Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-18
2004-05-04
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S218000, C514S223200, C514S228800, C514S230500, C514S241000, C514S252020, C514S252160, C514S255050, C514S274000, C514S275000, C540S601000, C540S553000, C544S063000, C544S096000, C544S098000, C544S105000, C544S116000, C544S119000, C544S216000, C544S316000, C544S331000, C546S238000, C546S295000, C546S296000
Reexamination Certificate
active
06730668
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones 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 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones 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 bicyclic 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) —O[CH
2
]
k
R
3
; or
b) —N R
4a
R
4b
;
R
3
is substituted or unsubstituted C
1
-C
4
alkyl, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 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
)]
m
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 heterocyclic, 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 m is from 0 to 5;
R
1
is:
a) substituted or unsubstituted aryl; or
b) substituted or unsubstituted heteroaryl;
each R
2
unit is independently selected from the group consisting of:
a) hydrogen;
b) —(CH
2
)
j
O(CH
2
)
n
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) —(CH
2
)
j
OCON(R
10
)
2
;
h) two R
2
units can be taken together to form a carbonyl unit;
i) 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, n is an index from 0 to 5;
Z is O, S, NR
11
, or NOR
11
; R
11
is hydrogen or C
1
-C
4
alkyl.
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.
Another aspect of the present invention relates to forms of the compounds of the present invention, which under normal physiological conditions, will release the compounds as described herein.
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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds which are capable of mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes.
For the purposes of the present invention the term “hydrocarbyl” is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various unsubstituted non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]-heptan-1-yl, and naphth-2-yl.
Included within the definition of “hydrocarbyl” are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexane, cyclohexenyl, cycloheptanyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
The term “heterocycle” includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.
An example of a unit defined by the term “alkylenearyl” is a benzyl unit having the formula:
whereas an example of a unit defined by the term “alkyleneheteroaryl” is a 2-picolyl unit having the formula:
The term “substituted” is used throughout the specification. The term “substituted” is defined h
Clark Michael Philip
De Biswanath
Djung Jane Far-Jine
Laufersweiler Matthew John
Natchus Michael George
Echler Sr. Richard S.
McKenzie Thomas
Shah Mukund J.
The Procter & Gamble & Company
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