Aminopyrrole compounds

Details Aminopyrrole compounds Aminopyrrole compounds

2002-08-29

2004-02-24

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S279100

Reexamination Certificate

active

06696471

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to aminopyrrole compounds and methods for preparing and using the same.
BACKGROUND OF THE INVENTION
TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Arend, W. P.
Arthritis & Rheumatism
38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin's disease (see., Benharroch, D.; et. al.
Euro. Cytokine Network
7(1): 51-57) and Alzheimer's disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((see., Maini, R. N.; et. al.
APMIS
. 105(4): 257-263, (1997); Feldmann, M.,
J. of the Royal College of Physicians of London
30(6): 560-570, (1996); Lorenz, H. M.; et. al.
J. of Immunology
156(4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al.
Clin. & Exp. Allergy
1038-1044, (1995) and Lassalle, P., et. al.
Clin. & Exp. Immunol
. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., Cooper, A. L., et. al.
Am. J. of Physiology
267(6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al.
J. of Neuroimmunol
. 72(2): 163-168, (1997)) and periodontal diseases.
Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammation and have positive therapeutic outcomes. It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((see., Lee, J. C., et al.
Nature.
372 (6508): 739-46, (1994)). Compounds that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.
It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.
SUMMARY OF THE INVENTION
One aspect of the present invention provides an aminopyrrole compound of the formula:
a prodrug, individual isomer, a mixture of isomers or a pharmaceutically acceptable salt thereof and methods for preparing or using the same, wherein
each of Ar
1
and Ar
2
is independently optionally substituted aryl; and
each of R
1
and R
2
is independently hydrogen, alkyl or a nitrogen protecting group.
Another aspect of the present invention provides a method for producing an aminopyrrole compound of the formula:
said method comprising forming an aminopyrrole ring system by contacting a cyano compound of the formula:
with an arylamine compound of the formula Ar
2
—NH
2
under conditions sufficient to produce the aminopyrrole compound of Formula I,
wherein
each of Ar
1
and Ar
2
is independently optionally substituted aryl.
Another aspect of the present invention provides a composition comprising a therapeutically effective amount of a compound of Formula I and an excipient.
Still another aspect of the present invention provides a method for inhibiting p38 MAP kinase in a cell comprising administering a compound of Formula I to the cell comprising p38 MAP kinase.
Yet another aspect of the present invention provides a method for treating a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration to the mammal a therapeutically effective amount of a compound of Formula I.
DEFINITIONS
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkyl” means a linear saturated monovalent hydrocarbon moiety of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
“Alkoxy” means a moiety —OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.
“Acyl” means a moiety —C(O)R where R is hydrogen, alkyl, haloalkyl, or heteroalkyl, e.g., acetyl, trifluoroacetyl, and the like.
“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like.
“Halide” means fluoride, chloride, bromide, or iodide.
“Haloalkyl” means alkyl substituted with one or more same or different halo atoms, e.g., —CH
2
Cl, —CF
3
, —CH
2
CF
3
, —CH
2
CCl
3
, and the like.
“Heteroalkyl” means an alkyl moiety as defined above, having one or more, preferably one, two or three, substituents selected from —NR
a
R
b
, —OR
c
wherein R
a
, R
b
and R
c
are independently of each other hydrogen, alkyl, or the corresponding protecting group. Representative examples include, but are not limited to, hydroxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, and the like.
“Heteroalkoxy” means a moiety —OR where R is heteroalkyl group as defined above, e.g., 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2,3-dihydroxy-1-methylpropoxy, 2-aminoethoxy, and the like.
“Optionally substituted aryl” means an aryl ring as defined above, which is optionally substituted independently with one or more, preferably one or two, substituents selected from alkyl, alkoxy, heteroalkyl, heteroalkyl, halide, cyano, acyl, —NRR′ (where R and R′ are independently selected from hydrogen, alkyl or acyl), —NHCOR (where R is alkyl),—NRS(O)
n
R′ (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R′ is hydrogen, alkyl or heteroalkyl), —NRS(O)
n
NR′R″ (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R′ and R″ are independently hydrogen, alkyl or heteroalkyl), —S(O)
n
R (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), —S(O)
n
NRR′ (where n is an integer from 0 to 2 and R and R′ are independently hydrogen, alkyl or heteroalkyl), —COOR, -(alkylene)COOR (where R is hydrogen or alkyl), —CONR′R″ or -(alkylene)CONR′R″ (where R′ and R″ are independently hydrogen or alkyl).
“Optionally substituted phenyl” means a phenyl which is optionally substituted independently with one or more, preferably one or two, substituents selected from alkyl, alkoxy, heteroalkyl, heteroalkyl, halide, cyano, acyl, —NRR′ (where R and R are independently selected from hydrogen, alkyl or acyl), —NHCOR (where R is alkyl), —NRS(O)
n
R′ (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R′ is hydrogen, alkyl or heteroalkyl), —NRS(O)
n
NR′R″ (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R′ and R″ are independently hydrogen, alkyl or heteroalkyl), —S(O)
n
R (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), —S(O)
n
NRR′ (where n is an integer from 0 to 2 and R and R′ are independently hydrogen, alkyl or heteroalkyl), —COOR, -(alkylene)COOR (where R is hydrogen or alkyl), —CONR′R″ or -(alkylene)CONR′R″ (where R′ and R″ are independently hydrogen or alkyl).
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl group optionally mono- or di-substituted with an alkyl group” means that t

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