Quinuclidine-substituted hetero-bicyclic aromatic compounds...

Details Quinuclidine-substituted hetero-bicyclic aromatic compounds... Quinuclidine-substituted hetero-bicyclic aromatic compounds...

2002-06-06

2004-12-07

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S133000, C546S115000, C546S114000, C546S113000, C514S303000, C514S302000, C514S301000, C514S300000, C514S299000

Reexamination Certificate

active

06828330

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional application Ser. No. 60/297,629 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,630 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,631 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,632 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/297,633 filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional application Ser. No. 60/328,548 filed on Oct. 11, 2001, under 35 USC 119(e)(i); and U.S. provisional application Ser. No. 60/373,496 filed on 18 Apr. 2002, under 35 USC 119(e)(i), which are incorporated herein by reference in their entirety.
FIELD OF INVENTION
Nicotinic acetylcholine receptors (nAChRs) play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety. The present invention relates to molecules that have a greater effect upon the &agr;7 nAChRs as compared to other closely related members of this large ligand-gated receptor family. Thus, the invention provides compounds that are active drug molecules with fewer side effects.
BACKGROUND OF THE INVENTION
Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The &agr;7 nAChR is one receptor system that has proved to be a difficult target for testing. Native &agr;7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar,
Nature
, 366(6454), p. 360-4, 1997). Another feature that makes functional assays of &agr;7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the &agr;7 nAChR (Eisele et al.,
Nature
, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT
3
receptor expressed well in
Xenopus oocytes
while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the &agr;7 nAChR receptor and the C-terminus of the mouse form of the 5-HT
3
gene. However, under physiological conditions the &agr;7 nAChR is a calcium channel while the 5-HT
3
R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken &agr;7 nAChR/mouse 5-HT
3
R behaves quite differently than the native &agr;7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT
3
R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the &agr;7 nAChR and the 5-HT
3
R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the &agr;7 nAChR.
SUMMARY OF THE INVENTION
The present invention discloses compounds of the Formula I:
wherein W
0
is a bicyclic moiety and is
X is O, or S;
R
1
is H, alkyl, cycloalkyl, halogenated alkyl, substituted phenyl, or substituted naphthyl;
R
2
is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;
R
3
is H, F, alkyl, halogenated alkyl, substituted alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy, R
7
, R
9
, —N(R
4
)-aryl, —N(R
4
)-substituted phenyl, —N(R
4
)-substituted naphthyl, —O-substituted phenyl, —O-substituted naphthyl, —S-substituted phenyl, —S-substituted naphthyl, or alkyl substituted on the &ohgr; carbon with R
15
where said &ohgr; carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the bicyclic moiety W
0
and the &ohgr; carbon being the carbon furthest, e.g., separated by the greatest number of carbon atoms in the chain, from said C-1 carbon;
W is C(H) where
V—Z—Y is selected from O—C(R
3
)═N, O—C(R
5
)(R
3
)—N(R
4
), O—C(R
5
)(R
3
)—S, O—N═C(R
5
), O—C(R
3
)(R
8
)—O, O—C(R
3
)(R
5
)—O, S—C(R
3
)═N, S—C(R
5
)(R
3
)—N(R
4
), S—N═C(R
5
), N═C(R
3
)—O, N═C(R
3
)—S, N═C(R
3
)—N(R
4
), N(R
4
)—N═C(R
5
), N(R
4
)—C(R
5
)(R
3
)—O, N(R
4
)—C(R
5
)(R
3
)—S, N(R
4
)—C(R
5
)(R
3
)—N(R
4
), C(R
4
)
2
—O—N(R
4
), C(R
5
)
2
—N(R
4
)—O, C(R
5
)
2
—N(R
4
)—S, C(R
5
)═N—O, C(R
5
)═N—S, C(R
5
)═N—N(R
4
), C(R
5
)
2
—O—C(R
5
)
2
, C(R
5
)
2
—S—C(R
5
)
2
, C(R
5
)
2
—N(R
4
)—C(R
5
)
2
, C(R
5
)(R
17
)—C(R
3
)(R
17
)—C(R
5
)(R
17
), or C(R
5
)
2
—C(R
3
)(R
5
)—C(R
5
)—C(R
5
)
2
;
Q is N(R
19
), O, or S;
W is N where
V—Z—Y is selected from O—C(R
3
)═N, O—C(R
5
)(R
3
)—N(R
4
), O—C(R
5
)(R
3
)—S, O—N═C(R
5
) O—C(R
3
)(R
5
)—O, S—C(R
3
)═N, S—C(R
5
)(R
3
)—N(R
4
), S—N═C(R
5
), N═C(R
3
)—O, N═C(R
3
)—S, N═C(R
3
)—N(R
4
), N(R
4
)—N═C(R
5
), N(R
4
)—C(R
5
)(R
3
)—O, N(R
4
)—C(R
5
)(R
3
)—S, N(R
4
)—C(R
5
)(R
3
)—N(R
4
), C(R
5
)
2
—O—N(R
4
), C(R
5
)
2
—N(R
4
)—O C(R
5
)
2
—N(R
4
)—S, C(R
5
)═N—O, C(R
5
)═N—S, C(R
5
)═N—N(R
4
), C(R
5
)═C(R
3
)—C(R
5
)
2
, or C(R
5
)
2
—C(R
3
)(R
5
)—C(R
5
)
2
;
W
1
, W
2
, W
3
, W
4
are each independently N or C(R
21
), provided that no more than two of W
1
, W
2
, W
3
, W
4
are N, and further provided when more than two of W
1
, W
2
, W
3
, W
4
are C(R
21
) that no more than two R
21
are other than H;
J is N(R
23
), S, or O;
R
4
is H, or alkyl;
R
5
is H, F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, —CN, —NO
2
, —OR
1
, —C(O)N(R
16
)
2
, —NHR
1
, —NR
1
COR
16
, —N(R
10
)
2
, —SR
1
, —C(O)R
16
, —CO
2
R
1
, aryl, R
7
, or R
9
;
R
6
is H, F, Cl, Br, I, —CN, —CF
3
, —OR
16
, —SR
16
, or —N(R
16
)
2
;
R
7
is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of —O—, ═N—, —N(R
19
)—, and —S—, and having 0-1 substituent selected from R
20
and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R
7
is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring and having the formula
wherein E is O, S, or NR
19
,
wherein E and G are independently selected from CR
18
, O, S, N, or NR
19
, and A is CR
18
or N, or
wherein E and G are independently selected from CR
18
, O, S, N, or NR
19
, and A is CR
18
or N, each 9-membered fused-ring moiety having 0-1 substituent selected from R
20
and further having 0-3 substituent(s) independently selected from F, Cl, Br, or I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety;
Each R
8
is independently F, Br, Cl, I, alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,

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