Amidinophenol derivatives

Abstract: Amidinophenol derivatives of the formula (I): wherein R¹ and R² are (i) H, (ii) C1-4 alkyl, (iii) C1-4 alkoxy, (iv) C2-5 acyl, (v) halogen, (vi) NO₂, (vii) benzoyl, (viii) COOR⁴(in which R⁴ is C1-3 alkyl); A is bond, C1-4 alkylene, -C(R⁵)=C(R⁶)- (in which R⁵ and R⁶ are H or C1-4 alkyl); R³ is (i) CON(R⁷)(R⁸), (ii) CON(R⁹)-CH(R⁷)(R⁸) or (iii) (in which R⁷ and R⁸ are (1) H, (2) phenyl, (3) C7-10 phenylalkyl, (4) pheny or C7-10 phenylalkyl substituted by 1or 2 C1-4 alkyl, halogen or R¹¹-COOR¹² (in which R¹¹ is bond, C1-8 alkylene, C2-8 alkenylene, C2-8 alkynylene; R¹² is H, C1-4 alkyl, C7-10 phenylalkyl, phenyl, allyl, propargyl), (5) C1-10 alkyl, (6) C2-10 alkenyl having 1 to 3 double bonds, (7) C2-10 alkynyl having 1 or 2 triple bonds, (8) R 11a -COXR¹²(in which R 11a is (a) bond, (b) C1-8 alkylene, (c) C2-8 alkylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (d) C2-8 alkenylene, (e) C4-8 alkenylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (f) C2-8 alkynylene, (g)C4-8 alkynylene in which 1 or 2 carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene; X is -O- or -NH-), (9) C1-4 alkyl substituted by a 7-14 membered, bi- or tri-cyclic hetero ring containing one N atom, (10) C3-7 cycloalkyl); R⁹ is (1) H, (2) C1-8 alkyl, (3) C7-10 phenylalkyl, (4) C2-10 alkenyl having 1 to 3 double bonds, (5) C2-10 alkynyl having 1 or 2 triple bonds, (6) R¹¹-COOR¹², (7) C3-7 cycloalkyl; is 4-7 membered, mono-cyclic hetero ring containing 1 or 2 N atom; R¹⁰ is H, C7-10 phenylalkyl or COOR¹³(in which R¹³ is H, C1-4 alkyl or C7-10 phenylalkyl)); with the proviso that (i) both R⁷ and R⁸ do not represent hydrogen at the same time, and (ii) when at least one group in R⁷, R⁸ and R⁹ represents the group containing t-butyl ester, the other groups do not represent the group containing carboxy; or an acid addition salt thereof, have inhibitory activities on PLA₂ and on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin, and are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure.

Description: The present invention relates to amidinophenol derivatives, processes for their preparation and pharmaceutical compositions containing them. Phospholipase A 2 (PLA 2 ) is an enzyme which acts on phospholipids existing in cell membrane and hydrolyzes an ester bond at the second position of the phospholipids. There are known two kinds of PLA 2 , i.e., membrane-associated PLA 2 and pancreatic PLA 2 . Membrane-associated PLA 2 acts on phospholipids to release archidonic acid (AA) from the phospholipids. The AA is converted into prostaglandins, thromboxanes and leukotrienes, which are physiologically active substances inducing various inflammatory diseases and allergic diseases. On the other hand, pancreatic PLA 2 degrades phospholipids and destructs cell membrane, thereby to produce lysolecithin having strong cytotoxicity. Recently, much importance has been attached to pancreatitis, severity in pancreatitis and multiple organ failure induced by such destructive activity on cell membrane, and it has been more remarkable. Further, it is reported that membrane-associated PLA 2 is also concerned with these diseases. Accordingly, the inhibition on PLA 2 leads to the suppression of the release of AA, a precursor of various physiologically active substances, and therefore, it is considered to be useful for the prevention and/or the treatment of various inflammatory and allergic diseases. Furthermore, it is considered to be useful for the prevention and/or the treatment of pancreatitis, severity in pancreatitis and multiple organ failure due to the inhibition of destructive activity on cell membrane. Many compounds having an inhibitory activity on PLA 2 are known. For example, there are known guanidinobenzoic acid derivatives such as camostat mesylate (code no. FOY-305) of the formula (X): and nafamostat mesylate (code no. FUT-175) of the formula (Y): (see Japan. J. Pharmacol., 52 , 23-34, 1990). Further, there are known compounds of the formula (Z) : where in R 1z is: (i) C1-4 alkyl, (ii) C1-4 alkoxy, (iii) carboxy, (iv) COOR 4z (in which R 4z is C1-4 alkyl), (v) halogen, (vi) nitro, (vii) sulfo, (viii) benzoyl or (ix) (in which R 5z is hydrogen or guanidino); R 2z and R 3z each, independently, is: (i) NHCO-R 6z (in which R 6z is C1-4 alkyl) or (ii) (in which A z is bond, methylene or ethylene, R 7z and R 8z each, independently, is (1) hydrogen, (2) C1-4 alkyl or (3) amino-protecting group (it refers to (a) COOR 9z in which R 9z is t-butyl or benzyl, (b) acetyl, (c) benzoyl, (d) tosyl or (e) nitro); (definitions not related are omitted) (see the specification of the U.S. Patent Nos. 4,514,416 and 4,570,006). It is disclosed that the compounds have an inhibitory activity on protease such as trypsin, plasmin and anti-complement effect, but it is not entirely known that the compounds have an inhibitory activity on PLA 2 . R 2z and R 3z in the formula (Z) hereinbefore depicted can represent NHCO-R 6z , but the nitrogen atom in the said group is attached directly to a benzene ring, and further R 6z represents only an alkyl group. In the compounds of the present invention, described hereinafter, a benzene ring is substituted by a group CON(R 7 )(R 8 ), CON(R 9 )-CH(R 7 )(R 8 ) or a group of the formula: the carbon atom in the said group being attached to a benzene ring via a group A which may represent, inter alia, a direct bond. From the above viewpoint, it can be said that the compounds of the present invention have a chemical structure quite different from the compounds of the formula (Z). Furthermore, it has never been known that amidinophenol derivatives (compounds of the formula (Z) hereinbefore depicted) have an inhibitory activity on PLA 2 though some guanidinobenzoic acid derivatives (compounds of the formulae (X) and (Y) hereinbefore depicted) have already been known to have the activity. Accordingly, it is quite unexpected from the related arts, that the amidinophenol derivatives of the present invention have an inhibitory activity on PLA 2 . The present invention relates to: compounds of the formula (I): wherein R 1 and R 2 each, independently, is: (i) hydrogen, (ii) C1-4 alkyl, (iii) C1-4 alkoxy, (iv) C2-5 acyl, (v) halogen, (vi) nitro, (vii) benzoyl or (viii) COOR 4 (in which R 4 is C1-3 alkyl); A is a bond, C1-4 alkylene or (in which R 5 and R 6 each independently, is hydrogen or C1-4 alkyl); R 3 is or (in which R 7 and R 8 each, independently, is (1) hydrogen, (2) phenyl, (3) C7-10 phenylalkyl, (4) phenyl or C7-10 phenylalkyl each of which is substituted by one or two substituents selected from C1-4 alkyl, halogen and R 11 -COOR 12 (in which R 11 is (a) a bond, (b) C1-8 alkylene, (c) C2-8 alkenylene or (d) C2-8 alkynylene, and R 12 is (a) hydrogen, (b) C1-4 alkyl, (c) C7-10 phenylalkyl, (d) phenyl, (e) allyl (i.e., -CH 2 CH=CH 2 ) or (f) propargyl (i.e., -CH 2 C≡CH), (5) C1-10 alkyl, (6) C2-10 alkenyl having one to three double bonds, (7) C2-10 alkynyl having one or two triple bonds, (8) R 11a -COXR 12 (in which R 11a is (a) a bond, (b) C1-8 alkylene, (c) C2-8 alkylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (d) C2-8 alkenylene, (e) C4-8 alkenylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (f) C2-8 alkynylene, or (g) C4-8 alkynylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, X is oxygen or -NH-, and R 12 is the same meaning as hereinbefore defined), (9) C1-4 alkyl which is substituted by a 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen, or (10) C3-7 cycloalkyl); R 9 is (1) hydrogen, (2) C1-8 alkyl, (3) C7-10 phenylalkyl, (4) C2-10 alkenyl having one to three double bonds, (5) C2-10 alkynyl having one or two triple bonds, (6) R 11 -COOR 12 (in which R 11 and R 12 are the same meaning as hereinbefore defined), or (7) C3-7 cycloalkyl; is 4-7 membered, mono-cyclic hetero ring containing one or two nitrogen; R 10 is (1) hydrogen, (2) C7-10 phenylalkyl or (3) COOR 13 (in which R 13 is hydrogen, C1-4 alkyl or C7-10 phenylalkyl)); with the proviso that (i) both R 7 and R 8 do not represent hydrogen at the same time, and (ii) when at least one group in R 7 , R 8 and R 9 represents the group containing t-butyl ester, the other groups do not represent the group containing carboxy; or an acid-addition salt thereof. The acid addition salts are preferred. The compounds of the invention may form hydrates: it is to be understood that such hydrates form part of the present invention and that references to the compounds in this specification including the accompanying claims are to be understood as embracing the hydrates. It will be understood that formulae (i) and (ii) may