Antineoplastic peptides

Abstract

The present invention provides antineoplastic peptides of formula I, R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I wherein R 1 , R 2 , X, A, B, D, E, G, K and s have the meanings stated in the description. The compounds have antineoplastic activity.

What is claimed is:  
     
         1 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is hydrogen, methyl; or ethyl;  
 R 2  is methyl; or ethyl; or  
 R 1 -N-R 2  together are a pyrrolidine ring;  
 A is a valyl, isoleucyl, allo-isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl, norleucyl or norvalyl residue;  
 B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-leucyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl, or N-methyl-norleucyl residue;  
 D is a prolyl, homoprolyl, hydroxyprolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl, homoprolyl, hydroxyprolyl, thiazolidine-4-carbonyl, trans-4-fluoro-L-prolyl, cis-4-fluoro-L-prolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl residue;  
 X is ethyl, propyl, butyl, isopropyl, sec. butyl, tert.-butyl, cyclopropyl, or cyclopentyl;  
 G is a L-2-tert.butylglycyl, D-2-terr.butylglycyl, D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, 1-aminopentyl-1-carbonyl, or 2,2-dimethylglycyl residue;  
 s is 0 or 1;  
 K is —NH-C 1-8 -alkyl, —NH-C 3-8 -alkenyl, —NH-C 3-8 -alkinyl, —NH-C 6-8 -cycloalkyl, —NH-C 1-4 -alkene-C 3-8 -cycloalkyl, C 1-4 -alkyl-N-C 1-6 -alkyl, in which residues one CH 2  group may be replaced by O or S, one H by phenyl or cyano, or 1, 2 or 3 H by F, except the N-methoxy-N-methylamino, N-benzylamino, or N-methyl-N-benzylamino residue, or K is  
                 
 
 and the salts thereof with physiologically tolerated acids.  
 
     
     
         2 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is hydrogen, methyl; or ethyl;  
 R 2  is methyl; or ethyl; or  
 R 1 -N-R 2  together are a pyrrolidine ring;  
 A is a valyl, isoleucyl, allo-isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl, norleucyl or norvalyl residue;  
 B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-leucyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl, or N-methyl-norleucyl residue;  
 D is a prolyl, homoprolyl, hydroxyprolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl, homoprolyl, hydroxyprolyl, thiazolidine-4-carbonyl, trans-4-fluoro-L-prolyl, cis-4-fluoro-L-prolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl residue;  
 X is ethyl, propyl, butyl, isopropyl, sec. butyl, tert.butyl, cyclopropyl, or cyclopentyl;  
 G is a L-2-tert.butylglycyl, D-2-terr.butylglycyl, D-valyl, D-isoleucyl, D-leucyl, D-norvalyl, 1-aminopentyl-1-carbonyl, or 2,2-dimethylglycyl residue;  
 s is 0 or 1;  
 K —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NH(CH 2 ) 3 CH 3 , —NH(CH 2 ) 4 CH 3 , —NH(CH 2 ) 5 CH 3 , —NH(CH 2 ) 6 CH 3 , —NHCH(CH 2 ) 7 CH 3 , —NHCH(CH 3 ) 2 , —NHCH(CH 3 )CH 2 CH 3 , —NHCH(CH 2 CH 3 ) 2 , —NHCH(CH 2 CH 2 CH 3 ) 2 , —NHC(CH 3 ) 3 , —NHCH(CH 2 CH 3 )CH 2 CH 2 CH 3 , —NHCH(CH 3 )CH(CH 3 ) 2 , —NHCH(CH 2 CH 3 )CH(CH 3 ) 2 , —NHCH(CH 3 )C(CH 3 ) 3 , —NH-cyclohexyl, —NH-cycloheptyl, —NH-cyclooctyl, —N(CH 3 )OCH 2 CH 3 , —N(CH 3 )OCH 2 CH 2 CH 3 , —N(CH 3 )OCH(CH 3 ) 2 , —N(CH 3 )O(CH 2 ) 3 CH 3 , —N(CH 3 )OCH 2 C 6 H 5 , —NH(CH 2 ) 2 C 6 H 5 , —NH(CH 2 ) 3 C 6 H 5 , —NHCH(CH 3 )C 6 H 5 , —NHC(CH 3 ) 2 C 6 H 5 , —NHC(CH 3 ) 2 CH 2 CH 3 , —NHC(CH 3 )(CH 2 CH 3 ) 2 , —NHCH[CH(CH 3 ) 2 ] 2 , —NHC(CH 3 ) 2 CN, —NHCH(CH 3 )CH(OH)C 6 H 5 , —NHCH 2 -cyclohexyl, —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CF 3 , —NHCH(CH 2 F) 2 , —NHCH 2 CH 2 F, —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 SCH 3 , —NHCH 2 CHCH 2 , —NH-C(CH 3 ) 2 CH═CH 2 , —NHC(CH 3 ) 2 C≡CH, —NHC(CH 2 CH 3 ) 2 C≡CH, —NHC(CH 3 ) 2 CH 2 CH 2 OH, —NH(CH 2 CH 2 O) 2 CH 2 CH 3 , —NHC(CH 3 ) 2 CH(CH 3 ) 2 , —NHC(CH 3 ) 2 CH 2 CH 2 CH 3 , —NHC(CH 3 ) 2 CH 2 C 6 H 5 , —N(OCH 3 )CH(CH 3 ) 2 , —N(OCH 3 )CH 2 CH 3 , —N(OCH 3 )CH 2 CH 2 CH 3 , —N(OCH 3 )CH 2 C 6 H 5 , —N(OCH 3 )C 6 H 5 , —N(CH 3 )OC 6 H 5 , —NHCH[CH(CH 3 ) 2 ] 2 , —N(OCH 3 )CH 2 CH 2 CH 2 CH 3 ,  
 or K is  
                 
