Peptide derivatives

Abstract

The invention concerns pharmaceutically useful peptide derivatives of the formula (I): P—R 1 —R 2 —R 3 —R 4 , in which P, R 1 , R 2 , R 3 and R 4 have various meanings defined herein, and their pharmaceutically acceptable salts, and pharmaceutical compositions containing them. The novel peptide derivatives are of value in treating MHC class II dependent T-cell medicated autoimmune or inflammatory diseases, such as rheumatoid arthritis. The invention further concerns processes for the manufacture of the novel peptide derivatives and the use of the compounds in medical treatment.

1 . A peptide derivative of the formula I, P—R 1 —R 2 —R 3 —R 4 , or a pharmaceutically acceptable salt thereof, wherein 
 P is a hydrophobic residue selected from: 
 (a) an aliphatic, aromatic or mixed aliphatic/aromatic organic group of from 5 to 20 carbon atoms, or a heteroaromatic or aliphatic/heteroaromatic organic group of from 5 to 20 carbon atoms and 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen;  
 (b) an L-amino acid selected from phenylalanine and hydrogenated analogues thereof, para-chloroPhe, 3-(2-thienyl)alanine, tyrosine, Tyr(Omethyl), tryptophan, biphenylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine and hydrogenated analogues thereof, 3-(1-adamantyl)alanine, Glu(OBenzyl), 3-(benzyloxy)Ala, 3-(benzylsulfanyl)Ala and 9-fluoroenylGly, each of which may optionally bear on the N-terminus a hydrophobic aliphatic, aromatic, heteroaromatic or mixed aliphatic/aromatic or aliphatic/heteroaromatic organic group as defined on (a); and  
 (c) a sequence of L-amino acids selected from Ala-Cha, Ala-Ala-Cha, Tyr-Ala-Ala-Cha, Tyr-Ala-Ala-Phe, Ala-Phe-Phe-Phe and Ala-Ala-Ala-Phe, wherein the first amino acid may also be a D-amino acid and may also optionally bear a hydrophobic aliphatic, aromatic, heteroaromatic or mixed aliphatic/aromatic or aliphatic/heteroaromatic organic group as defined in (a);  
 
 R 1  is a sequence of 2 L-amino acids and R 3  is a sequence of 4 L-amino acids;  
 R 2  is a group of formula III  
                     
  in which Rb is selected from hydrogen and (1-4C)alkyl and A is methylene or oxygen; and  
 R 4  is OH, NH 2  or NRcRd wherein Rc is selected from (1-4C) alkyl, 2-carbamoylcyclopentyl, 2-pyridylmethyl, 4-carbamoylcyclohexyl, 4-carbamoylcyclohexylmethyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 4-(carbamoylmethyl)phenyl, 4-(carboxymethyl)phenyl, 2-morpholinoethyl and a group of the formula —A 1 —G 1  in which 
 A 1  is 
 (3-7C)alkylene or A 1  is selected from 
 (1) a group of the formula —A 2 —B 2 — in which A 2  is p-phenylene or 1,4-cyclohexylene and B 2  is (1-4C)alkylene or A 2  is methylene and B 2  is  p -phenylene or 1,4-cyclohexylene; and  
 (2) a group of the formula —A 3 —B 3 —C 3 — in which A 3  is methylene, B 3  is  p -phenylene or 1,4-cyclohexylene and C 3  is (1-3C)alkylene; and  
 
 
 G 1  is a group of the formula —N═C[N(Rp) 2 ] 2  in which each Rp is independently selected from hydrogen, methyl, ethyl and propyl;  
 and Rd is hydrogen or (1-4C)alkyl; or  
 
 R 4  is 1-piperazinyl, 4-methyl-1-piperazinyl, 4-amidino-1-piperazinyl, 4-(2-(2-hydroxyethoxy)ethyl)-1 piperazinyl, 1-piperidyl or 4-substituted-1-piperidyl wherein the 4-substituent is selected from carboxy, carbamoyl, N-(2-aminoethyl)carbamoyl and N-(4-aminobutyl)carbamoyl; or  
 R 4  is a sequence of 1 to 6 amino acids or an amide thereof.  
 
