Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-12
2001-09-11
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S315000, C544S242000, C544S298000, C544S316000, C514S256000
Reexamination Certificate
active
06288068
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to di-N-substituted piperazines and 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer's disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-&agr;-chloroimperialine as a highly selective m2 muscarinic antagonist.
The present invention is predicated on the discovery of a class of di-N-substituted piperazines and 1,4-di-substituted piperidines, some of which have m2 selectivity even higher than that of 3-&agr;-chloroimperialine. Logemann et al (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain di-N-substituted piperazines, but these are different from the inventive compounds of the present invention. Furthermore, the compounds of Logemann et al. are not disclosed to have activity against cognitive disorders.
SUMMARY OF THE INVENTION
The present invention relates to compounds according to the structural formula I,
including all isomers and pharmaceutically acceptable salts, esters, and solvates thereof,
wherein one of Y and Z is N and the other is N, CH, or C-alkyl;
X is —O—, —S—, —SO—, —SO
2
—, —NR
6
—, —CO—, —CH
2
—, —CS—, —C(OR
5
)
2
—, —C(SR
5
)
2
—, —CONR
20
—, —C(alkyl)
2
—, —C(H)(alkyl)—, —NR
20
—SO
2
—, —NR
20
CO—,
hydrogen, acyl, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with up to two alkyl groups, cycloalkenyl, bicycloalkyl, arylalkenyl, benzyl, benzyl substituted with up to three independently selected R
3
groups, cycloalkylalkyl, polyhaloacyl, benzyloxyalkyl, hydroxyC
2
-C
20
alkyl, alkenylcarbonyl, alkylarylsulfonyl, alkoxycarbonylaminoacyl, alkylsulfonyl, or arylsulfonyl, additionally, when X is —CH
2
—, R may also be —OH; in further addition, when X is not N, R may also be hydroxymethyl, in further addition, R and X may combine to form the group Prot-(NOAA)
r
—NH—wherein r is an integer of 1 to 4, Prot is a nitrogen protecting group and when r is 1, NOAA is a naturally occuring amino acid or an enantiomer thereof, or when r is 2 to 4, each NOAA is a peptide of an independently selected naturally occuring amino acid or an enantiomer thereof;
R
1
and R
21
are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, alkynyl, cyano, aminoalkyl, alkoxycarbonyl, aminocarbonyl, hydroxyguanidino, alkoxycarbonylalkyl, phenyl alkyl, alkylcarbonlyoxyalkyl,
H, —H, (provided R
1
and R
21
are both not —H and Y is not N), formyl, —CO alkyl, —COacyl, —COaryl, and hydroxyalkyl; additionally R
1
and R
21
together may form the group
═C(halo)
2
, in further addition, R
1
and R
21
together with the carbon atom to which they are attached may form the group
or R
1
and R
21
together with the carbon atom to which they are attached may form a saturated heterocyclic ring containing 3 to 7 carbon atoms and one group selected from S, O, and NH;
R
2
is H, alkyl, alkenyl, cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R
3
groups, cycloalkenyl, hydroxyC
2
-C
20
alkyl, alkynyl, alkylamide, cycloalkylalkyl, hydroxyarylalkyl, bicycloalkyl, alkynyl, acylaminoalkyl, arylalkyl, hydroxyalkoxyalkyl, azabicyclo, alkylcarbonyl. alkoxyalkyl, aminocarbonylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylamino(alkyl)alkyl; alkylcarbonyloxyalkyl, arylhydroxyalkyl, alkylcarbonylamino(alkyl)alkyl, dialkylamino,
(wherein q is an integer of 0 to 2)
(wherein R
29
is H, alkyl, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl, arylsulfonyl),
(wherein Q is O, NOH, or NO-alkyl), or when Z is —CH—, R
2
may also be alkoxycarbonyl, hydroxymethyl, —N(R
8
)
2
;
R
3
, R
4
, R
22
, R
24
, and R
25
are independently selected from the group consisting of H, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, haloalkyl, polyhaloalkyl, nitro, cyano, sulfonyl, hydroxy, amino, alkylamino, formyl, alkylthio, polyhaloalkoxy, acyloxy, trialkylsilyl, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl alkylsulfinyl; —OCONH
2
, —OCONH-alkyl, —OCON(alkyl)
2
, —NHCOO-alkyl, —NHCO-alkyl, phenyl, hydroxyalkyl, or morpholino;
each R
5
and R
6
is independently selected from the group consisting of H and alkyl, provided that when X is C(OR
5
)
2
or C(SR
5
)
2
, both R
5
groups cannot be H, and in addition, when X is C(OR
5
)
2
or C(SR
5
)
2
, the two R
5
groups in X may be joined to form —(CH
2
)
p
— wherein p is an integer of 2 to 4;
R
7
is independently selected from the group consisting of H, alkyl, arylalkyl, cycloalkyl, aryl and aryl substituted with R
3
and R
4
as defined herein;
each R
8
is independently selected from the group consisting of H, hydroxyalkyl, or alkyl or two R
8
groups may be joined to form an alkylene group;
R
9
is H, alkyl, or acyl:
R
20
is H, phenyl or alkyl; and
R
27
and R
28
are independently selected from the group consisting of H, alkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolyalkyl, and indolyalkyl, additionally R
27
and R
28
may combine to form an alkylene group.
