Prolineamide derivatives

Abstract: A prolineamide derivative represented by the formula (I): or a salt or hydrate thereof or a pharmaceutically acceptable salt thereof, which has a protease inhibition activity and is usuful as an active ingredient of pharmaceutical compositions is provided.

Description: FIELD OF THE INVENTION The present invention relates to novel proline derivatives. More particularly, it relates to proline derivatives having a protease inhibition activity or pharmaceutically acceptable salts thereof and protease inhibitors containing the same as an active ingredient. BACKGROUND OF THE INVENTION It has been known that various proteases are present in the living body, for example, a group of serine proteases such as thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, kallikrein, C3/C5 convertase in the complement system, tryptase, etc. is known. Further, it is also known that these proteases cause various diseases when they are activated abnormally by some reason. Accordingly, substances which inhibit the activity of these proteases are useful as a clinical remedy. For example, antithrombin agents, anti-factor Xa agents and anti-factor VIIa agents are useful for treating thrombosis, antitrypsin agents are useful for treating pancreatitis, antiplasmin agents are useful as hemostatics, antiallergic agents and antiinflammatory agents, antikallikrein agents are useful as a remedy for inflammation and ulcer, and anticomplementary agents are useful as a remedy for nephritis and rheumatoid arthritis. Protease inhibitors having these actions have hitherto been developed, but they are not necessarily sufficient for practical use in view of protease inhibition activity, stability in the living body and the like. For example, tripeptide derivatives consist of arginine derivatives are known as protease inhibitors. That is, D-phenylalanyl-L-prolyl-L-arginal is known as a thrombin inhibitor (e.g. Folia Haematol., 109 , 22 (1982)) but is fairly unstable in the living body (J. Med. Chem., 33 , 1729 (1990)). Further, arginal derivatives (Japanese Laid-open Patent Publication No. 4-89498) or amidinophenylalanine derivatives (Thromb. Res., 17 , 425 (1980)) are reported as protease inhibitors but their inhibition activity is low. Under these circumstances, the present inventors have studied to develop structurally novel drugs having enzyme inhibition activity and stability in vivo, which are sufficient for practical use. As a result, it has been found that certain prolineamide derivatives can attain the desired object, thus the present invention has been established. SUMMARY OF THE INVENTION That is, the present invention provides a prolineamide derivative represented by the formula (I): wherein A is a carbon atom or a nitrogen atom; n is an integer of 0 to 2; a broken line is absent or a single bond; R 1 is {wherein D and E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group, -OR 6 (R 6 is a hydrogen atom, a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -SR 7 (R 7 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -SOR 8 (R 8 is an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -SO 2 R 9 (R 9 is an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -COR 10 (R 10 is a hydroxyl group, a C 1 -C 6 alkoxy group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -NHR 11 (R 11 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -NHCOR 12 (R 12 is a C 1 -C 6 alkoxy group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyloxy group), -NHSO 2 R 13 (R 13 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted 5- to 10-membered heterocyclic group), an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group, an optionally substituted 5- to 10-membered heterocyclic group or -SiR 14 R 15 R 16 (R 14 , R 15 , and R 16 independently indicate a C 1 -C 6 alkyl group); R 5 is a -OR 17 (R 17 is a hydrogen atom, -SiR 22 R 23 R 24 (R 22 , R 23 , and R 24 independently indicate a C 1 -C 6 alkyl group), a C 1 -C 6 alkyl group or an optionally substituted 5- to 10-membered heterocyclic group)), -OCOR 18 (R 18 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, an amino group, a C 1 -C 6 alkylamino group, a C 2 -C 12 dialkylamino group or a C 2 -C 7 alkenylamino group), -NHR 19 (R 19 is a hydrogen atom, a C 1 -C 6 alkyl group or an optionally substituted C 7 -C 12 aralkyl group), -NHCOR 20 (R 20 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 8 cycloalkyl group, a C 2 -C 7 carboxyalkyloxy group, a C 2 -C 7 alkenyloxy group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 6 -C 10 aryloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group, a C 2 -C 12 dialkylamino group or an optionally substituted C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 2 -C 7 carboxyalkyl group, an optionally substituted C 6 -C 10 aryl group, a C 3 -C 9 alkoxycarbonylalkyl group or an optionally substituted C 7 -C 12 aralkyl group); and m is 0 or 1}; each of said 5- to 10-membered heterocyclic groups is independently selected from a furan ring, a tetrahydrofuran ring, a pyran ring, a benzofuran ring, a chroman ring, a thiophene ring, a benzothiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a triazole ring, a pyridine ring, a piperidine ring, a pyrazine ring, a piperazine ring, a pyrimidine ring, an indole ring, a benzimidazole ring, a purine ring, a quinoline ring, a phthalazine ring, a quinazoline ring, a cinnoline ring, an oxazole ring, a thiazole ring and a morpholine ring; each of said optional substituents being independently selected from C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1- C 6 alkoxy group, a hydroxyl group, a carboxyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 carboxyalkyloxy group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkoxycarbonyloxy group, a C 8 -C 13 aralkyloxycarbonyl group, a C 3 -C 9 alkoxycarboxyalkoxy group and a halogen atom}; R 2 is a hydrogen atom or a C 1 -C 6 alkyl group; and R 3 is -C(=NR 25 )NH 2 (R 25 is a hydrogen atom or a hydroxyl group) or -NH 2 ; provided that R 3 is -C(=NR 25 )NH 2 (R 25 is as defined above) when A is a nitrogen atom, or a salt or hydrate thereof; with the proviso that if the substituent R 2 represents a hydrogen atom, the group "D" represents a single bond, and the index n is 1 or 2, then neither of the substituents R 4 or R 5 represents a group including an aminosulfonyl moiety; and pharmaceutical use thereof. DETAILED DESCRIPTION OF THE INVENTION The prolineamide derivative of the present invention is represented by the above formula (I). Examples of the optionally branched C 1 -C 6 alkylene group in the above definition include -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH(CH 3 )CH(CH 3 )- and the like. Examples of the C 1 -C 6 alkyl group include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group and the like. Examples of the C 1 -C 3 alkyl group include those having three carbon atoms or less among those illustrated above. Examples of the C 1 -C 6 alkoxy group include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butyloxy group, s-butyloxy group, i-butyloxy group, t-butyloxy group, n-pentyloxy group, n-hexyloxy group and the like. Examples of the C 2 -C 7 alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group and the like. Examples of the C 3 -C 8 cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Examples of the C 6 -C 10 aryl group include phenyl group, tolyl group, naphthyl group and the like. Examples of the C 7 -C 12 aralkyl group include benzyl group, phenylethyl group, phenylpropyl group, naphthylmethyl group and the like. Examples of the C 6 -C 10 aryloxy group include phenyloxy group, naphthyloxy group and the like. Examples of the C 7 -C 12 aralkyloxy group include benzyloxy group, phenylethyloxy group, phenylpropyloxy group, naphthylmethyloxy group and the like. Examples of the C 1 -C 6 haloalkyl group include chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, trifluoromethyl group and the like. Examples of the C 2 -C 7 carboxyalkyl group include carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group and the like. Examples of the C 2 -C 7 carboxyalkyloxy group include carboxymethoxy group, 2-carboxyethoxy group, 3-carboxypropoxy group, 4-carboxybutyloxy group, 5-carboxypentyloxy group, 6-carboxyhexyloxy group and the like. Examples of the C 2 -C 7 alkenyloxy group include vinyloxy group, aryloxy group, 2-propenyloxy group, isopropenyloxy group, 3-butenyloxy group, 4-pentenyloxy group, 5-hexenyloxy group and the like. Examples of the C 2 -C 7 alkenylamino group include vinylamino group, arylamino group, 2-propenylamino group, Isopropenylamino group, 3-butenylamino group, 4-pentenylamino group, 5-hexenylamino group and the like. Examples of the C 1 -C 6 alkylamino group include methylamino group, ethylamino group, n-propylamino group, n-butylamino group and the like. Examples of the C 2 -C 12 dialkylamino group include dimethylamino group, methylethylamino group, diethylamino group, di-n-propylamino group and the like. Examples of the C 2 -C 7 acyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaroyl group, hexanoyl group, heptanoyl group and the like. Examples of the C 2 -C 7 acyloxy group include acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaroyloxy group, hexanoyloxy group, heptanoyloxy group and the like. Examples of the C 2 -C 7 alkokycarbonyloxy group include methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, n-butyloxycarbonyloxy group, n-pentyloxycarbonyloxy group, n-hexyloxycarbonyloxy group and the like. Examples of the C 2 -C 7 hydroxyalkylcarbonyloxy group include hydroxymethylcarbonyloxy group, 2-hydroxyethylcarbonyloxy group, 3-hydroxypropylcarbonyloxy group, 4-hydroxybutylcarbonyloxy group, 5-hydroxypentylcarbonyloxy group, 6-hydroxyhexylcarbonyloxy group and the like. Examples of the C 3 -C 9 alkoxycarbonylalkoxy group include methoxycarbonylmethoxy group, ethoxycarbonylmethoxy group, propoxycarbonylmethoxy group, methoxycarbonylethoxy group, ethoxycarbonylethoxy group, propoxycarbonylethoxy group and the like. Examples of the C 3 -C 9 alkoxycarbonylalkyl group include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylmethyl group, propoxycarbonylethyl group and the like. Examples of the above "optional substituents" include those given above for the respective group of compounds. Examples of the C 8 -C 13 aralkyloxycarbonyl group include benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylproplyloxycarbonyl group, naphthylmethyloxycarbonyl group, etc. