Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-27
2002-06-25
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C514S330000
Reexamination Certificate
active
06410540
ABSTRACT:
TECHNICAL FIELD
The invention is directed to compounds that are useful in treating inflammation and that contain N-containing heterocycles such as piperazine or piperidine moieties coupled to phenyl and other aryl groups. More particularly, the invention concerns novel compounds of this type as well as methods to treat heart and kidney conditions using these and other compounds.
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 antiinflammatory agents.
PCT applications WO98/06715, WO98/07425, WO98/28292 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 or piperidine 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.
U.S. Pat. No. 5,719,135 describes tyrosine kinase inhibitors containing piperidine or piperazine rings linked through a methylene at position 1 of piperidine to various aromatic systems which must further contain a &ggr; lactam fused to a pyridine ring. Similar compounds are described in U.S. Pat. No. 5,663,346 and in WO096/22976. Other cyclic tyrosine kinase inhibitors are described in PCT application WO095/06032. In addition, WO094/20062 describes balanoids as protein kinase C inhibitors. The balanoid compounds contain multiple aromatic systems which include at least a ring containing at least seven members. Some of the compounds useful in the method of the present invention are known compounds.
DISCLOSURE OF THE INVENTION
The invention is directed to methods of treating inflammation generally, including specific conditions such as those described in the Background section above. The compounds of the invention have been found to inhibit p38 kinase and are thus useful in treating diseases mediated by this enzyme. These compounds also inhibit p38&agr; preferentially as compared to their inhibition of p38&bgr; as is further discussed below.
The compounds useful in the invention are of the formula
and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,
wherein
Z is N or CR
1
, R
1
is a noninterfering substituent,
each of X
1
and X
2
is a linker,
Ar
1
and Ar
2
are identical or different, and represent optionally substituted C1-C20 hydrocarbyl residues wherein at least one of Ar
1
and Ar
2
is an optionally substituted aryl group, with the proviso that when X
2
is CH
2
or an isostere thereof, X
1
is CO or an isostere thereof, and Ar
2
is optionally substituted phenyl, Ar
1
is other than an optionally substituted indolyl, benzimidazolyl or benzotriazolyl substituent, and wherein said optionally substituted phenyl is not an optionally substituted indolyl, benzimidazolyl, or benzotriazolyl,
Y is a noninterfering substituent, wherein n is an integer from 0-4, and
wherein m is an integer from 0-4 and 1 is an integer from 0-3.
Preferably, the compounds useful in the invention are of the formula
and the pharmaceutically acceptable salts thereof,
wherein Ar
1
is optionally substituted furanyl, thiophenyl, phenyl system having 0, 1, or 2 heterocyclic N atoms or naphthyl system having 0, 1, 2 or 3 heterocyclic N atoms;
X
1
is CO or an isostere thereof;
Y is optionally substituted alkyl (1-6C), optionally substituted aryl (6-10C), or optionally substituted arylalkyl (7-11C);
n is 0 or 1;
Z is CH or N;
X
2
is CH
2
or an isostere thereof; and
Ph is optionally substituted phenyl.
The optional substituents on the aryl moieties (including phenyl) include halo, nitro, optionally substituted alkyl (1-6C) or alkenyl (1-6C), CN, guanidino or CF
3
, as well as RCO, COOR, CONR
2
, SO
2
NR
2
, —OOCR, —NROCR, —NROCOR, NR
2
, OR or SR, wherein R is H or alkyl (1-6C), as well as substitution by phenyl, itself optionally substituted by the foregoing substituents. Any two substituents may form a 5-7 membered carbocyclic or heterocyclic ring subject to the proviso.
Thus, in one aspect, the invention is directed to compounds of the formulas set forth above and to pharmaceutical compositions containing them. In other aspects, the invention is directed to methods of treatment using compounds of the formula set forth above. The invention is also directed to specific classes of compounds within the genus of formula (1). In other aspects, the invention is directed to methods to produce the classes of compounds useful in the invention.
Modes of Carrying Out the Invention
The compounds of formula (1) set forth above are defined by the nature of the substituents on the heterocycloalkyl ring in the center of the formula. Piperazine or piperidine rings are preferred and piperidine rings are more preferred. The central piperazine or piperidine ring can be expanded or contracted using —CH
2
groups so that it includes from 4 members up to 11 members. The substitution on this ring is on the N or Z positions only. Although not bound by this theory, the function of the central heterocycloalkyl group is apparently to space the Ar
2
group, which is generally hydrophobic, from the Ar
1
group, which is preferably but not necessarily hydrophilic.
The central heterocycloalkyl ring can include from 1-2 N. If the ring contains only 1 N then Z is a —CR
1
wherein R
1
is a noninterfering substituent. Preferably, R
1
is alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, halogen, acyl, carboxy, or hydroxy. More preferably, R
1
is hydroxy, alkyl, or alkoxy.
The linker that couples the central heterocycloalkyl ring and the Ar
1
and Ar
2
groups on either end of the molecule are preferably saturated or unsaturated alkylene optionally containing 1-4 carbonyl, 1-4 SO
2
, and/or 1-3 heteroatoms, including a linker which is CO, SO
2
, SO or contains a heteroatom, and optionally substituted with a substituent selected from the group consisting of halo, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, arylalkyl, haloalkyl, polyhaloalkyl, haloalkoxy, polyhaloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, acyl, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, carboxy, hydroxy, tetrazolyl, imidazol
Chakravarty Sarvajit
Dugar Sundeep
Goehring R. Richard
Lewicki John A.
Liu David Y.
Jarvis William R. A.
Morrison & Foerster / LLP
Scios Inc.
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