US2010056432A1PendingUtilityA1
Template-fixed peptidomimetics with antibacterial activity
Est. expiryAug 20, 2022(expired)· nominal 20-yr term from priority
A61P 41/00A61P 9/00A61P 27/16A61P 35/00A61P 27/02A61P 27/00A61P 25/00A61P 31/00A61P 31/04A61P 31/18A61P 29/00C07K 1/047C07K 7/64A61P 13/02A61P 11/00A61P 15/08C07K 5/06165A61P 17/00A61P 19/08A61P 1/00A61P 1/12A61P 19/00A61P 17/02A61P 1/04A61P 13/08A61K 38/00A61P 13/00A61P 11/06Y02A50/30
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Claims
Abstract
Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 12 α-amino acid residues which, depend on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to selectively inhibit the growth of or to kill microorganisms such as Pseudomonas aeruginosa and Acinetobacter. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections. In a specific embodiment, the template is based on the D-Pro-L-Pro dipeptides. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid—and solution phase synthetic strategy.
Claims
exact text as granted — not AI-modified1 . Compounds of the general formula
is a group of one of the formulae
is the residue of an L-α-amino acid with B being a residue of formula —NR 20 CH(R 71 )— or the enantiomer of one of the groups A1 to A69 as defined hereinafter;
is a group of one of the formulae
R 1 is H; lower alkyl; or aryl-lower alkyl;
R 2 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 3 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 4 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) p (CHR 61 ) s COOR 57 ; —(CH 2 ) p (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) p (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; of —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 5 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 6 is H; alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 7 is alkyl; alkenyl; —(CH 2 ) q (CHR 61 ) s OR 55 ; —CH 2 ) q (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) q (CHR 61 ) s OCONR 33R 75 ; —(CH 2 ) q (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) r (CHR 61 ) s COOR 57 ; —(CH 2 ) r (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) r (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) r (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) r (CHR 61 ) s C 6 H 4 R 8 ;
R 8 is H; Cl; F; CF 3 ; NO 2 ; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 )NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s COR 64 ;
R 9 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 10 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) 0 (CHR 61 ) 2 NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 11 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 12 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) r (CHR 61 ) s COOR 57 ; —(CH 2 ) r (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) r (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) r (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) r (CHR 61 ) s C 6 H 4 R 8 ;
R 13 is alkyl; alkenyl; —(CH 2 ) q (CHR 61 ) s OR 55 ; —(CH 2 ) q (CHR 61 ) s SR 56 ; —(CH 2 ) q (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) q (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) q (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) q (CHR 61 ) s COOR 57 ; —(CH 2 ) q (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) q (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) q (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) q (CHR 61 ) s C 6 H 4 R 8 ;
R 14 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) q (CHR 61 ) s COOR 57 ; —(CH 2 ) q (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) q (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) q (CHR 61 ) s SOR 62 ; or —(CH 2 ) q (CHR 61 ) s C 6 H 4 R 8 ;
R 15 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 16 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 17 is alkyl; alkenyl; —(CH 2 ) q (CHR 61 ) s OR 55 ; —(CH 2 ) q (CHR 61 ) s SR 56 ; —(CH 2 ) q (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) q (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) q (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) q (CHR 61 ) s COOR 57 ; —(CH 2 ) q (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) q (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) q (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) q (CHR 61 ) s C 6 H 4 R 8 ;
