Peptide derivatives

Details Peptide derivatives Peptide derivatives

1999-05-26

2003-04-01

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S328000, C530S825000, C530S851000

Reexamination Certificate

active

06541453

ABSTRACT:

The present invention relates to certain novel peptide derivatives which possess pharmacologically useful properties for use in treating autoimmune diseases or medical conditions, such as rheumatoid arthritis and other MHC class II dependent T-cell mediated diseases. The invention also includes pharmaceutical compositions of the novel peptide derivatives, processes for their manufacture, and their use in treating one or more of the aforementioned diseases or medical conditions and in the production of novel pharmaceuticals for use in such medical treatments.
Stimulation of the human immune response is dependent on the recognition of protein antigens by T cells. However T cells cannot respond to antigen alone and are only triggered by antigen when it is complexed with major histocompatibility complex (MHC) molecules on the surface of an antigen presenting cell, such as a B cell, macrophage or dendritic cell.
MHC class I molecules elicit a T-killer cell response which results in the destruction of the cell bearing the antigen. MHC class II molecules elicit a T-helper cell response which controls the expansion and maturation of selected B cells (i.e. generation of antigen-specific antibodies) and activation of macrophages.
A critical requirement of the immune system is the ability to differentiate between “self” and “non-self” (i.e. foreign) antigens. This discrimination is required to enable the immune system to mount a response to invading foreign pathogens whilst maintaining tolerance to self-proteins and thereby preventing damage to normal tissues. An autoimmune disease results when self-tolerance breaks down allowing the immune system to react against self-tissues such as the joints in rheumatoid arthritis. It is thought that the maintenance of tolerance and thus avoidance of autoimmune disease is critically dependent on the function of MHC molecules.
The observation that many autoimmune diseases are linked to the inheritance of particular MHC alleles suggests a key role for MHC molecules in the pathogenesis of autoimmune disease. For instance multiple sclerosis is linked to the inheritance of HLA-DR2, insulin dependent diabetes mellitus to HLA-DR3 and/or HLA-DR4 and Hashimoto's thyroiditis to HLA-DR5. In particular, an especially strong association exists between predisposition to development of the chronic inflammatory joint disease rheumatoid arthritis and the inheritance of HLA-DR4Dw4 and/or HLA-DR4w14 and/or HLA-DR1. It is thought that the autoimmune disease associated MHC molecules bind to certain self-antigens and present them to T cells thus stimulating an autoimmune response. Other peptides which can bind to the autoimmune associated MHC molecules and/or either prevent the binding or displace already bound self-antigens and/or which inhibit T cell activation (especially the activity of pathogenic T cells (e.g. Th 1 cells)) and/or which increase the activity of protective T cells (e.g. Th 2 cells) or peptides which interact with MHC molecules by an alternative mechanism of action so as to prevent or modify stimulation of an autoimmune response mediated via said MHC molecules, may specifically suppress an autoimmune response.
An agent of this kind would offer therapy for the autoimmune disease whilst avoiding general suppression of the immune system, thus limiting deleterious side-effects. This kind of profile would have significant advantages over current therapy for diseases such as rheumatoid arthritis. It is contemporary practice to treat rheumatoid arthritis initially with symptom relief agents such as NSAIDs, which do not have any beneficial effect on disease progression and are often associated with unwanted side-effects. Treatment of more severe disease relies on the use of the so-called second-line agents. Often these are general cytotoxic compounds which are of limited efficacy and can cause severe toxicity problems. A rationally based, disease modifying agent, without associated non-specific cytotoxicity, would therefore offer significant benefits in the treatment of rheumatoid arthritis.
Peptides are disclosed in International Patent Application, Publication No's. WO 92/02543, WO 93/05011 and WO 95/07707 which bind to MHC molecules and inhibit T-cell activation.
Although a number of peptides have been discovered which inhibit HLA-DR restricted T cell activation by binding to HLA-DR molecules, there is a continuing need for alternative compounds which bind to such molecules and/or either prevent the binding or displace already bound self-antigens and/or inhibit T cell activation and/or increase the activity of protective T cells, or which interact with MHC molecules by an alternative mechanism of action, so as to prevent or modify stimulation of an autoimmune response that causes, a disease or condition referred to above.
We have discovered that the peptide derivatives of the present invention (set out below) surprisingly possess such pharmacologically useful properties and this is a basis for the present invention.
According to one aspect of the invention there is provided a peptide derivative of the formula I (set out hereinafter), 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
4
and AA
7
are selected from a residue of the L-amino acid of formula II (set out hereinafter)
wherein n is an integer 1, 2, 3 or 4;
X is —NH—CO—, —CO— (carbonyl) or —O.CO— (oxycarbonyl);
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, IVa, V or Va (set out hereinafter) 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, IVa, V or Va (set out hereinafter) in which Ra, Rb and Rz are independently selected from hydrogen and (1-4C)alkyl, and A is oxygen or methylene;
and Q is OH, NH
2
, NRcRd wherein Rc is selected from (1-4C)alkyl, 2-carbamoylcyclopentyl, 2-pyridylmethyl, 4-carbamoylcyclohexyl, 4-carbamnoylcyclohexylmethyl, 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 me

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