Peptides

Claim 1

A peptide of the formula X-A 6 -B 7 -C 8 -D 9 -E 10 -F 11 -G 12 -H 13 -I 14 -Z. wherein X is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) R 5 -O-CH 2 -C(O)-, ( d ) R 5 -CH 2 -0-C(0)-, (e) R 5 -O-C(O)-, ( f ) R 5 -(CH 2 ) n -C(O)-. (g) R 4 N(R 4 )-(CH 2 )n-C(O), ( h ) R 5 -SO 2 -(CH 2 ) q -C(O)-, or (i) R 5 -SO 2 -(CH 2 ) q -O-C(O)-; wherein A 6 is absent or a divalent moiety of the formula XL 1 , XL 2 , or XL 2 a wherein B 7 is absent or a divalent moiety of the formula XL b wherein C 8 is absent or a divalent moiety of the formula XL 1 , XL 2 or XL 2a as defined above, wherein D 9 is absent or a divalent moiety of the formula XL 3 or XL 2a ; wherein E 10 -F 11 is a divalent moiety of the formula XL 6 , XL 6a , XL 6b , XI 6c , XI 6d , or XL 6e , wherein *indicates an asymmetric center which is either in the R or S configuration; wherein G 12 is absent or a divalent moiety of the formula XL 4 or XL 4a wherein H 13 is absent or a divalent moiety of the formula XL 4 as defined above; wherein I 14 is absent or a divalent moiety of the formula XL 5 wherein Z is (a) -O-R 10 , (b) -N(R 4 )R 14 , or (c) C 4 -Cacyclic amino; wherein R is (a) isopropyl, (b) isobutyl, (c) phenylmethyl, or ( d ) C 3 -C 7 cycloalkyl; wherein R 1 is (a) hydrogen, (b) C 1 -C 5 a1ky1, (c) aryl, ( d ) C 3 -C 7 cyeloalkyl, (e) -Het, ( f ) C 1 - 3 alkoxy, or (g) C 1 -C 3 alkylthio; wherein R 2 is (a) hydrogen, or (b) -CH(R 3 )R 4 : Wherein R 3 is (a) hydrogen, (b) hydroxy, (c) C 1 -C 5 alkyl, ( d ) C 3 -C 7 cycloalicyl, (e) aryl, (f) -Bet, (g) C 1 -C 3 alkoxy, or (h) C 1 -C 3 alkylthio; wherein R 4 at each occurrence is the same or different and is (a) hydrogen, or (b) C 1 -C 5 alkyl; wherein R 5 is (a) C 1 -C 6 alkyl, ( b ) C 3 -C 7 cycloalkyl, (c) aryl, (d) -Het, or (e) 5-oxo-2-pyrrolidinyl; wherein R 6 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) -(CH 2 )p-aryl, (d) -(CH 2 )p-Het, ( e ) C 3 -C 7 cycloalkyl, or (f) 1- or 2-adamantyl; wherein R 7 is (a) hydrogen, (b) C 1 -C 5 alkyl, (c) hydroxy, (d) amino C 1 -C 4 alkyl-, (e) guanidinyl C 1 -C 3 alkyl-, (f) aryl, (g) -Het, (h) methylthio, ( i ) C 3 -C 7 cycloalkyl, or (j) amino; wherein R 8 is , (a) hydrogen, (b) C 1 -C 5 alkyl, (c) hydroxy, (d) aryl, (e) -Het, (f) guanidinyl C 1 -C 3 alkyl-, or ( g ) C 3 -C 7 cycloalkyl; wherein R 9 is U17 (a) hydrogen, (b) hydroxy, (c) amino C 1 -C 4 alkyl-, or (d) guanidin y l C 1 -C 3 alkyl-; wherein R 10 is (a) hydrogen, (b) C 1 -C 5 alkyl, ( 0 ) -(CH 2 ) n R 16 , (d) -(CH 2 ) n R 17 · ( e ) C 3 -C 7 cycloalkyl, (f) a pharmaceutically acceptable cation, (g)-(CHR 25 )-CH 2 -R 15 , or (h) -CH 2 -(CHR 12 )-R 15 ; wherein R 11 is -R or -R 2 ; wherein R 12 is -(CH 2 ) n -R 13 ; wherein R 13 is (a) aryl, (b) amino, (c) mono-, di or tri-C 1 -C 3 alkylamino, (d) -Het, (e) C 1 -C 5 alkyl (f) C 3 -C 7 cycloalkyl, (g) C 1 -C 5 alkenyl, ( h ) C 3 -C 7 cycloalkenyl, (i) hydroxy, (j) C 1 -C 3 alkoxy. (k) C 1 -C 3 alkanoyloxy, (1) mercapto, (m) C 1 -C 3 