R 18 is alkyl; alkenyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s SR 56 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) p (CHR 61 ) s COOR 57 ; —(CH 2 ) p (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) p (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 19 is lower alkyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s SR 56 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) p (CHR 61 ) s COOR 57 ; —(CH 2 ) p (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) p (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 18 and R 19 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 20 is H; alkyl; alkenyl; or aryl-lower alkyl;
R 21 is H; alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) 0 (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 22 is H; alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) 0 (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) 0 (CHR 61 ) s C 6 H 4 R 8 ;
R 23 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 24 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 25 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 26 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ; or
R 25 and R 26 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) r O(CH 2 ) r —; —(CH 2 ) r S(CH 2 ) r —; or —(CH 2 ) r NR 57 (CH 2 ) r —;
R 27 is H; alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s OCONR 35 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 28 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s —OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 29 is alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 30 is H; alkyl; alkenyl; or aryl-lower alkyl;
R 31 is H; alkyl; alkenyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 32 is H; lower alkyl; or aryl-lower alkyl;
R 33 is H; alkyl, alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 34 R 63 ; —(CH 2 ) m (CHR 61 ) s OCONR 75 R 82 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 78 R 82 ; —(CH 2 ) o (CHR 61 ) s COR 64 ; —(CH 2 ) o (CHR 61 ) s —CONR 58 R 59 , —CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 34 is H; lower alkyl; aryl, or aryl-lower alkyl;
R 33 and R 34 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 35 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) p (CHR 61 ) s COOR 57 ; —(CH 2 ) p (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) p (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) p (CHR 61 ) s C 6 H 4 R 8 ;
R 36 is H, alkyl; alkenyl; —CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) p (CHR 61 ) s COOR 57 ; —(CH 2 ) p (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) p (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 37 is H; F; Br; Cl; NO 2 ; CF 3 ; lower alkyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 38 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 39 is H; alkyl; alkenyl; or aryl-lower alkyl;
R 40 is H; alkyl; alkenyl; or aryl-lower alkyl;
R 41 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 42 is H; F; Br; Cl; NO 2 ; CF 3 ; alkyl; alkenyl; —(CH 2 ) p (CHR 61 ) s OR 55 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ; R 43 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) o (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 44 is alkyl; alkenyl; —(CH 2 ) r (CHR 61 ) s OR 55 ; —(CH 2 ) r (CHR 61 ) s SR 56 ; —(CH 2 ) r (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) r (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) r (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) r (CHR 61 ) s COOR 57 ; —(CH 2 ) r (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) r (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) r (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) r (CHR 61 ) s C 6 H 4 R 8 ;
R 45 is H; alkyl; alkenyl; —(CH 2 ) o (CHR 61 ) s OR 55 ; —(CH 2 ) o (CHR 61 ) s SR 56 ; —(CH 2 ) o (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) o (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) o (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) s (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) s (CHR 61 ) s PO(OR 60 ) 2 ; —(CH 2 ) s (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) s (CHR 61 ) s C 6 H 4 R 8 ;
R 46 is H; alkyl; alkenyl; or —(CH 2 ) o (CHR 61 ) p C 6 H 4 R 8 ;
R 47 is H; alkyl; alkenyl; or —(CH 2 ) o (CHR 61 ) s OR 55 ;
R 48 is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;
R 49 is H; alkyl; alkenyl; —(CHR 61 ) s COOR 57 ; (CHR 61 ) s CONR 58 R 59 ; (CHR 61 ) s PO(OR 60 ) 2 ; —(CHR 61 ) s SOR 62 ; or —(CHR 61 ) s C 6 H 4 R 8 ;
R 50 is H; lower alkyl; or aryl-lower alkyl;
R 51 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) p PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) p (CHR 61 ) s C 6 H 4 R 8 ;
R 52 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) p PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) p (CHR 61 ) s C 6 H 4 R 8 ;
R 53 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s SR 56 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; —(CH 2 ) o (CHR 61 ) p PO(OR 60 ) 2 ; —(CH 2 ) p (CHR 61 ) s SO 2 R 62 ; or —(CH 2 ) p (CHR 61 ) s C 6 H 4 R 8 ;
R 54 is H; alkyl; alkenyl; —(CH 2 ) m (CHR 61 ) s OR 55 ; —(CH 2 ) m (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) m (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 )COOR 57 ; —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ; or —(CH 2 ) o (CHR 61 ) s C 6 H 4 R 8 ;
R 55 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH 2 ) m (CHR 61 ) s OR 57 ; —(CH 2 ) m (CHR 61 ) s NR 34 R 63 ; —CH 2 ) m (CHR 61 ) s OCONR 75 R 82 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 78 R 82 ; —(CH 2 ) o (CHR 61 ) s —COR 64 ; —(CH 2 ) o (CHR 61 )COOR 57 ; or —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ;
R 56 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH 2 ) m (CHR 61 ) s OR 57 ; —(CH 2 ) m (CHR 61 ) s NR 34 R 63 ; —(CH 2 ) m (CHR 61 ) s OCONR 75 R 82 ; —(CH 2 ) m (CHR 61 ) s NR 20 CONR 78 R 82 ; —(CH 2 ) o (CHR 61 ) s —COR 64 ; or —(CH 2 ) o (CHR 61 ) s CONR 58 R 59 ;
R 57 is H; lower alkyl; lower alkenyl; aryl lower alkyl; or heteroaryl lower alkyl;
R 58 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl;
R 59 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-lower alkyl; or
R 58 and R 59 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 ; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 60 is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;
R 61 is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CH 2 ) m OR 55 ; —(CH 2 ) m NR 33 R 34 ; —(CH 2 ) m OCONR 75 R 82 ; —(CH 2 ) m NR 20 CONR 78 R 82 ; —(CH 2 ) o COOR 37 ; —(CH 2 ) o NR 58 R 59 ; or —(CH 2 ) o PO(COR 60 ) 2 ;
R 62 is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower alkyl;
R 63 is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —COR 64 ; —COOR 57 ; —CONR 58 R 59 ; —SO 2 R 62 ; or —PO(OR 60 ) 2 ;
R 34 and R 63 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 64 is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —(CH 2 ) p (CHR 61 ) s OR 65 ; —(CH 2 ) p (CHR 61 ) s SR 66 ; or —(CH 2 ) p (CHR 61 ) s NR 34 R 63 ; —(CH 2 ) p (CHR 61 ) s OCONR 75 R 82 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 78 R 82 ;
R 65 is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; —COR 57 ; —COOR 57 ; or —CONR 58 R 59 ;
R 66 is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl; heteroaryl-lower alkyl; or —CONR 58 R 59 ;
m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;
Z is a chain of 12 α-amino acid residues, the positions of said amino acid residues in said chain being counted starting from the N-terminal amino acid, whereby these amino acid residues are, depending on their position in the chain, Gly or Pro, or of formula -A-CO-, or of formula -B-CO-, or of one of the types
C: —NR 20 CH(R 72 )CO—;
D: —NR 20 CH(R 73 )CO—;
E: —NR 20 CH(R 74 )CO—;
F: —NR 20 CH(R 84 )CO—; and
H: —NP 20 —CH(CO—)—(CH 2 ) 4-7 —CH(CO—)—NR 20 —; —NR 20 —CH(CO—)—(CH 2 ) p SS(CH 2 ) p —CH(CO—)—NP 20 —; —NR 20 —CH(CO—)—(—(CH 2 ) p NR 20 CO(CH 2 ) p —CH(CO—)—NR 20 —; and —NR 20 —CH(CO—)—(—(CH 2 ) p NR 20 CONR 20 (CH 2 ) p —CH(CO—)—NR 20 —;
R 71 is H; lower alkyl; lower alkenyl; —(CH 2 ) p (CHR 61 ) s OR 75 ; —(CH 2 ) p (CHR 61 ) s SR 75 ; —(CH 2 ) p (CHR 61 ) s NR 33 R 34 ; —(CH 2 ) p (CHR 61 ) s OCONR 33 R 75 ; —(CH 2 ) p (CHR 61 ) s NR 20 CONR 33 R 82 ; —(CH 2 ) o (CHR 61 ) s COOR 75 ; —(CH 2 ) p CONR 58 R 59 ; —(CH 2 ) p PO(OR 62 ) 2 ; —(CH 2 ) p SO 2 R 62 ; or —(CH 2 ) o —C 6 R 67 R 68 R 69 R 70 R 76 ;
R 72 is H; lower alkyl; lower alkenyl; —(CH 2 ) p (CHR 61 ) s OR 85 ; or —(CH 2 ) p (CHR 61 ) s SR 85 ;
R 73 is —(CH 2 ) o R 77 ; —(CH 2 ) r O(CH 2 ) o R 77 ; —(CH 2 ) r S(CH 2 ) o R 77 ; or —(CH 2 ) r NR 20 (CH 2 ) o R 77 ;
R 74 is —(CH 2 ) p NR 78 R 79 ; —(CH 2 ) p NR 77 R 80 ; —(CH 2 ) p C(═NR 80 )NR 78 R 79 ; —(CH 2 ) p C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) p C(═NNR 78 R 79 )NR 78 R 79 , —(CH 2 ) p NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) p N═C(NR 78 R 80 )NR 79 R 80 ; —(CH 2 ) p C 6 H 4 NR 78 R 79 ; —(CH 2 ) p C 6 H 4 NR 77 R 80 ; —(CH 2 ) p C 6 H 4 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) p C 6 H 4 C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) p C 6 H 4 C(═NNR 78 R 79 )NR 78 R 79 ; —(CH 2 ) p C 6 H 4 NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) p C 6 H 4 N═C(NR 78 R 80 )NR 79 R 80 ; —CH 2 ) r O(CH 2 ) m NR 78 R 79 ; —CH 2 ) r O(CH 2 ) m NR 77 R 80 ; —CH 2 ) r O(CH 2 ) p C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C(═NNR 78 R 79 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) m NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) m N═C(NR 78 R 80 )NR 79 R 80 ; —(CH 2 ) r O(CH 2 ) p C 6 H 4 CNR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C 6 H 4 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C 6 H 4 C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C 6 H 4 C(═NNR 78 R 79 )NR 78 R 79 ; —(CH 2 ) r O(CH 2 ) p C 6 H 4 NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) m NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) m NR 77 R 80 ; —(CH 2 ) r S(CH 2 ) p C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C(═NNR 78 R 79 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) m NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) m N═C(NR 78 R 80 )NR 79 R 80 ; —(CH 2 ) r S(CH 2 ) p C 6 H 4 CNR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C 6 H 4 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C 6 H 4 C(═NOR 50 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C 6 H 4 C(═NNR 78 R 79 )NR 78 R 79 ; —(CH 2 ) r S(CH 2 ) p C 6 H 4 NR 80 C(═NR 80 )NR 78 R 79 ; —(CH 2 ) p NR 80 COR 64 ; —(CH 2 ) p NR 80 COR 77 ; —(CH 2 ) p NR 80 CONR 78 R 79 ; or —(CH 2 ) p C 6 H 4 NR 80 CONR 78 R 79 ;
R 75 is lower alkyl; lower alkenyl; or aryl-lower alkyl;
R 33 and R 75 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 75 and R 82 taken together can form: <CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 76 is H; lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH 2 ) o OR 72 ; —(CH 2 ) o SR 72 ; —(CH 2 ) o NR 33 R 34 ; —(CH 2 ) o OCONR 33 R 75 ; —(CH 2 ) o NR 20 CONR 33 R 82 ; —(CH 2 ) o COOR 75 ; —(CH 2 ) o CONR 58 R 59 ; —(CH 2 ) o PO(OR 60 ) 2 ; —(CH 2 ) p SO 2 R 62 ; or —(CH 2 ) o COR 64 ;
R 77 is —C 6 R 67 R 68 R 69 R 70 R 76 ; or a heteroaryl group of one of the formulae
R 78 is H; lower alkyl; aryl; or aryl-lower alkyl;
R 78 and R 82 taken together can form: —(CH 2 ) 2-6 ; —(CH 2 )O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 ; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 79 is H; lower alkyl; aryl; or aryl-lower alkyl; or
R 78 and R 79 , taken together, can be —(CH 2 ) 2-7 —; —(CH 2 ) 2 O(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 80 is H; or lower alkyl;
R 81 is H; lower alkyl; or aryl-lower alkyl;
R 82 is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;
R 33 and R 82 taken together can form: —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 ; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —;
R 83 is H; lower alkyl; aryl; or —NR 78 R 79 ;
R 84 is —(CH 2 ) m (CHR 61 ) s OH; —CH 2 ) p CONR 78 R 79 ; —(CH 2 ) p NR 80 CONR 78 R 79 ; —(CH 2 ) p C 6 H 4 CONR 78 R 79 ; or —(CH 2 ) p C 6 H 4 NR 80 CONR 78 R 79 ;
R 85 is lower alkyl; or lower alkenyl;
with the proviso that in said chain of 12 α-amino acid residues Z the amino acid residues in positions 1 to 12 are:
P1: of type C or of type D or of type E or of type F, or the residue is Pro;
P2: of type D;
P3: of type C, or of type D, or the residue is Pro;
P4: of type C, or of type D, or of type E;
P5: of type E, or of type D, or of type C, or of type F, or the residue is Gly or Pro;
P6: of type E, or of type For of formula -A-CO-, or the residue is Gly;
P7: of type C, or of type E or of type F or of formula -B-CO-;
P8: of type D, or of type C, or of type F, or the residue is Pro;
P9: of type C, or of type E or of type D or of type F;
P10: of type F, or of type D or of type C, or the residue is Pro;
P11: of type E or of type D or of type C or of type F; and
P12; of type C or of type D or of type E or of type F, or the residue is Pro; or
P4 and P9 and/or P2 and P11, taken together, can form a group of type H; and at P6 and
P7 also D-isomers being possible;
with the further proviso that
the amino acid residue in P4 is of type C; and/or
the amino acid residue in P5 is of type F; and/or
the amino acid residue in P7 is of type C; and/or
the amino acid residue in P8 is of type F; and/or
the amino acid residue in P9 is of type C; and/or
the amino acid residue in P10 is of type F; and/or
the amino acid residue in P11 is of type C or of type F;
and pharmaceutically acceptable salts thereof.
2 . Compounds according to claim 1 wherein
is a group of formula (a1) or (a2).
3 . Compounds according to claim 2 wherein A is a group of one of the formulae A1 to A69;
R 1 is hydrogen or lower alkyl; R 2 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; of lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —CH 2 ) 2-6 —; —(CH 2 ) 2l O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); (CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 3 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; of lower alkenyl); —(CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together and —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; of lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or <CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy). R 4 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 : is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy). R 5 is lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); (CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH (CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H or lower alkyl)—(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy): R 6 is H; lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 7 is lower alkyl; lower alkenyl; —(CH 2 ) q OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) q SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) q NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 ; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) r COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) q CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) r PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) r SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; of lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 2 ; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 9 is lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 ; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; of lower lower alkyl; R 33 is H; or lower alkyl; or lowe alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) n N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 10 is lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 : H is or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 11 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together and —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 ; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) r ; of —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 12 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) r COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) r CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) r PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy): R 13 is lower alkyl; lower alkenyl; —(CH 2 ) q OR 55 (where R 55 is is lower alkyl; of lower alkenyl); —(CH 2 ) q SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) q NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 arid R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lowe alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —CH 2 ) q N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) r COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) q CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) r PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) r SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 14 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) m SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl is R 82 : H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 15 is lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lowe alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —NR 20 COlower alkyl (R 20 ⊚H; or lower alkyl); being particularly favoured; —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or (CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 16 is lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —l where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lowe alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); and R 17 is lower alkyl; lower alkenyl; —(CH 2 ) q OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) q SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) q NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; of lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 )2NR 57(CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) q N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —CH 2 ) r COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) q CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) r PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) r SO 2 R 62 (where R 62 is lower alkyl; of lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy).
4 . Compounds according to claim 2 wherein A is a group of one of the formulae A5 (with R 2 being H); A8; A22; A25; A38 (with R 2 being H); A42; and A50.
5 . Compounds according to claim 4 wherein A is a group of formula
wherein R 20 is H or lower alkyl; and R 64 is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
6 . Compounds according to claim 5 wherein R 64 is n-hexyl; n-heptyl; 4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl; isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl; phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl; or n-nonyl.
