Transglutaminase inhibitors

Claim 1

A method for treating mammals which have a disease stated characterized by elevated transglutaminsase activity comprising administering to the mammals a therapeutically effective amount of a compound of the formula; ##STR38## or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 , together with the nitrogen atom to which they are attached, represent phthalimido; or R 1 and R 3 together form --CH 2 --CH 2 --CH 2 -- or CH 2 --CHOH--CH 2 ; or R 1 , R 2 and R 3 are defined as follows: R 1 is hydrogen or methyl; R 2 is selected from the group consisting of: (1) hydrogen; (2) alkyl; (3) lower alkyl sulfonyl; (4) aryl sulfonyl; (5) aryl sulfonyl substituted with lower alkyl on the aryl moiety; (6) 9-fluorenylmethyloxycarbonyl, succinyl or cinnamoyl; (7) a radical of the formula: ##STR39## wherein: R 9 is hydrogen; alkyl of 1 to 4 carbon atoms; aryl; aryl substituted with up to 2 substituents where the substituents are independently halo, lower alkyl, alkoxy, nitro, trifluoromethyl, carboxyl, or alkoxycarbonyl; aralkyl; pyridinyl; furanyl; alkoxy; aralkoxy; aralkoxy substituted on the aryl radical with up to 2 substituents where the substituents are independently halo, lower alkyl, alkoxy, nitro, or trifluoromethyl; adamantyloxy; aralkylamino; or aralkyl substituted on the aryl radical with up to 2 substituents where the substituents are independently hydroxy, alkoxy or halo; and (8) a radical of the formula: ##STR40## wherein: n=0 or 1; R 10 is independently hydrogen, alkyl or the radical defined by formula (II) above; R 11 is selected from the group consisting of: hydrogen; lower alkyl; --(CHR 12 ) m WR 13 wherein m is 1 or 2, W is oxygen or sulfur and R 12 and R 13 are independently hydrogen or methyl; --CH(CH 3 )--OCH 2 C 6 H 5 ; --(CH 2 ) k C(O)Y wherein k is 1 or 2 and Y is hydroxy, amino, alkoxy, or aralkoxy; --(CH 2 ) p NHCH(NHR 14 )NR 15 wherein p is 2,3, or 4 and R 14 and R 15 are independently hydrogen or lower alkyl; --(CH 2 ) q NH 2 wherein q is 2, 3, 4, or 5; --(CH 2 ) 4 NHCOOC(CH 3 ) 3 ; --(CH 2 ) 2 CHOHCH 2 NH 2 ; a radical of formula: ##STR41## wherein r is 1 or 2 and R 16 , R 17 and R 18 are independently hydrogen, hydroxy, halo, methoxy, lower alkyl, halo lower alkyl, amino, N-protected amino, guanidino, nitro cyano, --COOH, --CONH 2 , --COOR'" where R'" is lower alkyl, or --OR* where R* is an O-protecting group; and a radical chosen from ##STR42## wherein R 19 and R 20 are independently hydrogen, lower alkyl, halo or trifluoromethyl alkyl; R 21 is hydrogen, hydroxy or methoxy; and Z is hydrogen, hydroxy, or --OR* where R* is an O-protecting group; R 22 is hydrogen or an N-protecting group for imidazole or indole functionalities; R 3 is independently selected from the group recited for R 11 above; and X is selected from the group consisting of: halo; --OR, --SR, --S(O)R, --S(O 2 )R, --S(O) 2 NH 2 or --S(O) 2 NHR wherein R is lower alkyl, mono-, di- or tri-fluoro alkyl of 2 or 3 carbon atoms, aryl, or optionally substituted aryl; --NR'R" wherein R' and R" are independently hydrogen, lower alkyl, or aryl; and ##STR43##