alkylthio, (n) -COOH, (o) -CO-O-C 1 -C 6 alkyl, (p) -CO-O-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl) 2 , ( q) -CO-NR 22 R 26 ; (r) C 4 -C 7 cyclic amino, (s) C 4 -C 7 cyeloalkylamino, (t) guanidyl, (u) cyano, (v) N-cyanoguanidyl, (w) eyanoamino, ( x ) (hydroxy C 2 - C 4 alk y l)amino, or (y) di-(hydroxyC 2-C4 alkyl)amino; wherein R 14 is (a) hydrogen, ( b ) C 1 -C 10 alkyl, (c) -(CH 2 ) n -R 18 , ( d ) -(CH 2 ) n -R 19 , (e) -(CHR 25 )-CH 2 -R 2 -R 15 , ( f ) -CH 2 -(CHR 12 )-R 15 ' (g) (hydroxy C 1 -C 8 alkyl), or (h) (C 1 -C 3 alkoxy)C 1 -C 8 alkyl; wherein R 15 is (a) hydroxy, ( b ) C 3 -C 7 cycloalkyl , (c) aryl, (d) amino, (e) mono-, di-, or tri- C 1 -C 3 alkylamino, (f) mono- or di-Chydroxy C 2 -C 4 alkyl]amino, (g) -Het, (h) C 1 -C 3 alkoxy-, (i) C 1 -C 3 alkanoyloxy-, (j) mercapto, ( k ) C 1 -C 3 alkylthio-, (1) C 1 -C 5 alkyl, ( m ) C4-C 7 cyclic amino, (n) C 4 -C 7 eycloalkylamino, (o) C 1 -C 5 alkenyloxy, ( p ) C 3 -C 7 cycloalkenyl; wherein R 16 is (a) aryl, (b) amino, (c) mono- or di- C 1 -C 3 alkylamino, (d) hydroxy, (e) C 3 -C 7 Cycloalkyl, (f) C 4 - 7 cyclic aaino, or (g) C 1 -C 3 alkanoyloxy; wherein R 17 is (a) -Het, (b) C 1-5 alkenyl, (c) C 3 -C 7 cyeloalkenyl, (d) C 1 -C 3 alkoxy, (e) mercapto, ( f ) C 1 -C 3 alkylthio, (g) -COOH, (h) -CO-O-C 1 -C 6 alkyl, (i) -CO-O-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl)2, (j) -CO-NR 22 R 26 , (k) tri-C 1 -C 3 alkylamino, (1) guanidyl, (m) cyano, (n) N-cyanoguanidyl, (o) (hydroxy C 2 -C 4 alkyl)amino, (p) di-(hydroxy C2-C4alkyl)amino, or (q) cyanoamino; wherein R 18 is (a) amino, (b) mono-, or di- C 1 -C 3 alkylamino, (c) C 4 -C 7 cyclic amino, or (d) C 4 -C 7 cycloalkylamino; wherein R 19 is (a) aryl, (b) -Het, (c) tri-C 1 -C 3 alkylamino, (d) C 3 -C 7 eycloalkyl, (e) C 1 - 5 alkenyl, (f) C 3 -C 7 cyeloalkenyl, (g) hydroxy, (h) C 1 -C 3 alkoxy, (i) C 1 -C 3 alkanoyloxy, (j) mercapto; (k) C 1 -C 3 alkylthio, (1) -COOH, (m) -CO-O-C 1 -C 6 alkyl, (n) -CO-O-CH 2 -(C 1 -C 3 alkyl)-N(C 1 -C 3 alkyl) 2 , (o) -CO-NR22R26, (p) guanidyl, (q) cyano, (r) N-cyanoguanidyl, (s) cyanoamino, (t) (hydroxy C 2 -C 4 alkyl)amino, (u) di-(hydroxy C 2 -C 4 alkyl)amino; or (v) -SO 3 H; wherein R 20 is (a) hydrogen, (b) C 1 -C 5 alkyl, or (c) aryl-C 1 -C 5 alkyl; wherein R 21 is (a) =NH 2 , or (b) -OH; wherein R 22 is (a) hydrogen, or (b) C 1 -C 3 aIkyl; wherein R 23 is (a) -(CH 2 ) n -O H, (b) -(CH 2 ) n -NH 2 . (c) aryl, or (d) C 1 -C 3 alkyl; wherein R 24 is (a) -R 1 . (b) -(CH 2 ) n -OH, or (c) -(CH 2 ) n -NH 2 ; wherein R 25 is -(CH 2 ) n -R 13 ; wherein R 26 is (a) hydrogen, (b) C 1 - 3 alkyl, or (c) phenyl-C 1 -C 3 alkyl; wherein m is one or two; wherein for each occurrence n is independently zero-or an integer of from one to five; wherein p is zero, 1 or 2; wherein q is 1 to 5; wherein Q is (a) - CH 2 -, (b) -CH(OH)-, (c) -0-, or (d) -S-; and wherein M is (a) -CO-, or (b) -CH 2 -; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: (a) C 1 -C 3 alk y l, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) halo, (e) amino, (f) mono- or di-C 1 -C 3 alkylamino, (g) -CHO, (h) -COOH, (i) COOR 26 , (j) CONHR 26 , (k) nitro, (1) mercapto, (m) C 1 -C 3 alkylthio, (n) C 1 -C 3 alkylsulfinyl, (o) C 1 -C 3 alkylsulfonyl, (P) C 1 -C 3 alkylsulfonyl-N(R 4 )- (q) SO 3 H, (r) SO 2 NH 2 , (s) -CN, or (t) -CH 2 NH 2 ; wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following: (i) C 1 -C 6 alkyl, (ii) hydroxy, (iii) trifluoromethyl, (iv) C 1 -C 4 alkoxy, (v) halo, (vi) aryl, (vii) aryl C 1 -C4alkyl-, (viii) amino, and (ix) mono- or di-C 1 -C 4 alkylamino; with the overall provisos that (1) at least one of the following must occur: (i) A 6 is present and (A) A 6 is XL 1 or ( B ) A 6 is XL 2 wherein R 6 is Het which is N in- formyl-Trp, (ii) B 7 is present and R 4 of B 7 is other than hydrogen, (iii) C 8 is present and is XL 1 , (iv) D 9 is H α -methyl-histidine, (v) B 7 and C 8 both are present and B 7 is XL b wherein M is -CH 2 - and C 8 is XL 1 , (vi) E 10 -F 11 is XL 6 , Z is -N(R 4 )R 14 , R 14 is -(CH 2 ) n -R 19 , and R 19 is -Het, or (vii)X is R 5 -SO 2 -(CH 2 ) q -C(O)- or R 5 -SO 2 -C(CH 2 ) q -O-C(O)-; (2) E 10 F 11 is XL 6e only when G 12 , H 13 and I 14 are absent; (3) R 16 or R 17 is an amino-containing substituent, hydroxy, mercapto, or -Het bonded through the hetero atom only when n for that substituent is an integer from two to five; ( 4 ) R 18 or R 19 is hydroxy, mereapto, or amino, or a mono-substituted nitrogen containing group bonded through the nitrogen only when n is not one; ( 5 ) A 6 , B 7 , C 8 , H 13 and I 14 are all absent, D 9 and G 12 are both present,and -NR 4 -of D 9 is -NH- and Z is -OR 10 and R 10 is hydrogen, C 1 -C 5 alkyl, or -(CH 2 )m-R 16 or Z is -N(R 4 )R 14 and R 14 is hydrogen, C 1 -C 10 alkyl or -(CH 2 ) n -R 18 , or Z is C 4 -C 8 cyclic amino, only when R 5 -(CH 2 ) n - is other than C 1 -C 8 alkyl, C 5 -C 7 cycloalkyl or aryl; (6) A 6 , B 7 , C 8 , D 9 , H13 , I 14 are all absent and G 12 is present only when Z is -OR 10 and R 10 is -(CH 2 ) n -R 17 , -(CHR 25 )-CH 2 R 15 or - CH 2 -( CHR 12 )-R 15 or when Z is -N(R 4 )R 14 and R 14 is -(CH 2 ) n -R 19 , -(CHR 25 )-CH 2 R 15 , or -CH 2 -(CH R 12 ) -R 15 ; ( 7 ) R 12 is -(CH 2 )n-R 13 and n is zero and both R 13 and R 15 are oxygen-,.nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen; (8) when R 12 is -(CH 2 ) n -R 13 and n is zero, then R 13 and R 15 cannot both be -COOH; ( 9 ) R 25 is -(CH 2 ) n -R 13 and n is zero only when R 13 is other than a primary or secondary nitrogen-containing group hydroxy or mercapto group or when R 4 of -N(R 4 )R 14 is other than hydrogen; (10) Z is C 4 -C 8 cyclic amino, only when at least one of G12, H 13 , and 1 14 is present; ( 11 ) R 17 or R 19 is -Het, only when -Het is other than cyclic amino; ( 12 ) R 17 or R 19 is -COOH only when n for that moiety is other than zero; and ( 13 ) at least one of A 6 , B 7 , C 8 , D 9 , G 12 , H 13 or 1 14 must be present; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof.