Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-18
2002-04-23
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S305000
Reexamination Certificate
active
06376507
ABSTRACT:
The present invention relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.cf, during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in mammals, including humans, using an NK-1 antagonist. It also relates to a method of treating or preventing such disorders in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, pyrrolidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds that are substance P receptor antagonists.
The following references refer, collectively, to quinuclidine, piperidine, ethylene diamine, pyrrolidine and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992; U.S. Pat. No. 5,232,929, which issued on Aug. 3, 1993; World Patent Application WO 92/20676, published Nov. 26, 1992; World Patent Application WO 93/00331, published Jan. 7, 1993; World Patent Application WO 92/21677, published Dec. 10, 1992; World Patent Application WO 93/00330, published Jan. 7, 1993; World Patent Application WO 93/06099, published Apr. 1, 1993; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 92/06079, published Apr. 16, 1992; World Patent Application WO 92/12151, published Jul. 23, 1992; World Patent Application WO 92/15585, published Sep. 17, 1992; World Patent Application WO 93/10073, published May 27, 1993; World Patent Application WO 93/19064, published Sep. 30, 1993; World Patent Application WO 94/08997, published Apr. 28, 1994; World Patent Application WO 94/04496, published Mar. 3, 1994; U.S. patent application Ser. No. 988,653, filed Dec. 10, 1992; U.S. patent application Ser. No. 026,382, filed Mar. 4, 1993; U.S. patent application Ser. No. 123,306, filed Sep. 17, 1993, and U.S. patent application Ser. No. 072,629, filed Jun. 4, 1993. All of the foregoing World Patent Applications designate the United States and were filed in the U.S. Receiving Office of the PCT. The foregoing patents and patent applications are incorporated herein by reference in their entirety.
SUMMARY OF THE INVENTION
This invention relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to such mammal an amount of a substance P receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to such mammal an amount of a NK-1 receptor antagonist that is effective in treating or preventing such disorder.
This invention also relates to a method of treating or preventing a disorder selected from stroke, epilepsy, head trauma, spinal cord trauma, ischemic neuronal damage such as cerebral ischemic damage from stroke or vascular occlusion (e.g., during open heart surgery), excitotoxic neuronal damage (e.g., in stroke or epilepsy) and amyotrophic lateral sclerosis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR
2
R
3
is attached to a carbon atom of ring system A;
AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR
2
R
3
is attached to a carbon atom of AA;
AAA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the —CH
2
PR
3
sidechain is attached to a carbon atom of ring AAA;
P is NR
2
, O, S, SO or SO
2
;
Q is SO
2
, NH,
wherein the point of attachment of said
to ring AAA is the nitrogen atom and the point of attachment to X
5
is the sulfur atom;
W
1
is hydrogen, halo or (C
1
-C
6
)alkyl, S—(C
1
-C
3
)alkyl, halo or (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
W
2
is hydrogen, (C
1
-C
6
)alkyl, S—(C
1
-C
3
)alkyl, halo or (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
W is hydrogen, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, —S(O)
v
—(C
1
-C
6
)alkyl wherein v is zero, one or two, halo or (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms;
X
1
is hydrogen, (C
1
-C
10
)alkoxy optionally substituted with from one to three fluorine atoms or (C
1
-C
10
)alkyl optionally substituted with from one to three fluorine atoms;
X
2
and X
3
are independently selected from hydrogen, halo, nitro, (C
1
-C
10
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
10
)alkoxy optionally substituted with from one to three fluorine atoms, trif luoromethyl, hydroxy, phenyl, cyano, amino, (C
1
-C
6
)-alkylamino, di-(C
1
-C
6
)alkylamino,
(C
1
-C
6
)—
hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl,
X
5
is a four to six membered heterocyclic ring containing from one to three heteroatoms selected from sulfur, nitrogen and oxygen (e.g., thiazolyl, pyrrolyl, thienyl, triazolyl, oxazolyl, oxadiazolyl, thiadiazolyl or imidazolyl), wherein said heterocyclic ring may optionally be substituted with from one to three substituents, preferably with from zero to two substituents, independently selected from phenyl, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, (C
1
-C
6
)alkoxy optionally substituted with from one to three fluorine atoms and halo;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms and (C
1
-C
6
) alkoxy optionally substituted with from one to three fluorine atoms;
R
1
is selected from amino, (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino, —S(O)
v
—(C
1
-C
10
)-alkyl wherein v is zero, one or two, —S(O)
v
-aryl wherein v is zero, one or two, —O-aryl, —SO
2
NR
4
R
5
wherein each of R
4
and R
5
is, independently, C
1
-C
6
)alkyl, or R
4
and R
5
, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons,
wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, —N(SO
2
—(C
1
-C
10
)alkyl)
2
and
and wherein the aryl moieties of said —S(O)
v
-aryl, —O-aryl and
are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy and halo;
or R
1
is a group having the formula
wherein a is 0, 1 or 2 and the asterisk represents a position meta to the R
2
R
3
NCH
2
side chain;
the dotted lines in formula Ib represent that one of the X—Y and Y—Z bonds may optionally be a double bond;
X is selected from ═CH—, —CH
2
—, —O—, —S—, —SO—, —SO
2
—, —N(R
4
)—, —N
Lowe, III John A.
Nelson Robert B.
Ginsburg Paul H.
Gitomer Ralph
Joran A. David
Khare Devesh
Pfizer Inc.
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