Compounds and methods to treat cardiac failure and other...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C544S367000, C544S370000, C544S373000

Reexamination Certificate

active

06340685

ABSTRACT:

TECHNICAL FIELD
The invention is directed to compounds that are useful in treating inflammation and that contain piperazine or piperidine moieties coupled to the 5-or 6-position of indole, benzimidazole or benzotriazole. More particularly, the invention concerns novel ortho substituted indoles and N-substituted indoles as well as methods to treat heart and kidney conditions using these compounds and derivatives thereof.
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 WO98/28292, WO98/06715, WO98/07425, and WO96/40143, 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.
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. Certain novel compounds have been found to inhibit p38 kinase, in particular, p38 kinase &agr; 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 of Z
1
and Z
2
is independently CR
4
or N;
where each R
4
is independently H or is alkyl (1-6C) optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more of halo, OR, SR, NR
2
, RCO, COOR, CONR
2
, OOCR, or NROCR where R is H or alkyl (1-6C), or by CN or ═O, or by an aliphatic or aromatic 5 or 6 membered ring optionally containing 1-2 N heteroatoms; or
two R
4
taken together form a bridge optionally containing a heteroatom;
R
1
is
 wherein
X
1
is CO or an isostere thereof;
m is 0 or 1;
Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;
n is 0, 1 or 2;
Z
3
is CH or N;
X
2
is CH, CH
2
or an isostere thereof; and
Ar consists of one or two phenyl moieties directly coupled to X
2
optionally substituted by halo, nitro, alkyl (1-6C), alkenyl (1-6C), CN or CF
3
, or by RCO, COOR, CONR
2
, NR
2
, OR, SR, OOCR or NROCR wherein R is H or alkyl (1 -6C)
or by phenyl, itself optionally substituted by the foregoing substituents;
R
2
is H, or alkyl (1-6C) optionally including one or more heteroatoms which are O, S or N, and optionally substituted by one or more of halo, OR, SR, NR
2
, RCO, COOR, CONR
2
, OOCR, or NROCR where R is H or alkyl (1 -6C), or by CN or ═O, or by an aliphatic or aromatic 5 or 6 membered ring optionally containing 1-2 N heteroatoms;
R
3
is H, halo, NO
2
, alkyl (1-6C), alkenyl (1-6C), CN, OR, SR, NR
2
, RCO, COOR, CONR
2
, OOCR, or NROCR where R is H or alkyl (1-6C).
Thus, in one aspect, the invention is directed to compounds of the formulas 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 and other compounds described herein.
MODES OF CARRYING OUT THE INVENTION
The compounds of formulas 1-4 are useful in a variety of physiological contexts, as further described below. Preferred embodiments are those wherein both Z
1
and Z
2
are CH; thus, among the preferred compounds of the invention are derivatives of indole. Also preferred are those of forumulas (1) and (2); in embodiments wherein the compounds of the invention are substituted indoles, the substituent R
1
is thus in the 5-position. These compounds—i.e., those of formulas (1) and (2) wherein both Z
1
and Z
2
are CH are especially preferred. However, substituents may be placed at carbons in the 2- or 3-position of the indole ring. Especially preferred are substituents at the 3-position, especially those coupled through carboxarnide linkages.
Thus, preferred embodiments of R
4
are of the formula RNHCO- wherein R is alkyl or substituted alkyl.
In other preferred embodiments, the substituents shown for the compounds of the invention are as set forth below.
In regard to R
1
:
X
1
is CO or an isostere thereof. Thus, in addition to CO, X
1
may be CH
2
, SO, SO
2
, or CHOH. CO is preferred.
Z
3
is CH or N; Z
3
═CH is preferred.
Typically m is 1; however, in some compounds of the invention, m can be 0; thus, this substituent is a five-membered ring.
X
2
is CH
2
if Ar consists of a single phenyl moiety or CH if Ar consists of two phenyl moieties or may be an isostere thereof. Thus, for appropriate embodiments of Ar, X
2
may be any of the alternatives set forth above for X
1
.
The phenyl moieties represented by Ar may optionally be substituted by substituents including alkyl (1-6C), halo, RCO, COOR, CONR
2
, OR, SR, NR
2
, OOCR, NROCR, NO
2
, CN, or CF
3
, wherein R is H or alkyl (1-6C). The phenyl moieties may also be substituted with an additional phenyl residue, preferably at the 4-position. The additional phenyl residue may itself be substituted with the substituents set forth above. The additional phenyl may be substituted in all five positions, but preferably less, preferably in 1-2 positions or not at all. Preferred substituents include halo and OCH
3
. The substituents may occupy all five positions of the phenyl substituent, preferably 1-2 positions or the phenyl may be unsubstituted.
n may be 0, 1 or 2, and is preferably O. However, when n is 1, Y is present and may be alkyl, arylalkyl or aryl, all of which may optionally be substituted by the substituents set forth above with regard to Ar. When n is 2, both Y groups together may constitute an alkylene bridge. A preferred bridge is an ethylene bridge. Preferred embodiments of Y when n is 1 include unsubstituted alkyl and unsubstituted arylalkyl.
With regard to R
2
:
R
2
is preferably H, but may also be a suitable substituent. Such substituents are typically and preferably alkyl or substituted alkyl. The alkyl or substituted alkyl may optionally include a heteroatom which is O, N or S, preferably N. Permitted substituents are set forth above; preferre

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