Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-18
2004-11-23
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S236500, C514S274000, C514S275000, C544S122000, C544S123000, C544S296000, C544S316000, C544S031000, C544S332000
Reexamination Certificate
active
06821971
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said compounds and method for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.
BACKGROUND OF THE INVENTION
Interleukin-1 (IL-1) and Tumor Necrosis Factor-&agr; (TNF-&agr;) are among the important biological substances known collectively as “cytokines.” These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents.
These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states.
There is therefore a long felt need for compounds and pharmaceutical compositions which comprise compounds, which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them
SUMMARY OF THE INVENTION
The present invention meets the aforementioned needs in that it has been surprisingly found that certain [5,6] and [5,6,6] fused ring pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.
The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula:
wherein R is:
a) hydrogen;
b) —O(CH
2
)
k
R
3
; or
c) —NR
4a
R
4b
;
R
3
is substituted or unsubstituted C
1
-C
4
alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the index k is from 0 to 5;
R
4a
and R
4b
are each independently:
a) hydrogen; or
b) —[C(R
5a
R
5b
)]
x
R
6
;
each R
5a
and R
5b
are independently hydrogen, —OR
7
, —N(R
7
)
2
, —CO
2
R
7
, —CON(R
7
)
2
; C
1
-C
4
linear, branched, or cyclic alkyl, and mixtures thereof; R
6
is hydrogen, —OR
7
, —N(R
7
)
2
, —CO
2
R
7
, —CON(R
7
)
2
; substituted or unsubstituted C
1
-C
4
alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R
7
is hydrogen, a water-soluble cation, C
1
-C
4
alkyl, or substituted or unsubstituted aryl; the index x is from 0 to 5;
R
1
is:
a) substituted or unsubstituted aryl; or
b) substituted or unsubstituted heteroaryl;
R
2a
and R
2b
units are each independently selected from the group consisting of:
a) hydrogen;
b) —O(CH
2
)
j
R
8
;
c) —(CH
2
)
j
NR
9a
R
9b
;
d) —(CH
2
)
j
CO
2
R
10
;
e) —(CH
2
)
j
OCO
2
R
10
f) —(CH
2
)
j
CON(R
10
)
2
;
g) two R
2a
or two R
2b
units from the same carbon atom can be taken together to form a carbonyl unit;
h) one R
2a
and one R
2b
are taken together to form a double bond;
i) one R
2a
and one R
2b
are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consisting of:
i) carbocyclic;
ii) heterocyclic;
iii) aryl;
iv) heteroaryl;
v) bicyclic; and
vi) heterobicyclic;
j) and mixtures thereof;
R
8
, R
9a
, R
9b
, and R
10
are each independently hydrogen, C
1
-C
4
alkyl, and mixtures thereof; R
9a
and R
9b
can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R
10
units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; m is an index from 1 to 5, n is an index from 1 to 5; m+n=from 2 to 6.
Another aspect of the present invention relates to pharmaceutical compositions which can deliver the compounds of the present invention to a human or higher mammal, said compositions comprising:
a) an effective amount of one or more of the compounds according to the present invention; and
b) one or more pharmaceutically acceptable excipients.
A further aspect of the present invention relates to methods for controlling one or more inflammatory cytokine mediated or inflammatory cytokine modulated mammalian diseases or conditions, said method comprising the step of administering to a human or higher mammal and effective amount of a composition comprising one or more of the compounds according to the present invention.
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
REFERENCES:
patent: 3222366 (1965-12-01), Wagner-Jauregg et al.
patent: 2003/0134867 (2003-07-01), Clark et al.
patent: 529153 (1972-10-01), None
Holzheimer, PubMed Abstract (J. Chemother. 13 Spec. No. 1(1):159-72), Nov. 2001.*
van Deventer, PubMed Abstract (Intensive Care Med. 26 Suppl. 1:S98-102), 2000.*
Green et al., PubMed Abstract (Immunol. Rev. 169:11-22), Jun. 1999.*
Rasmussen, PubMed Abstract (Dan Med Bull. 47(2):94-114), Apr. 2000.*
Aleman et al., PubMed Abstract (Antivir Ther. 4(2):109-15), 1999.
Clark Michael Philip
De Biswanath
Djung Jane Far-Jine
Laufersweiler Matthew John
Echler Sr. Richard S.
Rao Deepak
The Procter & Gamble & Company
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