     
     
         2 . A peptide derivative, or pharmaceutically acceptable salt thereof, as claimed in  claim 1 , in which P is an aliphatic, aromatic or mixed aliphatic/aromatic organic group of from 5 to 20 carbon atoms, or a heteroaromatic or mixed aliphatic/heteroaromatic organic group of from 5 to 20 carbon atoms and 1, 2 or 3 heteroatoms selected from oxygen, sulphur and nitrogen.  
     
     
         3 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  or  2  wherein R 1  is a sequence of 2 L-amino acids represented as AA1-AA2 in which 
 AA1 is selected from Ala, Ile, Tyr, Val, Glu, Lys, Arg, Gly, Gap, GapMe 4  and 3,3,3-trifluoroalanine; and  
 AA2 is selected from Ala, Lys, Glu, Sar, Val, Arg, Gly, Pro, Ile, Tic, 3,3,3-trifluoroalanine and N 6 -diethylLys; and R 3  is a sequence of 4 L-amino acids represented as AA5-AA6-AA7-AA8 in which 
 AA5 is selected from Thr, Val, Ala, Gly, Dap, Dab, Pro, Hyp, Asn and N 3 -diethylDap;  
 AA6 is selected from Gly, Leu, Lys, Ala, Pro, Glu, Sar, His and Dap;  
 AA7 is selected from Pro, Ala, Lys, Arg, Glu, Sar, Gly, Oic and Dic; and  
 AA8 is selected from Ala, Gly, Dap, azaalanine and azaglycine.  
 
 
     
     
         4 . A peptide derivative as claimed in  claim 1  or  2  wherein R 1  is a sequence of 2 L-amino acids selected Ala-Arg, Ala-Ala, Ala-Lys, Ile-Ala, Arg-Ala, Ala-Ile, X-Ala where X is —NH.CH[CH 2 NH(═NH).NH 2 ]CO— or —NH.CH(CH 2 N═C[N(CH 3 ) 2 ] 2 .CO—.  
     
     
         5 . A peptide derivative as claimed in  claim 1  or  2  wherein R 3  is a sequence of 4 L-amino acids selected from Val-Ala-Ala-Ala, Val-Ala-Arg-Ala, Thr-Ala-Ala-Ala, Thr-Ala-Arg-Ala, Val-Ala-Lys-Ala, Val-Arg-Ala-Ala, Thr-Ala-Lys-Ala and Thr-Arg-Ala-Ala.  
     
     
         6 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  or  2  wherein said hydrophobic group P is 5-phenylvaleryl.  
     
     
         7 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  or  2  wherein R 4  is 4-carbamoyl-1-piperidyl, 4-(carbamoylmethyl)anilino or 4-(2-guanidinoethyl)anilino.  
     
     
         8 . A pharmaceutical composition which comprises a peptide derivative of the formula I, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  or  2 , in association with a pharmaceutically acceptable diluent or carrier.  
     
     
         9 . A process for the manufacture of a peptide derivative or pharmaceutically acceptable salt thereof, as claimed in  claim 1 , comprising sequentially coupling in the appropriate order suitably protected amino acids or sequences of two or more suitably protected amino acids, a suitably protected group of the formula H-III-OH and optionally suitably protected group of the formula H—R 4 , followed by optional functional group modification of the N-terminal amino group, to introduce a hydrophobic group P, and removal of any remaining protecting groups and any solid support.  
     
     
         10 . A method for treating a MHC class II dependent T-cell mediated autoimmune or inflammatory disease which comprises administering to a warm-blooded mammal in need of such treatment an effective amount of a peptide derivative of  claim 1  or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A method as claimed in  claim 10  for treating rheumatoid arthritis or multiple sclerosis.  
     
