsubstituted linear or cyclic alkylamino group. The peptide derivative of claim 6 comprising 1 to 5 units of the peptide sequence of the formula [I] or pharmaceutically acceptable salt thereof and the organic group being selected from those derived form polycarboxylic acids or polyamines. The peptide derivative of claim 6 comprising 1 to 10 units of the peptide sequence of the formula [I] or pharmaceutically acceptable salt thereof and the organic group being selected from those derived from polyethylene glycol. The peptide derivative of claim 6 comprising 1 to 10 units of the peptide sequence of the formula [I] or pharmaceutically acceptable salt thereof and the organic group being selected from those derived from monosaccharides, oligosaccharides and polysaccharide derivates. A pharmaceutical composition comprising one or more compounds defined in any of claims 1 to 12.

Inventors: AZUMA ICHIRO, KITAGUCHI HIROSHI, KOJIMA MASAYOSHI, KOMAZAWA HIROYUKI, MORI HIDETO, NISHIKAWA NAOYUKI, ONO MITSUNORI, ORIKASA ATSUSHI, SAIKI IKUO, SATOH HIDEAKI, AZUMA, ICHIRO, KITAGUCHI, HIROSHI, KOJIMA, MASAYOSHI, KOMAZAWA, HIROYUKI, MORI, HIDETO, NISHIKAWA, NAOYUKI, ONO, MITSUNORI, ORIKASA, ATSUSHI, SAIKI, IKUO, SATOH, HIDEAKI, AZUMA, ICHIRO, 3-2,MAKOMANAIKAMIMACI 5-CHOME,, Kitaguchi, Hiroshi, c/o Fuji Photo Film Co., Ltd., Kojima, Masayoshi, c/o Fuji Photo Film Co., Ltd., Komazawa, Hiroyuki, c/o Fuji Photo Film Co., Ltd., Mori, Hideto, c/o Fuji Photo Film Co., Ltd., Nishikawa, Naoyuki, c/o Fuji Photo Film Co., Ltd., Ono, Mitsunori, c/o Fuji Photo Film Co., Ltd., Orikasa, Atsushi, c/o Fuji Photo Film Co., Ltd., SAIKI, IKUO, 12-6, NISHI 5-CHOME,, Satoh, Hideaki, c/o Fuji Photo Film Co., Ltd.
Applicants: FUJI PHOTO FILM CO LTD, FUJI PHOTO FILM CO., LTD.
Application year: 1992
Main classification: C07K5
IPC codes: A61K38, C07K14, A61K47, C08F289, C08G69, C07K5, C07K7, A61P35, C07K9, C07K17