Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-17
2001-06-26
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254060, C544S366000, C544S368000
Reexamination Certificate
active
06251907
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to heteroarylpiperidines, pyrrolidines and piperazines. More particularly, this invention relates to heteroarylpiperidines, pyrrolidines and piperazines having antipsychotic activity and to their use as antipsychotic drugs.
The therapeutic treatment of schizophrenic patients by administration of neuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, and chemically closely related compounds, is widespread. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued. There exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses.
Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs include the so-called extrapyramidal symptoms, such as rigidity and tremor, continuous restless walking, and tardive dyskinesia which causes facial grimacing, and involuntary movements of the face and extremities. Orthostatic hypotension is also common. Thus, there also exists a need in the art for antipsychotic drugs that produce fewer or less severe manifestations of these common side effects.
In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without the side effects previously mentioned.
Moreover, there has been a need for drugs that can produce other biological effects. For example, relief from pain has been an age-old aspiration which has led to the discovery of natural and synthetic analgetics. Nevertheless, the need for safe and effective analgetics has continued to the present day.
SUMMARY OF THE INVENTION
This invention aids in fulfilling these needs in the art by providing a compound of the formula:
wherein
X is —O—, —S—, —NH—, or N(R
2
)—
R
2
is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl and phenylsulfonyl groups;
p is 1 or 2;
Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;
Q
1
is selected from the group consisting of:
where Z is
and
Y
2
is selected from the group consisting of:
in which
(R
1
) is —CR
24
R
27
—(CR
23
R
24
)
n
—CR
24
R
27
— where n is 0,1,2, or 3; or
—CHR
24
CH═CH—CHR
24
—,
—CHR
24
—C≡C—CHR
24
—,
—CHR
24
—CH═CH—CR
23
R
24
—CHR
24
—,
—CHR
24
—CR
23
R
24
—CH═CH—CHR
24
—,
—CHR
24
—C≡C—CR
23
R
24
—CHR
24
—, or
—CHR
24
—CR
23
R
24
—C≡C—CHR
24
—,
the —CH═CH— bond being cis or trans;
R and m are as defined hereinafter;
R
23
is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy, alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkyl oxy lower alkyl, alkanoyloxy lower alkyl or
where
Z
1
is lower alkyl, —OH, lower alkoxy, —CF
3
, —NO
2
, —NH
2
or halogen; and
R
24
is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or
where Z
1
is as previously defined;
R
27
is hydrogen or R
24
and R
27
taken together with the carbon to which they are attached form C═O or C═S;
and R and m are as defined hereinafter;
where R
1
is as previously defined, and R
3
is hydrogen or —OCH
3
;
where R
1
is as previously defined; and
R
4
is hydrogen, lower alkyl, lower alkoxy, hydroxy, tri(C
1
-C
6
)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl, amino, mono- or dialkylamino, (C
1
-C
18
)acyl amino, (C
1
-C
18
)alkanoyl trifluoromethyl, chlorine, fluorine, bromine, nitro, —O—C(═O)—(C
1
-C
18
straight or branched chain) alkyl or —C(═O)-aryl;
in which aryl is phenyl or
where R
5
is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy;
where R
1
and R
4
are as previously defined;
where either one of X
y
or X
z
is —C(═O)— and the other is —CH
2
—; and
R
5
