Patent ID: 6410684
Filing Date: 2002-06-25
Classification: A61K,A61P,C07D,C07K,Y02P

Abstract:
A serine protease inhibitor compound having the Formula I whereinA is H, substituted or unsubstituted D,L &agr;-hydroxyacetyl, R1, R1â€”Oâ€”C(O)â€”, R1â€”C(O)â€”, R1â€”SO2â€”, R2OOCâ€”(CHR2)mâ€”SO2â€”, R2OOCâ€”(CHR2)mâ€”, H2NCOâ€”(CHR2)mâ€”, or an N-protecting group, wherein R1 is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-8C)cycloalkyl, which groups may be substituted with (3-8C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, CF3, or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl groups of which may be substituted with (1-6C)alkyl, (3-8C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3 or halogen; each group R2 is independently H or has the same meaning as R1, m is 1, 2 or 3; B is a bond, an amino acid of the formula â€”NHâ€”CH[(CH2)pC(O)OH]â€”Câ€”(O)â€” or an ester derivative thereof with p being 0, 1, 2 or 3, â€”N((1-12C)alkyl)â€”CH2â€”COâ€”, â€”N((2-12C)alkenyl)â€”CH2â€”COâ€”, â€”N((2-12C)alkynyl)â€”CH2â€”COâ€”, â€”N(benzyl)CH2â€”COâ€”, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a L- or D-amino acid having a hydrophobic, basic or neutral side chain, which amino acid may be N-(1-6C)alkyl substituted; or A and B together are residue R3R4Nâ€”CHR5â€”C(O)â€”, wherein R3 and R4 independently are R1, R1â€”Oâ€”C(O)â€”, R1â€”C(O)â€”, R1SO2â€”, R2OOCâ€”(CHR2)mâ€”SO2â€”, R2OOCâ€”(CHR2)mâ€”, H2NCOâ€”(CHR2)m, or an N-protecting group, or one of R3 and R4 is connected with R5 to form a 5- or 6-membered ring together with â€œNâ€”Câ€  to which they are bound, which ring may be fused with an aliphatic or aromatic 6-membered ring; and R5 is a hydrophobic, basic or neutral side chain; X is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid that may contain an additional heteroatom selected from N, O and S, and may be substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or X is â€”NR2â€”CH2â€”C(O)â€” or the fragment wherein n is 2, 3 or 4, and W is CH or N; Y is H, â€”CHF2, â€”CF3, â€”COâ€”NH-(1-6C)alkylene-C6H5, â€”COOR6 with R6 being H or (1-6C)alkyl, â€”CONR7R8 with R7 and R8 being independently H or (1-6C)alkyl or R7 and R8 together being (3-6C)alkylene, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole, which heterocyles may be substituted with (1-6C)alkyl, phenyl, (1-6C)alkoxy, benzyloxy or oxo; and r is 0, 1, 2 or 3; or a compound of formula I, wherein the substituent variables are as defined above, and wherein the amino group of the alkynylamino side chain is protected with a substituent selected from the group consisting of hydroxy, (C1-6)alkoxy, and (C1-6) alkoxy carbonyl; or a salt thereof.