Claim 2

A method for treating mammals which have a disease stated characterized by elevated transglutaminsase activity comprising administering to the mammals a therapeutically effective amount of a compound of the formula; ##STR38## or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 , together with the nitrogen atom to which they are attached, represent phthalimido; or R 1 and R 3 together form --CH 2 --CH 2 --CH 2 -- or CH 2 --CHOH--CH 2 ; or R 1 , R 2 and R 3 are defined as follows: R 1 is hydrogen or methyl; R 2 is selected from the group consisting of: (1) hydrogen; (2) alkyl; (3) lower alkyl sulfonyl; (4) aryl sulfonyl; (5) aryl sulfonyl substituted with lower alkyl on the aryl moiety; (6) 9-fluorenylmethyloxycarbonyl, succinyl or cinnamoyl; (7) a radical of the formula: ##STR39## wherein: R 9 is hydrogen; alkyl of 1 to 4 carbon atoms; aryl; aryl substituted with up to 2 substituents where the substituents are independently halo, lower alkyl, alkoxy, nitro, trifluoromethyl, carboxyl, or alkoxycarbonyl; aralkyl; pyridinyl; furanyl; alkoxy; aralkoxy; aralkoxy substituted on the aryl radical with up to 2 substituents where the substituents are independently halo, lower alkyl, alkoxy, nitro, or trifluoromethyl; adamantyloxy; aralkylamino; or aralkyl substituted on the aryl radical with up to 2 substituents where the substituents are independently hydroxy, alkoxy or halo; and (8) a radical of the formula: ##STR40## wherein: n=0 or 1; R 10 is independently hydrogen, alkyl or the radical defined by formula (II) above; R 11 is selected from the group consisting of: hydrogen; lower alkyl; --(CHR 12 ) m WR 13 wherein m is 1 or 2, W is oxygen or sulfur and R 12 and R 13 are independently hydrogen or methyl; --CH(CH 3 )--OCH 2 C 6 H 5 ; --(CH 2 ) k C(O)Y wherein k is 1 or 2 and Y is hydroxy, amino, alkoxy, or aralkoxy; --(CH 2 ) p NHCH(NHR 14 )NR 15 wherein p is 2,3, or 4 and R 14 and R 15 are independently hydrogen or lower alkyl; --(CH 2 ) q NH 2 wherein q is 2, 3, 4, or 5; --(CH 2 ) 4 NHCOOC(CH 3 ) 3 ; --(CH 2 ) 2 CHOHCH 2 NH 2 ; a radical of formula: ##STR41## wherein r is 1 or 2 and R 16 , R 17 and R 18 are independently hydrogen, hydroxy, halo, methoxy, lower alkyl, halo lower alkyl, amino, N-protected amino, guanidino, nitro cyano, --COOH, --CONH 2 , --COOR'" where R'" is lower alkyl, or --OR* where R* is an O-protecting group; and a radical chosen from ##STR42## wherein R 19 and R 20 are independently hydrogen, lower alkyl, halo or trifluoromethyl alkyl; R 21 is hydrogen, hydroxy or methoxy; and Z is hydrogen, hydroxy, or --OR* where R* is an O-protecting group; R 22 is hydrogen or an N-protecting group for imidazole or indole functionalities; R 3 is independently selected from the group recited for R 11 above; and X is selected from the group consisting of: halo; --OR, --SR, --S(O)R, --S(O 2 )R, --S(O) 2 NH 2 or --S(O) 2 NHR wherein R is lower alkyl, mono-, di- or tri-fluoro alkyl of 2 or 3 carbon atoms, aryl, or optionally substituted aryl; --NR'R" wherein R' and R" are independently hydrogen, lower alkyl, or aryl; and ##STR43##