     
         12 . A process for the manufacture of a peptide derivative of the formula: P—R 1 —R 2 —R 3 —R 4  or a pharmaceutically acceptable salt thereof, wherein 
 P is a hydrophobic residue selected from: 
 (a) an aliphatic, aromatic or mixed aliphatic/aromatic organic group of from 5 to 20 carbon atoms, or a heteroaromatic or aliphatic/heteroaromatic organic group of from 5 to 20 carbon atoms and 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen;  
 (b) an L-amino acid selected from phenylalanine and hydrogenated analogues thereof, para-chloroPhe, 3-(2-thienyl)alanine, tyrosine, Tyr(Omethyl), tryptophan, biphenylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine and hydrogenated analogues thereof, 3-(1-adamantyl)alanine, Glu(OBenzyl), 3-(benzyloxy)Ala, 3-(benzylsulfanyl)Ala and 9-fluoroenylGly, each of which may optionally bear on the N-terminus a hydrophobic aliphatic, aromatic, heteroaromatic or mixed aliphatic/aromatic or aliphatic/heteroaromatic organic group as defined on (a); and  
 (c) a sequence of L-amino acids selected from Ala-Cha, Ala-Ala-Cha, Tyr-Ala-Ala-Cha, Tyr-Ala-Ala-Phe, Ala-Phe-Phe-Phe and Ala-Ala-Ala-Phe, wherein the first amino acid may also be a D-amino acid and may also optionally bear a hydrophobic aliphatic, aromatic, heteroaromatic or mixed aliphatic/aromatic or aliphatic/heteroaromatic organic group as defined in (a);  
 
 R 1  is a sequence of 2 L-amino acids and R 3  is a sequence of 4 L-amino acids;  
 R 2  is a group of formula II  
                     
  in which Ra is selected from hydrogen and (1-4C)alkyl and A is methylene or oxygen; and  
 R 4  is OH, NH 2  or NRcRd wherein Rc is selected from (1-4C) alkyl, 2-carbamoylcyclopentyl, 2-pyridylmethyl, 4-carbamoylcyclohexyl, 4-carbamoylcyclohexylmethyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 4-(carbamoylmethyl)phenyl, 4-(carboxymethyl)phenyl, 2-morpholinoethyl and a group of the formula —A 1 —G 1  in which 
 A 1  is 
 (3-7C)alkylene or A 1  is selected from 
 (1) a group of the formula —A 2 —B 2 — in which A 2  is p-phenylene or 1,4-cyclohexylene and B 2  is (1-4C)alkylene or A 2  is methylene and B 2  is  p -phenylene or 1,4-cyclohexylene; and  
 (2) a group of the formula —A 3 —B 3 —C 3 — in which A 3  is methylene, B 3  is  p -phenylene or 1,4-cyclohexylene and C 3  is (1-3C)alkylene; and  
 
 
 G 1  is a group of the formula —N═C[N(Rp) 2 ] 2  in which each Rp is independently selected from hydrogen, methyl, ethyl and propyl;  
 and Rd is hydrogen or (1-4C)alkyl; or  
 
 R 4  is 1-piperazinyl, 4-methyl-1-piperazinyl, 4-amidino-1-piperazinyl, 4-(2-(2-hydroxyethoxy)ethyl)-1 piperazinyl, 1-piperidyl or 4-substituted-1-piperidyl wherein the 4-substituent is selected from carboxy, carbamoyl, N-(2-aminoethyl)carbamoyl and N-(4-aminobutyl)carbamoyl; or  
 R 4  is a sequence of 1 to 6 amino acids or an amide thereof; 
 comprising sequentially coupling in the appropriate order suitably protected amino acids or sequences of two or more suitably protected amino acids, a suitably protected group of the formula H-II-OH and optionally suitably protected group of the formula H—R 4 , followed by optional functional group modification of the N-terminal amino group, to introduce a hydrophobic group P, and removal of any remaining protecting groups and any solid support.  
 
 
     
     
         13 . A method for treating a MHC class II dependent T-cell mediated autoimmune or inflammatory disease which comprises administering to a warm-blooded mammal in need of such treatment an effective amount of a peptide derivative of the formula P—R 1 —R 2 —R 3 —R 4 , as defined in  claim 12 , or a pharmaceutically acceptable salt thereof.  
     
     
         14 . A method as claimed in  claim 13  for treating rheumatoid arthritis or multiple sclerosis.