Quinazoline derivatives as inhibitors of P-38 &agr;

Details Quinazoline derivatives as inhibitors of P-38 &agr; Quinazoline derivatives as inhibitors of P-38 &agr;

1998-08-28

2001-02-06

Shah, Mukund J. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S063000, C544S180000, C544S284000, C544S293000

Reexamination Certificate

active

06184226

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to treating various disorders associated with the activity of the kinase p38-&agr;. More specifically, it concerns compounds that are derivatives of quinazoline 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 inflamniatory 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 antiinflammatory agents.
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, Gramnegative 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.
The compounds of the invention are quinazoline derivatives. Other quinazoline compounds for other uses have been described. U.S. Pat. No. 5,721,237 assigned to Rhone-Poulenc Rorer is directed to methods for selective treatment of cell growth and differentiation characterized by activity of human epidermal growth factor receptor type II using quinazoline substituted only in the 4-position with an aromatic moiety optionally coupled to the quinazoline through a linking moiety. U.S. Pat. No. 4,480,883 describes compounds that exhibit tyrosine kinase inhibition activity wherein the heterocyclic portion of a quinazoline or other fused ring nitrogen-containing aromatic system is substituted only once with an aromatic moiety, again optionally coupled through a linker. U.S. Pat. No. 5,616,582 assigned to Zeneca describes tyrosine kinase inhibitors which are quinazolines linked through an amino group at the 4-position to a substituted or unsubstituted phenyl. These compounds contain no substituents at position 2. U.S. Pat. No. 5,475,001 also assigned to Zeneca describes similar compounds with the same activity. U.S. Pat. No. 5,430,148 assigned to Agouron Pharmaceutical describes antiproliferative substituted quinazolinones and their counterparts wherein the keto group is replaced by a sulfone.
U.S. Pat. No. 5,719,157 to Takeda Chemical Industries describes pharmaceutical compositions for inhibiting bone resorption which include 4-phenyl quinoline derivatives which may further be substituted at the 2-position with an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
None of the foregoing patents describes 2, 4-substituted quinazolines which specifically inhibit p38-&agr;.
DISCLOSURE OF THE INVENTION
The invention is directed to compounds useful in treating inflammation generally, including specific conditions such as those described in the Background section above. These novel compounds have been found to inhibit p38 kinase, the &agr;-isoform in particular, and are thus useful in treating diseases mediated by this enzyme. The compounds of the invention are of the formula
and the pharmaceutically acceptable salts thereof
wherein each R
2
is independently a noninterfering substituent;
m is an integer of 0-4;
Z is CH or N;
R
1
is H, alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR
2
, SR, —OOCR, —NROCR, RCO, —COOR, —CONR
2
, —SO
2
NR
2
, CN, CF
3
, and NO
2
, wherein each R is independently H or lower alkyl (1-4C);
n is 0, 1 or 2;
Ar is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR
2
, SR, —OOCR, —NROCR, RCO, —COOR, —CONR
2
, SO
2
NR
2
, CN, CF
3
, and NO
2
, wherein each R is independently H or lower alkyl (1-4C); and
R
3
is a branched or cyclic alkyl group (5-7C) or is phenyl optionally substituted with 1-2 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR
2
, SR, —OOCR, —NROCR, RCO, —COOR, —CONR
2
, —SO
2
NR
2
, CN, CF
3
, and NO
2
, wherein each R is independently H or lower alkyl (1-4C).
Thus, in one aspect, the invention is directed to compounds of the formula set forth above. In other aspects, the invention is directed to methods to produce these compounds, to pharmaceutical compositions containing them, and to methods of treating inflammation using these compounds. The invention is also directed to treating conditions associated with cardiac failure using the invention compounds.
MODES OF CARRYING OUT THE INVENTION
The compounds of formula (1) are useful in treating conditions which are characterized by overactivity of p38 kinase, and in particular the &agr;-isoform. The compounds are derivatives of quinazoline containing mandatory substituents at the 2- and 4-positions.
With respect to the substituted amino substituent at the 4-position of the quinazoline, the preferred embodiment of R
1
is H, but R
1
may also be alkyl (1-6C) or arylalkyl where the aryl moiety may be substituted by 1-2 groups, preferably alkyl (1-6C), OR, SR or NR
2
wherein R is H or lower alkyl (1-4C). Preferably, R
1
is H or alkyl (1-6C).
n may be 0-2, and is preferably 0 or 1 and most preferably 0.
Ar is preferably indolyl, 6-pyrimidyl, or 3- or 4-pyridyl, or is optionally substituted phenyl.
For embodiments wherein Ar is optionally substituted phenyl, preferred substituents include halo, OR, SR, and NR
2
wherein R is H or methyl or ethyl. Particularly preferred is 3- or 4-pyridyl, especially 4-pyridyl in unsubstituted form. These substituents may occupy all five positions of the phenyl ring, preferably 1-2 positions, preferably one position.
Any of the aryl moieties, especially the phenyl moieties may also comprise two substituents which, when taken together, form a 5-7 membered carbocyclic or heterocyclic ring.
Thus, preferred embodiments of the substituents at the 4-position of the quinazoline include 2-(4-pyridyl)ethylamino; 4-pyridylamino; 3-pyridylamino; 2-pyridylamino; 4-indolylamino; 5-indolylamino; 3-methoxyanilinyl; 2-(2,5-difluorophenyl)ethylamino-, and the like.
Preferred embodiments of R
3
, the substituent at the 2-position of the quinazoline comprise a phenyl moiety optionally substituted with 1-2 substituents preferably halo, alkyl (1-6C), OR, NR
2
, and SR wherein R is as defined above. Preferred substituents at the 2-position of the quinazoline include phenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 4-fluorophenyl and the like. Other preferred embodiments of R
3
comprise a cyclopentyl or cyclo

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