Claim 6

A method for treating mammals which have a disease state characterized by elevated transglutaminase activity comprising administering to the mammal a thereapeutically effective amount of a compound of the formula: ##STR44## or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 , together with the nitrogen atom to which they are attached, represent phthalimido; or R 1 , R 2 and R 3 are defined as follows: R 1 is hydrogen; R 2 is selected from the group consisting of: aryl sulfonyl substituted with lower alkyl on the aryl moiety; 9-fluorenylmethyloxycarbonyl; succinyl; cinnamoyl; and a radical of the formula: ##STR45## wherein: R 9 is hydrogen, alkyl of 1 to 4 carbon atoms; aryl with up to 2 substituents where the substituents are independently halo, lower alkyl or alkoxy; aralkyl; aralkoxy; aralkoxy substituted on the aryl radical with up to 2 substituents where the substituents are independently halo, lower alkyl, or lower alkoxy; adamantyloxy; and a radical of the formula: ##STR46## wherein: n=0 or 1; R 10 is independently hydrogen, alkyl or the radical defined by formula (II) above; R 11 is selected from the group consisting of: hydrogen; lower alkyl; --(CHR 12 ) m WR 13 wherein m is 1 or 2, W is oxygen or sulfur and R 12 and R 13 are independently hydrogen or methyl; --(CH 2 ) k C(O)Y wherein k is 1 or 2 and Y is hydroxy or amino, --(CH 2 ) p NHCH(NHR 14 )NR 15 wherein p is 2,3, or 4 and R 14 and R 15 are independently hydrogen; --(CH 2 ) q NH 2 wherein q is 2, 3, 4, or 5; a radical of formula: ##STR47## wherein: r is 1 and R 16 , R 17 and R 18 are independently hydrogen, hydroxy, halo, methoxy, or amino, and a radical chosen from: ##STR48## wherein: R 19 and R 20 are independently hydrogen, R 21 is hydrogen, hydroxy or methoxy; and Z is hydrogen, hydroxy, or --OR* where R* is an O-protecting group; R 22 is hydrogen or an N-protecting group for imidazole or indole functionalities; R 3 is independently selected from the group recited for R 11 above; and X is selected from the group consisting of chloro and bromo.

Claim 7

A method for treating mammals which have a disease state characterized by elevated transglutaminase activity comprising administering to the mammal a thereapeutically effective amount of a compound of the formula: ##STR44## or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 , together with the nitrogen atom to which they are attached, represent phthalimido; or R 1 , R 2 and R 3 are defined as follows: R 1 is hydrogen; R 2 is selected from the group consisting of: aryl sulfonyl substituted with lower alkyl on the aryl moiety; 9-fluorenylmethyloxycarbonyl; succinyl; cinnamoyl; and a radical of the formula: ##STR45## wherein: R 9 is hydrogen, alkyl of 1 to 4 carbon atoms; aryl with up to 2 substituents where the substituents are independently halo, lower alkyl or alkoxy; aralkyl; aralkoxy; aralkoxy substituted on the aryl radical with up to 2 substituents where the substituents are independently halo, lower alkyl, or lower alkoxy; adamantyloxy; and a radical of the formula: ##STR46## wherein: n=0 or 1; R 10 is independently hydrogen, alkyl or the radical defined by formula (II) above; R 11 is selected from the group consisting of: hydrogen; lower alkyl; --(CHR 12 ) m WR 13 wherein m is 1 or 2, W is oxygen or sulfur and R 12 and R 13 are independently hydrogen or methyl; --(CH 2 ) k C(O)Y wherein k is 1 or 2 and Y is hydroxy or amino, --(CH 2 ) p NHCH(NHR 14 )NR 15 wherein p is 2,3, or 4 and R 14 and R 15 are independently hydrogen; --(CH 2 ) q NH 2 wherein q is 2, 3, 4, or 5; a radical of formula: ##STR47## wherein: r is 1 and R 16 , R 17 and R 18 are independently hydrogen, hydroxy, halo, methoxy, or amino, and a radical chosen from: ##STR48## wherein: R 19 and R 20 are independently hydrogen, R 21 is hydrogen, hydroxy or methoxy; and Z is hydrogen, hydroxy, or --OR* where R* is an O-protecting group; R 22 is hydrogen or an N-protecting group for imidazole or indole functionalities; R 3 is independently selected from the group recited for R 11 above; and X is selected from the group consisting of chloro and bromo.