overlap: formula (ii) should be construed as excluding those groupings already embraced by formula (i). The compounds of the invention possess inhibitory activity on PLA 2 and an inhibitory activity on various proteases such as trypsin, plasmin, thrombin, kallikrein, especially trypsin. Throughout the specification including claims, it may be easily understood by those skilled in the art, that all isomers are included in the present invention. For example, the alkyl, alkoxy, alkylene, alkenylene and alkynylene groups include straight-chain and also branched-chain ones, and the double bonds in the alkenylene group include E, Z and EZ mixture. Accordingly, all isomers produced by the existence of asymmetric carbon atoms are included in the present invention when branched-chain alkyl, alkoxy, alkylene, alkenylene, alkynylene etc. exist. In the formula (I), the C1-4 alkyl group represented by R 1 , R 2 , R 5 , R 6 , R 12 and R 13 , and that in R 7 and R 8 , means, methyl, ethyl, propyl, butyl and the isomer thereof. In the formula (I), the C1-4 alkoxy group represented by R 1 and R 2 , means methoxy, ethoxy, propoxy, butoxy and the isomers thereof. In the formula (I), the C1-3 alkyl group represented by R 4 , means methyl, ethyl, propyl and the isomers thereof. In the formula (I), the C2-5 acyl group represented by R 1 and R 2 means acetyl, propionyl, butyryl, valeryl and the isomers thereof. In the formula (I), the C1-10 alkyl group represented by R 7 and R 8 , means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the isomers thereof. In the formula (I), the C1-8 alkyl group represented by R 9 , means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof. In the formula (I), the C7-10 phenylalkyl group represented by R 7 , R 8 , R 9 , R 10 , R 12 and R 13 , means methyl, ethyl, propyl, butyl and the isomers thereof, which are substituted by a phenyl group. In the formula (I), the halogen atom represented by R 1 and R 2 , and that in R 7 and R 8 , mean fluorine, chlorine, bromine and iodine atoms. In the formula (I), the C1-4 alkylene group represented by A, means methylene, ethylene, trimethylene, tetramethylene and the isomers thereof. In the formula (I), the C1-8 alkylene group represented by R 11 and R 11a , means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof. The C2-8 alkenylene group means vinylene propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof. The C2-8 alkynylene group means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof. In the formula (I), the C2-8 alkylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, represented by R 11a , means thiaethylene (i.e., -CH 2 -S- and -S-CH 2 -), thiatrimethylene (i.e., -CH 2 -CH 2 -S-, CH 2 -S-CH 2 - and -S-CH 2 -CH 2 -), thiatetramethylene, thiapentamethylene, thiahexamethylene, thiaheptamethylene, thiaoctamethylene and the isomers thereof, or the group in which one of any methylene group in the said thiaalkylene group, is replaced by a phenylene group (e.g., -CH 2 -S-CH 2 -C 6 H 4 -). The C4-8 alkenylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, means thiabutenylene (i.e., -S-CH 2 -CH=CH- and -CH=CH-CH 2 -S-), thiapentenylene (i.e., -S-CH 2 -CH 2 -CH=CH-, -S-CH 2 -CH=CH-CH 2 - and -CH 2 -S-CH 2 CH=CH-), thiahexenylene, thiaheptenylene, thiaoctenylene and the isomers thereof, or the group in which one of any methylene groups in the said thiaalkenylene group, is replaced by a phenylene group (e.g., -S-CH 2 -CH=CH-C 6 H 4 -). The C4-8 alkynylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, means thiabutynylene (i.e., -S-CH 2 -C≡C- and -C≡C-CH 2 -S), thiapentynylene (i.e., -S-CH 2 -CH 2 -C≡C-, -C≡C-CH 2 -CH 2 -S-, -S-CH 2 -C≡C-CH 2 -, -CH 2 -C≡C-CH 2 -S-, CH 2 -S-CH 2 -C≡C- and -C≡C-CH 2 -S-CH 2 -), thiahexynylene, thiaheptynylene, thiaoctynylene and the isomers thereof, or the group in which one of any methylene groups in the said thiaalkynylene group, is replaced by a phenylene group (e.g., -S-CH 2 -C≡C-C 6 H 4 -). In the formula (I), examples of the 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen, represented by R 7 and R 8 , are indole, indoline, quinoline, 1,2,3,4-tetrahydroquinoline,carbazole etc. In the formula (I), examples of the 4-7 membered, mono-cyclic hetero ring containing one or two nitrogen atoms, represented by: are pyrrole, pyrrolidine, imidazole, imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, etc. In the formula (I), the C2-10 alkenyl having one to three double bonds, represented by R 7 and R 8 , means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatrienyl and the isomers thereof. The C2-10 alkynyl having one or two triple bonds, means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, nonadiynyl, decadiynyl and the isomers thereof. In the formula (I), the cycloalkyl group represented by R 7 , R 8 and R 9 , means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of representative compounds of the present invention are listed as follows: (1) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)ethoxycarbonylphenyl-N-ethoxycarbonylmethylamide, (2) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)ethoxycarbonylphenyl-N-benzyloxycarbonylmethylamide, (3) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)ethoxycarbonylphenyl-N-allyloxycarbonylmethylamide, (4) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)ethoxycarbonylphenyl-N-propargyloxycarbonylmethylamide, (5) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylmethyl)phenyl-N-ethoxycarbonylmethylamide, (6) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylmethyl)phenyl-N-benzyloxycarbonylmethylamide, (7) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylmethyl)phenyl-N-allyloxycarbonylmethylamide, (8) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylmethyl)phenyl-N-propargyloxycarbonylmethylamide, (9) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylphenyl)methyl-N-ethoxycarbonylmethylamide, (10) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylphenyl)methyl-N-benzyloxycarbonylmethylamide, (11) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylphenyl)methyl-N-allyloxycarbonylmethylamide, (12) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(o, m, p)(ethoxycarbonylphenyl)methyl-N-propargyloxycarbonylmethylamide, (13) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[(o, m, p)(ethoxycarbonylmethyl)phenyl]methyl-N-ethoxycarbonylmethylamide, (14) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[(o, m, p)(ethoxycarbonylmethyl)phenyl]methyl-N-benzyloxycarbonylmethylamide, (15) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[(o, m, p)-(ethoxycarbonylmethyl)phenyl]methyl-N-allyloxycarbonylmethylamide, (16) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[(o, m, p)(ethoxycarbonylmethyl)phenyl]methyl-N-propargyloxycarbonylmethylamide, (17) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethenyl-N-ethoxycarbonylmethylamide, (18) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethenyl-N-benzyloxycarbonylmethylamide, (19) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethenyl-N-allyloxycarbonylmethylamide, (20) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethenyl-N-propargyloxycarbonylmethylamide, (21) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-methyl-2-ethoxycarbonylethenyl-N-ethoxycarbonylmethylamide, (22) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-methyl-2-ethoxycarbonylethenyl-N-benzyloxycarbonylmethylamide, (23) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-methyl-2-ethoxycarbonylethenyl-N-allyloxycarbonylmethylamide, (24) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-methyl-2-ethoxycarbonylethenyl-N-propargyloxycarbonylmethylamide, (25) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonyl-1-propenyl-N-ethoxycarbonylmethylamide, (26) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonyl-1-propenyl-N-benzyloxycarbonylmethylamide, (27) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonyl-1-propenyl-N-allyloxycarbonylmethylamide, (28) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonyl-1-propenyl-N-propargyloxycarbonylmethylamide, (29) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethynyl-N-ethoxycarbonylmethylamide, (30) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethylny-N-benzyloxycarbonylmethylamide, (31) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethynyl-N-allyloxycarbonylmethylamide, (32) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-ethoxycarbonylethynyl-N-propargyloxycarbonylmethylamide, (33) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-1-phenylmethyl)methyl-N-ethoxycarbonylmethylamide, (34) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-benzyloxycarbonyl-1-phenylmethyl)methyl-N-ethoxycarbonylmethylamide, (35) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-1-phenylmethyl)methyl-N-benzyloxycarbonylmethylamide, (36) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)ethoxycarbonylphenyl-1-ethoxycarbonyl]methylamide, (37) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)ethoxycarbonyl-phenyl-1-benzyloxycarbonyl]methylamide, (38) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)ethoxycarbonyl