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and the like. In the compound represented by the above formula (I) of the present invention, a carbon atom is preferred as A. Examples of preferred compounds of the present invention include those of the formula (I), wherein A is a carbon atom; n is 1 or 2; R 1 is (wherein D and E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group: -OR 6 (R 6 is a C 1 -C 6 alkyl group; a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group): -SR 7 (R 7 is a C 1 -C 6 alkyl group, a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group): -COOH: a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group: a C 3 -C 8 cycloalkyl group: or -SiR 14 R 15 R 16 (R 14 , R 15 , and R 16 independently indicate a C 1 -C 6 alkyl group); R 5 is -OH, -OCOR 18 (R 18 is a C 1 -C 6 alkoxy group or a C 2 -C 7 alkenylamino group), -NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group, a C 6 -C 10 aryloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group, a C 2 -C 12 dialkylamino group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group, a C 2 -C 7 carboxyalkyl group, a C 6 -C 10 aryl group, a C 3 -C 9 alkoxycarbonylalkyl group or a C 7 -C 12 aralkyl group); and m is 0 or 1}; and R 2 is a hydrogen atom. As the more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R 1 is {wherein D arid E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a C 6 -C 10 aryl or C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group); -SR 7 (R 7 is a C 1 -C 6 alkyl group); a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group; or a C 3 -C 6 cycloalkyl group; R 5 is -OH, -NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group); and m is 1}; and R 2 is a hydrogen atom. As the more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R 1 is {wherein D is a single bond and E is a single bond or a C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a C 6 -C 10 aryl or C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group); -SR 7 (R 7 is a C 1 -C 6 alkyl group); a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group; or a C 3 -C 6 cycloalkyl group; R 5 is -NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group); and m is 1}; and R 2 is a hydrogen atom. As the still more preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R 1 is (wherein D is a single bond; E is a single bond or a C 1 -C 3 alkylene group; R 4 is a C 3 -C 6 alkyl group, -OR 6 (R 6 is a C 1 -C 6 alkyl group), a phenyl group or a C 3 -C 6 cycloalkyl group; R 5 is -OH, -NHR 19 (R 19 is a hydrogen atom), -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 3 alkyl group); and m is 1}; and R 2 is a hydrogen atom. As the particularly preferred compound of the present invention, there is a compound of the formula (I), wherein A is a carbon atom; n is 1; R 1 is {wherein D is a single bond; E is a single bond or a C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; R 5 is -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group); and mis 1}; R 2 is a hydrogen atom; and R 3 is -C(=NR 25 )NH 2 (R 25 is a hydrogen atom or a hydroxyl group)). As the most preferred compound of the present invention, there is trans-4-[(S)-N-((R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 461 in Table 1 in Example 33). The prolineamide derivatives represented by the above formula (I) can afford various stereoisomers. For example, concerning asymmetric carbon atoms, the absolute configuration may be D-configuration, L-configuration or DL configuration and all types thereof are included in the compounds of the present invention. Examples of the salt which can be formed with the compounds of the above formula (I) of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; organic acid salts such as succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate, etc. Further, the proline derivatives of the above formula (I) containing a free carboxyl group can also form a salt with a pharmaceutically acceptable base. Examples of the salt include alkaline metal salt, alkaline earth metal salt, ammonium salt, alkyl ammonium salt and the like. Further, the prolineamide derivatives of the above formula (I) and the salts thereof can also form a hydrate. Hereinafter, examples of the compounds of the present invention will be described. The following compounds were deleted during prosecution; 77-81, 104, 106-110, 112-163, 165-172, 230-233, 237, 239, 241, 243, 245-246, 250-253, 269-270, 274, 276, 283-284, 291-293, 295, 302-305, 317, 319, 321, 324, 326, 328, 382, 398-399, 437-442, 452, 501-504, 510, 515-746, 751, 759-760, 772-775, 788-792, 805-815, 820, 828-829, 834, 898-971, 973-976, 996-1002, 1004-1006. Compounds No. 105 and 776 were designated as Reference compounds. Hereinafter, the production process for the compounds of the present invention will be explained. The compounds of the present invention can be produced through any combination of reactions suitable for the objective compounds. Typical reaction schemes will be shown below, but they should not be construed to be limiting the scope of the present invention. wherein R 1 , R 2 , R 25 , n and broken line are as defined above; Q is an aminoprotecting group, such as benzyloxycarbonyl group, tertiary butyloxycarbonyl group, etc.; Z is a leaving group such as halogen atom, methanesulfonyloxy group, toluenesulfonyloxy group, trifluoromethylsulfonyloxy group, acetoxy (acetyloxy) group, etc. In the above reaction schemes, a known method for synthesizing amide can be used for synthesizing the compounds (IV), (VI), (XII), (XIV), (XIX) and (XXI). There are various conventional methods, for example, a method using dehydrating agents such as dicyclohexylcarbodiimide, 1-ethyl-3-(dimethylaminopropyl)carbodiimide, carbonyldiimidazole, etc., azido method, acid halide method, acid anhydride method, active ester method and the like.(e.q., see, "JIKKEN KAGAKU KOZA, 22, YUKI-GOSEI IV", pp. 259 - (1992), ed. "JAPAN Chemical Society", 4th. edition, published by Maruzen). The reaction is conducted under cooling or heating (or at room temperature) using an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, etc. in a conventional manner. In the above schemes, the compounds (V), (XIII), (XV) and (XX) can be synthesized by deprotection according to a method known in the peptide chemistry (e.g. see "The Principle and Experimental Procedures of Peptide Synthesis" written by Nobuo IZUMIYA et al., published by Maruzen). Further, the compound (VII) is synthesized by reacting imidate, which is obtained by reacting the compound (VI) with alcohol and an inorganic acid such as hydrochloric acid, with ammonia or an ammonium salt; or by reacting a thioamide compound, which is obtained by reacting the compound (VI) with hydrogen sulfide in the presence of an organic base such as triethylamine, pyridine, etc., with a lower alkylhalogen compound such as methyl iodide, etc., followed by reacting the resulting thioimidate compound with ammonia or an ammonium salt. Further, the compound (IX) is synthesized by reacting the compound (VI) with hydroxylamine or acid adduct thereof in a suitable solvent such as water, alcohol, tetrahydrofuran, etc. at room temperature or under heating. The respective compounds thus obtained can be isolated and purified by conventional chemical procedures such as extraction, crystallization, recrystallization, various chromatography and the like. When the compounds of the present invention are used for clinical application, a proportion of a therapeutically active ingredient to a carrier component varies within a range of 1 to 90% by weight. For example, the compounds of the present invention may be orally administered in the dosage form such as granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or intravenously, intramuscularly or subcutaneously administered in the form of injections. Further, they may also be used in the form of suppositories. They may also be formed into powders which can be converted into solutions or the like for injection before use. There can be used pharmaceutical organic or inorganic solid or liquid carriers or diluents which are suitable for oral, intestinal or parenteral administration for preparing the drugs of the present invention. As the excipient used for preparing solid preparations, for example, there can be used lactose, sucrose, starch, talc, cellulose, dextrin, kaoline, calcium carbonate and the like. Liquid preparations for oral administration, i.e. emulsions, syrups, suspensions, solutions, etc. contain inert diluents which are normally used, e.g. water, vegetable oil, etc. This preparation can contain adjuvants such as humectants, suspension auxiliary agents, sweeteners, aromatics, colorants, preservatives, etc., in addition to inert diluents. The resulting liquid preparations may be contained in a capsule of an absorbable substance such as gelatin. As the solvent or suspending agent used for preparing preparations for parenteral administration, i.e. injections, suppositories, etc., for example, there can be used water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. As the base used for preparing suppositories, for example, there can be used cacao butter, emulsified cacao butter, laurin tallow, witepsol and the like. Preparations may be prepared by a conventional method. The clinical dose varies depending upon age, pathology, condition of diseases and the like. For example, in the case of administering orally to an adult patient, the compounds of the present invention are normally administered with a dairy dose of about 0.01 to 1000 mg, preferably 10 to 1000 mg. The pharmaceutical composition of the present invention may be administered 1 to 3 times per day or administered intermittently with the above dairy dose. When using as injections, it is advantageous that the compounds of the present invention are administered continuously or intermittently to an adult patient with a single dose of 0.001 to 100 mg. The prolineamide derivatives of the present invention or the salts thereof have a strong inhibition activity to proteases such as thrombin, trypsin and the like. The