US2014213531A1PendingUtilityA1
Template-fixed beta-hairpin peptidomimetics with protease inhibitory activitiy
Est. expiryFeb 17, 2025(expired)· nominal 20-yr term from priority
Inventors:Steven J. DemarcoKerstin MoehleHeiko HenzeOdile SellierFrancoise JungFrank GombertDaniel ObrechtChristian Ludin
A61P 43/00A61P 9/00A61P 37/00A61P 31/00A61P 35/00A61P 29/00A61P 25/00A61K 38/10C07K 7/64C07K 7/08C07K 7/06C07K 1/061A61K 38/00A61K 38/04A61K 38/08
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Claims
Abstract
Template-fixed β-hairpin peptidomimetics of the general formulae wherein Z is a chain of 11 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or Pro(4NHCOPhe), 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 inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. 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
wherein
is a group of one of the formulae
wherein
is Gly or 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 ; or —(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 33 R 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 ) 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 7 ; —(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 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 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 ; or
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 ) 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 22 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 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 33 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 6 ; 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 6 ; 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 5 ; —(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 11 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 chains, Gly, Pro, Pro(4NHCOPhe) 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: —NR 20 —CH(CO—)—(CH 2 ) 4-7 —CH(CO—)—NR 20 —; —NR 20 —CH(CO—)—(CH 2 ) p SS(CH 2 ) p —CH(CO—)—NR 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 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 —(CR 86 R 87 ) 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(═NR 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(═NR 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 ; —(CH 2 ) p C 6 H 4 NR 80 CONR 78 R 79 ; or —(CH 2 ) p NR 20 CO—[(CH 2 ) u —X] t —CH 3 where X is —O—; —NR 20 —, or —S—; u is 1-3, and t is 1-6;
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 ) 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; —(CR 86 R 87 )pOR 80 ; —(CR 86 R 87 )pCOOR 80 ; —(CH 2 ) m (CHR 61 ) s SH; —(CR 86 R 87 )pSR 80 ; —(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 ; —(CR 86 R 87 ) o PO(OR 60 ) 2 ; —(CR 86 R 87 ) p SO 2 R 60 ; —(CR 86 R 87 ) p SOR 60 ; —(CH 2 ) m (CHR 61 ) s OPO(OR 60 ) 2 ; or —(CH 2 ) m (CHR 61 ) s OSO 2 R 60 ;
R 85 is lower alkyl; or lower alkenyl;
R 86 is H; lower alkyl, where H is maybe substituted by halogen; or halogen;
R 87 is H; lower alkyl, where H is maybe substituted by halogen; or halogen;
with the proviso that in said chain of 11 α-amino acid residues Z
if n is 11, the amino acid residues in positions 1 to 11 are:
P1: of type C or of type D or of type E or of type F;
P2: of type C or of Type D or of type E, or of type F;
P3: or of type C, of type F, or the residue is Gly;
P4: of type C, or of type D, or of type F, or of type E, or the residue is Gly or Pro;
P5: of type E, or of type C, or of type F, or the residue is Gly or Pro;
P6: of type D, or of type F, or of type E or of type C, or the residue is Gly or Pro;
P7: of type C, or of type E, or of type F, or of formula A-CO—, or the residue is Gly or Pro;
P8: of type D, or of type C, or of type F, or of formula A-CO, or the residue is Gly or Pro or Pro(4NHCOPhe);
P9: of type C, or of type D, or of type E, or of type F;
P10: of type D, or of type C, or of type F, or of type E; and
P11: of type C, or of type D, or of type E, or of type F; or
P2 and P10, taken together, can form a group of type H; and
with the further proviso that if the template is D Pro L Pro, the amino acid residues in positions P1 to P11 are other than
P1: Arg
P2: Cys, linked with Cys in position P10 by a disulfide bridge
P3: Thr
P4: Lys
P5: Ser
P6: Ile
P7: Pro
P8: Pro
P9: Ile
P10: Cys, linked with Cys in position P2 by a disulfide bridge; and
P11: Phe;
and pharmaceutically acceptable salts thereof.
2 . Compounds according to claim 1 wherein
is a group of formula (a1) or (a2) or (a3).
