Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-04-06
2001-10-16
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C514S617000, C514S619000, C514S622000, C514S825000
Reexamination Certificate
active
06303629
ABSTRACT:
The present invention relates to methods for treating inflammation and inflammatory diseases, arthritis, and stroke in animals. The invention also relates to methods for treating animals having toxicity resulting from infestation by lipopolysaccharides. These methods involve the use of therapeutically effective amounts of pADPRT inhibitory compounds.
BACKGROUND OF THE INVENTION
The use of pADPRT inhibitory compounds have been reported for treating cancer and viral infections. Examples of these methods are described in U.S. Pat. Nos. 5,464,871, 5,473,074; 5,482,975, 5,484,951; 5,516,941, and 5,583,155, the disclosures of which are incorporated herein by reference.
In the published literature, 5-iodo-6-amino-1,2-benzopyrone (INH
2
BP), a novel inhibitor of the nuclear enzyme poly-ADP ribose polymerase (PADPRT) has recently been shown to inhibit in vivo tumorigenicity in a Ha-ras transfected endothelial cell line (Bauer et al.,
Int. J. Oncol.
8:239-252 (1995) and Bauer et al.,
Biochimie
77:347-377 (1995)). Treatment with INH
2
BP has also resulted in changes in topoisomerase I and II and MAP kinase activity Based on the effects observed, a hypothesis regarding the potential use of INH
2
BP in the therapy of cancer has been put forward.
Malignant growth and inflammatory processes may feature the activation of certain common cellular signal transduction pathways, e.g., MAP kinase (Kyriakis et al.,
J. Biol. Chem.
271:24313-24316 (1996) and Ferrell,
TIBS
21:460-466 (1996)). Chronic inflammation frequently leads to carcinogenic transformation, as demonstrated, for example, in the case of the intestine. In our study, the production of multiple proinflammatory mediators was induced by bacterial lipopolysaccharide (endotoxin, LPS). LPS is known to induce a multitude of cellular reactions and triggers a systemic inflammatory response. LPS-induced pro-inflammatory mediators include tumor necrosis factor alpha (TNF), interleukin-1, interferon-gamma, whereas antiinflammatory mediators include interleukin-10 (IL-10) and interleukin-13 (Deltenre et al.,
Acta Gastroenterol Belg.
58:193-200 (1995), Beutler,
J. Invest. Med.
42:227-35 (1995), Liles et al.,
J. Infect Dis.
172:1573-80 (1995), and Giroir,
Critical Car. Med.
21:780-9 (1993)). As a consequence of the production of these inflammatory cytokines, LPS initiates the production of inflammatory free radicals (oxygen-centered, such as superoxide, and nitrogen-centered radicals, such as nitric oxide (NO) and of prostaglandins (Nathan,
FASEB J.
6:3051-3064 (1992), Vane,
Proc. Roy. Soc. Lond B
343:225-246 (1993), and Szabo,
New Horizons
3:3-32 (1995)). The production of NO in inflammation is due to the expression of a distinct isoform of NO synthase (iNOS), while the production of inflammatory cytokines is explained by the expression of a distinct isoform of cyclooxygenase (cyclooxygenase-2, COX-2), iNOS, COX-2, as well as other pro-inflammatory cytokines and free radicals which play an important role in the LPS-induced inflammatory response. Moreover, NO (or its toxic byproduct, peroxynitrite), has been implicated as a key mediator leading to the transformation of the inflammatory response into a carcinogenic process (Bartsch et al.,
Pharmacogenetics
2:272-7 (1994), Liu et al.,
Carcinogenesis
15:2875-7 (1992) and Ohshima et al.,
Mutation Res.
305:253-64 (1994)).
There are a multitude of intracellular processes which precede the production of proinflammatory mediators. Activation of tyrosine kinases (Levitzki, A.,
Eur. J. Biochem.
226:1-13 (1994), Novogrodsky et al.,
Science
264:1319-22 (1994), Marczin et al.,
Am. J. Physiol.