7 . Compounds according to claim 2 wherein A is a group of one of the formulae A70 to A104;
R 20 is H; or lower alkyl; R 18 is lower alkyl; R 19 is lower alkyl; lower alkenyl; —(CH 2 ) p OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) p SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) p NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 O(CH 2 ) 2 ; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); (CH 2 ) p COOR 57 (where R 57 : lower alkyl; or lower alkenyl); (CH 2 ) p CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; or lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) p SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or (CH 2 ) o C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 21 is H; lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 2 O(CH 2 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OXONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 22 is lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy); R 23 is H; lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —NR 20 COlower alkyl (R 20 ═H; or lower alkyl) being particularly favoured; —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 24 is lower alkyl; lower alkenyl; —(CH 2 ) o OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lowe alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —NR 20 COlower alkyl (R 20 ═H; or lower alkyl) being particularly favoured; —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 25 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 ; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl): —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); or lower alkoxy); R 26 is H; lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkehyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); or, alternatively, R 25 and R 26 taken together are —(CH 2 ) 2-6 —; —CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 34 (CH 2 ) 2 —; R 27 is H; lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 _ 13 ; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —CH 2 ) 2 S(CH 2 ) 2 —; or —CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); R 28 is lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); and R 29 is lower alkyl; lower alkenyl; —(CH 2 ) o R 55 (where R 55 is lower alkyl; or lower alkenyl); —(CH 2 ) o SR 56 (where R 56 is lower alkyl; or lower alkenyl); —(CH 2 ) o NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o NR 20 CONR 33 R 82 (where R 20 is II; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —l or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —NR 20 COlower-alkyl (R 20 ═H; or lower alkyl) being particularly favoured; —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy).
8 . Compounds according to claim 7 wherein R 23 , R 24 and R 29 are —NR 20 —CO-lower alkyl where R 20 is H; or lower alkyl.
9 . Compounds according to claim 7 wherein A is a group of one of the formulae A74 (with R 22 being H); a75; A76; A77 (with R 22 being H); A78; and A79.
10 . Compounds according to claim 2 wherein B is a group of formula —NR 20 CH(R 71 )— or an enantiomer of one of the groups A5 (with R 2 being H); A8; A22; A25; A38 (with R 2 being H); A42; A47; and A50.
11 . Compounds according to claim 10 wherein B-CO is Ala; Arg; Asn; Cys; Gin; Gly; His; Ile; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr; Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe; 2AmPhe; Phe(mC(NH 2 )═NH; Phe(pC(NH 2 )═NH; Phe(rnNHC (NH 2 )═NH; Phe(pNHC (NH 2 )═NH; Phg; Cha; C 4 al; C 5 al; Nlc; 2-Nal; 1-Nal; 4Cl-Phe; 3Cl-Phe; 2Cl-Phe; 3,4Cl 2 Phe; 4F-Phe; 3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso; AcLys; Dpr; A 2 Bu; Dbu; Abu; Aha; Aib; Y(Bzl); Bip; S(Bzl); T(Bzl); hCha; hCys; hSer, hArg; hPhe; Bpa; Pip; OctG; MePhe; MeNle; MeAla; MeIle; MeVal; or MeLeu.
12 . Compounds according to claim 10 wherein B is a group, having (L)-configuration, of formula
wherein R 20 is H; or lower alkyl; and R 64 is alkyl; alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
13 . Compounds according to claim 12 wherein R 64 is n-hexyl; n-heptyl; 4-(phenyl)benzyl; diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl; isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl; phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl; or n-nonyl.
14 . Compounds according to claim 1 wherein
is a group of formula (b1) or (1);
R 1 is H; or lower alkyl;
R 20 is H; or lower alkyl;
R 30 is H; or methyl;
R 31 is H; lower alkyl; lower alkenyl; —(CH 2 ) p OR 55 (where R 55 is lower alkyl; or lower alkenyl);
—(CH 2 ) p NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or
lower alkyl); —(CH 2 ) p OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 (CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or
—(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl;