phenyl-1-allyloxycarbonyl]methylamide, (39) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)ethoxycarbonylphenyl-1-propargyloxycarbonyl]methylamide, (40) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)(ethoxycarbonylmethyl)phenyl-1-ethoxycarbonyl]methylamide, (41) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)(ethoxycarbonylmethyl)phenyl-1-benzyloxycarbonyl]methylamide, (42) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)(ethoxycarbonylmethyl)phenyl-1-allyloxycarbonyl]methylamide, (43) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-(o, m, p)(ethoxycarbonylmethyl)phenyl-1-propargyloxycarbonyl]methylamide (44) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[2, 3-bis(ethoxycarbonyl)]phenylamide, (45) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[2, 4-bis(ethoxycarbonyl)]phenylamide, (46) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[2, 5-bis(ethoxycarbonyl)]phenylamide, (47) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[2, 6-bis(ethoxycarbonyl)]phenylamide, (48) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[3, 4-bis(ethoxycarbonyl)]phenylamide, (49) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[3, 5-bis(ethoxycarbonyl)]phenylamide, (50) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-3-benzyloxycarbonyl)propylamide, (51) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-benzyloxycarbonyl-3-ethoxycarbonyl)propylamide, (52) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1, 2-bis(ethoxycarbonyl)]ethylamide, (53) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-2-benzyloxycarbonyl)ethylamide, (54) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-be nzyloxycarbonyl-2-ethoxycarbonyl)ethylamide, (55) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[bis(ethoxycarbonyl)]methylamide, (56) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-1-benzyloxycarbonyl)methylamide, (57) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[bis(ethoxycarbonylmethyl)]methylamide, (58) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonylmethyl-2-benzyloxycarbonyl)ethylamide, (59) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-bis(1, 3-ethoxycarbonyl)-2-propenylamide, (60) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-3-benzyloxycarbonyl)-2-propenylamide, (61) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-benzyloxycarbonyl-3-ethoxycarbonyl)-2-propenylamide, (62) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-bis(1, 3-ethoxycarbonyl)-2-butenylamide, (63) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-3-benzyloxycarbonyl)-2-butenylamide, (64) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-benzyloxycarbonyl-3-ethoxycarbonyl)-2-butenylamide, (65) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[bis(1,3-ethoxycarbonyl)-2-methyl]propenylamide, (66) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-2-methyl-3-benzyloxycarbonyl)propenylamide, (67) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-benzyloxycarbonyl-2-methyl-3-ethoxycarbonyl)propenylamide, (68) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[ethoxycarbonyl-1-(3-quinolylmethyl)]methylamide, (69) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-[1-ethoxycarbonyl-1-(3-carbazoylmethyl)]methylamide, (70) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-phenylamide, (71) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-phenylmethylamide, (72) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-propargylamide, (73) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-(4-ethoxycarbonylphenyl)methylamide, (74) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-ethoxycarbonyl-N-(4-carboxyphenyl)methylamide, (75) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-(4-carboxyphenyl)methylamide, (76) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxy-2-propynyl-N-allylamide, (77) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-methyl-2-butynyl-N-carboxymethylamide, (78) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-ethoxycarbonyl-2-propynyl-N-carboxymethylamide, (79) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxy-2-propynyl-N-ethoxycarbonyl methylamide, (80) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxy-2-propynyl-N-carboxymethylamide, (81) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-ethoxycarbonylpropyl-N-(1-carboxy-1-ethoxycarbonyl)methylamide, (82) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-ethoxycarbonylpropyl-N-bis(carboxy)methylamide, (83) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxypropyl-N-bis(ethoxycarbonyl)methylamide, (84) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxypropyl-N-(1-ethoxycarbonyl-1-carboxy)methylamide, (85) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxypropyl-N-bis(carboxy) methylamide, (86) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxypropyl-N-allylamide, (87) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-2,4-hexadienylamide, (88) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-2-carboxyethyl-N-2-ethoxycarbonylethylamide, (89) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N,N-bis(2-carboxyethyl)amide, (90) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-propylamide, (91) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-2-carboxy)ethyl-N-2-ethoxycarbonylethylamide, (92) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-ethoxycarbonyl)ethyl-N-2-ethoxycarbonylethylamide, (93) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S),2-bis(carboxy)ethyl)-N-2-ethoxycarbonylethylamide, (94) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S),2-bis(ethoxycarbonyl)ethyl)-N-2-carboxyethylamide, (95) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)ethoxycarbonyl-2-carboxy)ethyl-N-2-carboxyethylamide, (96) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-ethoxycarbonyl)ethyl-N-2-carboxyethylamide, (97) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-(S),2-bis(carboxy)ethyl-N-2-carboxyethylamide, (98) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-3-ethoxycarbonyl)propylamide, (99) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-3-carboxy)propylamide, (100) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-(S),3-bis(carboxy)propylamide, (101) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-ethoxycarbonyl)ethylamide, (102) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-2-carboxy)ethylamide, (103) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-(S),2-bis(carboxy)ethylamide, (104) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(R)-carboxy-3-ethoxycarbonyl)propylamide, (105) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(R)-ethoxycarbonyl-3-carboxy)propylamide, (106) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1-(R),3-bis(carboxy)propylamide, (107) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(ethoxycarbonyl methylthio))ethylamide, (108) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-2-(carboxymethylthio))ethylamide, (109) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(carboxymethylthio))ethylamide, (110) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-3-benzyloxycarbonyl)propylamide, (111) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-benzyloxycarbonyl-3-carboxy)propylamide, (112) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-benzyloxycarbonyl-2-carboxy)ethylamide, (113) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-benzyloxycarbonyl)ethylamide, (114) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-carboxy-4-ethoxycarbonyl)butylamide, (115) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-4-carboxy)butylamide, (116) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1,4-bis(carboxy)butylamide, (117) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-carboxy-5-ethoxycarbonyl)pentylamide, (118) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-5-carboxy)pentylamide, (119) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1,5-bis(carboxy)pentylamide, (120) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethylamide, (121) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-carboxymethyl-1-ethoxycarbonylmethyl) methylamide, (122) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-1,1-bis(carboxymethyl)methylamide, (123) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(2-ethoxycarbonylethylthio))ethylamide, (124) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-2-(2-carboxyethylthio))ethylamide, (125) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(2-carboxyethylthio))ethylamide, (126) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(3-ethoxycarbonylpropylthio))ethylamide, (127) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-2-(3-carboxypropylthio))ethylamide, (128) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-carboxy-2-(3-carboxypropylthio))ethylamide, (129) p-(p-Amidinophenoxycarbonyl)cinnamic