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; 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 3 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 ) 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 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 5 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 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 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 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 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); —(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; 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; 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 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);
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 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 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 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 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 CO lower 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 —; 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; 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; 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; 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).
4 . Compounds according to claim 3 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; —[(CH 2 ) u —X] t —CH 3 , wherein X is —O—, —NR 20 — or —S—, u is 1-3 and t is 1-6; 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; n-nonyl; CH 3 —OCH 2 CH 2 —OCH 2 — or CH 3 —(OCH 2 CH 2 ) 2 —OCH 2 —.
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 ) 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 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 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 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); —(CH 2 ) o COOR 57 (where R 57 is lower alkyl; or lower alkenyl); —(CH 2 ) 2 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 CO lower 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 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 CO lower 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 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);
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 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, 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 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 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 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 (CH 2 ) 2 NR 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 29 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 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 CO lower-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 erg 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; Gln; Gly; His; Ile; Leu; Lys; Met; Phe; Pro; Pro(5RPhe), 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(mNHC (NH 2 )═NH; Phe(pNHC (NH 2 )═NH; Phg; Cha; C 4 al; C 5 al; Nle; 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; —[(CH 2 ) u —X] t —CH 3 , wherein X is —O—, —NR 20 — or —S—, u is 1-3 and t is 1-6; 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; n-nonyl; CH 3 —OCH 2 CH 2 —OCH 2 — or CH 3 —(OCH 2 CH 2 ) 2 —OCH 2 —.
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 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 ) 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 —; 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 ) 2 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 alky; 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 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).
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 11 in the chain Z are:
P1: of type C, or of type D, or of type E, or of type F;
P2: of type E, or of type F, or of type C;
P3: or of type C, of type F or the residue is Gly;
P4: of type C, or of type E, or of type F, or the residue is Gly or Pro;
P5: of type E, or of type F, or the residue is Gly or Pro;
P6: of type C, or of type D, or of type F, or the residue is Gly or Pro;
P7: of type F or of formula A-CO— or the residue is Gly or Pro;
P8: of type D, or of type C, or of formula -A-CO or the residue is Gly or Pro or Pro(4NHCOPhe);
P9: of type C, or of type D, or of type E, or of type F;
P10: of type F, or of type C, or type E;
P11: of type E, or of type F, or of type C or of type D; or
P2 and P10, taken together, form a group of type H;
with the proviso that if template is D Pro- L Pro the amino acid residues in positions P1 to P11 are other than
P1: Arg
P2: Cys, linked with Cys in position P10 by a disulfide bridge
P3: Thr
P4 Lys
P5 Ser
P6 Ile
P7 Pro
P8 Pro
P9 Ile
P10 Cys, linked with Cys in position P2 by a disulfide bridge; and
P11 Phe.
17 . Compounds according to claim 16 wherein the α-amino acid residues in positions 1 to 11 of the chain Z are:
P1: Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr, 2Cl-Phe, Trp, 1-Nal, Leu, Cha or Arg;
P2: Cys, Glu, Nle, Thr, or Gln;
P3: Thr, Ala or Abu;
P4: Lys, Nle, Ala, Abu, or Thr;
P5: Ser, AlloThr or Dpr;
P6: Ile, c5al, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA, Glu, or Asp;
P7: Pro;
P8: Pro, Ala, or Pro(4NHCOPhe);
P9: Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr, or Ala;
P10: Cys, Arg, Nle, Gln, Lys, Met, Thr, or Ser;
P11: Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr, Phe, Asp Asn, or Thr; and
Cys, if present at P2 and P10, may form a disulfide bridge.
18 . Compounds according to claim 1 wherein the α-amino acid residues in positions 1 to 11 in the chain Z are:
P1: of type C, or of type D, or of type E;
P2: of type F, or of type C;
P3: of type F;
P4: of type C, or of type E;
P5: of type E, or of type F;
P6: of type F;
P7: of type F, or of formula -A-CO—, or the residue is Gly or Pro;
P8: of type C, or of formula -A-CO—, or the residue is Gly or Pro or Pro(4NHCOPhe);
P9: of type C, or of type D, or of type F;
P10: of type F, or of type C, or type E;
P11: of type E, or of type D, or of type F; or
P2 and P10, taken together, form a group of type H;
19 . Compounds according to claim 18 wherein the α-amino acid residues in positions 1 to 11 are:
P1: Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe, Arg, 1-Nal, or Cha;
P2: Cys, Glu, or Nle;
P3: Thr;
P4: Lys, or Nle;
P5: Ser, AlloThr, or Dpr;
P6: Asp, or Glu;
P7: Pro;
P8: Pro;
P9: Ile, Nle, Cha, Gln, Tyr, or Ala;
P10: Cys, Arg, or Nle;
P11: Thr, Asp, Ser, Tyr, Phe, Asn, or Arg; and
Cys, if present at P2 and P10, may form a disulfide bridge.
