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Preparation of peptidyl heterocycles useful in the treatment of thrombin related disorders

Preparation of peptidyl heterocycles useful in the treatment of thrombin related disorders. Costanzo, Michael J.; Maryanoff, Bruce E. (Ortho Pharmaceutical Corp., USA). 75-86-5 are also occured in this study. PCT Int. Appl. WO 9640741 A1 19 Dec 1996, 134 pp. DESIGNATED STATES: W: AL, AM, AT, AU, AZ, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG; RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, DE, DK, ES, FI, FR, GA, GB, GR, IE, IT, LU, MC, NL, PT, SE. (English). (World Intellectual Property Organization). CODEN: PIXXD2. CLASS: ICM: C07K005-06. ICS: C07D263-40; C07D277-64; C07D417-06; A61K038-05; A61K031-33. ICI: C07D417-06, C07D207-16, C07D263-00; C07D417-06, C07D207-16, C07D277-00. APPLICATION: WO 1996-US8360 2 Jun 1996. PRIORITY: US 1995-482587 7 Jun 1995. DOCUMENT TYPE: Patent CA Section: 34 (Amino Acids, Peptides, and Proteins) Section cross-reference(s): 1, 63 Peptidyl heterocycles I [A = C1-8 alkyl, carboxy-C1-4 alkyl, C1-4 alkoxycarbonyl-C1-4 alkyl, (un)substituted phenyl-C1-4 alkyl, N-substituted D- or L-amino acid, N-substituted D- and/or L-amino acid-contg. dipeptide; R1 = H, C1-5 alkyl; R2 = amino-C2-5 alkyl, guanidino-C2-5 alkyl, C1-4 alkylguanidino-C2-5 alkyl, di-C1-4 alkylguanidino-C2-5 alkyl, amidino-C2-5 alkyl, C1-4 alkylamidino-C2-5 alkyl, di-C1-4 alkylamidino-C2-5 alkyl, C1-3 alkoxy-C2-5alkyl, (un)substituted phenyl; R3 = H, C1-5 alkyl; n = 0-3; p = 0, 1; E = heterocycle] and their pharmaceutically acceptable salts are compds. useful in the treatment of thrombin and trypsin related disorders. Thus, condensation of protected arginine aldehyde tripeptide II (Z = PhCH2O2C; R = CHO) with acetone cyanohydrin gave tripeptide cyanohydrin II [R = CH(OH)CN], which underwent methanolysis in the presence of HCl to give imidate salt II [R = CH(OH)C(OMe):NH.HCl], followed by cyclocondensation with 2-aminothiophenol to give benzothiazole deriv. II [R = CH(OH)Q; Q = 2-benzothiazolyl]. Oxidn. of II [R = CH(OH)Q] with Dess-Martin periodinane and deprotection gave the desired thrombin inhibitor III. III inhibited thrombin with Ki = 0.00023 mM in an in vitro assay. .