compounds of the present invention are also superior in oral absorptive action so that they are useful as oral antithrombin agents, i.e. oral anticoagulants, or oral antitrypsin agents, i.e. remedy for pancreas diseases such as pancreatitis. The following Examples and Experimental Examples further illustrate the present invention in detail but are not to be construed to limit the scope thereof. The conventional abbreviations used in Examples are as follows: THF:tetrahydrofuran, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, CDI: carbonyldiimidazole, DPPA: diphenylphosphorylazide, Z: benzyloxycarbonyl, Boc: tertiary butyloxycarbonyl. Further, NMR in physical properties stands for a nuclear magnetic resonance spectrum and the numeral is δ value in ppm, which is conventionally used for indicating the chemical shift. TMS (tetramethylsilane) was used as the internal standard. Further, the numeral shown in parenthesis following δ value is the number of hydrogen atoms, and the indications following the number of hydrogen atoms mean that s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad absorption peak, respectively. IR stands for an infrared spectrum and measured as potassium bromide tablets unless otherwise stated. The numerical means the wave number in cm -1 . Only main absorption peak was shown. Further, mp means the non-corrected melting point in °C. Reference Example 1 Synthesis of 4-amidino-[(S)-N-((R)-2-methylsulfonylaminocyclohexylacetyl) prolyl]aminomethylbenzene (Reference compound No. 105 of Table 1) hydrochloride. (a) N-4-cyanobenzylphthalimide To a solution of potassium phthalimide (76 g, 410 mmol) in DMF (250 ml), a solution of 4-cyanobenzyl bromide (73 g, 373 mmol) in THF (250 ml) is added and stirred at 50°C for 3 hours. Water (500 ml) is added to the mixture and a precipitated crystal was collected. Then, the crystal is washed with water and dried to give 96 g of the titled compound (99%). mp: 189-191°C. (b) 4-Cyano-[(S)-prolyl]aminomethylbenzene hydrochloride To a solution of the compound (39 g, 150 mmol) obtained in the item (a) in methanol (250 ml), hydrazine hydrate (9 ml) is added and refluxed for 6 hours. After the solvent is evaporated, an aqueous 40% sodium hydroxide solution (300 ml) is added to the residue and stirred. The reaction mixture is extracted with toluene and the organic layer is washed once with water and saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting crude product (15 g, 73%) is used for the next step. To a solution of (S)-N-Boc-proline (23.7 g, 110 mmol) in THF (250 ml), CDI (17.8 g, 110 mmol) is added at 0°C. After the reaction solution is stirred for 2 hours, a solution of the crude product obtained in the above reaction in THF (150 ml) is added. After stirring for 6 hours, the solvent is evaporated and water (300 ml) is added to the residue. The mixture is extracted with chloroform and the organic layer is washed three times with water and once with saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (hexane-ethyl acetate). The resulting oily product is dissolved in ethyl acetate (100 ml) and a 4N-hydrochloride in ethyl acetate (69 ml) is added and the mixture is stirred at 0°C for 3 hours. The precipitated white solid is collected, washed with ethyl acetate and dried under reduced pressure to give 25.9 g of the titled compound (89%). NMR (DMSO-d 6 ) 1.80-1.96 (m, 3H), 2.30-2.40 (m, 1H), 3.21 (br, 2H), 4.26 (br, 1H), 4.44 (d, 2H), 7.49 (d, 2H), 7.82 (d, 2H), 8.59 (br, 1H), 9.39 (t, 1H), 10.07 (br, 1H) (c) 4-Cyano-[(S)-N-((R)-2-t-butyloxycarbonylamino-cyclohexylacetyl) prolyl]aminomethylbenzene To a solution of the product (21 g, 79 mmol) obtained in the item (b) and (R)-N-t-butyloxycarbonylcyclohexylglycine (20.4 g, 79 mmol) in DMF (200 ml), a solution of triethylamine (22 ml, 159 mmol) and DPPA (22 g, 79 mmol) in DMF (50 ml) is added at 0°C. The mixture is allowed to stand at room temperature and then stirred for 12 hours. Water (400 ml) is added to the reaction mixture which is extracted with toluene-ethyl acetate (1:2). The organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. After the solvent is evaporated, the residue is purified with silica gel chromatography (chloroform-methanol) to give 26.7 g of the titled compound (72%). NMR (CDCl 3 ) 1.01-1.43 (m, 15H), 1.65-2.38 (m, 9H), 3.57 (q, 1H), 3.96-4.06 (m, 2H), 4.47 (dq, 2H), 4.69 (d, 1H), 5.12 (d, 1H), 7.35 (d, 2H), 7.59 (d, 2H), 7.73 (t, 1H) (d) 4-Cyano-[(S)-N-((R)-2-methylsulfonylamino-cyclohexylacetyl)prolyl] aminomethylbenzene To a solution of the compound (26.7 g, 57 mmol) obtained in the item (c) in chloroform (50 ml), a 4-N hydrochloride in ethyl acetate (30 ml) is added at 0 °C. The mixture is stirred for 3 hours and then the solvent is evaporated. The resulting residue was dissolved in dichloromethane (250 ml) and triethylamine (19 ml) is added. Then, a solution of methanesulfonyl chloride (7.9 g, 68 mmol) in dichloromethane (50 ml) is added at 0°C and the mixture is stirred for 3 hours. The organic layer is washed once with a saturated sodium bicarbonate solution, water and saturated brine, successively, and then dried over sodium sulfate. The resulting residue is purified with silica gel chromatography (hexane-ethyl acetate) to give 18.6 g of the titled compound (73%). NMR (CDCl 3 ) 0.9-1.29 (m, 5H), 1.60-1.85 (m, 5H), 2.0-2.4 (m, 5H), 2.89 (s, 3H), 3.55 (q, 1H), 3.80-3.88 (m, 2H), 4.43 (d, 2H), 4.61 (d, 2H), 5.60 (d, 2H), 7.31 (t, 1H), 7.37 (d, 2H), 7.60 (d, 2H) (e) 4-Amidino-[(S)-N-((R)-2-methylsulfonylamino-cyclohexylacetyl) prolyl]aminomethylbenzene chloride To a solution of the compound (18.6 g, 42 mmol) obtained in the item (d) in chloroform (100 ml), a 37% hydrochloride in ethanol (100 ml) is added at 0°C. The mixture is allowed to stand at 0°C for 48 hours and then the solvent is evaporated. The resulting residue is dissolved in methanol (100 ml) and ammonium carbonate (16 g, 166 mmol) is added at 0°C. After stirring for 6 hours, the solvent is evaporatéd and the resulting residue is purified with silica gel chromatography (chloroform-methanol) to give 5.2 g of the titled compound (73%). NMR (DMSO-d 6 ) 9.39 (br, 4H), 8.66 (t, 1H), 7.81 (d, 2H), 7.48 (d, 2H), 7.40 (m, 1H), 4.47-4.14 (m, 3H), 3.90 (m, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 2.79 (s, 3H), 2.13 (m, 1H), 1.88 (m, 3H), 1.69-1.53 (m, 5H), 1.14 (m, 6H) IR: 3366, 2930, 2855, 1636, 1541, 1489, 1451, 1152 According to the same procedures described above, the compounds shown in the following Examples were synthesized. Example 1 4-Amidino-[(S)-N-((R)-N'-formylphenylalanyl) prolyl] aminomethylbenzene (compound No. 94 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.56 (br, 2H), 9.36 (br, 2H), 8.97 (t, 1H), 8.70 - 8.60 (m, 1H), 7.86 (d, 1H), 7.83 (d, 2H), 7.46 (d, 2H), 7.37-7.17 (m, 5H), 4.36-4.16 (m, 4H), 3.60 - 2.70 (m, 4H), 2.40-1.20 (m, 4H) IR: 3370, 1647, 1541, 1489, 1454, 1404, 704 Example 2 4-Amidino-[(S)-N-[(R)-2-ethoxycarbonylamino-3-methyl-3-methylthiobutanoyl] prolyl]aminomethylbenzene (compound No. 98 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.89 (br, 2H), 8.66 (br, 2H), 7.77 (d, 2H), 7.33 (d, 2H), 6.27 (d, 1H), 4.65 (m, 1H), 4.46 (d, 1H), 4.37 (m, 2H), 3.97-3.72 (m, 4H), 2.62 (m, 1H), 2.15 (br, 3H), 2.04 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.05 (t, 3H) IR: 3323, 2926, 1635, 1535, 1439, 1242, 1055 Example 3 4-Amidino-[(S)-N-(4-phenylbutanoyl)prolyl] aminomethylbenzene (compound No. 3 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.39 (br, 2H), 9.22 (br, 2H), 8.55 (t, 1H), 7.80 (d, 2H), 7.48 (d, 2H), 7.31-7.13 (m, 5H), 4.37-4.30 (m, 3H), 3.60-3.30 (m, 2H), 2.60 (t, 2H), 2.34-1.75 (m, 8H) IR: 3264, 1618, 1541, 1491, 1451, 702 Example 4 4-Amidino-[(S)-N-(2-benzyloxyacetyl)prolyl] aminomethylbenzene (compound No. 55 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.41 (br, 2H), 9.23 (br, 2H), 8.66 (t, 1H), 7.80 (d, 2H), 7.49 (d, 2H), 7.42-7.27 (m, 5H), 4.61-4.08 (m, 7H), 3.56-3.40 (m, 2H), 2.20-1.78 (m, 4H) IR: 3262, 1645, 1539, 1489, 1454, 740 Example 5 Trans-4-amidino-[(S)-N-[(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl]prolyl] aminomethylcyclohexane (compound No. 263 of Table 1) hydrochloride (a) Trans-4-N-benzyloxycarbonylaminomethyl-cyclohexylnitrile To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (25 g, 159 mmol) and sodium carbonate (20 g, 191 mmol) in water (300 ml), benzyloxycarbonyl chloride (27 ml, 190 mmol) is added at 0°C. After stirring for 6 hours, 1N-hydrochloric acid is added until the pH of the reaction mixture indicates 2, and the precipitated white solid is collected, washed with water and dried. The resulting white solid is dissolved in THF (300 ml) and CDI (21 g, 130 mmol) is added at 0°C. After stirring for 3 hours, the reaction mixture is added dropwise to a mixed solution of 33% ammonia in water (50 ml) and THF (150 ml) at 0°C. After stirring for 5 hours, the solvent is evaporated and water (500 ml) is added, and the precipitated white solid is collected, washed with water and dried. To a solution of the resulting compound in 1,2-dichloroethane (500 ml), thionyl chloride (19 ml, 260 mmol) is added and heated to an inner temperature of 70°C. After stirring for 5 hours, the reaction mixture is poured into ice water and neutralized with an aqueous 1N-sodium hydroxide solution. After extracting with chloroform, the organic layer is washed twice with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting crude product is recrystallized (hexane-ethyl acetate) to give 22.8 g of the titled compound (53%). mp: 90-92°C (b) Trans-4-(S)-prolylaminomethyl-cyclohexylnitrile The compound obtained in the item (a) is dissolved in ethanol (250 ml) and the catalytic hydrogenation is conducted at room temperature and atomospheric pressure in the presence of palladium black (1 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated. To a solution of (S)-N-benzyloxycarbonylproline (20.7 g, 83 mmol) in THF (150 ml), CDI (13.5 g, 83 mmol) is added at 0'C. After stirring for 3 hours, a solution of the compound obtained in the above reaction in THF (200 ml) is added at 0°C. After stirring for 12 hours, the solvent is evaporated, and chloroform (400 ml) is added to the resulting residue. The organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the resulting residue is purified with