Quinoline derivatives as tyrosine kinase inhibitors

Details Quinoline derivatives as tyrosine kinase inhibitors Quinoline derivatives as tyrosine kinase inhibitors

2001-08-20

2003-10-07

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S397000, C514S398000, C514S320000, C544S106000, C544S111000, C544S363000, C546S152000, C546S153000, C548S146000, C548S300100

Reexamination Certificate

active

06630489

ABSTRACT:

This invention concerns certain novel quinoline derivatives which possess pharmacological properties of use in the treatment of autoimmune diseases or medical conditions, for example T cell mediated disease such as transplant rejection or rheumatoid arthritis. The invention also concerns processes for the manufacture of the quinoline derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of T cell mediated disease.
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 foreign proteins such as those on the surface of pathogens whilst maintaining tolerance to endogenous proteins and thereby preventing damage to normal tissues. An autoimmune disease results when self-tolerance breaks down and the immune system reacts against tissues such as the joints in rheumatoid arthritis or nerve fibres in multiple sclerosis. Stimulation of the human immune response is dependent on the recognition of protein antigens by T cells. However T cells do not become activated by and respond to antigen alone but are only triggered into action when the antigen 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.
Thus T cell activation requires the docking into the T cell receptor of the peptide/MHC complex expressed on an antigen presenting cell. This interaction, which confers the antigen specificity to the T cell response, is essential for full activation of T lymphocytes. Subsequent to this docking, some of the earliest signal transduction events leading to full T cell activation are mediated through the action of multiple tyrosine-specific protein kinases (E. Hsi et al.,
J. Biol. Chem.,
1989, 264, 10836) including p56
lck
and ZAP-70. The tyrosine kinase p56
lck
is a lymphocyte specific member of the src family of non-receptor protein tyrosine kinases (J. D. Marth et al.,
Cell,
1985, 43, 393). The enzyme is associated with the inner surface of the plasma membrane where it binds to the T cell receptor associated glycoproteins CD4 (in helper T cells) and CD8 (in cytotoxic or killer T cells) (C. E. Rudd et al.,
Proc. Natl. Acad. Sci. USA,
1988, 85, 5190 and M. A. Campbell et al,
EMBO J,
1990, 9, 2125).
It is believed that p56
lck
tyrosine kinase plays an essential role in T cell activation as, for example, the loss of p56
lck
expression in a human Jurkat T cell line prevents the normal T cell response to stimulation of the T cell receptor (D. B. Straus et al.,
Cell,
1992, 70, 585) and a deficiency in p56
lck
expression causes severe immune deficiency in humans (F. D. Goldman et al.,
J. Clin. Invest.,
1998, 102, 421).
Certain autoimmune conditions or diseases such as inflammatory diseases (for example rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and lung fibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma and insulin-dependent diabetes are believed to be associated with inappropriate T cell activation (see, for example, J. H. Hanke et al,
Inflamm. Res.,
1995, 44, 357). In addition the acute rejection of transplanted organs can also be interpreted as a consequence of inappropriate T cell activation. Therefore, compounds which modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation, for example by way of inhibition of p56
lck
tyrosine kinase, are expected to provide therapeutic agents for such pathological conditions.
Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation, for example by way of inhibition of p56
lck
tyrosine kinase.
In particular, the quinoline derivatives of the invention are expected to be useful as immunoregulation or immunosuppressive agents for the prevention or treatment of organ rejection following transplant surgery.
Agents of this kind would offer therapy for transplant rejection and autoimmune diseases whilst avoiding toxicities associated with the commonly used, less selective immunosuppressants. The leading agent for the prevention or treatment of transplant rejection is cyclosporin A which, although effective, is often associated with side-effects such as renal damage and hypertension which results in kidney failure in a substantial number of patients. 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. A rationally based, disease modifying agent, without such deleterious side-effects, would therefore offer significant benefits in the prevention or treatment of transplant rejection or autoimmune conditions such as rheumatoid arthritis.
The present invention is based, in particular, on the discovery that the quinoline derivatives of the invention modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation. Accordingly compounds of the present invention possess higher inhibitory potency against particular non-receptor tyrosine kinases such as p56
lck
tyrosine kinase than against other non-receptor tyrosine kinases or against receptor tyrosine kinases (RTKs) such as epidermal growth factor (EGF) RTK or vascular endothelial growth factor (VEGF) RTK. Nevertheless, whilst the quinoline derivatives of the present invention are generally potent inhibitors of p56
lck
tyrosine kinase, they do also, in general, possess weaker activity against certain other tyrosine kinase enzymes. In particular, the quinoline derivatives of the present invention, in general, possess some inhibitory activity against EGF RTK and, in general, they may possess some weaker activity against VEGF RTK.
In general, the quinoline derivatives of the invention possess sufficient potency in inhibiting non-receptor tyrosine kinases such as p56
lck
tyrosine kinase that they may be used in an amount sufficient to inhibit, for example, p56
lck
tyrosine kinase whilst demonstrating reduced potency, preferably whilst demonstrating no significant activity, against RTKs such as EGF RTK or VEGF RTK. Thus the quinoline derivatives of the invention can be used in the clinical management of those particular diseases which are sensitive to inhibition of such non-receptor tyrosine kinases, for example autoimmune diseases or medical conditions, for example T cell mediated disease such as transplant rejection or rheumatoid arthritis.
Nevertheless, at appropriate higher doses, the quinoline derivatives of the present invention demonstrate pharmacologically useful inhibition of other tyrosine kinase enzymes, for example of RTKs such as EGF RTK and/or VEGF RTK. In that event, the quinoline derivatives of the invention are also useful in the treatment of further tyrosine kinase dependent diseases or conditions such as EGF-sensitive cancers and VEGF-sensitive angiogenesis.
It is disclosed in International Patent Application WO 96/09294 that certain quinoline and quinazoline derivatives may be useful as protein tyrosine kinase inhibitors. Whilst a few 4-benzyloxy- and 4-phenoxy-quinazoline derivatives were disclosed, there was no disclosure of any examples of 4-benzyloxy- or 4-phenoxy-quinoline derivatives.
It is disclosed in International Paten

Affiliated with

Also associated with

Rating

Quinoline derivatives as tyrosine kinase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Quinoline derivatives as tyrosine kinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinoline derivatives as tyrosine kinase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3172667