US 6,184,207 B2Granted

Inhibitors of peptide binding to MHC class II proteins

AssigneeZeneca Limited

InventorsRichard William Arthur Luke, Ronald Cotton

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Abstract

The invention concerns pharmacologically useful peptide derivatives of the formula (I): P-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Q, and pharmaceutically acceptable salts thereof, wherein either AA3 together with AA4, or AA4 together with AA5, or AA6 together with AA7 form a group of formula (II): in which Ra is selected from hydrogen and (1-4C)alkyl, and the remainder of AA1, AA2, AA3, AA4, AA5, AA6, AA7, and AA8 are L-amino acid residues; P is a hydrophobic residue; and Q is OH, NH2 or NRcRd. The invention further concerns processes for the manufacture of the novel peptide derivatives and the use of the compounds, and pharmaceutical compositions containing them, in treating MHC class II dependent T-cell mediated autoimmllne or inflammatory diseases, such as rheumatoid arthritis.

Claims12

Dependent claims

A peptide of the formula I, P-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Q, or a pharmaceutically acceptable salt thereof, wherein

either AA3 together with AA4, or AA4 together with AA5, or AA6 together with AA7 form a group of the formula II
in which Ra is selected from hydrogen and (1-4C)alkyl, and the remainder of AA1, AA2, AA3, AA4, AA5, AA6, AA7 and AA8 are L-amino acid residues;
P is a hydrophobic residue;
and
Q is OH, NH2 or NRcRd wherein Rc is selected from (1-4C)alkyl, 2-carbamoylcyclopentyl, 2-pyridylmethyl, 4-carbamoylcyclohexyl, 4-carbamoylcyclohexylmethyl, 3-carbamnoylphenyl, 4-carbamoylphenyl, 4-(carbamoylmethyl)phenyl, 4-(carboxymethyl)phenyl, 2-morpholinoethyl and a group of the formnula -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-cyclohexyiene 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-amidino-1-piperazinyl, 4-(2-(2-hlydroxyethoxy)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
Q is a sequence of 1 to 6 amino acids or an amide thereof;
or a pharmaceutically acceptable salt thereof.

13 more elements

Dependencies are inferred from the claim text.