265:H1014-1018 (1993)), mitogen-activated protein kinase (MAP kinase, Matsuda et al.,
J. Leukocyte Biol.
56:548-53 (1994), L'Allemain,
Progr. Growth Factor Res.
5:291-334 (1994), and Cowley et al.,
Cells
77:841-52 (1994)); and the nuclear factor kappa B (NF-kB) pathway (Baeuerle et al.,
Ann. Rev. Immunol.
12:141-79 (1994), Schreck et al.,
Free Radical Res. Comm.
17:221-37 (1992) and Muller et al.,
Immunobiol.
187:233-56 (1993)) are recognized as important factors in the inflammatory response and contribute to the expression or production of inflammatory mediators.
SUMMARY OF THE INVENTION
One aspect of the invention is a method for treating inflammation or inflammatory disease in an animal or mammal, which comprises the steps of administering an effective amount of a pADPRT inhibitory compound.
Another aspect of the invention is a method for treating inflammation or inflammatory disease in an animal or mammal, which comprises the steps of administering an effective amount of a pADPRT inhibitory compound wherein the pADPRT inhibitory compound is selected from the group consisting of:
a compound having the formula:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
are each selected from the group consisting of hydrogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl or phenol, optionally substituted with alkyl, alkoxy, hydroxy or halo, and only one of R
1
, R
2
, R
3
, R
4
, R
5
, and R
6
is selected from the group consisting of amino, nitroso or nitro; a compound having the formula:
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are each selected from the group consisting of hydrogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl or phenol, optionally substituted with alkyl, alkoxy, hydroxy or halo, and only one of R
1
, R
2
, R
3
, R
4
, and R
5
is selected from the group consisting of amino, nitroso or nitro; and a compound having the formula:
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are each selected from the group consisting of hydrogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl or phenol, optionally substituted with alkyl, alkoxy, hydroxy or halo, and only one of R
1
, R
2
, R
3
, R
4
, and R
5
is amino. Preferred pADPRT compounds include: 6-amino-1,2-benzopyrone, 3-nitrosobenzamide, 5-amino-1(2H)-isoquinolinone, 7-amino-1(2H)-isoquinolinone, and 8-amino-1(2H)-isoquinolinone. Particularly preferred is the compound 5-iodo-6-amino-1,2-benzopyrone.
Still another aspect of the invention is a method of treating arthritis in an animal comprising the step of administering an effective amount of or a pADPRT inhibitory compound wherein the compound has the structural formula noted above as compounds I, II or III. Especially preferred is the compound 5-iodo-6-amino-1,2-benzopyrone.
Still another aspect of the invention is a method of treating cerebrovascular accidents such as stroke in an animal comprising the step of administering an effective amount of or a pADPRT inhibitory compound wherein the compound has the structural formula noted above as compounds I, II or III. Especially preferred is the compound 5-iodo-6-amino-1,2-benzopyrone.
The pADPRT inhibitory compounds of the invention may be prepared by the methods described in U.S. Pat. Nos. 5,464,871, 5,473,074; 5,482,975, 5,484,951, 5,516,941, and 5,583,155, the disclosures of which are incorporated herein by reference.
The preferred compounds for use in the methods of the invention include those where the halo group is iodo, and one of the R groups is amino. Also, it has been found that the pADPRT inhibitory activity is strongly exhibited when an iodo moiety is adjacent to an amino moiety. In any event, the compounds to be used in the methods of the invention should have pADPRT inhibitory activity. The compounds may be used as is, or preferably in combination with a pharmaceutically acceptable acid addition salt or other suitable pharmaceutical carrier known in the art.
Those of skill in the art will readily understand that the pathologies and disease states expressly stated herein are not intended to be limiting. Rather, the compounds of the present invention may be used to treat any disease which features an inflammatory response. That is, the compounds of the present invention have pADPRT inhibitory activity and may be effectively administered to ameliorate any disease state which is mediated all or in part by pADPRT.
REFERENCES:
patent: 5262564 (1993-11-01), Kun et al.
patent: 5464871 (1995-11-01), Kun et al.
patent: 5473074 (199
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Kung Viola T.
Octamer, Inc.
Travers Russell
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