Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-10
2002-08-27
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252010
Reexamination Certificate
active
06440967
ABSTRACT:
The present invention relates to a combination of a COX-2 inhibitor, NSAID, estrogen or vitamin E and an inverse agonist of the GABA
A
&agr;5 receptor subtype, and the use of the combination in treating neurodegenerative conditions such as Alzheimer's Disease.
Alzheimer's Disease is a poorly understood neurodegenerative condition mainly affecting the elderly but also younger people who are generally genetically predispositioned to it.
In a first embodiment the present invention provides a new and surprisingly effective synergistic combination of a COX-2 inhibitor and an inverse agonist of the GABA
A
&agr;5 receptor subtype for separate, sequential or simultaneous administration.
In a second embodiment the present invention provides a new and surprisingly effective synergistic combination of an NSAID and an inverse agonist of the GABA
A
&agr;5 receptor subtype for separate, sequential or simultaneous administration.
In a third embodiment the present invention provides a new and surprisingly effective synergistic combination of an estrogen and an inverse agonist of the GABA
A
&agr;5 receptor subtype for separate, sequential or simultaneous adminstration.
In a fourth embodiment the present invention provides a new and surprisingly effective synergistic combination of Vitamin E and an inverse agonist of the GABA
A
&agr;5 receptor subtype for separate, sequential or simultaneous adminstration.
The present invention provides a greater than expected improvement in the condition of subjects suffering from a neurodegenerative with an associated cognitive deficit, such as Alzheimer's Disease or Parkinson's disease, or from a cognitive deficit which may arise from a normal process such as aging or from an abnormal process such as injury, than would be expected from administration of the active ingredients alone. Further, the combination allows for a lower overall dose of each of the active ingredients to be administered thus reducing side effects and decreasing any reduction in the effectiveness of each of the active ingredients over time.
Any inverse agonist of the GABA
A
&agr;5 receptor subtype may be used which fulfills the criteria of WO-A-9625948. The inverse agonist may be either binding selective for the &agr;
5
subtype or functionally selective, or both. Thus the inverse agonist is preferably an antagonist, or has insignificant agonist or inverse agonist properties at the other GABA
A
&agr; receptor subtypes when measured in oocytes as described in WO-A-9625948.
Thus the inverse agonist preferably has a functional efficacy at the &agr;
5
receptor subunit of less than −20% inverse agonism or greater, for example −30% and functional efficacies at the &agr;
1
, &agr;
2
and &agr;
3
receptor subunits of between −20 and +20%. By functional efficacy is meant the percentage modulation of the EC
20
response produced by GABA, upon coadministration of the inverse agonist, in oocytes expressing GABA
A
receptor channels containing the &agr; receptor subunit under test. Details of this measurement are given in WO-A-9625948.
The inverse agonist preferably binds selectively to GABA
A
receptors containing the &agr;
5
subunit 10, 25 and particularly 50 times compared to GABA
A
receptors subunits containing the &agr;
1
, &agr;
2
or &agr;
3
subunits. Preferably this binding selectivity is shown over all these subunits.
A preferred class of inverse agonists, which are disclosed in WO-A-9850385, are of formula I:
wherein:
R
1
is hydrogen, halogen or CN or a group C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy or C
2-4
alkynyloxy, each of which groups is unsubstituted or substituted with one or two halogen atoms or with a pyridyl or phenyl ring each of which rings may be unsubstituted or independently substituted by one or two halogen atoms or nitro, cyano, amino, methyl or CF
3
groups;
R
2
is hydrogen, halogen or CN or a group C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy or C
2-4
alkynyloxy each of which groups is unsubstituted or substituted with one or two halogen atoms;
L is O, S or NR
n
where R
n
is H, C
1-6
alkyl or C
3-6
cycloalkyl;
X is a 5-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur, or a 6-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, the 5- or 6-membered heteroaromatic ring being optionally fused to a benzene ring and the heteroaromatic ring being optionally substituted by R
x
and/or R
y
and/or R
z
, where R
x
is halogen, R
3
, OR
3
, OCOR
3
, NR
4
R
5
, NR
4
COR
5
, tri(C
1-6
alkyl)silylC
1-6
alkoxyC
1-4
alkyl, CN or R
9
, R
y
is halogen, R
3
, OR
3
, OCOR
3
, NR
4
R
5
, NR
4
COR
5
or CN and R
z
is R
3
, OR
3
or OCOR
3
, where R
3
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, hydroxyC
1-6
alkyl and R
3
is optionally mono, di- or tri-fluorinated, R
4
and R
5
are each independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or CF
3
or R
4
and R
5
, together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom, and R
9
is benzyl or an aromatic ring containing either 6 atoms, 1, 2 or 3 of which are optionally nitrogen, or 5 atoms, 1, 2 or 3 of which are independently chosen from oxygen, nitrogen and sulphur, at most one of the atoms being oxygen or sulphur, and R
9
is optionally substituted by one, two or three substituents independently chosen from halogen atoms and C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, C
2-4
alkenyloxy and C
2-4
alkynyloxy groups each of which groups is unsubstituted or substituted by one, two or three halogen atoms, and when X is a pyridine derivative, the pyridine derivative is optionally in the form of the N-oxide and providing that when X is a tetrazole derivative it is protected by a C
1-4
alkyl group; or X is phenyl optionally substituted by one, two or three groups independently selected from halogen, cyano, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl and C
3-6
cycloalkyl;
Y is optionally branched C
1-4
alkylidene optionally substituted by an oxo group or Y is a group (CH
2
)
j
O wherein the oxygen atom is nearest the group X and j is 2, 3 or 4;
Z is a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the heteroatoms being oxygen or sulphur and providing that when two of the heteroatoms are nitrogen an oxygen or sulphur atom is also present and that when one of the atoms is oxygen or sulphur then at least one nitrogen atom is present, or a 6-membered heteroaromatic ring containing 2 or 3 nitrogen atoms, Z being optionally substituted by R
v
and/or R
w
, where R
v
is halogen, R
6
, NR
7
R
8
, NR
7
COR
8
, CN, furyl, thienyl, phenyl, benzyl, pyridyl or a 5-membered heteroaromatic ring containing at least one nitrogen atom and optionally 1, 2 or 3 other heteroatoms independently selected from oxygen, nitrogen and sulphur, at most one of the other heteroatoms being oxygen or sulphur and R
w
is R
6
or CN;
R
6
is C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, hydroxyC
1-6
alkyl, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, CH
2
F or CF
3
; and
R
7
and R
8
are each independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl or CF
3
or R
7
and R
8
, together with the nitrogen atom to which they are attached, form a 4-7 membered heteroaliphatic ring containing the nitrogen atom as the sole heteroatom;
or a pharmaceutically acceptable salt thereof.
As used herein, the expression “C
1-6
alkyl” includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as “C
1-4
alkyl”, “C
2-4
alkenyl”, “C
2-6
alkenyl”, “hydroxyC
1-6
alkyl”, “C
2-4
alkyl” and “C
2-6
alkynyl” are
Block Gilbert A.
Lines Christopher R.
Criares Theodore J.
Lee Shu Muk
Merck & Co. , Inc.
Rose David L.
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