20 . Compounds according to claim 1 wherein the α-amino acid residues in positions 1 to 11 in the chain Z are:
P1: of type C, or of type D;
P2: of type F;
P3: of type F or of type C;
P4: of type C or of type F;
P5: of type F;
P6: of type C;
P7: of formula A-CO—, or the residue is Gly or Pro;
P8: of formula -A-CO—, or the residue is Gly or Pro or Pro(4NHCOPhe);
P9: of type D, or of type F or of type C;
P10: of type F, or of type C, or type E;
P11: of type E, or of type F, or of type D; or
P2 and P10, taken together, form a group of type H.
21 . Compounds according to claim 20 wherein the α-amino acid residues in positions 1 to 11 are:
P1: Ile, Nle, Aoc, hLeu, Chg, OctG, or hPhe;
P2: Cys, Glu, Thr, or Gln;
P3: Thr, Ala, or Abu;
P4: Ala, Thr, or Abu;
P5: Ser;
P6: OctG, Ile, Cha, Leu, c5al, Nle, Aoc, Chg, tBuA, or hLeu;
P7: Pro;
P8: Pro, or Pro(4NHCOPhe);
P9: Gln, Tyr, ILe, or Phe;
P10: Cys, Lys, Gln, Thr, Met, or Arg;
P11: Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha, or Phg; and
Cys, if present at P2 and P10, may form a disulfide bridge.
22 . Compounds according to claim 1 wherein the α-amino acid residues in positions 1 to 11 in the chain Z are:
P1: of type C, or of type D, or of type E;
P2: of type F;
P3: of type F;
P4: of type E;
P5: of type F;
P6: of type C or of type D;
P7: of type F or of formula -A-CO—, or the residue is Gly or Pro;
P8: of type C, or of formula -A-CO—, or the residue is Gly or Pro;
P9: of type C, or of type E, or of type F;
P10: of type F;
P11: of type E, or of type D; or
P2 and P10, taken together, form a group of type H;
with the proviso that if the template is D Pro- L Pro, the amino acid residues in positions P1 to P11 are other than
P1: Arg
P2: Cys, linked with Cys in position P10 by a disulfide bridge
P3: Thr
P4 Lys
P5 Ser
P6 Ile
P7 Pro
P8 Pro
P9 Ile
P10 Cys, linked with Cys in position P2 by a disulfide bridge; and
P11 Phe.
23 . Compounds according to claim 22 wherein the α-amino acid residues in positions 1 to 11 of the chain Z are:
P1: Cha, Tyr, or Trp
P2: Cys
P3: Thr
P4: Lys
P5: Ser
P6: Leu
P7: Pro
P8: Pro
P9: Lys
P10: Cys
P11: Arg; and
the Cys residues present at P2 and P10 may form a disulfide bridge.
24 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Phe;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
25 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Ile;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Nle;
P10: Cys;
P11: Arg;
Cys at P2 and P10 forming a disulfide bridge.
26 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Ile;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Cha;
P10: Cys;
P11: Arg;
Cys at P2 and P10 forming a disulfide bridge.
27 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Ile;
P2: Cys;
P3: Thr;
P4: Nle;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Arg
Cys at P2 and P10 forming a disulfide bridge.
28 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Phe;
P2: Cys;
P3: Thr;
P4: Nle;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
29 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Chg;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
30 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Arg;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Phe;
Cys at P2 and P10 forming a disulfide bridge.
31 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Nle;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Ile;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Gln;
Cys at P2 and P10 forming a disulfide bridge.
32 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Nle;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Ile;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
33 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: hPhe;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: OctG;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Gln
Cys at P2 and P10 forming a disulfide bridge.
