Peptide derivatives

Abstract

Novel peptide derivatives, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing them are useful in treating MHC class II dependent T-cell method autoimmune or inflammatory diseases, such as rheumatoid arthritis.

What we claim is:  
     
         1 . A peptide derivative of the formula I, 
 P-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Q    or a pharmaceutically acceptable salt thereof, wherein    P is a hydrophobic residue;    AA 1 , AA 2 , AA 3 , AA 4 , AA 5 , AA 6 , AA 7  and AA 8  are L-amino acid residues in which 1, 2 or 3 of AA 1 , AA 2  and AA 3  are selected from a residue of the L-amino acid of formula II                          wherein n is an integer 1, 2, 3 or 4;    X is —NH—CO—, —CO— or —O.CO—;    R 1  and R 2  are selected from (A), (B) and (C) wherein 
 (A) is a group of the formula —(CH 2 ) a —CO—N(R 3 )(R 4 ) in which a is an integer 1 or 2 and R 3  and R 4  are independently selected from a group —[(CH 2 ) b O] m —R a  in which R a  is methyl or ethyl and m is an integer 1, 2, 3, 4 or 5; when m is 1, b is 2 or 3 and when m is 2, 3, 4 or 5, the value of b in each —(CH 2 ) b O— unit is independently selected from 2 and 3;  
 (B) is a group of the formula —(CH 2 ) c O(CH 2 ) d —CO—N(R 5 )(R 6 ) in which c is an integer 2 or 3, d is an integer 1, 2 or 3 and R 5  and R 6  are independently selected from a group —[(CH 2 ) e O] p —R b  in which R b  is methyl or ethyl and p is an integer 1, 2, 3, 4 or 5; when p is 1, e is 2 or 3 and when p is 2, 3, 4 or 5, the value for e in each —(CH 2 ) e O— unit is independently selected from 2 and 3; and  
 (C) is a group of the formula —[(CH 2 ) f O] g —R 7  in which R 7  is methyl or ethyl and g is an integer 1, 2, 3, 4 or 5; when g is 1, f is 2 or 3 and when g is 2, 3, 4 or 5, the value for f in each—(CH 2 ) f O— unit is independently selected from 2 and 3;  
   or AA 1 , AA 2 , AA 3 , AA 6 , AA 7 , and AA 8  are L-amino acid residues in which one or both of AA 1  and AA 7  are selected from a residue of the L-amino acid of formula II as defined above and AA 4  together with AA 5  form a group of the formula III, IIIa, IV or IVa;                          in which Ra, Rb and Rz are independently selected from hydrogen and (1-4C)alkyl, and A is oxygen or methylene;    or AA 1 , AA 2 , AA 3 , AA 4 , AA 5  and AA 8  are L-amino acid residues in which one or both of AA 1  and AA 4  are selected from a residue of the L-amino acid of formula II as defined above and AA 6  together with AA 7  form a group of the formula III, IIIa, IV or IVa as defined above;    and Q is OH, NH 2 , 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 Q is 1-piperazinyl, 4-methyl-1-piperazinyl, 4-(2-(2-hydroxyethoxy)ethyl)-1-piperazinyl, 4-amidino-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 Q is a sequence of 1 to 6 amino acid residues or an amide thereof.    
     
     
         2 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  which is a peptide derivative of the formula P-AA 1 -AA 2 -AA 3 -II-AA 5 -AA 6 -AA 7 -AA 8 -Q wherein AA 1 , AA 2 , AA 3 , AA 5 , AA 6 , AA 7  and AA 8  are L-amino acid residues, P and Q have any of the meanings defined in  claim 1 , and II is a residue of an L-amino acid of formula II as defined in  claim 1 .  
     
