Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-20
2004-04-13
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S234000
Reexamination Certificate
active
06720338
ABSTRACT:
TECHNICAL FIELD
The present invention relates to substituted N-acylsulfonamides which are useful for promoting apoptosis, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Apoptosis is a mode of cell death in which the cell commits suicide either to ensure proper development of the organism or to destroy cells that represent a threat to the organism's integrity. Morphologically, apoptosis is characterized by blebbing of the plasma membrane, shrinking of the cytoplasm and nucleus, and fragmenting into particles which are engulfed by phagocytic cells. Although apoptosis plays a critical role in normal development, its impairment is thought to be a significant factor in the etiology of such diseases as cancer, autoimmune disorders, inflammatory diseases, and viral infections. Conversely, increased apoptosis has been linked to AIDS and neurodegenerative diseases such as Parkinson's disease, stroke, and Alzheimer's disease.
BCL-X1 is a protein which, in healthy cells, is expressed in the outer membranes of the mitochondria, the endoplasmic reticulum, and the nuclear envelope. Its function is to bind to specific protein/protease complexes and prevent cell apoptosis. Upon internal damage to the cell the protein/protease complexes are released, and cause the process of apoptosis to begin. An over-expression of BCL-X1, often present in cancerous and other diseased cells, results in the blocking of apoptotic signals and allows the cells to proliferate (
Cancer
1999, 85, 164-170; and references cited therein). It is believed that by blocking BCL-X1, apoptosis can be induced in diseased cells, and can provide an effective therapy for cancer and other diseases caused by the impairment of the apoptotic process. Based on these findings and the absence of BCL-X1 inhibitors from current cancer therapies, there is a continuing need for compounds which can trigger apoptosis through the inhibition of the BCL family of proteins.
SUMMARY OF THE INVENTION
In its principle embodiment the present invention provides a compound of formula (I):
or a therapeutically acceptable salt thereof wherein
A is selected from the group consisting of phenyl and a five- or six-membered aromatic carbocyclic ring wherein from one to three carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein A is substituted through carbon atoms in the ring;
R
1
is selected from the group consisting of alkyl, haloalkyl, nitro, and —NR
5
R
6
;
R
2
, and R
3
are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkylsulfanyl, alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl, arylsulfanylalkoxy, carbonyloxy, cycloalkylalkoxy, cycloalkyloxy, halo, haloalkoxy, haloalkyl, heterocycle, (heterocycle)oxy, hydroxy, nitro, and —N
5
R
6
,
R
4
is selected from the group consisting of aryl, arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, halo, heterocycle, and (heterocycle)alkoxy;
R
5
and R
6
are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)sulfanylalkyl, hydroxyalkyl, a nitrogen protecting group, and —N═CR
7
R
8
; or
R
5
and R
6
, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of imidazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, thiomorpholinyl, and thiomorpholinyl dioxide; and
R
7
and R
8
are alkyl, or
R
7
and R
8
, together with the carbon atom to which they are attached, form an aryl group; and
R
15
is selected from the group consisting of hydrogen, alkyl, and halo.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; and R
1
-R
8
and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; and R
1
, R
2
, R
4-8
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is selected from the group consisting of arylsulfanylalkoxy, cycloalkylalkoxy, and cycloalkyloxy; and R
1
, R
4
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; and R
1
, R
4
, R
7
, R
8
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is selected from the group consisting of alkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, heterocyclesulfanylalkyl, and —N═CR
7
R
8
; and the other is hydrogen; and R
1
, R
4
, R
7
, R
8
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is (cycloalkyl)alkyl and the other is arylsulfanylalkyl; and R
1
, R
4
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is cycloalkyl and the other is hydrogen; and R
1
, R
4
and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is (cycloalkyl)alkyl and the other is hydrogen; and R
1
, R
4
, and R
5
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is arylsulfanylalkyl and the other is hydrogen; and R
1
, R
4
, and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R
3
is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R
2
is —NR
5
R
6
; one of R
5
and R
6
is arylalkylsulfanyl and the other is hydrogen; R
4
is selected from the group consisting of arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, and (heterocycle)alkoxy; and R
1
and R
15
are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyr
Augeri David J.
Baumeister Steven A.
Bruncko Milan
Dickman Daniel A.
Ding Hong
Abbott Laboratories
Donner B. Gregory
Morris Patricia L.
Steele Gregory W.
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