34 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Gln;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Ile;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Thr;
P11: Tyr.
35 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: hPhe;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Cha;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Phe;
Cys at P2 and P10 forming a disulfide bridge.
36 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Glu;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Ile;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Lys;
P11: Tyr.
37 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Cha;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Phe;
Cys at P2 and P10 forming a disulfide bridge.
38 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: hPhe;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Cha;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Gln;
Cys at P2 and P10 forming a disulfide bridge.
39 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Cha;
P7: Pro;
P8: Pro(4NHCOPhe);
P9: Gln;
P10: Cys;
P11: Gln;
Cys at P2 and P10 forming a disulfide bridge.
40 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: hPhe;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: OctG;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
41 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Chg;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Thr;
Cys at P2 and P10 forming a disulfide bridge.
42 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Chg;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Asp;
P7: Pro;
P8: Pro;
P9: Ile;
P10: Cys;
P11: Asp;
Cys at P2 and P10 forming a disulfide bridge.
43 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Cha;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Gln;
Cys at P2 and P10 forming a disulfide bridge.
44 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: Ile;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Tyr;
Cys at P2 and P10 forming a disulfide bridge.
45 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: OctG;
P2: Cys;
P3: Thr;
P4: Ala;
P5: Ser;
P6: OctG;
P7: Pro;
P8: Pro;
P9: Gln;
P10: Cys;
P11: Gln;
Cys at P2 and P10 forming a disulfide bridge.
46 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Cha;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Leu;
P7: Pro;
P8: Pro;
P9: Lys;
P10: Cys;
P11: Arg;
Cys at P2 and P10 forming a disulfide bridge.
47 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Tyr;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Leu;
P7: Pro;
P8: Pro;
P9: Lys;
P10: Cys;
P11: Arg;
Cys at P2 and P10 forming a disulfide bridge.
48 . A compound of formula I according to claim 1 wherein the template is D Pro- L Pro and the amino acid residues in position 1-11 are:
P1: Trp;
P2: Cys;
P3: Thr;
P4: Lys;
P5: Ser;
P6: Leu;
P7: Pro;
P8: Pro;
P9: Lys;
P10: Cys;
P11: Arg;
Cys at P2 and P10 forming a disulfide bridge.
49 . Enantiomers of the compounds of formula I as defined in claim 1 .
50 . Compounds according to claim 1 for use as therapeutically active substances.
51 . Compounds according to claim 50 having selective protease inhibitory activity in particular against Cathepsin G or Elastase or Tryptase and/or anticancer activity and/or anti inflammatory activity and/or anti infective activity and/or anticardiovascular activity and/or antiimmunological activity and/or antineurodegenerative activity.
52 . A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically inert carrier.
53 . Compositions according to claim 52 in a form suitable for oral, topical, transdermal, buccal, transmucosal or pulmonary administration or for administration by injection or inhalation.
54 . Compositions according to claim 52 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories.
55 . The use of compounds according to claim 1 for the manufacture of a medicament for use as an inhibitor of protease enzymes.
56 . The use according to claim 55 wherein said protease inhibiting medicament is intended to be used for preventing infections in healthy individuals or for slowing infections in infected patients; or where cancer is mediated or resulting from; or where an immunological diseases are mediated or resulting from protease activity or where inflammation is mediated or resulting from protease activity; or where immunological reaction is mediated or resulting from protease activity.
57 . The use of compounds according to claim 18 , for the manufacture of a medicament for use as an inhibitor of Cathepsin G.
58 . The use of compounds according to claim 20 , for the manufacture of a medicament for use as an inhibitor of Elastase.
59 . The use of compounds according to claim 22 , for the manufacture of a medicament for use as an inhibitor of Tryptase.
60 . 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
wherein
is as defined in claim 1 and X is an N-protecting group or, alternatively, if
is to be group (a1) or (a2) as defined in claim 1 ,
(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 in claim 1 , 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; and, respectively, if
is to be group (a3) as defined in claim 1 ,
(fa′) coupling the product obtained in step (e) with an appropriately N-protected derivative of an amino acid of the above general formula III, 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 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) 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 11, 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;
(i) 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 11, 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;
(n) if desired, forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the product cleaved from the solid support;
(q) 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
(r) 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.