 
 And the salts thereof with physiologically tolerated acids.  
 
     
     
         3 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is hydrogen, methyl; or ethyl;  
 R 2  is methyl; or ethyl;  
 A is a valyl, isoleucyl, 2-tert-butylglycyl, 2-ethylglycyl, norleucyl or norvalyl residue;  
 B is a N-methyl-valyl, N-methyl-norvalyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl, or N-methyl-norleucyl residue;  
 D is a prolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl, homoprolyl, thiazolidine-4-carbonyl, trans-4-fluoro-L-prolyl, cis-4-fluoro-L-prolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl residue;  
 X is ethyl, propyl, isopropyl, sec. butyl, tert.-butyl, or cyclopropyl;  
 G is a L-2-tert.butylglycyl, D-2-terr.butylglycyl, D-valyl, D-isoleucyl, D-leucyl, or 2,2-dimethylglycyl residue;  
 s is 0 or 1;  
 K is —NH-C 1-8 -alkyl, —NH-C 6-8 -cycloalkyl, —NH-CH 2 -cyclohexyl, C 1-4 -alkyl-N-C 1-6 -alkyl, in which residues one CH 2  group may be replaced by O, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamino, N-benzylamino or N-methyl-N-benzylamino residue, or K is  
                 
 
 
     
     
         4 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is methyl;  
 R 2  is methyl;  
 A is a valyl, isoleucyl, 2-tert-butylglycyl, or 2-ethylglycyl;  
 B is a N-methyl-valyl, N-methyl-isoleucyl, N-methyl-2-tert-butylglycyl, N-methyl-2-ethylglycyl, or N-methyl-norleucyl residue;  
 D is a prolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl, trans-4-fluoro-L-prolyl, cis-4-fluoro-L-prolyl, trans-4-chloro-L-prolyl or cis-4-chloro-L-prolyl residue;  
 X is ethyl, isopropyl, sec. butyl, or tert.butyl;  
 G is a L-2-tert.butylglycyl, D-2-terr.butylglycyl, D-valyl, D-isoleucyl, D-leucyl, or 2,2-dimethylglycyl residue;  
 s is 0 or 1;  
 K is —NH-C 1-8 -alkyl, —NH-C 6-8 -cycloalkyl, —NH-CH 2 -cyclohexyl, C 1-4 -alkyl-N-C 1-6 -alkyl, in which residues one CH 2  group may be replaced by O, one H by phenyl or 1 or 2 H by F, except the N-methoxy-N-methylamino, N-benzylamino or N-methyl-N-benzylamino residue, or K is  
                 
 
 
     
     
         5 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is methyl;  
 R 2  is methyl;  
 A is a valyl, isoleucyl, or 2-tert-butylglycyl residue;  
 B is a N-methyl-valyl, N-methyl-isoleucyl, or N-methyl-2-tert-butylglycyl residue;  
 D is a prolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl, cis-4-fluoro-L-prolyl or cis-4-chloro-L-prolyl residue;  
 X is isopropyl, sec. butyl, or tert.-butyl;  
 s is 0 or 1;  
 K is —NHC(CH 3 ) 3 , —NHCH(CH 2 CH 2 )CH(CH 3 )  2 , —NHCH(CH 3 )C(CH 3 ) 3 , —N(CH 3 )OCH 2 CH 3 , —N(CH 3 )OCH 2 CH 2 CH 3 , —N(CH 3 )OCH(CH 3 ) 2 , —N(CH 3 )O(CH 2 ) 3 CH 3 , —N(CH 3 )OCH 2 C 6 H  5 , —NHC(CH 3 ) 2 C 6 H 5 , —NHC(CH 3 ) 2 CH 2 CH 3 , —NHC(CH 3 )(CH 2 CH 3 ) 2 , —NHCH[CH(CH 3 ) 2 ] 2 , —NHC(CH 3 ) 2 CN, —NHCH(CH 3 )CH(OH)C 6 H 5 , —NH-C(CH 3 ) 2 CH≡CH 2 , —NHC(CH 3 ) 2 C≡CH, —NHC(CH 2 CH 3 ) 2 C≡CH, —NHC(CH 3 ) 2 CH 2 CH 2 OH, —NHC(CH 3 ) 2 CH(CH 3 ) 2 , —NHC(CH 3 )  2 CH 2 CH 2 CH 3 , —NHC(CH 3 ) 2 CH 2 C 6 H 5 , —N(OCH 3 )CH(CH  3 ) 2 , —N(OCH 3 )CH 2 CH 3 , —N(OCH 3 )CH 2 CH 2 CH 3 , —N(OCH 3 )CH 2 C 6 H 5 , —N(OCH 3 )C 6 H 5 , —N(CH 3 )OC 6 H 5 , —N(OCH 3 )CH 2 CH 2 CH 2 CH 3 ,  
 or K is  
                 