or lower alkenyl); or —(CH 2 ) r C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); most preferably —CH 2 CONR 58 R 59 (where R 58 is H; or lower alkyl; and R 59 is lower alkyl; or lower alkenyl);
R 32 is H; or methyl;
R 33 is lower alkyl; lower alkenyl; —(CH 2 ) m OR 55 (where R 55 is lower alkyl; or lower alkenyl);
—(CH 2 ) m NR 34 R 63 (where R 34 is lower alkyl; or lower alkenyl; R 63 is H; or lower alkyl; or R 34 and R 63 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 75 R 82 (where R 75 is lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl;
or R 75 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or
—(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 78 R 82 (where R 20 is H; or lower alkyl; R 78 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 78 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —l where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 : H; or lower alkyl);
R 34 is H; or lower alkyl;
R 35 : is H; lower alkyl; lower alkenyl; (CH 2 ) m OR 55 (where R 55 : lower alkyl; or lower alkenyl);
—(CH 2 ) m NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or
—(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) m N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl; or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl);
R 36 : lower alkyl; lower alkenyl; or aryl-lower alkyl;
R 37 is H; lower alkyl; lower alkenyl; —(CH 2 ) p OR 55 (where R 55 is lower alkyl; or lower alkenyl);
—(CH 2 ) p NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl);- (CH 2 ) p OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —CH 2 ) 2 S(CH 2 ) 2 —; or
—(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl;
or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy); and
R 38 is H; lower alkyl; lower alkenyl; —(CH 2 ) p OR 55 (where R 55 is lower alkyl; or lower alkenyl);
—(CH 2 ) p NR 33 R 34 (where R 33 is lower alkyl; or lower alkenyl; R 34 is H; or lower alkyl; or R 33 and R 34 taken together sre —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or
lower alkyl); —(CH 2 ) p OCONR 33 R 75 (where R 33 is H; or lower alkyl; or lower alkenyl; R 75 is lower alkyl; or
R 33 and R 75 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p NR 20 CONR 33 R 82 (where R 20 is H; or lower alkyl; R 33 is H; or lower alkyl; or lower alkenyl; R 82 is H; or lower alkyl; or R 33 and R 82 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl); —(CH 2 ) p N(R 20 )COR 64 (where: R 20 is H; or lower alkyl; R 64 is lower alkyl; or lower alkenyl); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) o CONR 58 R 59 (where R 58 is lower alkyl, or lower alkenyl; and R 59 is H; lower alkyl; or R 58 and R 59 taken together are —(CH 2 ) 2-6 —; —(CH 2 ) 2 O(CH 2 ) 2 —; —(CH 2 ) 2 S(CH 2 ) 2 —; or —(CH 2 ) 2 NR 57 (CH 2 ) 2 —; where R 57 is H; or lower alkyl);
—(CH 2 ) o PO(OR 60 ) 2 (where R 60 is lower alkyl; or lower alkenyl); —(CH 2 ) o SO 2 R 62 (where R 62 is lower alkyl; or lower alkenyl); or —(CH 2 ) q C 6 H 4 R 8 (where R 8 is H; F; Cl; CF 3 ; lower alkyl; lower alkenyl; or lower alkoxy).
15 . Compounds according to claim 14 wherein R 1 is H; R 20 is H; R 30 is H; R 31 is carboxymethyl; or lower alkoxycarbonylmethyl; R 32 is H; R 35 is methyl; R 36 is methoxy; R 37 is H and R 38 is H.
16 . Compounds according to claim 1 wherein the α-amino acid residues in positions 1 to 12 of the chain Z are:
P1: of type C or of type D or of type E or of type F; P2: of type D; P3: of type C; P4: of type E, or of type C; P5: of type E, or of type F; P6: of type E, or of type F, or of formula -A-CO-; P7: of type E, or of type F, or of formula -B-CO-; P8: of type D, or of type C, or of Type F; P9: of type C, or of type E; P10: of type F, or of type D, or of type C; P11: of type D, or of type C, or of type F; P12: of type C or of type D or of type E or of type F;
at P6 and P7 also D-isomers being possible;
with the proviso that
the amino acid residue in position P4 is of type C; and/or
the amino acid residue in position P5 is of type F; and/or
the amino acid residue in position P8 is of type F; and/or
the amino acid residue in position P9 is of type C; and/or
the amino acid residue in position P10 is of type F; and/or
the amino acid residue in position P11 is of type C or F.
17 . Compounds according to claim 16 wherein the α-amino acid residues in positions 1 to 12 of the chain Z are:
P1: Arg; P2: Tip; P3: Leu; P4: Lys or Val; P5: Lys; P6: Arg; P7: Arg; P8: Tip; P9: Leu, Val or Lys; P10: Tyr, Thr or Gln; P11: Val, Leu, Tyr or Gin; and P12: Arg; with the proviso that the amino acid residue in position P4 is Val; and/or the amino acid residue in position P9 is Leu or Val; and/or the amino acid residue in position P10 is Thr or Gin; and/or the amino acid residue in position P11 is Val or Leu or Gin.