acid N-(1-(S)-carboxy-3-ethoxycarbonyl)propylamide, (130) p-(p-Amidinophenoxycarbonyl)cinnamic acid N-(1-(S)-ethoxycarbonyl-3-carboxy)propylamide, (131) p-(p-Amidinophenoxycarbonyl)cinnamic acid N-(1-(S),3-bis(carboxy)propyl)amide, (132) p-(p-Amidinophenoxycarbonyl)-β-methylcinnamic acid N-(1-(S)-carboxy-3-ethoxycarbonyl)propylamide, (133) p-(p-Amidinophenoxycarbonyl)-β-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-3-carboxy)propylamide, (134) p-(p-Amidinophenoxycarbonyl)-β-methylcinnamic acid N-(1-(S),3-bis(carboxy)propyl)amide; and N-benzyl, N-allyl and N-propargyl compounds corresponding to compounds (33) to (66) and (99) to (134) hereinbefore described; and (135) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(2-ethoxycarbonylperhydroazepinyl)amide, (136) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(2-ethoxycarbonylpiperidino)amide; and further the compounds prepared in Examples hereinafter described. Acid Addition Salts The compounds of the formula (I), of the present invention may be converted into the corresponding acid addition salts by known method. Non toxic and water-soluble salts are preferable. Suitable acid addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid and nitric acid, and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid. According to a feature of the present invention, the compounds of the formula (I) of the present invention, in which all of R 7 , R 8 , R 9 and R 10 , in R 3 , represent groups not containing COOH and COOt-Bu, i.e., the compounds of the formula (la): wherein R 1 , R 2 and A are the same meanings as hereinbefore defined, and R 3a is the same meaning as hereinbefore defined for R 3 , provided that all of R 7 , R 8 R 9 and R 10 , in R 3 , are groups not containing COOH and COOt-Bu, may be prepared by esterification of a compound of the formula (IIa): wherein R 2 , R 3a and A are the same meanings as hereinbefore defined, with a compound of the formula (III): wherein R 1 is the same meaning as hereinbefore defined. The said esterification is known and can be carried out by methods for example: (1) using an acid halide, (2) using a mixed acid anhydride, (3) using a condensing agent etc. Each of these methods can be carried out, for example, as follows: (1) the method using an acid halide may be carried out, for example, by reacting a carboxylic acid with an acid halide (e.g., oxalyl chloride, thionyl chloride etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at from -20°C to the reflux temperature of the solvent, and then by reacting the acid halide obtained with a corresponding alcohol in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0°C to 40°C, (2) the method using a mixed acid anhydride may be carried out, for example, by reacting a carboxylic acid and an acid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (e.g., ethyl chloroformate, isobutyl chloroformate etc.) in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without a solvent at a temperature of from 0°C to 40°C, and then by reacting the mixed acid anhydride obtained with a corresponding alcohol in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), at a temperature of from 0°C to 40°C, and (3) the method using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 2-chloro-1-methylpyridinium iodide etc.) may be carried out, for example, by reacting a carboxylic acid with a corresponding alcohol using a condensing agent in the presence or absence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inert organic solvent (e.g., chloroform, methylene chloride, dimethyl formamide,diethyl ether etc.) or without a solvent at a temperature of from 0°C to 40°C. The reactions (1), (2) and (3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (e.g., argon, nitrogen etc.) under anhydrous conditions. In the compounds of the formula (I), those in which at least one group of R 7 , R 8 and R 9 , in R 3 , represents a group containing COOt-Bu and the other groups represent ones not containing COOH, or R 10 represents COOt-Bu, i.e., the compounds of the formula (Ib): wherein R 1 , R 2 and A are the same meanings as hereinbefore defined and R 3b is the same meaning as hereinbefore defined for R 3 , provided that at least one group of R 7 , R 8 and R 9 , in R 3 , is a group containing COOt-Bu and the other groups are ones not containing COOH, or R 10 is COOt-Bu, may be prepared by amidation of a compound of the formula (IIb): wherein the various symbols are the same meanings as hereinbefore defined, with a compound of the formula (IIIb): wherein R 7b , R 8b , R 9b and R 10b are the same meanings as hereinbefore defined for R 7 , R 8 R 9 and R 10 , respectively, provided that at least one group of R 7b , R 8b and R 9b is a group containing COOt-Bu and the other groups are ones not containing COOH, or R 10b is COOt-Bu. The said amidation can be carried out by the same condition as hereinbefore described for the esterification using an amine of the formula (IIIb) instead of an alcohol of the formula (III). In the compounds of the formula (I), those in which at least one group of R 7 , R 8 and R 9 , in R 3 . represents a group containing COOH and the other groups represent ones not containing COOt-Bu, or R 10 represents COOH, i.e., the compounds of the formula (Ic): wherein R 1 , R 2 and A are the same meanings as hereinbefore defined and R 3c is the same meaning as hereinbefore defined for R 3 , provided that at least one group of R 7 , R 8 and R 9 , in R 3 , is a group containing COOH and the other groups are ones not containing COOt-Bu, or R 10 is COOH, may be prepared by the hydrolysis of t-butyl ester group, of a compound of the formula (Ib) in which the various symbols are the same meanings as hereinbefore defined. The hydrolysis of t-butyl ester group may be carried out, for example, by using an organic acid (e.g., trifluoroacetic acid etc.) or an inorganic acid (e.g., hydrochloric acid etc.), or the mixture thereof, in an inert organic solvent (e.g., methylene chloride, chloroform, methanol, dioxane, ethyl acetate, anisole etc.) at a temperature of from 0°C to 90°C. In the compounds of the formula (IIa), those in which all of R 7 , R 8 and R 9 , in R 3a , represent groups not containing benzyloxycarbonyl, allyloxycarbonyl and propargyloxycarbonyl, or R 10 in R 3a represents a group other than benzyloxycarbonyl, i.e., the compounds of the formula (IIa-1): wherein R 2 and A are the same meanings as hereinbefore defined and R 31a is the same meaning as hereinbefore defined for R 3a , provided that all of R 7 , R 8 and R 9 , in R 3a , are groups not containing benzyloxycarbonyl, allyloxycarbonyl and propargyloxycarbonyl, or R 10 in R 3a is not benzyloxycarbonyl, may be prepared by methods known per se, for example, by a series of reactions depicted in the following Scheme A. In the Scheme A, R 2 , A and R 31a are the same meanings as hereinbefore defined and R 71a , R 81a and R 91a are the same meanings as hereinbefore defined for R 7 , R 8 and R 9 , respectively, provided that all of R 7 R 8 and R 9 are groups not containing benzyloxycarbonyl, allyloxycarbonyl and propargyloxycarbonyl, or R 101a is the same meaning as hereinbefore defined for R 10 , provided that R 10 is not benzyloxycarbonyl. In the compounds of the formula (IIa), those in which at least one group of R 7 , R 8 and R 9 , in R 3a , represents a group containing benzyloxycarbonyl, allyloxycarbonyl or propargyloxycarbonyl, or those in which R 10 in R3a represents benzyloxycarbonyl, i.e., the compounds of the formula (IIa-2): wherein R 2 and A are the same meanings as hereinbefore defined and R 32a is the same meaning as hereinbefore defined for R 3a , provided that at least one group of R 7 , R 8 and R 9 , in R 3a , is a group containing benzyloxycarbonyl, allyloxycarbonyl or propargyloxycarbonyl, or R 10 in R 3a is benzyloxycarbonyl, may be prepared by methods known per se, for example, by a series of reactions depicted in the following Scheme B. In the Scheme B, R 2 , A and R 32a are the same meanings as hereinbefore defined and R 72a , R 82a and R 92a are the same meanings as hereinbefore defined for R 7 , R 8 and R 9 , respectively, provided that at least one group of R 7 , R 8 and R 9 is a group containing benzyloxycarbonyl, allyloxycarbonyl or propargyloxycarbonyl, and R 102a is benzyloxycarbonyl. The compounds of the formula (llb) may be prepared by methods known per se, for example, by a seried of reactions depicted in the following Scheme C. In the Scheme C, A, R 1 and R 2 are the same meanings as hereinbefore defined. In the Scheme A, B and C, CH 3 SO 3 H is methanesulfonic acid, CF 3 COOH is trifluoroacetic acid. The reactions in schemes hereinbefore depicted may be carried out by methods known per se. The compounds of the formulae (IV), (V), (VI) and (VII) used as starting materials in the schemes hereinbefore depicted, are known per se or may be easily prepared by methods known per se. In each reaction in the present specification, products may be purified by conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions. Other starting materials and each reagents are known per se or may be prepared by known methods. Pharmacological Activity It has been confirmed that the compounds of the formula (I), of the present invention have inhibitory activities on PLA 2 and on various proteases such as trypsin, plasmin, thrombin and kallikrein, especially trypsin. For example, in laboratory tests the following results were obtained. Method (1) Inhibitory activity on PLA 2 A reaction solution including 50 mM tris-HCl buffer (pH7.5, 874 µl; containing 100 mM sodium chloride, 1 mM EDTA), 1M calcium chloride (6 µl), 1% bovine serum albumin (10 µl) and 2.5 mM 10PY-PC (10 µl), was prepared. To the solution were added a test compound in various concentration or water (50 µl), and a solution of 10 mU/ml PLA 2 (derived from hog pancreas) (50 µl). The appearance of fluorescence was measured (Ex=345 nm, Em=396 nm). Percentage (%) of the strength of fluorescence in the presence of a test compound was calculated when the strength of that in the absence thereof was regarded as 100%, and therefrom IC 50 value was calculated. The results are shown in the following Table 1. Inhibitory Activity on PLA 2 Compound (Example No.) IC 50 (µM) 1 4.8 1 (d) 63 1 (g) 5.3 1 (i) 28 1 (k) 3.1 1 (t) 24 2 (a) 15 2 (f) 32 (2) Inhibitory activity on trypsin To a mixture of a 0.2M HEPES·sodium hydroxide buffer solution (pH8.0, 100 µl) and distilled water (640 µl), were added a test compound in various concentration or water (10 µl), and a solution of 80 mU/ml trypsin (derived from bovine pancreas) (50 µl) and then the mixture was preincubated for one minute at 30°C. To the solution thus obtained was added 2.5 mM BAPNA (200 µl) and the mixture was incubated for 30 min. The absorbance at 405 nm was measured. Percentage (%) of the absorbance in the presence of a test compound was calculated when the absorbance in the absence thereof was regarded as 100%, and therefrom IC 50 value was calculated. The results are shown in the following Table 2. Inhibitory Activity on trypsin Compound (Example No.) IC 50 (µM) 1 0.14 1 (d) 0.13 1 (g) 0.14 1 (i) 0.13 1 (k) 0.22 1 (p) 0.15 1 (t) 0.22 2 (a) 0.14 2 (f) 0.14 4 0.10 In the methods hereinbefore described, 10PY-PC represents 3'-palmitoyl-2-(1-pyrenedecanoyl)-L-α-phosphatidylcholine, HEPES represents 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, and BAPNA represents α-N-benzoyl-DL-arginine-p-nitroanilide hydrochloride. The toxicity of the compounds of the present invention is very weak. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for pharmaceutical use. Application for pharmaceuticals The inhibition on PLA 2 and on various proteases such as trypsin, plasmin, thrombin and kallikrein, especially trypsin in mammals including human beings, especially human beings are useful for the prevention and/or the treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis and multiple organ failure. For the purpose hereinbefore described, the compounds of the formula (I) of the present invention and non-toxic acid addition salts thereof may be normally administered systemically or partially, usually by oral or parenteral administration. The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 1 mg and 100 mg, by parenteral administration (preferably, intravenously) up to several times per day, or continuous administration between 1 and 24 hrs. per day from vein. As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified-above may be used. When administering the compounds of the present invention, it is used as solid compositions, liquid compositions or other compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration. Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules. In such compositions, one or more of the active compound(s) is or are admixed with at least one inert diluent (such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.). The compositions may also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (such as magnesium stearate etc.), disintegrating agents (such as cellulose calcium glycolate, etc.), stabilizing agents (such as lactose, etc.), and assisting agents for dissolving (such as glutamic acid, asparaginic acid etc.). The tablets or pills may, if desired, be coated with a film of gastric or enteric material (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phtalate etc.), or be coated with more than two films. And further, coating may include containment within capsules of absorbable materials such as gelatin. Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs. The compositions may also comprise inert diluents commonly used in the art (purified water, ethanol etc.). Besides inert diluents, such compositions may also comprise adjuvants (such as wetting agents, suspending agents, etc.), sweetening agents, flavouring agents, perfuming agents, and preserving agents. Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (sodium sulfate etc.), isotonic buffer (sodium chloride, sodium citrate, citric acid, etc.). For preparation of such spray compositions, for example, the method described in the United States Patent No. 2868691 or 3095355 may be used. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsion. In such compositions, one more of active compound(s) is or are admixed with at least one of inert aqueous diluent(s) (distilled water for injection, physiological salt solution etc.) or inert non-aqueous diluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol, POLYSORBATE80 (registered trade mark) etc.). Injections may comprise additional other than inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent (lactose etc.), assisting agents such as assisting agents for dissolving (glutamic acid, asparaginic acid etc.). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions, for example, by freeze-drying, and which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before used. Other compositions for parenteral administration include endermic ones such as liquids for external use, ointment, and endermic liniments, and suppositories and pessaries for intrarectal administration which comprise one or more of the active compound(s) and may be prepared by per se known methods. Examples The following reference examples and examples illustrate, but not limit, the present invention. The solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. Unless otherwise specified, "IR" was measured by KBr method, and "NMR" was measured in a solution of deuteromethanol. Reference Example 1 p-Benzyloxycarbonyl-α-methylcinnamic acid t-butyl ester To a suspension of sodium hydride (0.8 g, containing 60% oil) in tetrahydrofuran (25 ml) was added slowly dropwise a solution of 2-(diethylphosphono) propionic acid t-butyl ester (4.8 g) in tetrahydrofuran (6 ml) under cooling with ice, and the mixture was stirred for 30 min. at room temperature. After the reaction mixture was cooled with ice, a solution of p-benzyloxycarbonylbenzaldehyde (4.0 g) in tetrahydrofuran (15 ml) was added slowly dropwise thereto. The mixture was stirred for 30 min. at room temperature, water was added thereto, and then the reaction mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (hexane : ethyl acetate=20:1→15:1) to give the title compound (5.2 g) having the following physical data: TLC: Rf 0.34 (hexane : ethyl acetate=10:1). Reference Example 2 p-Benzyloxycarbonyl-α-methylcinnamic acid To a solution of the compound prepared in Reference Example 1 (56.0 g) in anisole (40 ml) was added trifluoroacetic acid (75 ml) under cooling with ice. After stirred for two hours at room temperature, the reaction