Gamma Secretase inhibitors

Details Gamma Secretase inhibitors Gamma Secretase inhibitors

2002-08-01

2004-01-27

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S153000

Reexamination Certificate

active

06683091

ABSTRACT:

BACKGROUND
WO 00/50391, published Aug. 13, 2000, discloses compounds having a sulfonamide moiety that are useful for the treatment and prevention of Alzheimer's Disease and other diseases relating to the deposition of amyloid protein.
In view of the present interest in the treatment or prevention of neurodegenerative diseases, such as Alzheimer's disease, a welcome contribution to the art would be compounds for use in such treatment or prevention. This invention provides such a contribution.
SUMMARY OF THE INVENTION
This invention provides compounds that are inhibitors (e.g., antagonists) of Gamma Secretase and have the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(A) R
1
is selected from:
(1) unsubstituted aryl;
(2) aryl substituted with one or more (e.g., 1-3) R
5
groups;
(3) heteroaryl; or
(4) heteroaryl substituted with one or more (e.g., 1-3) R
5
groups;
(B) R
2
is selected from:
(1) alkyl;
(2) —X(CO)Y;
(3) —(CR
3
2
)
1-4
X(CO)Y; or
(4) any of the groups for R
1
;
(C) Each R
3
is independently selected from:
(1) H, or
(2) alkyl;
(D) Each R
3A
is independently selected from:
(1) H; or
(2) alkyl;
(E) R
4
is independently selected from:
(1) halogen;
(2) —CF
3
;
(3) —OH;
(4) —Oalkyl;
(5) —OCF
3
;
(6) —CN;
(7) —NH
2
;
(8) —CO
2
alkyl;
(9) —CONR
6
R
7
;
(10) -alkylene-NR
6
R
7
;
(11) —NR
6
COalkyl;
(12) —NR
6
COaryl;
(13) —NR
6
COheteroaryl; or
(14) —NR
6
CONR
6
R
7
;
(F) R
5
is independently selected from:
(1) halogen;
(2) —CF
3
;
(3) —OH;
(4) —Oalkyl;
(5) —OCF
3
;
(6) —CN;
(7) —NH
2
;
(8) —CO
2
alkyl;
(9) —CONR
6
R
7
;
(10) alkylene-NR
6
R
7
;
(11) —NR
6
COalkyl;
(12) —NR
6
COaryl;
(13) —NR
6
COheteroaryl;
(14) —NR
6
CONR
6
R
7
;
(G) X is selected from:
(1) —O—;
(2) —NH;
(3) —N-alkyl; or
(H) Y is selected from:
(1) —NR
6
R
7
; or
(2) —N(R
3
)(CH
2
)
2-6
NR
6
R
7
;
(I) R
6
and R
7
are independently selected from:
(1) H;
(2) alkyl;
(3) cycloalkyl;
(4) -arylalkyl;
(5) -heteroarylalkyl;
(6)
(7)
(J) R
6
and R
7
taken together with the nitrogen atom to which they are bound form a heterocycloalkyl group selected from:
(K) Each R
8
is independently selected from:
(1) alkyl; or
(2) alkyl substituted with 1 to 4 hydroxy groups;
(L) Each R
9
is independently selected from:
(1) H;
(2) alkyl;
(3) alkyl substituted with 1 to 4 hydroxy groups;
(4) cycloalkyl;
(5) cycloalkyl substituted with 1 to 4 hydroxy groups;
(6) -arylalkyl;
(7) -heteroarylalkyl;
(8) —COOalkyl; or
(9) any of the groups for R
1
;
(M) Each R
10
is independently selected from:
(1) H; or
(2) alkyl;
(N) m is 0 to 3, and n is 0 to 3, such that m+n is 1, 2, 3 or 4;
(O) p is 0 to 4;
(P) r is 0 to 4;
(Q) s is 0 to 3; and
(R) with the proviso that compounds of formula 1.0 do not include:
This invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula 1.0 and at least one pharmaceutically acceptable carrier.
This invention also provides a method for inhibiting gamma-secretase comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of treating neurodegenerative diseases comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of inhibiting the deposition of amyloid protein (e.g., amyloid &bgr; protein) in, on or around neurological tissue (e.g., the brain) comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
This invention also provides a method of treating Alzheimer's disease comprising administering an effective amount of a compound of formula 1.0 to a patient in need of treatment.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the following terms have the following meanings unless otherwise defined:
Patient includes both humans and other mammals. “Mammal” means, humans and other animals.
alkoxy: represents a —Oalkyl group wherein alkyl is as defined below;