Claim 8

A method for treating a hyman having a disease state characterized by elevated transglutaminase activity comprising administering to the human a therapeutically effective amount of a compound, or an optical isomer thereof, selected from the group consisting of: 5-(N-benzyloxycarbonyl-L-phenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-ortho-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-naphthylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-para-chlorophenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-aspartic acid-α-amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-N-ε-tert-butoxycarbonyl-L-lysine-amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-β-benzyl-L-aspartic acid amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-glutamic acid amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-β-benzyl-L-aspartic acid amidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-acetyl-L-naphthylalaninamidomethyl)-3-bromo-4,5-diihydroisoxazole; 5-(N-benzyloxycarbonyl-glycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-isoleucinamidomethyl)-3-bromo-4,5-dihydroisoxazole 5-(N-(9-fluorenylmethyloxycarbonyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-O-benzyl-L-threoninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-threoninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-phenylalaninyl-L-alaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-alanyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzoyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-naphthylmethylglycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-γ-glutamine amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-phthaloyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D,L-meta-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-ortho-tyrosinamidomethyl)-3-cloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-meta-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-meta-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-2-methoxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-4-methoxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3,4-dihydroxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxy-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxy-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-histidinamidomethyl-3-bromo-4,5-dihydroisoxazole; 5-(N-im-benzoyl-N-α-benzyloxycarbonyl-L-histidinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-toluenesulfonyl glycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzylcarbamoyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-4-(R)-hydroxyl-L-prolinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-methoxy-L-phenyl-alaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α, O-dibenzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N,O,O-tribenzyloxycarbonyl-(±)-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-para-fluorophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-L-phenylalanyl-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α,N-dibenzyloxycarbonyl-L-4-aminophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α -benzyloxycarbonyl-N in -formyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-para-amino-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(L-phenylalanyl-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole-para-toluene-sulfonic acid; 5-(N-benzyloxycarbonyl-S-benzyl-L-cysteinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-methioninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-O-acetyl-L-tyrosinamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N,O-dibenzyloxycarbonyl-3-methoxy-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-para-iodophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-2-(S)-(6methoxy-2-naphthyl)-propionyl-L-tyrosinamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-α-benzyloxycarbonyl-L-glutamic acid α-amidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-para-methoxybenzyloxycarbonyl-L-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(2-(S)-(6-methoxy-2-naphthyl)-propionyl)-L-tyrosinamidomethyl) 5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(2-naphthyl-acetyl)-L-tyrosinamidomethyl-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(1-naphthyl-acetyl)-L-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-isobutyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-succinyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-threonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-cinnamoyl-L-phyenylalaninamidomethyl)3-bromo-4,5-dihydroisoxazole; 5-(N-(2(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(2(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)5-(R)-3-bromo-4,5-dihydroisoxazole; 5-(N-(2-(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-adamantyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-2-chlorobenzyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaminamidomethyl)-5-(R)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaninamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-tertbutoxycarbonyl-glycyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-α-benzyloxycarbonyl-L-lysinamidomethyl)-3-bromo-4,5-dihydroisoxazole oxalic acid; 5-(glycyl-L-phenylalaninamidomethyl)-3-bromo-4,5--hydroisoxazole oxalate salt; 5-(N-(6-methoxy-2-naphthyl)acetyl-L-phenylalaninamidomethyl)-3-chloro-4,5-dihydrosoxazole; and 5-(N-(6-methoxy-2-naphthyl)acetyl)-L-tyrosinamidomethyl)3-chloro-4,5-diydroisoxazole; or an optical isomer thereof.

