Inhibitors of p38 kinase

Details Inhibitors of p38 kinase Inhibitors of p38 kinase

2001-11-20

2004-11-23

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S231500, C514S254090, C514S252110, C514S254040, C544S121000, C544S373000, C544S357000, C544S364000, C544S369000, C540S598000, C546S187000, C546S201000

Reexamination Certificate

active

06821966

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to treating various disorders associated with enhanced activity of kinase p38-&agr;. More specifically, it concerns compounds that are related to indole-type derivatives coupled to piperazine- or piperidine-type moieties as useful in these methods.
BACKGROUND ART
A large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory response. A large number of cytokines participate in this response, including IL-1, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation rely at least in part on the activation of an enzyme on the cell signaling pathway, a member of the MAP kinase family generally known as p38 and alternatively known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
Eye diseases associated with a fibroproliferative condition include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post glaucoma drainage surgery.
PCT applications WO98/06715, WO98/07425, and WO 96/40143, all of which are incorporated herein by reference, describe the relationship of p38 kinase inhibitors with various disease states. As mentioned in these applications, inhibitors of p38 kinase are useful in treating a variety of diseases associated with chronic inflammation. These applications list rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke, reperfusion injury, CNS injuries such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, graft-versus-host reaction, Crohn's Disease, ulcerative colitis including inflammatory bowel disease (IBD) and pyresis.
The above-referenced PCT applications disclose compounds which are p38 kinase inhibitors said to be useful in treating these disease states. These compounds are either imidazoles or are indoles substituted at the 3- or 4-position with a piperazine ring linked through a carboxamide linkage. Additional compounds which are conjugates of piperazines with indoles are described as insecticides in WO97/26252, also incorporated herein by reference.
Certain aroyl/phenyl-substituted piperazines and piperidines which inhibit p38-&agr; kinase are described in PCT publication WO00/12074 published Mar. 9, 2000. In addition, indolyl substituted piperidines and piperazines which inhibit this enzyme are described in PCT publication No. WO99/61426 published 2, Dec. 1999. Carbolene derivatives of piperidine and piperazine as p38-&agr; inhibitors are described in PCT/US00/07934 filed 24, Mar. 2000.
None of the foregoing patents describes the indole derivatives described herein which specifically inhibit p38-&agr;.
DISCLOSURE OF THE INVENTION
The invention is directed to methods and compounds useful in treating conditions that are characterized by enhanced p38-&agr; activity. These conditions include inflammation, proliferative diseases, and certain cardiovascular disorders as well as Alzheimer's disease as further described below.
Compounds of the invention have been found to inhibit p38 kinase, the &agr;-isoform in particular, and are thus useful in treating diseases mediated by these activities. The compounds of the invention are of the formula
and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein
represents a single or double bond;
B is —W
i
—COX
j
Y wherein Y is COR
2
or an isostere thereof and R
2
is hydrogen or a noninterfering substituent, each of W and X is a spacer of 2-6 Å, and each of i and j is independently 0 or 1;
each R
3
is independently a noninterfering substituent, where n is 0-3;
Z
3
is NR
7
or O; wherein R
7
is H or a noninterfering substituent;
one Z
2
is CA or CR
8
A and the other is CR
1
, CR
1
2
, NR
6
or N wherein each R
1
, R
6
and R
8
is independently hydrogen or noninterfering substituent; wherein A is:
such that Z
1
is CR
5
or N wherein R
5
is hydrogen or a noninterfering substituent;
each of 1 and k is an integer from 0-2 wherein the sum of 1 and k is 0-3;
Ar is an aryl group substituted with 0-5 noninterfering substituents, wherein two noninterfering substituents can form a fused ring;
each R
4
is independently a noninterfering substituent where m is 0-4;
each of L
1
and L
2
is a linker; and
the distance between the atom of Ar linked to L
2
and the center of the &bgr; ring is 4.5-24 Å.
Modes of Carrying Out the Invention
The compounds of formula (1) are useful in treating conditions which are characterized by overactivity of p38 kinase, in particular the &agr;-isoform. Conditions “characterized by enhanced p38-&agr; activity” include those where this enzyme is present in increased amount or wherein the enzyme has been modified to increase its inherent activity, or both. Thus, “enhanced activity” refers to any condition wherein the effectiveness of these proteins is undesirably high, regardless of the cause.
The compounds of the invention are useful in conditions where p38-&agr; kinase shows enhanced activity. These conditions are those in which fibrosis and organ sclerosis are caused by, or accompanied by, inflammation, oxidation injury, hypoxia, altered temperature or extracellular osmolarity, conditions causing cellular stress, apoptosis or necrosis. These conditions include ischemia-reperfusion injury, congestive heart failure, progressive pulmonary and bronchial fibrosis, hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis, interstitial renal fibrosis, chronic scarring diseases of the eyes, bladder and reproductive tract, bone marrow dysplasia, chronic infectious or autoimmune states, spinal chord injury and traumatic or surgical wounds. These conditions, of course, would be benefited by compounds which inhibit p38-&agr;. Methods of treatment with the compounds of the invention are further discussed below.
The Invention Compounds
The compounds useful in the invention are derivatives of indole-type compounds containing a mandatory substituent, B, preferably at a position corresponding to the 5 position of the indole nucleus and a mandatory substituent A at a position corresponding to the 2- or 3-position of indole. In general, an indole-type nucleus is preferred, although alternatives within the scope of the invention are also illustrated below.
In the description above, certain positions of the molecule are described as permitting “noninterfering substituents.” This terminology is used because the substituents in these positions generally speaking are not relevant to the essential activity of the molecule taken as a whole. A wide variety of substituents can be employed in these positions, and it is well within ordinary skill to determine whether any particular arbitrary substituent is or is not “noninterfering.”
As used herein, a “noninterfering substituent” is a substituent which leaves the ability of the compound of formula (1) to inhibit p38-&agr; activity qualitatively intact. Thus, the substituent may alter the degree of inhibition of p38-&agr;. However, as long as the compound of formula (1) retains the ability to inhibit p38-&agr; activity, the substituent will be classified as “noninterfering.” A number of assays for determining the ability of any compound to inhibit p38-&agr; activity are available in the art. A whole blood assay for this evaluation is illustrated below: the gene for p38-&agr; has been cloned and the protein can be prepared recombinantly and its activity assessed, including an assessment of the ability of an arbitrar

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