 
 and the salts therof with physiologically tolerated acids.  
 
     
     
         6 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is methyl;  
 R 2  is methyl;  
 A is a valyl residue;  
 B is a N-methyl-valyl residue;  
 D is a prolyl residue;  
 E is a prolyl residue;  
 X is isopropyl;  
 s is 0 or 1;  
 K is —NHC(CH 3 ) 3 , —NHCH(CH 2 CH 2 )CH(CH 3 ) 2 , —NHCH(CH 3 )C(CH 3 ) 3 , —N(CH 3 )OCH 2 CH 3 , —N(CH 3 )OCH 2 CH 2 CH 3 , —N(CH 3 )OCH(CH 3 ) 2 , —N(CH 3 )O(CH 2 ) 3 CH 3 , —N(CH 3 )OCH 2 C 6 H 5 , —NHC(CH 3 ) 2 C 6 H 5 , —NHC(CH 3 ) 2 CH 2 CH 3 , —NHC(CH 3 )(CH 2 CH 3 ) 2 , —NHCH[CH(CH 3 ) 2 ] 2 , —NHC(CH 3 ) 2 CN, —NHCH(CH 3 )CH(OH)C 6 H 5 , —NH-C(CH 3 ) 2 CH═CH 2 , —NHC(CH 3 ) 2 C≡CH, —NHC(CH 2 CH 3 ) 2 C≡CH, —NHC(CH 3 ) 2 CH 2 CH 2 OH, —NHC(CH 3 ) 2 CH(CH 3 ) 2 , —NHC(CH 3 ) 2 CH 2 CH 2 CH 3 , —NHC(CH 3 ) 2 CH 2 C 6 H 5 , —N(OCH 3 )CH(CH  3 ) 2 , —N(OCH 3 )CH 2 CH 3 , —N(OCH 3 )CH 2 CH 2 CH 3 , —N(OCH 3 )CH 2 C 6 H 5 , —N(OCH 3 )C 6 H 5 , —N(CH 3 )OC 6 H 5 , —N(OCH 3 )CH 2 CH 2 CH 2 CH 3 ,  
 or K is  
                 
 
 and the salts thereof with physiologically tolerated acids.  
 
     
     
         7 . Novel peptides of the formula I  
       R 1 R 2 N-CHX-CO-A-B-D-E-(G) s -K  I 
       where 
 R 1  is methyl;  
 R 2  is methyl;  
 A is a valyl, isoleucyl, or 2-tert-butylglycyl residue;  
 B is a N-methyl-valyl, N-methyl-isoleucyl, or N-methyl-2-tert-butylglycyl residue;  
 D is a prolyl, or thiazolidine-4-carbonyl residue;  
 E is a prolyl residue;  
 X is isopropyl, sec. butyl, or tert.-butyl;  
 G is a D-2-tert.butylglycyl, D-isoleucyl, 2,2-dimethylglycyl residue, D-valyl or L-2-tert.butylglycyl;  
 s is 1;  
 K is —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NH(CH 2 ) 3 CH 3 , —NH(CH 2 ) 4 CH 3 , —NH(CH 2 ) 5 CH 3 , —NHCH(CH 3 ) 2 , —NHCH(CH 3 )CH 2 CH 3 , —NHCH(CH 2 CH 3 ) 2 , —NHC(CH 3 ) 3 , —NH-cyclohexyl, —NHC(CH 3 ) 2 CN, —NCH(CH 3 ) 2 C≡CH or —NHC(CH 3 ) 2 CONH 2 ;  
 or K is  
                 
 
 and the salts thereof with physiologically tolerated acids.  
 
     
     
         8 . Compounds of formula I or salts thereof for use in treating diseases.  
     
     
         9 . The method or preparing compounds of formula I according to    claim 1    characterized in that they are prepared according to known methods of peptide chemistry.