Claim 9

A method for treating a hyman having a disease state characterized by elevated transglutaminase activity comprising administering to the human a therapeutically effective amount of a compound, or an optical isomer thereof, selected from the group consisting of: 5-(N-benzyloxycarbonyl-L-phenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-ortho-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-naphthylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-para-chlorophenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-aspartic acid-α-amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-N-ε-tert-butoxycarbonyl-L-lysine-amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-β-benzyl-L-aspartic acid amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-glutamic acid amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-β-benzyl-L-aspartic acid amidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-acetyl-L-naphthylalaninamidomethyl)-3-bromo-4,5-diihydroisoxazole; 5-(N-benzyloxycarbonyl-glycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-isoleucinamidomethyl)-3-bromo-4,5-dihydroisoxazole 5-(N-(9-fluorenylmethyloxycarbonyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-O-benzyl-L-threoninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-threoninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-phenylalaninyl-L-alaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-alanyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzoyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-naphthylmethylglycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-γ-glutamine amidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-phthaloyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-D,L-meta-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-ortho-tyrosinamidomethyl)-3-cloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-meta-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-meta-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-2-methoxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-4-methoxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3,4-dihydroxyphenylalaninamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxy-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-3-methoxy-tyrosinamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-histidinamidomethyl-3-bromo-4,5-dihydroisoxazole; 5-(N-im-benzoyl-N-α-benzyloxycarbonyl-L-histidinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-toluenesulfonyl glycinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzylcarbamoyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-4-(R)-hydroxyl-L-prolinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-para-methoxy-L-phenyl-alaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α, O-dibenzyloxycarbonyl-L-5-hydroxytryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N,O,O-tribenzyloxycarbonyl-(±)-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-3,4-dihydroxyphenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-para-fluorophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-tert-butoxycarbonyl-L-phenylalanyl-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α,N-dibenzyloxycarbonyl-L-4-aminophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N.sup.α -benzyloxycarbonyl-N in -formyl-L-tryptophanamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-para-amino-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(L-phenylalanyl-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole-para-toluene-sulfonic acid; 5-(N-benzyloxycarbonyl-S-benzyl-L-cysteinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-methioninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-O-acetyl-L-tyrosinamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N,O-dibenzyloxycarbonyl-3-methoxy-L-tyrosinamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-(±)-para-iodophenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-2-(S)-(6methoxy-2-naphthyl)-propionyl-L-tyrosinamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-α-benzyloxycarbonyl-L-glutamic acid α-amidomethyl)-3-chloro-4,5-dihydroisoxazole; 5-(N-para-methoxybenzyloxycarbonyl-L-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(2-(S)-(6-methoxy-2-naphthyl)-propionyl)-L-tyrosinamidomethyl) 5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(2-naphthyl-acetyl)-L-tyrosinamidomethyl-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-(1-naphthyl-acetyl)-L-tyrosinamidomethyl)-5-(S)-3-chloro-4,5-dihydroisoxazole; 5-(N-isobutyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-succinyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-benzyloxycarbonyl-L-threonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-cinnamoyl-L-phyenylalaninamidomethyl)3-bromo-4,5-dihydroisoxazole; 5-(N-(2(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(2(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)5-(R)-3-bromo-4,5-dihydroisoxazole; 5-(N-(2-(S)-6-methoxy-2-naphthylpropionyl)-L-phenylalaninamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-adamantyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-2-chlorobenzyloxycarbonyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaminamidomethyl)-5-(R)-3-bromo-4,5-dihydroisoxazole; 5-(N-(4-methoxybenzyloxycarbonyl)-L-phenylalaninamidomethyl)-5-(S)-3-bromo-4,5-dihydroisoxazole; 5-(N-tertbutoxycarbonyl-glycyl-L-phenylalaninamidomethyl)-3-bromo-4,5-dihydroisoxazole; 5-(N-α-benzyloxycarbonyl-L-lysinamidomethyl)-3-bromo-4,5-dihydroisoxazole oxalic acid; 5-(glycyl-L-phenylalaninamidomethyl)-3-bromo-4,5--hydroisoxazole oxalate salt; 5-(N-(6-methoxy-2-naphthyl)acetyl-L-phenylalaninamidomethyl)-3-chloro-4,5-dihydrosoxazole; and 5-(N-(6-methoxy-2-naphthyl)acetyl)-L-tyrosinamidomethyl)3-chloro-4,5-diydroisoxazole; or an optical isomer thereof.