mixture was concentrated under reduced pressure. Thus obtained white solid was washed with isopropyl ether, filtered, and dried under reduced pressure to give the title compound (39.57 g) as white crystal having the following physical data: TLC: Rf 0.26 (hexane : ethyl acetate : acetic acid=12 : 4 : 1). Reference Example 3 p-(Benzyloxycarbonyl)acetophenone To a solution of p-acetylbenzoic acid (16.4 g) in dimethylformamide (100 ml) were added successively potassium carbonate (27.6 g) and benzyl bromide (13 ml). The mixture was stirred for 13 hours at room temperature. After quenched by addition of water, the reaction mixture was extracted with a mixture of hexane and ethyl acetate (3 : 1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (hexane : ethyl acetate=9 : 1→6 : 1 ) to give the title compound (16 g) having the following physical data: TLC : Rf 0.63 (hexane : ethyl acetate : acetic acid=12 : 4 : 1). Reference Example 4 p-(Benzyloxycarbonyl)-β-methylcinnamic acid By the same procedure as a series of reactions of Reference Example 1→Reference Example 2, using the compound prepared in Reference Example 3 instead of p-benzyloxycarbonylbenzaldehyde, the title compound having the following physical data was given: TLC: Rf 0.45 (hexane : ethyl acetate : acetic acid=12 : 4 : 1). Reference Example 5 p-(t-Butoxycarbonyl)benzaldehyde To a solution of p-(t-butoxycarbonyl)benzoic acid (13.32 g) in tetrahydrofuran (100 ml) and triethylamine (10 ml), was added slowly dropwise ethyl chloroformate (6.8 ml) under cooling with ice, under an atmosphere of argon. After the mixture was stirred for two hours at room temperature, triethylamine·hydrochloride precipitated was filtered off. To the filtrate thus obtained were added slowly sodium borohydride (4.54 g) and water (20 ml) under cooling with ice. After stirred for one hour at room temperature, the reaction mixture was quenched by addition with water. The reaction mixture was extracted with a mixture of hexane and ethyl acetate (1 : 1). The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=10 : 1→4 : 1). To a solution of p-(t-butoxycarbonyl)benzyl alcohol (7.28 g) thus obtained in dimethyl sulfoxide (90 ml) and triethylamine (25 ml) was added a solution of sulfur trioxide-pyridine complex (19.75 g) in dimethyl sulfoxide (70 ml). After stirred for 30 min. at room temperature, the reaction mixture was quenched by addition of water. The reaction mixture was acidified by addition of 1N hydrochloric acid, and then extracted with a mixture of hexane and ethyl acetate (3 : 1). The extract was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give the title compound (7.2 g) having the following physical data: TLC : Rf 0.59 (hexane : ethyl acetate=2 : 1). Reference Example 6 p-(t-Butoxycarbonyl)-α-methylcinnamic acid ethyl ester By the same procedure as Reference Example 1, using the compound prepared in Reference Example 5 instead of p-benzyloxycarbonylbenzaldehyde, the title compound having the following physical data was given: TLC : Rf 0.58 (hexane : ethyl acetate=4 : 1). Reference Example 7 p-(t-Butoxycarbonyl)-α-methylcinnamic acid To a solution of the compound prepared in Reference Example 6 (8.1 g) in ethanol (60 ml) was added 5N aqueous solution of sodium hydroxide (6 ml) under cooling with ice. After stirred overnight at room temperature, the reaction mixture was quenched by addition of 2N hydrochloric acid (15 ml), and then evaporated till the volume of the solution became 1/2. An aqueous solution thus obtained was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give the title compound (7.3 g) having the following physical data: TLC: Rf 0.41 (hexane : ethyl acetate : acetic acid=12 : 6 : 1). Reference Example 8 p-(p-Methoxybenzyloxycarbonyl)cinnamic acid To a solution of (p-carboxy)benzaldehyde (15 g) in dimethylformamide (200 ml) were added successively potassium carbonate (27.6 g) and p-methoxybenzyl chloride (15 ml). After stirred for 17 hours at room temperature, the reaction mixture was quenched by addition of water and then extracted twice with a mixture of hexane and ethyl acetate (2 : 1). The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. To a solution of the aldehyde compound thus obtained in pyridine (100 ml) were added successively malonic acid (20.8 g) and piperidine (5 ml). After stirred for one hour at 80°C, the reaction mixture was quenched by addition of ice-water, and then neutralized by addition of 1N hydrochloric acid. The crystals thus obtained were filtered, washed with water and ether, successively, and then dried to give the title compound (17.4 g) as white solid having the following physical data: TLC: Rf 0.37 (chloroform : methanol=9 : 1). Reference Example 9 p-Benzyloxycarbonyl-α-methylcinnamic acid N-ethoxycarbonylmethyl-N-phenylmethylamide A suspension of the compound prepared in Reference Example 2 (4 g) in methylene chloride (15 ml) was added oxalyl chloride (5.8 ml) at room temperature. The mixture was stirred for one hour at room temperature and then evaporated. A solution of acid chloride thus obtained, in methylene chloride (20 ml) was added slowly dropwise to a solution of N-ethoxycarbonylmethyl-N-phenylmethylamine (2.61 ml) in a mixture of methylene chloride (28 ml) and pyridine (2.2 ml) under cooling with ice. The reaction mixture was stirred for 30 min. at room temperature, water was added thereto and then the reaction mixture was extracted with ether. The extract was washed with 1N hydrochloric acid, 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (hexane : ethyl acetate=9 : 1→3 : 1) to give the title compound (5.78 g) having the following physical data: TLC : Rf 0.39 (hexane : ethyl acetate=2:1). Reference Example 10 p-Carboxy-α-methylcinnamic acid N-ethoxycarbonylmethyl-N-phenylmethylamide To a solution of the compound prepared in Reference Example 9 (5.7 g) in anisole (60 ml), was added methanesulfonic acid (33 ml) under cooling with ice. The reaction mixture was stirred for two hours at room temperature and evaporated. To the residue were added ice-water and ether, and the mixture was separated into two layers. The organic layer was further extracted with water and a saturated aqueous solution of sodium bicarbonate. All aqueous layers were collected and were acidified by addition of 1N hydrochloric acid under cooling with ice, and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated to give the title compound (3.79 g) having the following physical data: TLC : Rf 0.18 (hexane : ethyl acetate : acetic acid=12 : 4 : 1). Reference Example 11 p-(p-methoxybenzyloxycarbonyl)cinnamic acid N'-phenylmethylpiperazinylamide To a solution of the compound prepared in Reference Example 8 (4.22 g) in dimethylformamide (40 ml), were added successively N-benzylpiperazine (2.35 ml) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (3.1 g). After the reaction mixture was stirred for two hours at room temperature, ice-water was added thereto. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane : ethyl acetate=2 : 1→1 : 2) to give the title compound (3.4 g) having the following physical data: TLC : Rf 0.67 (ethyl acetate). Reference Example 12 p-Carboxycinnamic acid N'-phenylmethylpiperazinylamide hydrochloride By the same procedure as Reference Example 2, using the compound prepared in Reference Example 11 instead of that prepared in Reference Example 1, the free compound of the title compound was obtained. The free compound was converted into the corresponding hydrochloride salt by a conventional manner to give the title compound having the following physical data: TLC : Rf 0.21 (ethyl acetate). Reference Example 13 p-(t-Butoxycarbonyl)cinnamic acid To a solution of p-(t-butoxycarbonyl)benzaldehyde (4.05 g) in pyridine (16 ml), were added successively malomic acid (4.16 g) and piperidine (0.6 ml). The reaction mixture was stirred for four hours at 80°C, and then diluted with ethyl acetate. The mixture was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue thus obtained was washed with n-hexane and dried to give the title compound (4.65 g) having the following physical data: TLC: Rf 0.28 (hexane : ethyl acetate : acetic acid=2 : 1 : 1 drop). Reference Example 14 3-(p-(t-butoxycarbonyl)phenyl)propionic acid To a solution of the compound prepared in Reference Example 12 (4.65 g) in a mixture of methanol (50 ml) and chloroform (50 ml) was added 10% palladium-carbon (0.5 g). The mixture was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was filtered off and the solution was evaporated. To a solution of the residue thus obtained, in dioxane (30 ml) was added 1N aqueous solution of sodium hydroxide (20 