silica gel chromatography (chloroform-methanol). The resulting compound is dissolved in ethanol (250 ml) and the catalytic hydrogenation is conducted at room temperature and atomospheric pressure in the presence of palladium black (1 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated to give 18.8 g of the titled compound (95%). NMR (DMSO-d 6 ) 0.88-1.06 (m, 2H), 1.38-1.52 (m, 3H), 1.68-2.03 (m, 7H), 2.20-2.40 (m, 1H), 2.52-2.67 (m, 1H), 2.80-3.20 (m, 4H), 4.03-4.10 (m, 1H), 7.53 (br, 1H), 8.65-8.70 (m, 1H) (c) Trans-4-amidino-[(S)-N-[(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexane hydrochloride According to the same manner as that described in the items (c) to (e) of Example 1, the titled compound can be synthesized from the compound obtained in the item (b) and (R)-2-t-butyloxycarbonylamino-4,4-dimethylpentanoic acid. NMR (DMSO-d 6 ) 8.95 (br, 2H), 8.69 (br, 2H), 7.60 (br, 1H), 6.32 (br, 1H), 4.56 (m, 1H), 4.39 (m, 1H), 4.18 (q, 2H), 4.10 (m, 1H), 3.52 (m, 1H), 3.19 (m, 1H), 2.89 (m, 1H), 2.69 (m, 1H), 2.14-1.59 (m, 12H), 1.26 (t, 3H), 0.98 (s, 9H), 0.98-0.89 (m, 2H) IR: 3314, 2954, 1686, 1639, 1543, 1449, 1250, 1059 According to the same procedures, the compounds shown in the following Examples were synthesized. Example 6 Trans-4-amidino-[(S)-N-[(R)-2-ethoxycarbonylamino-3-cyclohexylpropanoyl] prolyl]aminoethylcyclohexane (compound No. 227 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.93 (br, 2H), 8.81 (br, 2H), 7.53 (br, 1H), 7.38 (t, 1H), 4.50-4.15 (m, 1H), 4.10-3.90 (m, 2H), 3.73-3.17 (m, 2H), 3.05-2.80 (m, 3H), 2.39 (br, 1H), 2.00-0.68 (m, 29H) IR: 3297, 2926, 2853, 1684, 1543, 1449, 1262, 1053 Example 7 Trans-4-amidino-[(S)-N-[(R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexane (compound No. 265 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.91 (br, 2H), 8.78 (br, 2H), 7.55 (br, 1H), 7.28 (t, 1H), 4.78-4.70 (m, 1H), 4.30-3.92 (m, 1H), 3.80-3.20 (m, 3H), 3.0-2.75 (m, 2H), 2.50-1.37 (m, 14H), 1.18-1.00 (m, 6H), 1.0-0.81 (m, 1H) IR: 3285, 2953, 2870, 1684, 1541, 1449, 1250, 1111 Example 8 Trans-4-amidino-[(S)-N-((R)-2-isopropoxycarbonylamino-2-cyclohexylacetyl) prolyl]aminomethylcyclohexane (compound No. 228 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.91 (br, 2H), 8.69 (br, 2H), 7.36 (br, 1H), 5.99 (d, 1H), 4.84-4.79 (m, 1H), 4.58 (br, 2H), 4.53-4.50 (m, 2H), 4.10-3.90 (m, 2H), 3.60-3.40 (m, 1H), 2.50-0.97 (m, 30H) IR: 3297, 2980, 2930, 2855, 1684, 1539, 1451, 1258 Example 9 Trans-4-amidino-[(S)-N-((R)-2-ethoxycarbonylamino-4-ethyl-hexanoyl) prolyl]aminomethylcyclohexane (compound No. 264 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.91 (br, 2H), 8.70 (br, 2H), 7.54 (m, 1H), 6.34 (m, 1H), 4.56 (m, 1H), 4.38 (m, 1H), 4.11 (m, 3H), 3.48 (m, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.68 (m, 1H), 2.30-1.19 (m, 18H), 1.26 (t, 3H), 0.96 (m, 2H), 0.86 (t, 6H) IR: 3279, 2962, 1685, 1639, 1541, 1448, 1257, 1059, 752 Example 10 Trans-4-amidino-[(S)-N-[(R)-2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexane (compound No. 266 of Table 1) glycolate NMR (DMSO-d 6 ) 9.54 (br, 2H), 8.72 (br, 2H), 7.54 (br, 1H), 7.01 (t, 1H), 4.60-4.00 (m, 4H), 3.40 (m, 2H), 3.10-2.75 (m, 3H), 2.35 (br, 1H), 2.00-1.20 (m, 24H), 0.91 (s, 9H) IR: 3316, 2953, 1686, 1543, 1449, 1368, 1167 Example 11 4-[(S)-N-[(R)-2-t-butyloxycarbonylamino-cyclohexylacetyl] prolyl] aminomethyl-benzamidoxime (compound No. 396 of Table 1) To a solution of the compound (0.94 g, 2 mmol) obtained in the item (c) of Example 1 in ethanol (15 ml), a solution of sodium carbonate (0.17 g, 1.6 mmol) in water (3 ml) and hydroxyamine hydrochloride (0.22 g, 3.2 mmol) are added. After the reaction mixture is heated at reflux for 8 hours, the solvent is evaporated and the resulting residue is purified with silica gel column chromatography (chloroform-methanol) to give 0.84 g of the titled compound (84%). NMR (CDCl 3 ) 1.0-1.49 (m, 14H), 1.5-2.4 (m, 10H), 3.56 (br, 1H), 3.97 (br, 1H), 4.09 (t, 1H), 4.41 (dq, 2H), 4.67 (d, 1H), 4.94 (br, 2H), 5.41 (d, 1H), 7.20 (d, 2H), 7.23-7.27 (m, 1H), 7.50 (d, 2H), 7.75 (br, 1H) IR: 3345, 2978, 2930, 2855, 1640, 1528, 1449, 1167 According to the same procedures, the compounds shown in the following Examples were synthesized. Example 12 4-[(S)-N-phenylacetylprolyl] aminomethyl-benzamidoxime (compound No. 374 of Table 1) NMR (CDCl 3 ) 8.11 (t, 1H), 7.37 (d, 2H), 7.28-7.23 (m, 5H), 7.08 (d, 2H), 4.88 (s, 2H), 4.68 (d, 1H), 4.51 (m, 1H), 4.21 (m, 1H), 3.71 (s, 2H), 3.63-3.51 (m, 2H), 2.40-2.01 (m, 4H) IR: 3315, 2968, 1637, 1543, 1244, 1155, 927, 709 Example 13 4-[(S)-N-[(R)-N'-ethoxycarbonylphenylalanyl] prolyl]aminomethylbenzamidoxime (compound No. 387 of Table 1) NMR (CDCl 3 ) 7.54 (d, 2H), 7.27-7.19 (m, 7H), 6.31 (d, 1H), 5.05 (br, 2H), 4.65-4.42 (m, 3H), 4.24-4.10 (m, 1H), 3.80-3.40 (m, 3H), 3.10-2.95 (m, 2H), 2.60-2.50 (m, 1H), 2.14 (br, 1H), 1.95-1.50 (m, 3H), 0.99 (t, 3H) IR: 3339, 1641, 1539, 1451, 1260, 752, 702 Example 14 4-[(S)-N-[(R)-2-t-butyloxycarbonylamino-3-cyclohexylpropanoyl] prolyl]aminomethyl-benzamidoxime (compound No. 397 of Table 1) NMR (CDCl 3 ) 7.75 (br, 1H), 7.50 (d, 2H), 7.21 (d, 2H), 5.40 (d, 1H), 4.94 (br, 2H), 4.64 (br, 1H), 4.40-4.25 (m, 3H), 3.95 (br, 1H), 3.50-3.40 (m, 1H), 2.0-0.80 (m, 26H) IR: 3337, 2978, 2924, 2851, 1642, 1536, 1449, 1167 Example 15 4-[(S)-N-[(R)-2-ethoxycarbonylamino-3-methyl-3-methylthlobutanoyl] prolyl]aminomethyl-benzamidoxime (compound No. 419 of Table 1) NMR (CDCl 3 ) 7.66 (t, 1H), 7.53 (d, 2H), 7.23 (d, 2H), 5.64 (d, 1H), 4.91 (s, 2H), 4.68 (d, 1H), 4.58-4.30 (m, 3H), 3.90 (m, 1H), 3.87-3.76 (m, 2H), 3.62 (m, 1H), 2.37 (m, 1 H), 2.09-2.00 (m, 3H), 2.06 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.09 (t, 3H) IR: 3339, 2978, 1641, 1535, 1439, 1249, 1057, 929, 754 Example 16 4-[(S)-N-[(R)-phenylalanyl] prolyl]aminomethyl-benzamidoxime (compound No. 390 of Table 1) dihydrochloride NMR (DMSO-d 6 ) 11.24 (br, 1H), 9.02 (br, 2H), 8.91 (t, 1H), 8.80 (br, 3H), 7.66 (d, 2H), 7.44 (d, 2H), 7.35-7.22 (m, 5H), 4.30-4.16 (m, 4H), 3.57-2.95 (m, 3H), 2.45-2.30 (m, 1H), 1.90-1.20 (m, 4H) IR: 3059, 1649, 1539, 1491, 1454 Example 17 Trans-4-[(S)-N-((R)-2-isopropoxycarbonylamino-2-cyclohexylacetyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 430 of Table 1) NMR (CDCl 3 ) 7.14 (br, 1H), 5.70 (d, 1H), 4.85-4.80 (m, 1H), 4.70-4.50 (m, 3H), 4.17-4.08 (m, 2H), 3.96 (br, 1H), 3.54 (q, 1H), 3.05 (t, 2H), 2.40-2.20 (m, 1H), 2.09-0.88 (m, 30H) IR: 3342, 2978, 2928, 2855, 1653, 1449, 1256, 1111 Example 18 Trans-4-[(S)-N-((R)-2-t-butoxycarbonylamino-3-cyclohexylpropanoyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 435 of Table 1) NMR (CDCl 3 ) 7.14 (br, 1H), 5.40 (d, 1H), 4.60-4.33 (m, 5H), 3.88 (br, 1H), 3.43 (q, 1H), 3.20-3.11 (m, 1H), 3.0-2.96 (m, 1H), 2.40-2.30 (m, 1H), 2.0-0.84 (m, 35H) IR: 3356, 2926, 2853, 1649, 1537, 1448, 1167 Example 19 Trans-4-[(S)-N-((R)-2-t-butoxycarbonylamino-2-cyclohexylacetyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 433 of Table 1) NMR (CDCl 3 ) 7.15 (br, 1H), 5.28 (d, 1H), 4.58 (br, 4H), 4.09 (t, 1H), 3.92 (br, 1H), 3.53 (q, 1H), 3.20-2.90 (m, 2H), 2.40 (br, 1H), 2.10-0.91 (m, 33H) IR: 3347, 2930, 2855, 1649, 1541, 1451, 1169 Example 20 Trans-4-[(S)-N-[(R)-2-t-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 461 of Table 1) NMR (CDCl 3 ) 7.06 (t, 1H), 5.56 (d, 1H), 4.57-4.39 (m, 4H), 4.11 (q, 2H), 3.98 (m, 1H), 3.47 (m, 1H), 3.05 (m, 2H), 2.39 (m, 1H), 2.04-1.78 (m, 10H), 1.57 (d, 2H), 1.56-1.12 (m, 2H), 1.24 (t, 3H), 0.99 (s, 9H), 0.99-0.89 (m, 2H) IR: 3356, 2934, 1649, 1541, 1446, 1249, 1059, 927 Example 21 Trans-4-[(S)-N-[(R)-2-methoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 458 of Table 1) NMR (CDCl 3 ) 7.04 (t, 1H), 5.53 (d, 1H), 4.68 (s, 2H), 4.56 (d, 1H), 4.43 (m, 1H), 3.98 (m, 1H), 3.66 (s, 3H), 3.47 (m, 1H), 3.07 (m, 2H), 2.39 (m, 1H), 2.19-1.77 (m, 8H), 1.57 (d, 2H), 1.55-1.25 (m, 4H), 0.99 (s, 9H), 0.93 (m, 2H) IR: 3344, 2949, 1712, 1649, 1548, 1448, 1249, 1059 Example 22 Trans-4-[(S)-N-[(R)-2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 467 of Table 1) NMR (CDCl 3 ) 7.12 (t, 1H), 5.14 (d, 1H), 4.58 (d, 1H), 4.53 (s, 2H), 4.37 (m, 1H), 3.92 (m, 1H), 3.45 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.42 (m, 1H), 2.06-1.79 (m, 8H), 1.53 (d, 2H), 1.52-1.34 (m, 4H), 1.43 (s, 9H), 0.99 (s, 9H), 1.00-0.89 (m, 2H) IR: 3358, 2930, 1649, 1535, 1448, 1367, 1249, 1168 Example 23 Trans-4-[(S)-N-[(R)-2-benzyloxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 469 of Table 1) NMR (CDCl 3 ) 7.36-7.27 (m, 5H), 7.04 (t, 1H), 5.63 (d, 1H), 5.16-5.00 (m, 2H), 4.58-4.46 (m, 4H), 3.97 (m, 1H), 3.47 (m, 1H), 3.06-2.92 (m, 2H), 2.43-2.38 (m, 1H), 2.01-1.72 (m, 8H), 1.58 (d, 2H), 1.50-1.23 (m, 4H), 0.98 (s, 9H), 0.98-0.88 (m, 2H) IR: 3356, 2928, 1649, 1541, 1448, 1249, 1053 929 Example 24 Trans-4-[(S)-N-[(R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 464 of Table 1) NMR (CDCl 3 ) 7.11 (t, 1H), 5.49 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.42 (dd, 1H), 3.98 (m, 1H), 3.47 (dd, 1H), 3.04 (m, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.92 (m, 3H), 1.80 (m, 3H), 1.57 (d, 2H), 1.39 (m, 4H), 1.21 (m, 6H), 0.99 (s, 9H), 0.94 (m, 2H) IR: 3343, 1649, 1541, 1449, 1275 Example 25 Trans-4-[(S)-N-[(R)-2-isopropoxycarbonylamino-2-cyclopentylacetyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 429 of Table 1) NMR (CDCl 3 ) 7.14 (t, 1H), 5.42 (d, 1K), 4.83 (m, 1H), 4.60 (d, 1H), 4.52 (s, 2H), 4.13 (m, 1H), 3.98 (m, 1H), 3.56 (m, 1H), 3.04 (m, 2H), 2.35 (m, 1H), 2.24 (m, 1H), 2.10-1.30 (m, 20H), 1.23 (dd, 6H), 1.01-0.93 (m, 2H) IR: 3344, 2934, 1649, 1541, 1448, 1275, 1111, 754 Example 26 Trans-4-[(S)-N-((R)-2-t-butoxycarbonylamino-2-cyclopentylacetyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 432 of Table 1) NMR (CDCl 3 ) 7.16 (t, 1H), 5.16 (d, 1H), 4.60 (d, 1H), 4.51 (s, 2H), 4.14 (t, 1H), 3.94 (m, 1H), 3.52 (m, 1H), 3.01 (m, 2H), 2.38 (m, 1H), 2.23-1.39 (m, 21H), 1.43 (s, 9H), 1.17-0.90 (m, 2H) IR: 3350, 2932, 1649, 1541, 1448, 1367, 1251, 1167, 929 Example 27. Trans-4-[(S)-N-((R)-2-ethoxycarbonylamino-3-cyclohexylpropanoyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 428 of Table 1) NMR (CDCl 3 ) 7.08 (br, 1H), 5.53 (d, 1H), 4.80-4.40 (m, 4H), 4.10-3.85 (m, 4H), 3.44 (q, 1H), 3.06 (t, 3H), 2.15-0.90 (m, 29H) IR: 3343, 2926, 2853, 1649, 1541, 1449, 1260, 1053 