alkyl: represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, said alkyl group being optionally substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from: (1) halogen, (2) —OH, (3) —O(alkyl), preferably —O(C
1
-C
6
)alkyl, and most preferably —OCH
3
, (4) —NH
2
, (5) —NH(alkyl), preferably —NH((C
1
-C
6
)alkyl), and most preferably —NHCH
3
, (6) —N(alkyl)
2
wherein each alkyl group is independently selected, preferably —N((C
1
-C
6
)alkyl)
2
wherein each alkyl group is independently selected, and most preferably —N(CH
3
)
2
or (7) —S(alkyl), preferably —S((C
1
-C
6
)alkyl), and most preferably —SCH
3
;
alkylene: represents a —(CH
2
)
q
— group wherein q is 1 to 20, generally 1 to 6 and more usually 1 to 4, optionally one or more (e.g., 1 to 3, or 1 to 2) hydrogens in said alkylene group can be replaced with the same or different alkyl group (preferably —(C
1
-C
6
)alkyl, most preferably —(C
1
to C
3
)alkyl, more preferably —(C
1
-C
2
)alkyl) such that the total number of carbons in the entire alkylene group is 2 to 20, also said alkylene group can be optionally substituted with one or more (e.g., 1 to 3) substituents independently selected from the group consisting of: (1) halo; (2) —OH; (3) —O(alkyl), preferably —O((C
1
-C
6
)alkyl), and most preferably —OCH
3
; (4) —NH
2
; (5) —NH(alkyl), preferably —NH((C
1
-C
6
)alkyl), and most preferably —NHCH
3
; (6) —N(alkyl)
2
wherein each alkyl group is independently selected, preferably —N((C
1
-C
6
)alkyl)
2
wherein each alkyl group is independently selected, and most preferably —N(CH
3
)
2
; and
(7) —S(alkyl), preferably —S((C
1
-C
6
)alkyl), and most preferably —SCH
3
;
ar: represents aryl as defined below;
aralkyl (arylalkyl): represents an aryl group, as defined below, bound to an alkyl group, as defined above, wherein said alkyl group is bound to a molecule (e.g., a compound of the claimed invention or an intermediate to a compound of the invention);
aryl: represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., phenyl, naphthyl, phenanthryl, tetrahydronaphthyl or indanyl), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment; said carbocyclic group being optionally substituted with one or more (e.g., 1 to 3) substituents independently selected from: (1) halo, (2) alkyl (preferably —(C
1
to C
6
)alkyl), (3) hydroxy, (4) alkoxy (preferably —(C, to C
6
)alkoxy), (5) —CN, (6) —CF
3
, (7) amino (—NH
2
), (8) alkylamino, (9) dialkylamino (wherein each alkyl group is independently selected), (10) aryl (e.g., phenyl) (provided that if this aryl group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (11) aralkoxy (provided that if the aryl moiety of said aralkoxy (i.e., arylalkoxy) group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (12) aryloxy (e.g., phenoxy) (provided that if the aryl moiety of said aryloxy group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (13) —S(O)
0-2
-aryl (provided that if the aryl moiety of said —S(O)
0-2
-aryl group is optionally substituted with one or more aryl groups these latter aryl groups are not further substituted with aryl groups), (14) —COOR
11
or (15) —NO
2
; wherein said R
11
represents H, alkyl, aryl (provided that if said aryl moiety is optionally substituted with one or more aryl containing groups these latter aryl containing groups are not further substituted with aryl containing groups), or aralkyl (e.g., benzyl) (provided that if said aryl moiety of said aralkyl group is optionally substituted with one or more aryl containing groups these latter aryl containing groups are not further substituted with aryl containing groups); preferably said optional subs

Affiliated with

Also associated with

Rating

Gamma Secretase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Gamma Secretase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Gamma Secretase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3218412