Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-23
2003-03-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S317000, C514S318000, C514S331000, C544S242000, C544S333000, C544S334000, C544S335000, C546S192000, C546S193000, C546S194000, C546S229000
Reexamination Certificate
active
06537996
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the fields of molecular biology and pharmaceutical methods of treatment. More particularly, the invention relates to compounds, compositions, and methods for modulating p38 MAP kinase activity.
BACKGROUND OF THE INVENTION
Activation of members of the mitogen-activated protein kinase (MAPK) family represents one of the major mechanisms used by eukaryotic cells to transduce extracellular signals into cellular response (J. Blenis,
Proc Natl Acad Sci USA
(1993) 90:5889). One member of this kinase family, p38, has been implicated in signaling pathways used by biologically important stimuli including products of microbial pathogens, cytokines, UV light and increased extracellular osmolarity. Most recently p38 activation was found to be correlated with apoptosis in neuronal cells following withdrawal of nerve growth factor. The kinase p38 is activated by a subset of the known dual-specificity MAPK kinases (MEKs or MKKs); low molecular weight GTP-binding proteins RAC1 and Cdc42 have also been shown to play a role in regulating p38 activation by some stimuli. A complete understanding of how p38 activation regulates cellular responses requires identification of specific substrates for this enzyme.
SUMMARY OF THE INVENTION
We have now identified compounds that modulate the activity of p38.
One aspect of the invention is a compound of formula 1:
wherein R
1
is H, lower alkyl, or—OR
5
, where R
5
is aryl, heterocyclyl, acyl, N—R
6
-4-piperidinyl, N—R
6
-4-piperidinylmethyl, or N—R
6
-4-piperidinylethyl, where aryl and heterocyclyl are substituted with 1-3 R
6
substituents selected from the group consisting of H, lower alkyl, lower alkenyl, OH, NO
2
, NH
2
, halo, trihalomethyl, —CN, SH, SO, SO
2
, SO
3
H, —OR, —COR, —COOR, —CONHR, —OCOR, and —NCOR, where R is lower alkyl; R
2
is H or lower alkyl; R
3
is aryl substituted with 1-3 R
6
substituents as set forth above; R
4
is H, lower alkyl, aryl, aralkyl, —OH, —NH
2
, —NHR, or —OR, where R is lower alkyl or aryl-lower alkyl; and A is —CH— or —N—; and pharmaceutically acceptable salts thereof.
Another aspect of the invention is a pharmaceutical composition, comprising a compound of formula 1 and a pharmaceutically acceptable excipient.
Another aspect of the invention is a method for modulating p38 activity in a cell, comprising administering an effective amount of a compound of formula 1 to said cell.
DETAILED DESCRIPTION
Definitions:
“Compound of formula 1” refers to compounds having the structure
wherein R
1
is H, lower alkyl, or OR
5
, where R
5
is aryl, heterocyclyl, acyl, N—R
6
-4-piperidinyl, N—R
6
-4-piperidinylmethyl, or N—R
6
-4-piperidinylethyl, where aryl and heterocyclyl are substituted with 1-3 R
6
substituents selected from the group consisting of H, lower alkyl, lower alkenyl, OH, NO
2
, NH
2
, halo, trihalomethyl, —CN, SH, SO, SO
2
, SO
3
H, —OR, —COR, —COOR, —CONHR, —OCOR, and —NCOR, where R is lower alkyl; R
2
is H or lower alkyl; R
3
is aryl substituted with 1-3 R
6
substituents as set forth above; R
4
is H, lower alkyl, aryl, aralkyl, —OH, —NH
2
, —NHR, or —OR, where R is lower alkyl or aryl-lower alkyl; and A is —CH— or —N—; and pharmaceutically acceptable salts and esters thereof. It should be noted that the two amidine nitrogen atoms can tautomerize if R
2
is H, in which case either R
1
or R
3
can be bound to the imide nitrogen (the nitrogen double-bonded to carbon). Thus, no absolute geometry is indicated or intended around the R
1
—N═C bond.
The term “lower alkyl” refers to radicals containing carbon and hydrogen, without unsaturation, having from one to six carbon atoms, inclusive. Lower alkyl radicals can be straight or branched. Exemplary lower alkyl radicals include, without limitation, methyl, ethyl, propyl, isopropyl, hexyl, t-butyl, and the like. The term “lower alkenyl” refers to a hydrocarbon radical having 2-6 carbon atoms, and at least one double bond. Exemplary lower alkenyl radicals include, without limitation, vinyl, propenyl, butenyl, and the like.
The term “aryl” refers to an aromatic carbocyclic or heterocyclic moiety, having one, two, or three rings. Exemplary aryl radicals include, without limitation, phenyl, naphthyl, pyridyl, pyrimidyl, triazyl, quinazolinyl, pyranyl, thiazolyl, and the like. The terms “aralkyl” and “aryl-lower alkyl” refer to an aryl moiety joined to a lower alkyl moiety, for example benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl, and the like.
The term “halo” refers to fluoro, chloro, bromo, and iodo.
The term “leaving group” refers to a radical that is easily displaced by a nucleophile in an S
N
2 displacement reaction. Exemplary leaving groups include, without limitation, sulfonates such as tosylate and mesylate, silanes such as t-butyl-dimethylsilane, halogens such as bromo and chloro, and the like.
The term “pharmaceutically acceptable salts and esters” refers to derivatives of compounds of formula 1 obtained by addition of an acid or base to the compound, or condensation with an alcohol or carboxylic acid to form an ester. In either case, the acid, base, alcohol, or carboxylic acid must not be unacceptably toxic at the concentrations at which the compound is administered. Suitable acids include, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.
The term “modulate” as used herein refers to an alteration in p38 MAP kinase activity, and includes both increases and decreases in activity. Modulation of activity can occur as the result of direct interaction of a compound with p38, interaction with another compound or protein that affects p38 activity directly or indirectly, or by altering the expression of p38 or of a protein that interacts with p38 directly or indirectly.
General Method:
Compounds of the invention are prepared by any suitable synthetic scheme. For example, an intermediate of formula A can be treated with an alcohol (R—OH) and NaH or Na—OR to form intermediate B.
Intermediate B can then be treated with an intermediate of the form R
1
—L (where L is a leaving group) in the presence of a strong, hindered base to provide an intermediate of formula C. This intermediate is then treated with an amine of the formula HNR
2
R
3
under acidic or basic catalysis to provide the compound of formula 1.
Compounds of the invention can be tested for activity by any available assay suitable for determining p38 activity or interference therewith.
Compounds of the invention can be administered to a subject, or can be applied directly to cells, for example in a cell culture. If administered to a cell culture, the compound is preferably first suspended or dissolved in a suitable carrier. Suitable carriers include, without limitation, water, saline solution, dimethylsulfoxide (DMSO) and solutions thereof, cell culture media, and the like.
Useful pharmaceutical carriers for the preparation of the pharmaceutical compositions hereof can be solids or liquids. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Other suitable
Morgans, Jr. David J.
Sun Dongxu
Thode Silke
Iconix Pharmaceuticals Inc.
Raymond Richard L.
Robins & Pasternak LLP
Truong Tamthom N.
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