Example 28 Trans-4-[(S)-N-((R)-2-isopropoxycarbonylamino-3-cyclohexylpropanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 431 of Table 1) NMR (CDCl 3 ) 7.12 (br, 1H), 5.51 (d, 1H), 4.85-4.70 (m, 1H), 4.60-4.30 (m, 4H), 4.0-3.85 (m, 1H), 3.44 (q, 1H), 3.10-2.95 (m, 3H), 2.45-2.35 (m, 1H), 2.05-0.80 (m, 32H) IR: 3347, 2978, 2926, 2853, 1649, 1539, 1449, 1261, 1111 Example 29 Trans-4-[(S)-N-((R)-2-isopropoxycarbonylamino-4-ethyl-hexanoyl) prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 463 of Table 1) NMR (CDCl 3 ) 7.11 (t, 1H), 5.41 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.39 (m, 1H), 3.94 (m, 1H), 3.46 (m, 1H), 3.02 (m, 2H), 2.39 (m, 1H), 2.10-1.20 (m, 20H), 1.22 (dd, 6H), 1.02-0.84 (m, 2H), 0.86 (t, 6H) IR: 33346, 2962, 2930, 1653, 1541, 1448, 1271, 1113 Example 30 Trans-4-[(S)-N-((R)-2-t-butoxycarbonylamino-4-ethyl-hexanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 466 of Table 1) NMR (CDCl 3 ) 7.19 (t, 1H), 5.14 (d, 1H), 4.60 (d, 1H), 4.50 (s, 2H), 4.33 (m, 1H), 3.89 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.40 (m, 1H), 2.10-1.19 (m, 20H), 1.43 (s, 9H), 1.04-0.89 (m, 2H), 0.86 (t, 6H) IR: 3346, 2964, 2930, 1649, 1541, 1448, 1367, 1280, 1251, 1168, 929 Example 31 Trans-4-[(S)-N-((R)-2-ethoxycarbonylamino-heptanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 459 of Table 1) NMR (CDCl 3 ) 7.08 (t, 1H), 5.60 (d, 1H), 4.58 (m, 3H), 4.35 (m, 1H), 4.07 (m, 2H), 3.92 (m, 1H), 3.48 (m, 1H), 3.06 (m, 2H), 2.40 (m, 1H), 2.04-1.32 (m, 20H), 1.24 (t, 3H), 0.89 (t, 3H), 0.98 (m, 2H) IR: 3346, 2928, 1649, 1541, 1448, 1255, 1055, 927 Example 32 Trans-4-[(S)-N-((R)-N'-t-butoxycarbonylamino-methionyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 468 of Table 1) NMR (CDCl 3 ) 7.07 (m, 1H), 5.31 (d, 1H), 4.55 (m, 4H), 3.56 (m, 1H), 3.10 (m, 2H), 2.57 (t, 2H), 2.37 (m, 1H), 2.11 (s, 3H), 2.06-1.29 (m; 14H), 1.43 (s, 9H), 1.00 (m, 2H) IR: 3354, 2928, 1647, 1541, 1448, 1367, 1251, 1167 Example 33 Trans-4-[(S)-N-((R)-2-hydroxy-4,4-dimethyl-pentanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 454 of Table 1) NMR (CDCl 3 ) 7.19 (t, 1H), 4.68 (s, 2H), 4.50 (d, 1H), 4.36 (1, 1H), 3.64 (t, 1H), 3.39 (m, 1H), 3.06 (m, 2H), 2.35 (m, 2H), 2.16-1.79 (m, 9H), 1.44 (d, 2H), 1.43-1.25 (m, 3H), 1.00-0.95 (m, 2H), 1.02 (s, 9H) IR: 3337, 2944, 1653, 1620, 1566, 1448, 1386, 1248, 1087 Example 34 Trans-4-[(S)-N-((R)-2-ethoxycarbonylamino-4-ethyl-hexanoyl) prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 460 of Table 1) NMR (CDCl 3 ) 7.07 (t, 1H), 5.53 (d, 1H), 4.56 (m, 3H), 4.40 (m, 1H), 4.11 (q, 2H), 3.96 (m, 1H), 3.45 (m, 1H), 3.05 (m, 2H), 2.36 (m, 1H), 2.09-1.77 (m, 10H), 1.61-1.21 (m, 8H), 1.24 (t, 3H), 1.02-0.83 (m, 2H), 0.86 (t, 6H) IR: 3342, 2962, 2930, 1649, 1541, 1448, 1379, 1269, 1059, 929 Reference Example 2 Trans-4-amino-[(S)-N-[(R)-N'-methanesulfonylphenyalanyl] prolyl] aminomethylcyclohexane (Reference compound No. 776 of Table 1) L-tartrate. (a) Trans-4-t-butyloxycarbonylamino-benzyloxycarbonylaminomethylcyclohexane To a solution of trans-4-aminomethylcyclohexanecarboxylic acid (15.7 g, 100 mmol) and sodium hydroxide (4.0 g, 100 mmol) in water (30 ml), benzyloxycarbonyl chloride (15.6 ml, 110 mmol) and sodium hydroxide (4.4 g, 110 mmol) in water (30 ml) are added dropwise at 0°C, simultaneously. After stirring for 4 hours, the mixture is extracted once with ether and 1 N-hydrochloric acid is added to the aqueous layer until the pH of the mixture indicates 2. Then, the precipitated white solid is collected and dried. To a solution of the resulting compound (12.8 g, 50 mmol) in t-butanol (150 ml), triethylamine (8.3 ml, 60 mmol) and DPPA (13.7 g, 50 mmol) are added and heated at reflux for 8 hours. After the solvent is evaporated, water is added to the residue and the mixture is extracted with chloroform. The organic layer is washed once with an aqueous sodium carbonate (5%), once with an aqueous potassium hydrogensulfate (5%), twice with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the residue is purified with silica gel column chromatography (hexane-ethyl acetate) to give 8.6 g of the titled compound (47%). NMR (CDCl 3 ) 0.85-1.37 (m, 14H), 1.60-1.85 (m, 4H), 2.84 (t, 1H), 3.12 (br, 1H), 5.00 (s, 2H), 6.62 (d, 1H), 7.23-7.39 (m, 6H) (b) Trans-4-t-butyloxycarbonylamino-[(S)-N-benzyloxycarbonylprolyl] aminomethylcyclohexane The compound (4.4 g, 12 mmol) obtained in the item (a) is dissolved in methanol (200 ml) and the catalytic hydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.4 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated. To a solution of (S)-Z-proline (3.0 g, 12 mmol) in THF (30 ml), CDI (2.0 g, 12 mmol) is added at 0°C. After stirring for 3 hours, a solution of the compound obtained in the above reaction in THF (150 ml) is added at 0°C. After stirring for 6 hours, the solvent is evaporated and water (50 ml) is added to the residue. The mixture is extracted with chloroform and the organic layer is washed three times with water and once with saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (chloroform-methanol) to give 4.2 g of the titled compound (77%). NMR (CDCl 3 ) 0.85-1.06 (m, 4H), 1.44 (s, 9H), 1.60-2.35 (m, 9H), 2.94-3.20 (m, 2H), 3.20-3.55 (m, 3H), 4.31 (br, 1H), 4.47 (br, 1H), 5.14 (s, 2H), 6.90 (br, 1H), 7.15-7.40 (m, 5H) (c) Trans-4-t-butyloxycarbonylamino-[(S)-N-[(R)-N'-benzyloxycarbonylphenylalanyl] prolyl] aminomethylcyclohexane The compound (3.6 g, 7.9 mmol) obtained in the item (b) is dissolved in methanol (50 ml) and the catalytichydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.3 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated. To a solution of (R)-Z-phenylalanine (2.4 g, 7.9 mmol) in THF (30 ml), CDI (1.3 g, 7.9 mmol) is added at 0°C. After stirring for 4 hours, a solution of the compound obtained in the above reaction in THF (60 ml) is added. After stirring for 8 hours, the solvent is evaporated and water is added to the reaction mixture. The mexture is extracted with chloroform and the organic layer is washed three times with water and once with saturated brine, successively, and then dried over sodium sulfate. The solvent is evaporated and the residue is purified with silica gel column chromatography (chloroform-methanol) to give 4.2 g of the titled compound (89%). NMR (CDCl 3 ) 0.85-1.06 (m, 5H), 1.33-2.0 (m, 15H), 2.10-2.22 (m, 1H), 2.50-2.60 (m, 1H), 2.94-3.01 (m, 5H), 3.30 (br, 1H), 3.57 (t, 1H), 4.32-4.59 (m, 3H), 5.08 (d, 2H), 5.69 (d, 1H), 7.02 (br, 1H), 7.18-7.37 (m, 10H) (d) Trans-4-amino-[(S)-N-[(R)-N'-methanesulfonylphenylalanyl]prolyl] aminomethylcyclohexane L-tartrate. The compound (2.4 g, 3.9 mmol) obtained in the item (c) is dissolved in methanol (40 ml) and the catalytic hydrogenation is conducted at room temperature and under atomospheric pressure in the presence of palladium black (0.2 g). After the completion of the reaction, the catalyst is filtered off and the solvent is evaporated. To a solution of the resulting compound in dichloromethane (40 ml), triethylamine (0.65 ml, 4.7 mmol) is added and a solution of methanesulfonyl chloride (0.47 g, 4.1 mmol) in dichloromethane (100 ml) is further added at 0°C. After stirring for 3 hours, an aqueous saturated sodium bicarbonate solution is added and the organic layer is washed once with water and saturated brine, successively. After drying over sodium sulfate, the solvent is evaporated and the residue is purified with silica gel chromatography (chloroform-methanol), The resulting compound is dissolved in chloroform (10 ml) and a 4N-dioxane hydrochloride in dioxane (10 ml) is added at 0°C. After stirring for 2 hours, the solvent is evaporated and chloroform (10 ml) and a 1N-sodium hydroxide solution (10 ml) are added to the residue and, further, the mixture is stirred for 10 minutes. The organic layer is dried over sodium sulfate and a solution of L-tartaric acid (0.34 g, 2.26 nm) in methanol (5 ml) is added. The solvent is evaporated and ether (20 ml) is added, and then the precipitated white solid is collected and dried to give 1.36 g of the titled compound (58%). NMR (DMSO-d 6 ) 7.77 (m, 4H), 7.28 (m, 5H), 4.28 (m, 1H), 4.16 (m, 1H), 3.57-3.45 (m, 8H), 2.73 (s, 3H), 1.91-1.75 (m, 9H), 1.54 (m, 1H), 1.25 (m, 4H), 0.93 (m, 2H) IR: 3324, 2934, 1734, 1638, 1545, 1453, 1308, 1148 According to the same procedures, the compounds shown in the following Examples were synthesized. Example 35 Trans-4-amino-[(S)-N-((RS)-3-methylsulfonylamino-3-phenylpropanoyl) prolyl]aminomethylcyclohexane (compound No. 777 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.08 (m, 3H), 7.34 (m, 5H), 4.78 (m, 1H), 4.15 (m, 2H), 3.51 (m, 1H), 3.36 (m, 2H), 2.86 (m, 4H), 2.68 (s, 3H), 2.51 (m, 2H), 2.00-1.69 (m, 6H), 1.27 (m, 4H), 0.92 (m, 2H) IR: 3409, 2936, 1638, 1453, 1314, 1148 Example 36 Trans-4-amino-[(S)-N-((R)-2-isopropoxycarbonylamino-4,4-dimethylpentanoyl) prolyl]aminomethylcyclohexane (compound No. 797 of Table 1) NMR (CDCl 3 ) 7.19 (m, 1H), 5.32 (d, 1H), 4.82 (m, 1H), 4.53 (m, 2H), 4.00 (m, 1H), 3.48 (m, 1H), 3.03-2.16 (m, 6H), 2.00-1.81 (m, 6H), 1.57 (d, 2H), 1.49 (m, 4H), 1.24 (m, 6H), 1.00 (s, 9H), 0.95 (m, 2H) IR: 3326, 2949, 1640, 1541, 1449, 1248 Example 37 Trans-4-amino-[(S)-N-((R)-N'-ethoxycarbonyl-phenylalanyl) prolyl] aminomethylcyclohexane (compound No. 780 of Table 1) hydrochloride NMR (DMSO-d 6 ) 7.98 (m, 3H), 7.37 (t, 1H), 7.26 (m, 5H), 4.37 (dd, 1H), 4.16 (m, 1H), 4.02 (m, 2H), 3.88 (m, 1H), 3.59 (m, 1H), 3.43 (m, 1H), 2.86 (m, 5H), 1.93-1.75 (m, 7H), 1.28 (m, 4H), 1.15 (t, 3H), 0.92 (m, 2H) IR: 3349, 2936, 1642, 1537, 1451, 1258 Example 38 Trans-4-amino-[(S)-((R)-phenylalanyl) prolyl]aminomethylcyclohexane (compound No. 779 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.69 (br, 3H), 8.09 (br, 4H), 7.37-7.20 (m, 5H), 4.19 (br, 1H), 4.09-4.06 (m, 1H), 3.20-2.82 (m, 5H), 2.0-0.85 (m, 15H) IR: 3426, 2936, 1649, 1539, 1497, 1454 Example 39 Trans-4-amino-[(S)-N-((R)-2-ethoxycarbonyloxy-3-phenylpropanoyl) prolyl]aminomethylcyclohexane (compound No. 785 of Table 1) hydrochloride NMR (DMSO-d 6 ) 7.78 (m, 3H), 7.30 (m, 5H), 7.15 (d, 1H), 5.22 (t, 1H), 4.20 (m, 1H), 4.08 (m, 3H), 3.64 (m, 1H), 3.02-2.88 (m, 5H), 1.92-1.72 (m, 7H), 1.20-0.94 (m, 9H) IR: 3397, 2938, 1740, 1655, 1453, 1269 Example 40 Trans-4-amino-[(S)-N-((R)-2-allylcarbamoyloxy-3-phenylpropanoyl) prolyl]aminomethylcyclohexane (compound No. 787 of Table 1) hydrobromide NMR (DMSO-d 6 ) 7.90 (m, 3H), 7.30 (m, 5H), 7.14 (m, 1H), 5.72 (m, 2H), 5.06 (m, 2H), 4.76 (m, 1H), 4.17 (m, 1H), 3.60 (m, 1H), 2.98-2.85 (m, 5H), 1.87-1.70 (m, 7H), 1.23 (m, 7H), 0.90 (m, 2H) IR: 3364, 2936, 1707, 1645, 1543, 1454, 1256 Example 41 Trans-4-amino-[(S)-N-((R)-2-hydroxy-2-cyclohexylacetyl) prolyl] aminomethylcyclohexane (compound No. 768 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.21 (br, 3H), 7.95 (m, 1H), 4.53 (m, 1H), 4.18 (d, 1H), 3.95 (m, 1H), 3.07 (m, 3H), 2.18-1.55 (m, 22H), 1.30-1.03 (m, 2H) IR: 3422, 2928, 2854, 1637, 1450, 1388, 1240, 1114, 1045 Example 42 Trans-4-amino-[(S)-N-((R)-2-hydroxy-2-phenylacetyl) prolyl] aminomethylcyclohexane (compound No. 783 of Table 1) hydrochloride NMR (DMSO-d 6 ) 7.98 (br, 3H), 7.37-7.28 (m, 5H), 5.48 (br, 1H), 5.23 (d, 1H), 4.23 (d, 1H), 3.70-3.35 (m, 2H), 3.0-2.80 (m, 4H), 2.0-1.60 (m, 8H), 1.40-0.90 (m, 5H) IR: 3329, 2935, 1667, 1626, 1552, 1448 Example 43 Trans-4-amino-[(S)-N-[(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl]aminomethylcyclohexane (compound No. 794 of Table 1) NMR (CDCl 3 ) 7.16 (m, 1H), 5.68 (d, 1H), 4.53 (d, 1H), 4.38 (m, 1H), 4.10 (q, 2H), 4.01 (m, 1H), 3.46-3.07 (m, 4H), 2.30-1.81 (m, 8H), 1.58 (m, 5H), 1.26 (t, 3H), 1.00 (s, 9H), 0.95 (m, 2H) IR: 3329, 2949, 1642, 1541, 1447, 1248, 1059 According to the same procedure as that described in Reference Example 1, the following compounds of Examples 44 and 45 were synthesized. Example 44 4-Amidino-[(S)-N-[(R)-2-hydroxy-cyclohexylacetyl] prolyl] aminomethylbenzene (compound No. 82 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.29 (br, 2H), 8.93 (br, 2H), 8.51 (t, 1H), 7.75 (d, 2H), 7.49 (d, 2H), 4.37 (m, 3H), 3.96 (d, 1H), 3.70 (m, 1H), 3.60-3.40 (m, 2H) 2.20-1.0 (m, 14H) IR: 3227, 2922, 1657, 1607, 1539, 1485, 1458, 1323, 1246, 1032 Example 45 4-Amidino-[(S)-N-[(R)-N'-ethoxycarbonylphenylalanyl] prolyl] aminomethylbenzene (compound No.972 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.40 (br, 2H), 9.24 (br, 2H), 8.14 (t, 1H), 7.80 (d, 2H), 7.59 (t, 1H), 7.45 (d, 2H), 7.31-7.15 (m, 5H), 4.50-4.26 (m, 4H), 3.90-3.57 (m, 3H), 3.0-2.7 (m, 3H), 1.9-1.6 (m, 4H), 1.10-1.0 (m, 3H) IR: 3279, 2364, 1637, 1539, 1491, 1450, 1255, 704 According to the same procedures as that described in Example 5 the following compounds of Examples 46 to 53 were synthesized. Example 46 Trans-4-amidino-[(S)-N-[(R)-N'-ethoxycarbonyl-O-t-butyloxy-seryl]prolyl] aminomethylcyclohexane (compound No. 240 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.88 (br, 2H), 8.71 (br, 2H), 7.72 (m, 1H), 6.39 (m, 1H), 4.59 (m, 1H), 4.52 (m, 1H), 4.11 (m, 2H), 3.86-3.71 (m, 2H), 3.58 (m, 2H), 3.22 (m, 2H), 2.79-0.88 (m, 15H), 1.24 (t, 3H), 1.15 (s, 9H) IR: 3271, 2976, 1685, 1647, 1541, 1448, 1257, 1192, 1095, 1055 Example 47 Trans-4-amidino-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-(1',1'-dimethylpropyl)-seryl] prolyl]aminomethylcyclohexane (compound No. 977 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.74 (br, 4H), 7.68 (m, 1H), 6.01 (m, 1H), 4.83 (m, 1H), 4.57 (m, 2H), 3.74 (m, 2H), 3.50 (m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.5-0.9 (m, 16H), 1.24 (dd, 6H), 1.09 (s, 6H), 0.81 (t, 3H) IR: 3314, 2978, 1693, 1641, 1543, 1450, 1375, 1261, 1111, 1059 Example 48 Trans-4-amidino-[(S)-N-[(R)-N'-ethoxycarbonyl-O-(1',1'-dimethylpropyl)-seryl] prolyl]aminomethylcyclohexane (compound No. 978 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.75 (br, 4H), 7.55 (m, 1H), 6.40 (m, 1H), 4.52 (m, 2H), 4.13 (m, 2H), 3.88-3.70 (m, 2H), 3.55 (m, 2H), 3.28 (m, 1H), 2.87-2.70 (m, 1H), 2.20-1.20 (m, 14H), 1.27 (t, 3H), 1.09 (s, 6H), 0.81 (t, 3H), 1.10-0.90 (m, 2H) IR: 3292, 2974, 1689, 1645, 1543, 1448, 1259, 1095, 1055 Example 49 Trans-4-amidino-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-(1'-ethyl-1'-methyl-propyl)-seryl] prolyl]aminomethylcyclohexane (compound No. 979 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.78 (s, 2H), 8.69 (s, 2H), 7.55 (br, 1H), 5.99 (br, 1H), 4.84 (m, 1H), 4.54 (m, 2H), 3.71 (m, 2H), 3.49 (m, 2H), 3.20-0.90 (m, 16H), 1.64 (q, 4H), 1.23 (t, 6H), 1.03 (s, 3H), 0.78 (t, 6H) IR: 3315, 2976, 2934, 1685, 1641, 1543, 1450, 1375, 1261, 1111 Example 50 Trans-4-amidino-[(S)-N-[(R)-N'-ethoxycarbonyl-S-t-butyl-cystinyl]prolyl] aminomethylcyclohexane (compound No. 980 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.82 (br, 2H), 8.74 (br, 2H), 7.47 (m, 1H), 6.63 (m, 1H), 4.60-4.40 (m, 2H), 4.20-4.21 (m, 2H), 4.00 (m, 1H), 3.72 (m, 1H), 3.24 (m, 1H), 2.87 (m, 2H), 2.65 (m, 1H), 2.18-1.31 (m, 12H), 1.31 (s, 9H), 1.27 (t, 3H), 1.10-0.90 (m, 2H) IR: 3298, 2932, 1693, 1641, 1541, 1448, 1304, 1257, 1161, 1047 Example 51 Trans-4-amidino-[(S)-N-[(R)-N'-isopropoxycarbonyl-0-(1'-methylcyclopentyl)-seryl] prolyl]aminomethylcyclohexane (compound No. 981 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.79 (br, 4H), 7.64 (m, 1H), 5.97 (m, 1H), 4.83 (m, 1H), 4.55 (m, 2H), 3.76 (m, 2H), 3.52 (m, 2H), 3.15-1.20 (m, 22H), 1.27-1.13 (m, 9H), 1.13-0.95 (m, 2H) IR: 3329, 2934, 1684, 1639, 1541, 1450, 1261, 1182, 1111, 1060, 918 Example 52 Trans-4-amidino-[(S)-N-[(R)-N'-isopropoxycarbonyl-0-t-butyl-threonyl] prolyl]aminomethylcyclohexane (compound No. 982 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.74 (m, 4H), 7.80 (m, 1H), 5.66 (m, 1H), 4.85 (m, 1H), 4.57 (m, 1H), 4.29 (m, 1H), 3.80-3.60 (m, 3H), 3.05 (m, 2H), 2.60 (m, 1H), 2.50-1.20 (m, 1H), 1.27-1.22 (m, 15H), 1.15 (d, 3H), 1.10-0.90 (m, 2H) IR: 3331, 2978, 1697, 1639, 1543, 1450, 1375, 1265, 1182, 1111 Example 53 Trans-4-amidino-[(S)-N-[(R)-2-ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl] prolyl]aminomethylcyclohexane (compound No. 983 of Table 1) hydrochloride NMR (DMSO-d 6 ) 9.13 (br, 2H), 8.46 (br, 2H), 7.30 (m, 1H), 5.85 (m, 1H), 4.55 (m, 1H), 4.36 (m, 1H), 4.15-3.85 (m, 3H), 3.69 (m, 1H), 3.02 (m, 2H), 2.30 (m, 1H), 2.00-1.20 (m, 13H), 1.48 (s, 3H), 1.33 (s, 3H), 1.30-1.20 (m, 9H), 1.05-0.85 (m, 2H) IR: 3420, 2974, 1635, 1556, 1521, 1448, 1385, 1298, 1259, 1060 According to the same procedures as that described in Example 11, the following compounds of Examples 54 to 80 were synthesized. Example 54 4-[(S)-N-[(R)-2-hydroxy-cyclohexylacetyl] prolyl] aminomethylbenzamidoxime (compound No. 391 of Table 1) NMR (DMSO-d 6 ) 9.55 (br, 1H), 8.31 (t, 1H), 7.59 (d, 2H), 7.24 (d, 2H), 5.73 (br, 2H), 4.57 (m, 1H), 4.26-4.32 (m, 3H), 3.91 (br, 1H), 3.40-3.60 (m, 2H), 2.05-0.80 (m, 15H) IR: 3375, 2926, 2853, 1638, 1561, 1451, 1385, 1244 Example 55 4-[(S)-N-[(R)-N'-isopropoxycarbonyl-phenylalanyl] prolyl] aminomethylbenzamidoxime (compound No. 395 of Table 1) NMR (CDCl 3 ) 7.65 (br, 1H), 7.53 (d, 2H), 7.29-7.19 (m, 8H), 5.89 (d, 2H), 5.01 (br, 2H), 4.58-4.45 (m, 4H), 4.27 (dd, 1H), 3.65 (br, 1H), 3.10-2.93 (m, 2H), 2.58 (q, 1H), 2.17 (br, 1H), 1.90-1.50 (m, 2H), 1.11 (d, 4H), 0.96 (d, 2H) IR: 3331, 2980, 2880, 2365, 1639, 1539, 1452, 126 Example 56 4-[(S)-N-[(R)-2-ethoxycarbonylamino-phenylacetyl] prolyl] aminomethylbenzamidoxime (compound No. 403 of Table 1) NMR (CDCl 3 ) 7.80 (br, 1H), 7.47 (d, 2H), 7.40-7.14 (m, 8H), 6.11 (dd, 1H), 5.43 (dd, 1H), 4.98 (br, 2H), 4.70-4.54 (m, 2H), 4.50-4.20 (m, 1H), 4.15-4.00 (m, 1H), 4.00-3.80 (m, 2H), 3.25-3.19 (m, 1H), 2.30-1.80 (m, 4H), 1.16 (dt, 3H) IR: 3339, 2980, 2365, 1641, 1524, 1437, 1385, 1057 Example 57 4-[(S)-N-[(R)-N'-ethoxycarbonyl-valyl]prolyl] aminomethylbenzamidoxime (compound No. 407 of Table 1) NMR (CDCl 3 ) 7.57 (br, 1H), 7.54 (d, 2H), 7.20 (d, 2H), 5.98 (d, 1H), 4.97 (br, 2H), 4.68-4.59 (m, 2H), 4.24 (dd, 1H), 4.07 (t, 1H), 4.10-4.00 (m, 1H), 3.90-3.80 (m, 1H), 3.60-3.45 (m, 2H), 2.31 (br, 1H), 2.20-1.95 (m, 4H) 1.88 (d, 1H), 1.01 (t, 3H), 0.97 (d, 6H) IR: 3337, 2971, 2878, 2363, 1640, 1539, 1445, 1277, 1238 Example 58 4-[(S)-N-[(R)-2-ethoxycarbonylamino-3,3-dimethylbutanoyl] prolyl] aminomethylbenzamidoxime (compound No. 409 of Table 1) NMR (DMSO-d 6 ) 8.01 (br, 1H), 7.59 (d, 2H), 7.21 (d, 2H), 7.19-7.15 (m, 1H), 5.73 (br, 2H), 4.36-4.24 (m, 4H), 4.0-3.60 (m, 4H), 2.10-1.80 (m, 5H), 1.06 (t, 3H), 0.96 (s, 9H) IR: 3345, 2966, 2364, 1647, 1535, 1443, 1240 Example 59 4-[(S)-N-[(R)-2-ethoxycarbonylamino-heptanoyl) prolyl] aminomethylbenzamidoxime (compound No. 411 of Table 1) NMR (CDCl 3 ) 7.63 (m, 1H), 7.51 (d, 2H), 7.20 (d, 2H), 5.85 (d, 2H), 4.99 (br, 1H), 4.67-4.58 (m, 2H), 4.35-4.28 (m, 2H), 3.99 (br, 1H), 3.86-3.80 (m, 1H), 3.58-3.50 (m, 2H), 2.31 (br, 1H), 2.07-1.90 (m, 3H), 1.80-1.50 (m, 2H), 1.40-1.10 (m, 5H), 1.03 (t, 3H), 1.01-0.84 (m, 3H) IR: 3347, 2961, 2363, 2342, 1641, 1541, 1447, 1263, 1049 Example 60 4-[(S)-N-[(R)-2-t-butyloxycarbonylamino-heptanoyl] prolyl] aminomethylbenzamidoxime (compound No. 412 of Table 1) NMR (CDCl 3 ) 7.74-7.70 (m, 1H), 7.49 (d, 2H), 7.27 (t, 1H), 7.20 (d, 2H), 5.43 (d, 1H), 4.93 (br, 2H), 4.65 (d, 1H), 4.48-4.25 (m, 3H), 3.93 (br, 1H), 3.50 (q, 1H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.70-1.50 (m, 2H), 1.42-1.21 (m, 13H), 0.92-0.80 (m, 3H) IR: 3337, 2961, 2934, 2363, 1641, 1535, 1449, 1368, 1165 Example 61 4-[(S)-N-[(R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylbenzamidoxime (compound No. 418 of Table 1) NMR (CDCl 3 ) 7.58-7.51 (m, 1H), 7.53 (d, 2H), 7.20 (d, 2H), 5.87 (d, 1H), 5.01 (br, 2H), 4.64-4.56 (m, 2H), 4.40 (q, 1H), 4.26 (dd, 1H), 4.10-4.00 (m, 1H), 3.84-3.78 (m, 1H), 3.53-3.47 (m, 2H), 2.32 (br, 1H), 2.10-1.90 (m, 3H), 1.61 (d, 2H), 1.00 (t, 3H), 0.97 (s, 9H) IR: 3324, 2957, 2263, 2342, 1642, 1541, 1445, 1248, 1059 Example 62 4-[(S)-N-[(R)-N'-(ethoxycarbonylmethyl)oxycarbonyl-phenylalanyl] prolyl]aminomethylbenzamidoxime (compound No. 984 of Table 1) NMR (CDCl 3 ) 7.54 (d, 2H), 7.41 (br, 1H), 7.28-7.20 (m, 8H), 6.70 (d, 1H), 5.09 (br, 2H), 4.66 (dd, 1H), 4.60-4.55 (m, 2H), 4.22-4.00 (m, 4H), 4.03 (q, 2H), 3.62 (br, 1H), 3.10-3.02 (m, 2H), 2.60-2.40 (m, 1H), 2.14 (br, 1H), 2.00-1.50 (m, 3H), 1.22 (t, 3H) IR: 3356, 3063, 2980, 2364, 1717, 1641, 1539, 1451, 1213, 702 Example 63 4-[(S)-N-[(R)-2-ethoxycarbonylamino-cyclohexylacetyl] prolyl] aminomethylbenzamidoxime (compound No. 985 of Table 1) NMR (CDCl 3 ) 7.52 (d, 2H), 7.54-7.50 (m, 1H), 7.20 (d, 2H), 6.03 (br, 1H), 4.97 (br, 2H), 4.68 (q, 2H), 4.22 (dd, 1H), 4.12-4.03 (m, 2H), 3.64-3.47 (m, 1H), 3.20 (s, 3H), 2.32 (br, 1H), 2.05-1.60 (m, 9H), 1.28-0.97 (m, 6H) IR: 3343, 2928, 2853, 2365, 1639, 1541, 1449, 1260 Example 