61 . A process for the manufacture of compounds according to claim 1 which process comprises
(a′) coupling an appropriately functionalized solid support with a compound of the general formula
wherein
is as defined in claim 1 and X is an N-protecting group or, alternatively, if
is to be group (a1) or (a2) as defined in claim 1 ,
(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 in claim 1 , 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; and, respectively, if
is to be group (a3) as defined in claim 1 ,
(a′a′) coupling said appropriately functionalized solid support with an appropriately N-protected derivative of an amino acid of the above general formula III, 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 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′), (a′c) 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 11, 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, 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′) if desired forming an interstrand linkage between side-chains of appropriate amino acid residues at positions 2 and 10;
(j′) detaching the product thus obtained from the solid support;
(k′) cyclizing the product cleaved from the solid support;
(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.
62 . A modification of the process according to claim 60 for the manufacture of enantiomers of compounds of the general formula I:
wherein
is a group of one of the formulae
wherein
is Gly or 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 ; or —(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 33 R 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 ) 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 7 ; —(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 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 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 ; or
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 ) 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 22 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 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 33 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 6 ; 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 6 ; 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 5 ; —(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 11 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 chains, Gly, Pro, Pro(4NHCOPhe) 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: —NR 20 —CH(CO—)—(CH 2 ) 4-7 —CH(CO—)—NR 20 —; —NR 20 —CH(CO—)—(CH 2 ) p SS(CH 2 ) p —CH(CO—)—NR 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 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 —(CR 86 R 87 ) 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(═NR 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(═NR 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 ; —(CH 2 ) p C 6 H 4 NR 80 CONR 78 R 79 ; or —(CH 2 ) p NR 20 CO—[(CH 2 ) u —X] t —CH 3 where X is —O—; —NR 20 —, or —S—; u is 1-3, and t is 1-6;
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 ) 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; —(CR 86 R 87 )pOR 80 ; —(CR 86 R 87 )pCOOR 80 ; —(CH 2 ) m (CHR 61 ) s SH; —(CR 86 R 87 )pSR 80 ; —(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 ; —(CR 86 R 87 ) o PO(OR 60 ) 2 ; —(CR 86 R 87 ) p SO 2 R 60 ; —(CR 86 R 87 ) p SOR 60 ; —(CH 2 ) m (CHR 61 ) s OPO(OR 60 ) 2 ; or —(CH 2 ) m (CHR 61 ) s OSO 2 R 60 ;
R 85 is lower alkyl; or lower alkenyl;
R 86 is H; lower alkyl, where H is maybe substituted by halogen; or halogen;
R 87 is H; lower alkyl, where H is maybe substituted by halogen; or halogen;
with the proviso that in said chain of 11 α-amino acid residues Z
if n is 11, the amino acid residues in positions 1 to 11 are:
P1: of type C or of type D or of type E or of type F;
P2: of type C or of Type D or of type E, or of type F;
P3: or of type C, of type F, or the residue is Gly;
P4: of type C, or of type D, or of type F, or of type E, or the residue is Gly or Pro;
P5: of type E, or of type C, or of type F, or the residue is Gly or Pro;
P6: of type D, or of type F, or of type E or of type C, or the residue is Gly or Pro;
P7: of type C, or of type E, or of type F, or of formula A-CO—, or the residue is Gly or Pro;
P8: of type D, or of type C, or of type F, or of formula A-CO, or the residue is Gly or Pro or Pro(4NHCOPhe);
P9: of type C, or of type D, or of type E, or of type F;
P10: of type D, or of type C, or of type F, or of type E; and
P11: of type C, or of type D, or of type E, or of type F; or
P2 and P10, taken together, can form a group of type H; and
with the further proviso that if the template is D Pro L Pro, the amino acid residues in positions P1 to P11 are other than
P1: Arg
P2: Cys, linked with Cys in position P10 by a disulfide bridge
P3: Thr
P4: Lys
P5: Ser
P6: Ile
P7: Pro
P8: Pro
P9: Ile
P10: Cys, linked with Cys in position P2 by a disulfide bridge; and
P11: Phe;
and pharmaceutically acceptable salts thereof, in which enantiomers of all chiral starting materials are used.Join the waitlist — get patent alerts
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