Peptide derivatives
AssigneeSyngenta Limited
InventorsKEITH OLDHAM, PHILIP NEIL EDWARDS, RICHARD WILLIAM ARTHUR LUKE, RONALD COTTON
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Abstract
The invention concerns pharmaceutically useful peptide derivatives of the formula (I), P-AA I -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Q, in which P, AA 1, AA 2, AA 3 , AA 4, AA 5, AA 6, AA 7, AA 8, and Q have the various meanings defined herein and their pharmaceutically accentable salts, and pharmaceutical compositions containing them. The novel peptide derivatives are of value in treating MHC class II dependent T-cell mediated 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.
Claims19
A peptide derivative of the formula I,
- P-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Q
- or a pharmaceutically acceptable salt thereof, wherein
- P is a hydrophobic residue;
- AA1, AA2, AA3, AA4, AA5, AA6, AA7 and AA8 are L-amino acid residues in which 1, 2 or 3 of AA1, AA4 and AA7 are selected from a residue of the L-amino acid of formula II
- 18
- wherein n is an integer 1, 2, 3 or 4;
- X is —NH—CO—, —CO— or —O.CO—;
- R1 and R2 are selected from (A), (B) and (C) wherein
- (A) is a group of the formula —(CH2)a—CO—N(R3)(R4) in which a is an integer 1 or 2 and R3 and R4 are independently selected from a group —[(CH2)bO]m—Ra in which Ra 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 —(CH2)bO— unit is independently selected from 2 and 3;
- (B) is a group of the formula —(CH2)cO(CH2)d—CO—N(R5)(R6) in which c is an integer 2 or 3, d is an integer 1, 2 or 3, and R5 and R6 are independently selected from a group —[(CH2)eO]p—Rb in which Rb 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 —(CH2)eO— unit is independently selected from 2 and 3;
- and
- (C) is a group of the formula —[(CH2)fO]gR7 in which R7 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 —(CH2)fO— unit is independently selected from 2 and 3;
- or AA1, AA2, AA3, AA6, AA7, and AA8 are L-amino acid residues in which one or both of AA1 and AA7 are selected from a residue of the L-amino acid of formula II as defined above and AA4 together with AA5 form a group of the formula III, IIIa, IV, IVa, V or Va;
- 19
- in which Ra, Rb and Rz are independently selected from hydrogen and (1-4C)alkyl, and A is oxygen or methylene;
- or AA1, AA2, AA3, AA4, AA5 and AA8 are L-amino acid residues in which one or both of AA1 and AA4 are selected from a residue of the L-amino acid of formula II as defined above and AA6 together with AA7 form a group of the formula III, IIIa, IV, IVa, V or Va as defined above;
- and Q is OH, NH2, 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 —A1—G1 in which A1 is (3-7C)alkylene or
- A1 is selected from
- (1) a group of the formula —A2—B2— in which A2 is p-phenylene or 1,4-cyclohexylene and B2 is (1-4C)alkylene or A2 is methylene and B2 is p-phenylene or 1,4-cyclohexylene;
- and
- (2) a group of the formula —A3—B3—C3— in which A3 is methylene, B3 is p-phenylene or 1,4-cyclohexylene and C3 is (1-3C)alkylene;
- and
- G1 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.
A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim, wherein AA1 to AA8 when present are selected from residues of the following amino acids:
- AA1 selected from Ala, Ile, Tyr, Val, Glu, Lys, Arg, Gly, Gap, GapMe4 and 3,3,3-trifluoroalanine;
- AA2 selected from Ala, Lys, Glu, Sar, Val, Arg, Gly, Pro, Ile, Tic, 3,3,3-trifluoroalanine and N6-diethylLys;
- AA3 selected from Ala, His, Gln, Val, Thr, Glu, Gly, Asp, Asn and N3-diethylDap;
- AA4 selected from Ala, Lys, Asn, Arg, Thr, Glu, Sar, Gly, Pro, His and N6-diethylLys;
- AA5 selected from Thr, Val, Ala, Gly, Dap, Dab, Pro, Hyp, Asn, Ser, and N3-diethylDap;
- AA6 selected from Gly, Leu, Lys, Ala, Pro, Glu, Sar, His and Dap;
- AA7 selected from Pro, Ala, Lys, Arg, Glu, Sar, Gly, Oic and Dic;
- and
- AA8 selected from Ala, Gly, Dap, azaalanine and azaglycine.
A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim, wherein Q is selected from 4-carbamoyl-1-piperidyl and 4-(carbamoylmethyl)anilino.
A peptide derivative, or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim wherein hydrophobic group P is 5-phenylvaleryl.
Dependencies are inferred from the claim text.