64 4-[(S)-N-[(R)-2-ethoxycarbonylamino-2'-thienylacetyl] prolyl] aminomethylbenzamidoxime (compound No. 986 of Table 1) NMR (CDCl 3 ) 7.80-7.60 (m, 1H), 7.46 (dd, 2H), 7.40-6.95 (m, 5H), 6.13 (dd, 1H), 5.71 (dd, 1H), 4.99 (br, 2H), 4.75-4.20 (m, 3H), 4.00-3.80 (m, 2H), 3.70-3.50 (m, 1H),3.40-3.30 (m, 1H), 2.40-1.80 (m, 4H), 1.16 (dt, 3H) IR: 3337, 2978, 2364, 1641, 1524, 1443, 1240, 1057, 710 Example 65 4-[(S)-N-[(R)-2-ethoxycarbonylamino-4'-fluorophenylacetyl] prolyl] aminomethylbenzamidoxime (compound No. 987 of Table 1) NMR (CDCl 3 ) 7.80 (t, 1H), 7.46-7.27 (m, 4H), 7.19-6.92 (m, 4H), 6.19-6.15 (m, 1H), 5.50 (dd, 1H), 5.02 (br, 2H), 4.70-4.20 (m, 3H), 4.10-3.70 (m, 4H), 3.22-3.15 (m, 1H), 2.25-1.80 (m, 4H), 1.16 (dt, 3H) IR: 3345, 3073, 2980, 2363, 2344, 1641, 1510, 1143 Example 66 4-[(S)-N-[(R)-N'-benzyloxycarbonyl-phenylalanyl] prolyl] aminomethylbenzamidoxime (compound No. 988 of Table 1) NMR (CDCl 3 ) 7.50 (d, 2H), 7.49-7.30 (m, 1H), 7.26-7.12 (m, 12H), 6.40-6.10 (m, 1H), 4.85 (br, 2H), 4.90-4.70 (m, 1H), 4.55-4.40 (m, 4H), 4.30-4.20 (m, 1H), 3.70-3.60 (m, 1H), 3.03-2.95 (m, 1H), 2.20-2.15 (m, 1H), 2.00-1.45 (m, 3H) Example 67 4-[(S)-N-(R)-2-t-butyloxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylbenzamidoxime (compound No. 989 of Table 1) NMR (CDCl 3 ) 7.67 (t, 1H), 7.53 (d, 2H), 7.22 (d, 2H), 5.34 (d, 1H), 4.91 (br, 2H), 4.65 (d, 1H), 4.42-4.34 (m, 3H), 4.00-3.90 (m, 1H), 3.48 (q, 1H), 2.40-2.30 (m, 1H), 2.02-1.95 (m, 3H), 1.56-1.53 (m, 2H), 1.31 (s, 9H), 0.98 (s, 9H) IR: 3345, 2959, 2367, 1641, 1535, 1446, 1367, 1167 Example 68 4-[(S)-N-[(R)-N'-dimethylcarbamoyl-phenylalanyl] prolyl] aminomethylbenzamidoxime (compound No. 990 of Table 1) NMR (DMSO-d 6 ) 9.56 (s, 1H), 8.11 (t, 1H), 7.56 (d, 2H), 7.18 (d, 2H), 7.29-7.16 (m, 5H), 6.70 (d, 1H), 5.74 (br, 2H), 4.40-4.05 (m, 4H), 2.94 (d, 2H), 2.93-2.70 (m, 2H), 2.60 (s, 6H), 1.90-1.60 (m, 4H) IR: 3306, 2932, 2880, 2363, 2341, 1634, 1541, 1453 Example 69 4-[(S)-N-[(S)-N'-benzyloxycarbonyl-β-t-butylaspartyl] prolyl] aminomethylbenzamidoxime (compound No. 991 of Table 1) NMR (CDCl 3 ) 7.63 (br, 1H), 7.51 (d, 2H), 7.33-7.26 (m, 5H), 7.18 (d, 2H), 6.07 (d, 1H), 5.08 (dd, 2H), 4.92 (br, 2H), 4.90-4.70 (m, 1H), 4.66 (d, 1H), 4.40 (d, 2H), 3.90-3.80 (m, 2H), 3.0-2.90 (m, 1H), 2.55 (dd, 1H), 2.35-2.20 (m, 1H), 2.08-1.90 (m, 3H), 1.25 (s, 9H) IR: 3364, 3063, 2978, 2363, 2343, 2343, 1717, 1641, 1539, 1450, 1369, 1253 1157 Example 70 Trans-4-[(S)-N-[(R)-N'-ethoxycarbonyl-O-t-butoxy-seryl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 485 of Table 1) NMR (CDCl 3 ) 7.16 (m, 1H), 5.53 (m, 1H), 4.60-4.53 (m, 2H), 4.47 (s, 2H), 4.13-4.06 (m, 2H), 3.76 (br, 2H), 3.60-3.50 (m, 2H), 3.07 (br, 2H), 2.41 (m, 2H), 2.04-1.20 (m, 12H), 1.27 (t, 3H), 1.16 (s, 9H), 1.03-0.94 (m, 2H) IR: 3352, 2930, 1701, 1651, 1541, 1448, 1259, 1053, 754 Example 71 Trans-4-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-t-butylseryl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 486 of Table 1) NMR (CDCl 3 ) 7.19 (m, 1H), 5.40 (d, 1H), 4.87 (m, 1H), 4.61-4..53 (m, 2H), 4.47 (br, 2H), 3.75 (m, 2H), 3.60-3.40 (m, 2H), 3.08 (t, 2H), 2.40 (m, 1H), 2.20-1.20 (m, 12H), 1.21 (dd, 6H), 1.19 (s, 9H), 1.10-0.90 (m, 2H) IR: 3356, 2976, 1697, 1649, 1541, 1448, 1261, 1190, 1109, 1022 Example 72 Trans-4-[(S)-N-[(R)-N'-ethoxycarbonyl-O-t-(1',1'-dimethylpropyl]-seryl)prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 487 of Table 1) NMR (CDCl 3 ) 7.14 (m, 1H), 5.51 (d, 1H), 4.60-4.50 (m, 2H), 4.48 (br, 2H), 4.09 (m, 2H), 3.78 (m, 2H), 3.55-3.45 (m, 2H), 3.06 (m, 2H), 2.35 (m, 1H), 2.20-0.90 (m, 16H), 1.24 (t, 3H), 1.10 (s, 6H), 0.82 (t, 3H) IR: 3346, 2976, 2930, 1649, 1543, 1448, 1261, 1176, 1095, 1055 Example 73 Trans-4-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-(1',1'-dimethylpropyl)-seryl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 488 of Table 1) NMR (CDCl 3 ) 7.18 (m, 1H), 5.38 (d, 1H), 4.86 (m, 1H), 4.61-4.50 (m, 2H), 4.47 (br, 2H), 3.77 (m, 2H), 3.57-3.42 (m, 2H), 3.06 (t, 2H), 2.39 (m, 1H), 2.20-0.90 (m, 16H), 1.23 (dd, 6H), 1.10 (s, 6H), 0.82 (t, 3H) IR: 3346, 2976, 1703, 1651, 1541, 1448, 1263, 1178, 1109, 1030 Example 74 Trans-4-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-(1'-ethyl-1'-methyl-propyl)-seryl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 490 of Table 1) NMR (CDCl 3 ) 7.17 (br, 1H), 5.35 (br, 1H), 4.86 (m, 1H), 4.60-4.50 (m, 2H), 4.47 (br, 2H), 3.78 (m, 2H), 3.53-3.38 (m, 2H), 3.07 (t, 2H), 2.37-1.20 (m, 17H), 1.23 (t, 6H), 1.06 (s, 3H), 1.06-0.82 (m, 2H), 0.79 (t, 6H) IR: 3350, 2976, 2932, 1651, 1541, 1450, 1375, 1263, 1109, 1026 Example 75 Trans-4-[(S)-N-[(R)-N'-ethoxycarbonyl-S-t-butyl-cystinyl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 492 of Table 1) NMR (CDCl 3 ) 7.27 (m, 1H), 5.81 (m, 1H), 4.60-4.40 (m, 2H), 4.88 (br, 2H), 4.11 (m, 2H), 3.87 (m, 1H), 3.68 (m, 1H), 3.06 (m, 2H), 2.90-2.70 (m, 2H), 2.37 (m, 1H), 2.10-1.20 (m, 12H), 1.32 (s, 9H), 1.25 (t, 3H), 1.10-0.90 (m, 2H) IR: 3346, 2930, 1699, 1649, 1541, 1448, 1257, 1163, 1051, 929 Example 76 Trans-4-[(S)-N-[(R)-2-ethoxycarbonylamino-3-isopropylthio-3-methylbutanoyl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 497 of Table 1) NMR (CDCl 3 ) 7.16 (m, 1H), 5.62 (m, 1H), 4.61 (d, 1H), 4.47 (br, 2H), 4.35 (d, 1H), 4.12 (m, 2H), 3.96 (m, 1H), 3.76 (m, 1H), 3.10 (m, 1H), 3.00 (m, 2H), 2.38 (m, 1H), 2.00-1.20 (m, 12H), 1.47 (s, 3H), 1.40 (s, 3H), 1.33-1.25 (m, 9H), 1.00-0.90 (m, 2H) IR: 3354, 2928, 1653, 1541, 1446, 1367, 1302, 1251, 1155, 1055 Example 77 Trans-4-[(S)-N-[(S)-N'-t-butyloxycarbonyl-seryl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 992 of Table 1) NMR (CDCl 3 ) 7.76 (br, 1H), 6.10 (br, 1H), 5.40 (br, 1H), 4.60 (br, 4H), 3.96 (br, 4H), 3.16-1.21 (m, 15H), 1.40 (s, 9H), 0.99 (br, 2H) IR: 3314, 2978, 1691, 1639, 1541, 1450, 1367, 1165, 1049 Example 78 Trans-4-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-t-butyl-threonyl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 993 of Table 1) NMR (CDCl 3 ) 7.24 (m, 1H), 5.43 (d, 1H), 4.85 (m, 1H), 4.57 (d, 1H), 4.47 (br, 2H), 4.23 (t, 1H), 3.92 (t, 1H), 3.80-3.70 (m, 2H), 3.06 (m, 2H), 2.36 (m, 1H), 2.00-1.20 (m, 12H), 1.23 (s, 9H) 1.23 (dd, 6H), 1.15 (d, 3H), 1.10-0.90 (m, 2H) IR: 3354, 2978, 1699, 1649, 1543, 1448, 1373, 1257, 1192, 1111, 1032 Example 79 Trans-4-[(S)-N-[(R)-2-acetoxy-cyclohexylacetyl] prolyl] aminomethylcyclohexanecarboxamidoxime (compound No. 994 of Table 1) NMR (CDCl 3 ) 6.80 (br, 1H), 4.61 (t, 2H), 4.49 (br, 2H), 3.90-3.84 (m, 1H), 3.51-3.40 (m, 1H), 3.10-2.85 (m, 2H), 2.38 (br, 1H), 2.11 (s, 3H), 2.06-0.80 (m, 25H) IR: 3484, 3389, 2928, 2855, 1725, 1649, 1451, 1250 Example 80 Trans-4-[(S)-N-[(R)-N'-isopropoxycarbonyl-O-(1'-methylcyclopentyl)-seryl] prolyl]aminomethylcyclohexanecarboxamidoxime (compound No. 995 of Table 1) NMR (CDCl 3 ) 7.18 (m, 1H), 5.42 (m, 1H), 4.85 (m, 2H), 4.60-4.49 (m, 4H), 3.73 (m, 2H), 3.57-3.42 (m, 2H), 3.08 (m, 1H), 2.40 (m, 1H), 2.04-1.20 (m, 21H), 1.27-1.20 (m, 9H), 1.03-0.94 (m, 2H) IR: 3356, 2932, 1695, 1653, 1541, 1448, 1263, 1111, 1030, 918 According to the same procedures as that described in Reference Example 2, the following compound of Example 81 was synthesized. Example 81 Trans-4-amino-[(S)-N-[(R)-N'-ethoxycarbonyl-O-t-butyloxy-seryl] prolyl] aminomethylcyclohexane (compound No. 1003 of Table 1) hydrochloride NMR (DMSO-d 6 ) 8.29 (s, 3H), 7.20 (s, 1H), 5.69 (d, 1H), 4.58-4.47 (m, 2H), 4.12 (m, 2H), 3.82 (m, 1H), 3.61-3.48 (m, 2H), 3.09 (m, 2H), 2.32-0.86 (m, 15H), 1.27 (t, 3H), 1.16 (s, 9H) IR: 3358, 2974, 1645, 1541, 1448, 1257, 1192, 1053 According to the same procedures as that described in Example 67, the following compounds 126 to 130 were synthesized. Experimental Example 1: Determination of antithrombin activity (i) The measuring method for hydrolysis inhibition of synthetic substrate (S-2238) S-2238 (manufactured by Kabi Co.) is dissolved in a Tris hydrochloric acid buffer solution (pH: 8.3) to prepare a S-2238-0.4 M Tris hydrochloric acid solution having a concentration of 80 µm. To 175 µl of the solution, an aqueous solution of a compound of the present invention (515 µl) is added. After incubating at 37°C for one minute, 10 µl of a bovine thrombin solution (4.4 units/ml, manufactured by Mochida Co., Ltd.) is added. A hydrolysis reaction rate of the substrate is determined by measuring a change in absorbance of 405 nm at 37°C. The inhibitor concentration exhibiting an absorbance which is half as large as that obtained in case of adding no inhibitor (compound of the present invention) was determined as IC 50 (µm). (ii) The measuring method for coagulation inhibition of rat plasma The compound of the present invention is dissolved in water or saline to form a solution of a total volume of 0.1 ml. To the solution, 0.1 ml of rat plasma is added and the mixture is incubated at 37°C for 30 seconds. Then, 0.1 ml of bovine thrombin (8 units/ml, Mochida Co., Ltd.) is added and the coagulation time is measured at 37°C. The concentration of the inhibitor (i.e., the compound of the present invention) which doubles the coagulation time that obtained in the absence of the inhibitor was determined as IC 50 (µm). (iii) The measuring method for antithrombin activity of rat plasma on oral administration To a rat abstained from bait overnight, an aqueous solution or suspension of the present compound (inhibitor) (30 mg/kg) is orally administered using an oral sound. After one hour, 2 ml of blood is collected from cava abdominalis and the antithrombin activity in plasma is measured using a method of the above item (ii). As a control experiment, the coagulation time of blood collected from a rat which has not been administered the inhibitor was measured. The extension effect on the coagulation time is represented by the numerical value obtained by comparing the data with those obtained in control experiment, wherein the numerical value obtained in the control experiment was assumed to be 1. Experimental Example 2: Determination of Antitrypsin activity (i) The measuring method for hydrolysis inhibition of synthetic substrate (S-2222) S-2222 (manufactured by Kabi Co.) is dissolved in a Tris hydrochloric acid (pH: 8.3) to prepare a S-2222-0.4M Tris hydrochloric acid solution having a concentration of 400 µm. To the solution (175 µl), 515 µl of a solution of a compound of the present invention is added. After incubating at 37°C for one minute, 10 µl of a bovine trypsin solution (1 to 2 mg/ml, manufactured by Sigma Co.) is added. A hydrolysis reaction rate of the substrate is determined by measuring a change in absorbance of 405 nm at 37°C. The inhibitor concentration exhibiting an absorbance which is half as large as that obtained in case of adding no inhibitor (compound of the present invention) was determined as IC 50 (µm). The results are shown in Table 2. Antithrombin activity IC 50 (µm) Example No. Synthetic substrate method Rat plasma method Antitrypsin activity IC 50 (µm) Thrombin coagulation time extension coagulation on oral administration Ref 1 1 0.056 3.16 3 0.72 0.59 5 0.011 0.038 2.2 6 0.021 1.7 7 0.015 0.053 3.2 8 0.021 1.0 9 0.014 0.94 10 0.017 0.058 3.6 11 3.28 12 > 300 2.82 13 4.16 14 3.52 15 4.35 17 2.75 18 2.77 19 3.58 20 3.99 22 3.72 23 2.85 24 4.37 26 2.37 27 2.70 28 2.94 29 4.36 30 3.09 33 2.16 34 2.34 Ref 2 0.13 0.045 14 4.10 36 0.13 0.080 14 2.10 37 0.082 38 0.097 2.35 41 0.056 42 0.088 2.18 43 0.13 1.25 Experimental Example 3: Acute toxicity test Acute toxicity was determined in rat. An approximate lethal dose was determined by conducting an oral acute toxicity test using rats. The results are shown in Table 3. Approximate lethal dose mg/kg Male Female Example No. Ref 2 Not less than 2000 Not less than 2000 20 Not less than 2000 Not less than 2000 24 Not less than 2000 Not less than 2000