ml) and the mixture was stirred for one hour at 50°C. The reaction mixture was concentrated and the residue thus obtained was washed with n-hexane and then dried to give the title compound (3.67 g) having the following physical data: TLC: Rf 0.14 (hexane : ethyl acetate=2 : 1). Example 1 p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-ethoxycarbonylmethyl-N-phenylmethylamide hydrochloride To a solution of the compound prepared in Reference Example 10 (2.67 g) in pyridine (35 ml), were added successively p-amidinophenol hydrochloride (1.21 g) and 1,3-dicyclohexylcarbodiimide (1.73 g). After stirred overnight at room temperature, the reaction mixture was filtered. The filtrate was evaporated. The residue was purified by silica gel column chromatography (chloroform : methanol : acetic acid=30 : 2 : 1) to give the title compound (2.29 g) as white powder having the following physical data: TLC : Rf 0.43 (chloroform : methanol : acetic acid=15 : 2 : 1); IR : ν 3352, 1741, 1678, 1606, 1480, 1411, 1375, 1267, 1214, 1176, 1067, 1015, 976, 888, 736, 699, 630, 521 cm -1 ; NMR : δ 8.10 (2H, d, J=8.0 Hz), 7.95 (2H, d, J=8.0 Hz), 7.55 (4H, brd, J=7.5 Hz), 7.40 (5H, brs), 6.75 (1H, brs), 4.82-4.70 (2H, m), 4.21-4.00 (4H, m), 2.15 (3H, s), 1.35-1.20 (3H, m). Example 1(a)∼(vvv) By the same procedure as a series of reactions of Reference Example 9→Reference Example 10→Example 1, using, as starting materials, the compound prepared in Reference Example 2, that prepared in Reference Example 4 p-benzyloxycarbonylbenzoic acid or p-methoxycarbonylbenzoic acid, using proper amines instead of N-ethoxycarbonylmethyl-N-phenylmethylamine, and further using p-amidimophenol or its derivatives, the compounds of the present invention shown in Table 3 were given. Example 2 p-(p-Amidinophenoxycarbonyl)cinnamic acid N'-phenylmethyl piperazinylamide bishydrochloride By the same procedure as Example 1, using the compound prepared in Reference Example 12 instead of that prepared in Reference Example 10, the title compound having the following physical data was given. TLC : Rf 0.24 (chloroform : methanol=8 : 2); IR: ν 3402,1741, 1678, 1644, 1606, 1479, 1415, 1263, 1216, 1174, 1123, 1070, 1016, 951, 872, 844, 765, 753, 703, 538 cm -1 ; NMR (CD 3 OD+d 6 -DMSO) : δ 8.10 (2H, d), 7.95 (2H, d), 7.86 (2H, d), 7.70 (1H, d), 7.62-7.45 (7H, m), 7.40 (1H, d), 4.80-4.50 (2H, m), 3.80-3.40 (3H, m), 3.50-3.00 (3H, m). Example 2(a)∼2(ll) By the same procedure as a series of reactions of Reference Example 11→Reference Example 12→Example 2, using, as starting materials, the compound prepared in Reference Example 7, that prepared in Reference Example 8, that prepared in Reference Example 14 or p-t-butoxycarbonylbenzoic acid, and further using proper amines instead of N-benzylpiperazine, the compounds of the present invention shown in Table 4 were given. Reference Example 15 p-Methoxycarbonyl-α-methylcinnamic acid t-butyl ester By the same procedure as Reference Example 1, using p-methoxycarbonylbenzaldehyde instead of p-benzyloxycarbonylbenzaldehyde, the title compound having the following physical data was given: TLC : Rf 0.67 (hexane : ethyl acetate = 4 : 1). Reference Example 16 p-Carboxy-α-methylcinnamic acid t-butyl ester By the same procedure as Reference Example 7, using the compound prepared in Reference Example 15, the title compound having the following physical data was given: TLC : Rf 0.42 (ethyl acetate). Reference Example 17 p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid t-butyl ester By the same procedure as Example 1, using the compound prepared in Reference Example 16, the title compound having the following physical data was given.: TLC : Rf 0.41 (chloroform : methanol : acetic acid=10 : 2 : 1). Reference Example 18 p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid hydrochloride To a solution of the compound prepared in Reference Example 17 (4.79 g) in chloroform (100 ml), were added successively a solution of 4N hydrochloric acid in ethyl acetate (50 ml) and dioxane (10 ml). The mixture was stirred for two hours at room temperature and evaporated. The residue thus obtained was washed with ether, filtered and then dried to give the title compound (4.15 g) having the following physical data: TLC : Rf 0.38 (chloroform : methanol : acetic acid=10 : 2 : 1); NMR δ 8.21 (2H, d, J=8.0 Hz), 7.95 (2H, d, J=8.0 Hz), 7.75 (1H, s), 7.60 (2H, d, J=8 .0 Hz), 7.54 (2H, d, J=8.0 Hz), 2.12 (3H, s). Example 3 p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-t-butoxycarbonylmethyl-N-allylamide acetate To a suspension of the compound prepared in Reference Example 18 (3.2 g) in a mixture of pyridine (50 ml) and dimethylformamide (5 ml), were added successively a solution of N-t-butoxycarbonylmethyl-N-allylamine (1.52 g) in pyridine (5 ml) and a solution of 1.3-dicyclohexylcarbodiimide (2.20 g) in pyridine (5 ml). The mixture was stirred overnight at room temperature and evaporated. The residue thus obtained was purified by silica gel column chromatography (chloroform : methanol : acetic acid=50 : 2 : 1→40 : 2 :1→30 : 2 : 1→10 : 2 : 1) to give the title compound (683 mg) having the following physical data: TLC : Rf 0.36 (chloroform : methanol : acetic acid=10 : 2 : 1). Example 3(a)∼3(g) By the same procedure as Example 3, using, as a starting material, the compound prepared in Reference Example 18, and further using a corresponding amine instead of N-t-butoxycarbonylmethyl-N-allylamine, the compounds of the present invention shown in Table 5 were given. Example 4 p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-allylamide methanesulfonate To a solution of the compound prepared in Example 3 (683 mg) in chloroform (10 ml), was added a solution of 4N hydrochloric acid in ethyl acetate (6 ml). The mixture was stirred for one hour at room temperature, and then evaporated. The residue thus obtained was purified by silica gel column chromatography (chloroform : methanol : acetic acid=50 : 2 : 1→40 : 2 : 1→30 : 2 : 1→10 : 2 : 1). To the purified compound thus obtained, was added methanesulfonic acid. The mixture was stirred for 10 min. at room temperature and evaporated. The residue was crystallized from a mixture of ether and acetone. The crystals thus obtained was collected by filtration and dried to give the title compound (286 mg) having the following physical data: TLC : Rf 0.32 (chloroform : methanol : acetic acid=10 : 2 : 1); NMR : δ 8.20 (2H, d, J=8.0 Hz), 7.95 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 6.80-6.62 (1H, ml, 6.78-6.00(1H, m), 5.40-5.20 (2H, m), 4.20-4.05 (4H, m), 2.70 (6H, s), 2.19-2.05 (3H, m). Example 4(a) p-(p-Amidi nophenoxycarbonyl)-α-methylcinnamic acid N-3-carboxypropyl-N-allylamide methanesulfonate By the same procedure as a series of reactions of Example 3→Example 4, using, as a starting material, the compound prepared in Reference Example 18, and further using a corresponding amine, the title compound having the following physical data was given. TLC : Rf 0.48 (chloroform : methanol : acetic acid=10 : 2 : 1); NMR : δ 8.21 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0 Hz), 7.55 (2H, d, J=8.0 Hz), 6.62 (1H, s), 6.02-5.79 (1H, m), 5.38-5.20 (2H, m), 4.10 (2H, d, J=5.0 Hz), 3.50 (2H, t, J=7.5 Hz), 2.75 (3H, s, MeSO 3 H), 2.48-2.30 (2H, m), 1.98 (2H, tt, J=7.5, 5.0 Hz). Example 4(b) p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-(S)-ethoxycarbonyl-3-carboxy)propylamide hydrochloride By the same procedure as a series of reactions of Example 3→Example 4, using, as a starting material, the compound prepared in Reference Example 18, and further using a corresponding amine, the title compound having the following physical data was given. TLC : Rf 0.32 (chloroform : methanol : acetic acid=10 : 2 : 1) ; NMR : δ 8.22 (2H, d, J=9.0Hz), 7.93 (2H, d, J=9.0Hz), 7.60 (2H, d, J=9.0Hz), 7.54 (2H, d, J=9.0Hz), 7.35 (1H, s), 4.52 (1H, dd, J=9.0Hz, 5.0Hz), 4.21 (2H, q, J=7.0Hz), 2.48 (2H, t, J=7.0Hz), 2.35-1.97 (2H, m), 2.13 (3H, s), 1.28 (3H, t, J=7.0Hz). Example 5(a)∼5(gg) By the same procedure as a series of reactions of Reference Example 2→Example 3 or Reference Example 9→Reference Example 2 (and then purified by silica gel column chromatography (chloroform : methanol : acetic acid = 50 : 2 : 1→40 : 2 : 1→30 : 2 : 1→10 : 2 : 1), and further subjected to salt-exachange reaction, if necessary), using, as a starting material, the compound prepared in Reference Example 17, and further using a corresponding amine, the compounds of the present invention shown in Table 6 were given. Formulation Example Formulation Example 1 The following components were admixed in conventional manner and punched out to obtain 100 tablets each containing 50 mg of active ingredient. p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide acetate 5.0 g Carboxymethylcellulose calcium 0.2 g (disintegrating agent) Magnesium stearate (lubricating agent) 0.1 g Microcrystalline cellulose 4.7g Formulation Example 2 The following components were admixed in conventional manner. The solution was sterilized in conventional manner, placed 5 ml portions into ampoules and freeze-dried to obtain 100 ampoules each containing 20 mg of active ingredient. p-(p-Amidinophenoxycarbonyl)-α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide acetate 2g Anhydrous citric acid 200 mg Distilled water 500 ml

Claims: A compound of the formula (I): wherein R 1 and R 2 each, independently, is: (i) hydrogen, (ii) C1-4 alkyl, (iii) C1-4 alkoxy, (iv) C2-5 acyl, (v) halogen, (vi) nitro, (vii) benzoyl or (viii) COOR 4 (in which R 4 is C1-3 alkyl); A is a bond, C1-4 alkylene or (in which R 5 and R 6 each independently, is hydrogen or C1-4 alkyl); R 3 is or (in which R 7 and R 8 each, independently, is (1) hydrogen, (2) phenyl, (3) C7-10 phenylalkyl, (4) phenyl or C7-10 phenylalkyl each of which is substituted by one or two substituents selected from C1-4 alkyl, halogen and R 11 -COOR 12 (in which R 11 is (a) a bond, (b) C1-8 alkylene, (c) C2-8 alkenylene or (d) C2-8 alkynylene, and R 12 is (a) hydrogen, (b) C1-4 alkyl, (c) C7-10 phenylalkyl, (d) phenyl, (e) allyl or (f) propargyl), (5) C1-10 alkyl, (6) C2-10 alkenyl having one to three double bonds, (7) C2-10 alkynyl having one or two triple bonds, (8) R 11a -COXR 12 (in which R 11a is (a) a bond, (b) C1-8 alkylene, (c) C2-8 alkylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (d) C2-8 alkenylene, (e) C4-8 alkenylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, (f) C2-8 alkynylene, or (g) C4-8 alkynylene in which one or two carbon atoms in the main chain are replaced by sulfur, or sulfur and phenylene, X is oxygen or -NH-, and R 12 is the same meaning as hereinbefore defined), (9) C1-4 alkyl which is substituted by a 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen, or (10) C3-7 cycloalkyl); R 9 is (1) hydrogen, (2) C1-8 alkyl, (3) C7-10 phenylalkyl, (4) C2-10 alkenyl having one to three double bonds, (5) C2-10 alkynyl having one or two triple bonds, (6) R 11 -COOR 12 (in which R 11 and R 12 are the same meaning as hereinbefore defined), or (7) C3-7 cycloalkyl; is 4-7 membered, mono-cyclic hetero ring containing one or two nitrogen; R 10 is (1) hydrogen, (2) C7-10 phenylalkyl or (3) COOR 13 (in which R 13 is hydrogen, C1-4 alkyl or C7-10 phenylalkyl)); with the proviso that (i) both R 7 and R 8 do not represent hydrogen at the same time, and (ii) when at least one group in R 7 , R 8 and R 9 represents the group containing t-butyl ester, the other groups do not represent the group containing carboxy; or an acid-addition salt thereof. A compound according to claim 1, wherein R 3 is or in which the various symbols are as defined in claim 1. A compound according to claim 1, wherein R 3 is in which the various symbols are as defined in claim 1. A compound according to claim 3, wherein is 4-7 membered, mono-cyclic hetero ring containing one nitrogen. A compound according to claim 3, wherein is 4-7 membered, mono-cyclic hetero ring containing two nitrogen. A compound according to claim 2, wherein one of R 7 and R 8 is (9) C1-4 alkyl which is substituted by a 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen. A compound according to claim 2, wherein one of R 7 and R 8 is (2) phenyl, (3) C7-10 phenylalkyl, (4) phenyl or C7-10 phenylalkyl which is substituted by one or two substituents optionally selected from C1-4 alkyl, halogen and R 11 -COOR 12 (in which R 11 and R 12 are as defined in claim 1) (8) R 11a -COXR 12 (in which R 11a (c) C2-8 alkylene in which two carbon atoms in the main chain are replaced by sulfur and phenylene, (e) C4-8 alkenylene in which two carbon atoms in the main chain are replaced by sulfur and phenylene, (g) C4-8 alkynylene in which two carbon atoms in the main chain are replaced by sulfur and phenylene, (in which X and R 12 are as defined in claim 1) or (10) C3-7 cycloalkyl. A compound according to claim 2, wherein one of R 7 and R 8 is (5) C1-10 alkyl, (6) C2-10 alkenyl having one to three double bonds, (7) C2-10 alkynyl having one or two triple bonds, or (8) R 11a -COXR 12 (in which R 11a (a) bond, (b) C1-8 alkylene, (c) C2-8 alkylene in which a carbon atom in the main chain is replaced by sulfur, (d) C2-8 alkenylene, (e) C4-8 alkenylene in which a carbon atom in the main chain is replaced by sulfur, (f) C2-8 alkynylene, or (g) C4-8 alkynylene in which a carbon atom in the main chain is replaced by sulfur, (in which X and R 12 are as defined in claim 1). A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-allyl-N-ethoxycarbonylmethylamide or an acid addition salt thereof. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(2-ethoxycarbonylperhydroazepinyl)amide. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(2-ethoxycarbonylpiperidino)amide, or p-(p-amidinophenoxycarbonyl)cinnamic acid N-(2-ethoxycarbonylpyrrolidinyl)amide. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N'-phenylmethylpiperazinylamide. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)benzoic acid N-[1-ethoxycarbonyl-2-(3-indolyl)]ethylamide. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-ethoxycarbonylmethyl-N-phenylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-2-phenyl)ethylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-3,5-bis(ethoxycarbonyl)phenylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1-ethoxycarbonyl-2-(4-ethoxycarbonylphenylmethylthio))ethylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-cyclopropyl-N-ethoxycarbonylmethylamide or p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-cyclohexyl-N-carboxymethylamide. A compound according to claim 1, which is p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(2-ethoxycarbonylethyl)-N-isopropylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-carboxymethyl-N-allylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-propargyl-N-ethoxycarbonylmethylamide, p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-allyl-N-((1-ethoxycarbonyl-2-ethoxycarbonylmethylthio)ethyl)amide or p-(p-amidinophenoxycarbonyl)-α-methylcinnamic acid N-(1,1-bis(ethoxycarbonyl)methyl)-N-ethoxycarbonylmethylamide, A compound according to any one of the preceding claims in the form of an acid addition salt. A process for the preparation of the compounds of the formula (I) claimed in claim 1, which is characterized by: (i) esterification of a compound of the formula (IIa): wherein R 3a is the same meaning as hereinbefore defined for R 3 , provided that all of R 7 , R 8 R 9 and R 10 , in R 3 , are groups not containing COOH and COOt-Bu, and R 2 and A are as defined in claim 1, with a compound of the formula (III) : wherein R 1 is as defined in claim 1; (ii) amidation of a compound of the formula (IIb): wherein the various symbols are as defined in claim 1, with a compound of the formula (IIIb): wherein R 7b , R 8b , R 9b and R 10b are the same meanings as hereinbefore defined for R 7 , R 8 R 9 and R 10 , respectively, provided that at least one group of R 7b , R 8b and R 9b is a group containing COOt-Bu and the other groups are ones not containing COOH, or R 10b is COOt-Bu; or (iii) hydrolysis of t-butyl ester group, of a compound of the formula (Ib): wherein R 1 , R 2 and A are as defined in claim 1 and R 3b has the same meaning as defined in claim 1 for R 3 , provided that at least one group of R 7 , R 8 and R 9 , in R 3 , is a group containing COOt-Bu and the other groups are ones not containing COOH, or R 10 is COOt-Bu. A pharmaceutical composition which comprises, as active ingredient, an effective amount of a compound of the formula (I) depicted in claim 1, or an acid addition salt thereof, with a carrier or coating. A compound of the formula (I) or an acid addition salt thereof for use in the manufacture of pharmaceutical composition for the prevention and/or treatment of various inflammatory diseases, allergic diseases, disseminated intravascular coagulation, pancreatitis, severity in pancreatitis or multiple organ failure.

Inventors: KAWAMURA MASANORI, MIYAMOTO TSUMORU, NAKAI HISAO, KAWAMURA, MASANORI, MIYAMOTO, TSUMORU, NAKAI, HISAO, Kawamura, Masanori, c/o Minase Research Inst., Ono, Nakai, Hisao, c/o Minase Research Inst., Ono
Applicants: ONO PHARMACEUTICAL CO, ONO PHARMACEUTICAL CO., LTD.
Application year: 1993
Main classification: C07C257
IPC codes: C07C257, C07C323, C07D209, C07D295, C07D207