18 - 19 . (canceled)
20 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-12 are:
P1: Arg; P2: Tip; P3: Leu; P4: Lys; P5: Lys; P6: Arg; P7: Arg; P8: Tip; P9: Lys; P10: Thr; P11: Tyr; and P12: Arg
21 - 24 . (canceled)
25 . Enantiomers of the compounds of formulae I as defined in claim 1 .
26 . Compounds according to claim 1 for use as therapeutically active substances.
27 . Compounds according to claim 26 having selective antimicrobial activity being in particular against Pseudomonas aeruginosa or Acinetobacter.
28 . A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically inert carrier.
29 . Compositions according to claim 28 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration.
30 . Compositions according to claim 28 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories.
31 . The use of compounds according to claim 1 for the manufacture of a medicament for treating or preventing infections or diseases related to such infections.
32 . The use according to claim 31 wherein said infections are related to respiratory diseases such as cystic fibrosis, emphysema and asthma; related to skin or soft tissue diseases such as surgical wounds, traumatic wounds or burn Wounds; related to gastrointestinal diseases such as epidemic diarrhea, necrotizing enterocolitis or typhlitis; related to eye diseases such as keratitis or endophthalmitis; related to ear diseases such as otitis; related to CNS diseases such as brain abscess or meningitis; related to bone diseases such as osteochondritis or osteomyelitis; related to cardiovascular diseases such as endocartitis or pericarditis; related to gastrourinal diseases such as epididymitis, prostatitis or urethritis; related to cancer; or related to HIV.
33 . The use of compounds according to claim 1 as disinfectants or preservatives for foodstuffs, cosmetics, medicaments and other nutrient-containing materials.
34 . A process for the manufacture of compounds according to claim 1 which process comprises
(a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid Which in the desired end-product is in position 5, 6 or 7, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (b) removing the N-protecting group from the product thus obtained; (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position nearer the N-terminal amino acid residue, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; (d) removing the N-protecting group from the product thus obtained; (e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced; (f) coupling the product thus obtained with a compound of the general formula
is as defined above and X is an N-protecting group or, if
is to be group (a1) or (a2), above, alternatively
(fa) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV
wherein B and A are as defined above, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(fb) removing the N-protecting group from the product thus obtained; and
(fc) coupling the product thus obtained with an appropriately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(g) removing the N-protecting group from the product obtained in step (f) or (fc);
(h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(i) removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(k) removing the N-protecting group from the product thus obtained;
(l) repeating steps (j) and (k) until all amino acid residues have been introduced;
(m) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the product cleaved from the solid support;
(q) if desired, forming one or two interstrand lihkage(s) between side-chains of appropriate amino acid residues at opposite positions of the p-strand region;
(r) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; and
(s) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.
35 . A process for the manufacture of compounds according to claims 1 which process comprises
(a′) coupling an appropriately functionalized solid support with a compound of the general formula
is as defined above and X is an N-protecting group or, if
is to be group (a1) or (a2), above, alternatively
(a′a) coupling said appropriately functionalized solid support with an appropriately N-protected derivative of an amino acid of the general formula
HOOC-B-H III or HOOC-A-H IV
wherein B and A are as defined above, any functional group Which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(a′b) removing the N-protecting group from the product thus obtained; and
(a′c) coupling the product thus obtained with an appropriately N-protected derivative of an amino acid of the above general formula IV and, respectively, III, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(b′) removing the N-protecting group from the product obtained in step (a′) or (a′c);
(c′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(d′) removing the N-protecting group from the product thus obtained;
(e′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(f) removing the N-protecting group from the product thus obtained;
(g′) repeating steps (e′) and (f′) until all amino acid residues have been introduced;
(h) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;
(i′) detaching the product thus obtained from the solid support;
(j′) cyclizing the product cleaved from the solid support;
(k′) if desired forming one or two interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the p-strand region;
(l′) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, if desired, any protecting group(s) which may in addition be present in the molecule; and
(m′) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound of formula I or into a different, pharmaceutically acceptable, salt.Cited by (0)
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