In a preferred group of compounds Y and Z are N
In another preferred group of compounds Y is CH and Z is N
In another preferred group of compounds R is
and X is O, SO or SO
2
.
In another preferred group of compounds R
3
and R
4
are H and either R
1
is cycloalkyl, alkyl, or CN and R
21
is H or R
1
and R
21
together form ═CH
2
or ═O.
In another preferred group of compounds R is
X is O, SO or SO
2
, R
3
and R
4
are H and either R
1
is cycloalkyl, alkyl, or CN and R
21
is H or R
1
and R
21
together form ═CH
2
or ═O.
In another preferred group of compounds Y and Z are N, R
1
is cycloalkyl, alkyl or CN, R
21
is H and R
2
is cycloalkyl or
In another preferred group of compounds Y is CH, Z is N, and R
2
is cycloalkyl or
In another preferred group of compounds at least one of R
27
and R
28
is alkyl.
In another preferred group of compound one of R
27
or R
28
is methyl and the other is hydrogen.
In another preferred group of compounds R is
Another preferred group of compounds is the group represented by the formula
wherein R, X, R
1
, R
27
, and R
21
are as defined in the following table
# from
table of
compounds
R
X
R
1
R
21
R
27
169
4(CH
3
O)—C
6
H
4
SO
CN
H
H
iso
A
227(−)
2-pyrimidinyl
O
cyclohexyl
H
H
289
4(CH
3
O)—C
6
H
4
SO
CN
CH
3
H
269
2-pyrimidinyl
O
CH
3
H
CH
3
214
4(CH
3
O)—C
6
H
4
SO
2
CO
2
CH
3
H
H
232
2-pyrimidinyl
O
i-propyl
H
H
123
4(CH
3
O)—C
6
H
4
SO
CH
3
H
H
236
4(CH
3
O)—C
6
H
4
SO
H
H
296
4-(CH
3
O)—C
6
H
4
SO
CH
3
CO
2
Me
H
or having the structural formula
Another group of preferred compounds of formula I are:
(in the table that follows, when R
2
is substituted cyclohexyl, the substituent positions are numbered as follows:
compound #
600
601
602
603
604
605
606
607
R
CH
3
4-(CH
3
O)— C
6
H
4
4-(CH
3
O)— C
6
H
4
4(—CH
3
O)— C
6
H
4
R
1
CH
3
CH
3
CH
3
CH
3
COOCH
3
chex
CH
3
CN
R
2
cyclohexyl
chex
chex
chex
chex
chex
chex
chex
(chex)
R
3
H
H
2-Cl
H
H
H
H
H
R
4
H
H
H
H
H
H
H
H
R
21
CH
3
H
H
H
H
H
H
H
R
27
H
H
H
H
H
H
H
H
R
28
H
H
H
H
H
H
H
H
X
SO
SO
SO
S
SO
2
SO
Y
N
N
N
CH
N
N
N
N
Z
N
N
N
N
N
N
N
N
comp. no.
608
609
610
611
612
613
614
615
616
R
4-(CH
3
O)— C
6
H
4
4-(CH
3
O)— C
6
H
4
*see below
4-(CH
3
O)— C
6
H
4
4-(CH
3
O)— C
6
H
4
4-(CH
3
O)— C
6
H
4
4-(CH
3
O)— C
6
H
4
C
6
H
5
R
1
CN
CN
CN
CN
CH
3
CN
CN
CN
CN
R
2
chex
chex
chex
chex
chex
chex
chex
chex
chex
R
3
H
H
H
H
H
H
H
H
H
R
4
H
H
H
H
H
H
H
H
H
R
21
H
CH
3
H
CH
3
Asberom Theodros
Barnett Allen
Berger Joel G.
Browne Margaret E.
Chackalamannil Samuel
Magatti Anita W.
Qazi Sabiha
Schering Corporation
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