′ is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, or bromine; and
R
1
is as previously defined;
where R
1
and R
4
are as previously defined;
where A is —C(═O)—, —C(═S)—, —C(═CH
2
)—, —C(═O)CH
2
—, —CH
2
CH
2
—, —CR
26
═N—, —CR
25
R
26
—; or
R
25
is hydrogen, lower alkyl, hydroxy or alkanoyloxy;
R
26
is hydrogen or lower alkyl;
either one of B
y
and B
z
is CH or N and the other is CH;
U is O or S;
q is 1, 2, 3 or 4, and R
1
and R
4
are as previously defined;
where R
1
is as previously defined;
wherein R
1
, R
4
and q are as defined above; and
R
28
is hydrogen, (C
1
-C
6
)alkyl, aryl(C
1
-C
6
)alkyl, phenyl or substituted phenyl;
wherein R
1
, R
4
and q are as defined above;
R
29
and R
30
are hydrogen, (C
1
-C
6
)alkyl, aryl(C
1
-C
6
)alkyl phenyl or substituted phenyl;
R
31
and R
32
are hydrogen, hydroxy, (C
1
-C
6
)alkyl, aryl(C
1
-C
6
)alkyl, phenyl, substituted phenyl, hydroxymethyl, or CHOR
33
where R
33
is (C
1
-C
18
)alkanoyl; or
either R
29
and R
30
taken together or R
31
and R
32
taken together with the carbon group to which they are attached form a C═O or C═S group;
where R
1
, R
4
, R
28
, R
29
, R
30
, R
31
, R
32
and q are as defined above;
where R
1
, R
4
, R
28
, R
29
, R
30
, R
31
, R
32
and q are as defined above;
wherein R
1
and R
4
are previously defined and m is defined hereinafter;
where R
1
is as previously defined;
Q
2
is S, NH, or —CH
2
—; and
R and m are as defined hereinafter;
where R
1
is as previously defined;
where R
1
, R
4
and are as previously defined and m is as defined hereinafter;
wherein R
1
, and R
4
are as previously defined and m as defined hereinafter;
—R
1
—O—R
12
(18)
where R
12
is selected from the group consisting of:
hydrogen,
alkyl,
—C(═O)—(C
1
-C
18
straight chain or branched) alkyl,
—C(═O)—NR
13
R
14
,
—C(═O)—NR
15
R
16
,
—S(═O)
2
—R
17
, and
where R
13
is selected from the group consisting of hydrogen and (C
1
-C
18
)alkyl groups;
where R
14
is selected from the group consisting of hydrogen and (C
1
-C
18
)alkyl groups;
where NR
15
R
16
taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl;
where R
17
is selected from the group consisting of lower alkyl and aryl groups;
where R
4
is previously defined and m is defined hereinafter;
—R
1
—NR
18
R
19
(19)
where R
18
and R
19
are independently selected from the group consisting of:
hydrogen,
(C
1
-C
12
straight or branched chain)alkyl,
—C(═O)—O—(C
1
-C
18
)alkyl,
—C(═O)—(C
1
-C
18
)alkyl;
—C(═O)-pyridyl or
where NR
18
R
19
taken together form a ring structure selected from the group consisting of piperidinyl, morpholinyl and piperazinyl; where the piperidinyl or piperazinyl ring is optionally substituted by
where R
1
, X, Y, p, R
4
and R
28
are as previously defined and m is defined hereinafter;
—R
1
—S—R
12
(20)
where R
1
and R
12
are as previously defined;
where R
1
, R
4
and R
28
are as previously defined; and
where
R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, formyl,
—C(═O)-alkyl,
—C(═O)—O-alkyl,
—C(═O)-aryl,
—C(═O)-heteroaryl,
—CH(OR
7
)-alkyl,
—C(═W)-alkyl,
—C(═W)-aryl, and
—C(═W)-heteroaryl;
alkyl is (C
1
-C
18
)alkyl;
aryl is as previously defined;
heteroaryl is
Q
3
is —O—, —S—, —NH—, —CH═N—;
W is CH
2
or CH
8
or N—R
9
;
R
7
is hydrogen, alkyl, or alkanoyl;
R
8
is lower alkyl;
R
9
is hydroxy, alkoxy, or —NHR
10
; and
R
10
is hydrogen, alkyl,
Bordeau Kenneth J.
Chiang Yulin
Glamkowski Edward J.
Helsley Grover C.
Nemoto Peter A.
Aventis Pharmaceuticals Inc.
Coleman Brenda
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Shah Mukund J.
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