Claims: A prolineamide derivative represented by the formula (I): wherein A is a carbon atom or a nitrogen atom; n is an integer of 0 to 2; a broken line is no bond or a single bond; R 1 is {wherein D and E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a hydrogen atom, a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -SR 7 (R 7 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -SOR 8 (R 8 is an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -SO 2 R 9 (R 9 is an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -COR 10 (R 10 is a hydroxyl group, a C 1 -C 6 alkoxy group, an optionally substituted C 6 -C 10 aryl group or an optionally substituted C 3 -C 8 cycloalkyl group), -NHR 11 (R 11 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyl group), -NHCOR 12 (R 12 is a C 1 -C 6 alkoxy group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group or an optionally substituted C 7 -C 12 aralkyloxy group), -NHSO 2 R 13 (R 13 is a C 1 -C 6 alkyl group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group, an optionally substituted C 7 -C 12 aralkyl group, or an optionally substituted 5- to 10-membered heterocyclic group), an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 3 -C 8 cycloalkyl group, an optionally substituted 5- to 10-membered heterocyclic group or -SiR 14 R 15 R 16 (R 14 , R 15 , and R 16 independently indicate a C 1 -C 6 alkyl group); R 5 is a -OR 17 (R 17 is a hydrogen atom, -SiR 22 R 23 R 24 (R 22 , R 23 , and R 24 independently indicate a C 1 -C 6 alkyl group), a C 1 -C 6 alkyl group, or an optionally substituted 5- to 10-membered heterocyclic group)), -OCOR 18 (R 18 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, an amino group, a C 1 -C 6 alkylamino group, a C 2 -C 12 dialkylamino group or a C 2 -C 7 alkenylamino group), -NHR 19 (R 19 is a hydrogen atom, a C 1 -C 6 alkyl group or an optionally substituted C 7 -C 12 aralkyl group), -NHCOR 20 (R 20 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 8 cycloalkyl group, a C 2 -C 7 carboxyalkyloxy group, a C 2 -C 7 alkenyloxy group, an optionally substituted C 6 -C 10 aryl group, an optionally substituted C 6 -C 10 aryloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group, a C 2 -C 12 dialkylamino group or an optionally substituted C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 2 -C 7 carboxyalkyl group, an optionally substituted C 6 -C 10 aryl group, a C 3 -C 9 alkoxycarbonylalkyl group or an optionally substituted C 7 -C 12 aralkyl group); and m is 0 or 1 ; each of said 5- to 10-membered heterocyclic groups is independently selected from a furan ring, a tetrahydrofuran ring, a pyran ring, a benzofuran ring, a chroman ring, a thiophene ring, a benzothiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a triazole ring, a pyridine ring, a piperidine ring, a pyrazine ring, a piperazine ring, a pyrimidine ring, an indole ring, a benzimidazole ring, a purine ring, a quinoline ring, a phthalazine ring, a quinazoline ring, a cinnoline ring, an oxazole ring, a thiazole ring and a morpholine ring; each of said optional substituents being independently selected from C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group, a C 1- C 6 alkoxy group, a hydroxyl group, a carboxyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 carboxyalkyloxy group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 alkoxycarbonyloxy group, a C 8 -C 13 aralkyloxycarbonyl group, a C 3 -C 9 alkoxycarboxyalkoxy group and a halogen atom}; R 2 is a hydrogen atom or a C 1 -C 6 alkyl group; and R 3 is -C(=NR 25 )NH 2 (wherein R 25 is a hydrogen atom or a hydroxyl group) or -NH 2 ; provided that R 3 is -C(=NR 25 )NH 2 (R 25 is as defined above) when A is a nitrogen atom, or a salt or hydrate thereof; with the proviso that if the substituent R 2 represents a hydrogen atom, the group "D" represents a single bond, and the index n is 1 or 2, then neither of the substituents R 4 or R 5 represents a group including an aminosulfonyl moiety. A compound according to Claim 1, wherein A is a carbon atom. A compound according to Claim 1 or Claim 2, wherein n is 1 or 2; R 1 is {wherein D and E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a C 1 -C 6 alkyl group; a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group); -SR 7 (R 7 is a C 1 -C 6 alkyl group; a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; or a C 7 -C 12 aralkyl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group); -COOH; a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, a C 2 -C 7 alkoxycarbonyl group, a C 2 -C 7 carboxyalkyl group, a C 2 -C 7 acyl group, a C 2 -C 7 acyloxy group, a C 2 -C 7 alkoxycarbonyloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group and a benzyloxycarbonyl group; a C 3 -C 8 cycloalkyl group; or -SiR 14 R 15 R 16 (R 14 , R 15 , and R 16 independently indicate a C 1 -C 6 alkyl group); R 5 is -OH, -OCOR 18 (R 18 is a C 1 -C 6 alkoxy group or a C 2 -C 7 alkenylamino group), -NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group, a C 6 -C 10 aryloxy group, a C 3 -C 9 alkoxycarbonylalkoxy group, a C 2 -C 12 dialkylamino group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group, a C 2 -C 7 carboxyalkyl group, a C 6 -C 10 aryl group, a C 3 -C 9 alkoxycarbonylalkyl group or a C 7 -C 12 aralkyl group); and m is 0 or 1}; and R 2 is a hydrogen atom. A compound according to Claim 1 or Claim 2, wherein n is 1; R 1 is {wherein D and E independently indicate a single bond or an optionally branched C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group or C 7 -C 12 aralkyl group); -SR 7 (R 7 is a C 1 -C 6 alkyl group); a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group; or a C 3 -C 6 cycloalkyl group; R 5 is -OH, NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group); and m is 1}; and R 2 is a hydrogen atom, A compound according to Claim 1 or Claim 2, wherein n is 1; R 1 is {wherein D is a single bond; E is a single bond or a C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; -OR 6 (R 6 is a C 6 -C 10 aryl group which may be substituted with at least one substituent selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group or C 7 -C 12 aralkyl group); -SR 7 (R 7 is a C 1 -C 6 alkyl group); a C 6 -C 10 aryl group which may be substituted with at least one or more substituents selected from the group consisting of a C 1 -C 6 alkyl group, a halogen atom, a carboxyl group, a C 2 -C 7 carboxyalkyl group and a benzyloxycarbonyl group; or a C 3 -C 6 cycloalkyl group; R 5 is -NH 2 , -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group or a C 7 -C 12 aralkyloxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group); and m is 1}; and R 2 is a hydrogen atom. A compound according to claim 1, wherein A is a carbon atom; n is 1; R 1 is {wherein D is a single bond; E is a single bond or a C 1 -C 3 alkylene group; R 4 is a C 3 -C 6 alkyl group),-OR 6 (R 6 is a C 1 -C 6 alkyl group, a phenyl group, or a C 3 -C 6 cycloalkyl group; R 5 is -OH,-NHR 19 (R 19 is a hydrogen atom), -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group) or -NHSO 2 R 21 (R 21 is a C 1 -C 3 alkyl group); and m is 1}; and R 2 is a hydrogen atom. A compound according to Claim 1 or Claim 2, wherein n is 1; R 1 is {D is a single bond; E is a single bond or a C 1 -C 6 alkylene group; R 4 is a C 1 -C 6 alkyl group; R 5 is -NHCOR 20 (R 20 is a C 1 -C 6 alkoxy group); and m is 1}; R 2 is a hydrogen atom; and R 3 is -C(=NR 25 )NH 2 (R 25 is a hydrogen atom or a hydroxyl group). Trans-4-[(S)-N-((R)-2-ethoxycarbonylamino-4,4-dimethylpentanoyl) prolyl]aminomethylcyclohexanecarboxamidoxime or a salt or hydrate thereof. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 8 and a pharmaceutically acceptable carrier therefor. The use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament effective as a protease inhibitor. A compound according to any of claims 1-8 for use as a medicament. Use of a compound according co any of claims 1-8 for the manufacture of an anti-coagulant medicament. Use of a compound according to any of claims 1-8 for the manufacture of a medicament for the treatment of pancreatitis.

Inventors: IWASE NORIMICHI, MORINAKA YASUHIRO, OHSHIMA MASAHIRO, OKITSU MISAO, SUGAWARA KOICHI, SUGIYAMA SHIGEO, TAMAO YOSHIKUNI, IWASE, NORIMICHI, MORINAKA, YASUHIRO, OHSHIMA, MASAHIRO, OKITSU, MISAO, SUGAWARA, KOICHI, SUGIYAMA, SHIGEO, TAMAO, YOSHIKUNI, IWASE, NORIMICHI, MITSUBISHI CHEMICAL CORP., MORINAKA, YASUHIRO, MITSUBISHI CHEMICAL CORP., OHSHIMA, MASAHIRO, MITSUBISHI CHEMICAL CORP., OKITSU, MISAO, MITSUBISHI CHEMICAL CORP., SUGAWARA, KOICHI, MITSUBISHI CHEMICAL CORP., SUGIYAMA, SHIGEO, MITSUBISHI CHEMICAL CORP., TAMAO, YOSHIKUNI, MITSUBISHI CHEMICAL CORP.
Applicants: MITSUBISHI CHEM CORP, MITSUBISHI CHEMICAL CORPORATION
Application year: 1995
Main classification: C07D207
IPC codes: C07D211, C07D409, C07K5, C07D405, C07D401, C07D207, A61K38