Aryl fused azapolycyclic compounds

Details Aryl fused azapolycyclic compounds Aryl fused azapolycyclic compounds

2002-08-13

2004-03-16

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S284000, C514S287000, C514S387000, C546S043000, C546S097000, C540S476000, C540S480000, C540S482000, C548S149000, C548S217000, C548S241000

Reexamination Certificate

active

06706702

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to aryl fused azapolycyclic compounds, as defined more specifically by formula I below. Compounds of formula I bind to neuronal nicotinic acetylcholine specific receptor sites and are useful in modulating cholinergic function. Such compounds are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, stroke, traumatic brain injury (TBD, obsessive-compulsive disorder, psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome.
The compounds of this invention may also be used in combination with an antidepressant such as, for example, a tricyclic antidepressant or a serotonin reuptake inhibiting antidepressant (SRI), in order to treat both the cognitive decline and depression associated with AD, PD, stroke, Huntington's Chorea or traumatic brain injury (TBI); in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors for the treatment, for example, of ALS, cognitive dysfunction, age related cognitive decline, AD, PD, stroke, Huntington's Chorea and TBI; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement for the treatment, for example, of ALS, cognitive dysfunction, age related cognitive decline, AD, PD stroke, Huntington's Chorea and TBI; or in combination with agents that slow or arrest AD such as cognition enhancers, amyloid aggregation inhibitors, secretase Inhibitors, tau kinase inhibitors, neuronal antiinflammatory agents and estrogen-like therapy.
Other compounds that bind to neuronal nicotinic receptor sites are referred to in U.S. patent application Ser. No. 08/963,852, which was filed on Nov. 4, 1997, and In U.S. Provisional Patent Application No. 60/070,245, which was filed on Dec. 31, 1997. Both of the foregoing applications are owned in common with the present application, and both are incorporated herein by reference in their entireties.
SUMMARY OF THE INVENTION
This invention relates to aryl fused azapolycyclic compounds of the formula
wherein Z is CH
2
, C(═O) or CF
2
;
R
1
is hydrogen, (C
1
-C
6
)alkyl, unconjugated (C
3
-C
6
)alkenyl, benzyl, XC(═O)R
13
or —CH
2
CH
2
—O—(C
1
-C
4
)alkyl;
R
2
and R
3
are selected independently, from hydrogen, (C
2
-C
6
) alkenyl, (C
2
-C
6
) alkynyl, hydroxy, nitro, amino, halo, cyano, —SO
q
(C
1
-C
6
)alkyl wherein q is zero, one or two, (C
1
-C
6
)alkylamino, [(C
1
-C
6
)alkyl]
2
amino, CO
2
R
4
, CONR
5
R
6
, SO
2
NR
7
R
8
, C(═O)R
13
, XC(═O)R
13
, aryl-(C
0
-C
3
) alkyl or aryl-(C
0
-C
3
)alkyl-O— wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C
0
-C
3
)alkyl or heteroaryl-(C
0
-C
3
)alkyl-O—, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X
2
(C
0
-C
6
)alkoxy-(C
0
-C
6
)alkyl, wherein X
2
is absent or X
2
is (C
1
-C
6
)alkylamino or [(C
1
-C
6
)alkyl]
2
amino, and wherein the (C
0
-C
6
)alkoxy-(C
0
-C
6
)alkyl moiety of said X
2
(C
0
-C
6
)alkoxy-(C
0
-C
6
)alkyl contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C
0
-C
6
)alkoxy-(C
0
-C
6
)alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C
0
-C
6
)alkoxy-(C
0
-C
6
)alkyl may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl(C
0
-C
6
)alkyl and said heteroaryl-(C
0
-C
3
)alkyl may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C
1
-C
6
) alkyl optionally substituted with from one to seven fluorine atoms, (C
1
-C
6
) alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), hydroxy, nitro, cyano, amino, (C
1
-C
6
) alkylamino and [(C
1
-C
6
) alkyl]
2
amino;
or R
2
and R
3
, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C
0
-C
6
) alkoxy-(C
0
-C
6
)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, hydroxy, amino, (C
1
-C
6
)alkylamino, [(C
1
-C
6
) alkyl]
2
amino, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as in the definition of R
2
and R
3
above;
each R
4
, R
5
, R
6
, R
7
, R
8
and R
13
is selected, independently, from hydrogen and (C
1
-C
6
) alkyl, or R
5
and R
6
, or R
7
and R
8
together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperizine, —N—(C
1
-C
6
)alkylpiperizine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and
each X is, independently, (C
1
-C
6
)alkylene;
with the proviso that: (a) at least one of R
1
, R
2
and R
3
must be the other than hydrogen, (b) when R
2
and R
3
are hydrogen, R
1
cannot be methyl or hydrogen; and (c) no fluorine atom in any of the fluoro substituted alkyl or alkoxy moieties of R
2
and R
3
can be attached to a carbon that is attached to a heteroatom;
and the pharmaceutically acceptable salts of such compounds.
Examples of heteroaryl groups that each of R
2
and R
3
can be are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrroyl and the following groups:
wherein one of R
9
and R
18
is hydrogen or (C
1
-C
6
) alkyl, and the other is a bond to the benzo ring of formula I.
Examples of compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein R
2
and R
3
, together with the benzo ring of formula I, form a bicyclic ring system selected from the following:
wherein R
10
and R
17
are selected, independently, from (C
0
-C
6
) alkoxy-(C
0
-C
6
)alkyl wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven

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