     
         3 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1  which is a peptide derivative of the formula P-AA 1 -AA 2 -AA 3 -IIIa-AA 6 -II-AA 8 -Q wherein AA 1 , AA 2 , AA 3 , AA 6  and AA 8  are L-amino acid residues, P and Q have any of the meanings defined in  claim 1 , II is a residue of an L-amino acid of formula II as defined in  claim 1 , and IIIa is a group of the formula IIIa as defined in  claim 1 .  
     
     
         4 . A peptide derivative, or a pharmaceutically acceptable salt thereof, a claimed in  claim 1  which is a peptide derivative of the formula formula P-II-AA 2 -AA 3 -AA 4 -AA 5 -IIIa-AA 8 -Q wherein AA 2 , AA 3 , AA 4 , AA 5  and AA 8  are L-amino acid residues, P and Q have any of the meanings defined in  claim 1 , II is a residue of an L-amino acid of formula II as defined in  claim 1 , and IIIa is a group of the formula IIIa as defined in  claim 1 .  
     
     
         5 . A peptide derivative, or pharmaceutically acceptable salt thereof, as claimed in  claim 1 ,  2 ,  3  or  4  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.  
     
     
         6 . A peptide derivative, or a phamaceutically acceptable salt thereof, as claimed in  claim 1 ,  2 ,  3  or  4  wherein, in the residue of the L-amino acid of formula II, n=1 or 2, X=carbonyl and R 1  and R 2  are both identical groups of the formula (A) or are both identical groups of the formula (C) as defined in  claim 1 .  
     
     
         7 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 6  wherein R 1  and R 2  are both. —CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3  or are both —CH 2 CON(CH 2 CH 2 OCH 3 ) 2  or are both —CH 2 CON[(CH 2 CH 2 O) 3 CH 3 ] 2 .  
     
     
         8 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 ,  2 ,  3  or  4 , wherein AA 1  to AA 8  when present are selected from residues of the following amino acids: 
 AA 1  selected from Ala, Ile, Tyr, Val, Glu, Lys, Arg, Gly, Gap, GapMe 4  and 3,3,3-trifluoroalanine;  
 AA 2  selected from Ala, Lys, Glu, Sar, Val, Arg, Gly, Pro, Ile, Tic, 3,3,3-trifluoroalanine and N6-diethylLys;  
 AA 3  selected from Ala, His, Gln, Val, Thr, Glu, Gly, Asp, Asn and N 3 -diethylDap;  
 AA 4  selected from Ala, Lys, Asn, Arg, Thr, Glu, Sar, Gly, Pro, His and N 6 -diethylLys;  
 AA5 selected from Thr, Val, Ala, Gly, Dap, Dab, Pro, Hyp, Asn, Ser, and N 3 -diethylDap;  
 AA 6  selected from Gly, Leu, Lys, Ala, Pro, Glu, Sar, His and Dap;  
 AA 7  selected from Pro, Ala, Lys, Arg, Glu, Sar, Gly, Oic and Dic; and  
 AA 8  selected from Ala, Gly, Dap, azaalanine and azaglycine.  
 
     
     
         9 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 ,  2 ,  3  or  4 , wherein Q is selected from 4-carbamoyl-1-piperidyl and 4-(carbamoylmethyl)anilino.  
     
     
         10 . A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 ,  2 ,  3  or  4  wherein hydrophobic group P is 5-phenylvaleryl.  
     
     
         11 . A pharmaceutical composition which comprises a peptide derivative of the formula I or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , in association with a pharmaceutically acceptable diluent or carrier.  
     
     
         12 . A process for the manufacture of a peptide derivative, or a 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-II-OH, H-III-OH, H-IIIa-OH, H—IV—OH or H—IVa-OH and optionally a suitably protected group of the formula H-Q, 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 formula I, or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 .  
     
     
         14 . A method as claimed in  claim 13  for treating rheumatoid arthritis or cystic fibrosis.  
     
     
         15 . A protected or unprotected amino acid of the formula II, or a salt thereof, wherein n, X, R 1  and R 2  are as defined in  claim 1.