7-azabicyclo[2.2.1]-heptane and -heptene...

Details 7-azabicyclo[2.2.1]-heptane and -heptene... 7-azabicyclo[2.2.1]-heptane and -heptene...

1998-02-13

2001-07-03

Kight, John (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06255490

ABSTRACT:

This invention is in the area of 7-azabicyclo[2.2.1]heptane and -heptene derivatives and their method of manufacture and pharmaceutical use.
BACKGROUND OF THE INVENTION
Opiates, and in particular, morphine, are routinely administered for the treatment of moderate to severe pain. Agents that are less potent than morphine, such as codeine, mixed agonist-antagonist opioids, and non-opiate analgesics, including non-steroidal anti-inflammatory drugs (NSAIDS) are often used to relieve mild to moderate pain. Because of the well-known side effects of opiates, including chemical dependence and respiratory depression, there is a strong need for a non-opiate based analgesic for moderate to severe pain that would equal or exceed the potency of opiate analgesics, yet lack the serious side effects associated with the administration of opiates.
Spande, et al., reported in 1992 that a potent nonopiate analgesic had been isolated from the skins of the Ecuadoran poison frog,
Epipedobates tricolor.
Spande, et al., 1992
J. Am. Chem. Soc.,
114, 3475-3478. The structure of the compound was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance as exo-2-(2-chloro-5-pyridyl)-7-azabicyclo [2.2.1]heptane (see FIG. 1). The compound, which was named epibatidine, is the first member of the class of 7-azabicyclo[2.2.1]heptane compounds to be found in nature. Limited pharmacological evaluation of epibatidine indicated that it is approximately 500 times more potent than morphine in eliciting the Straub-tail response, and that this effect is not reversed by the opiate antagonist naloxone. In the hot plate analgesia assay, epibatidine is approximately 200 times as potent as morphine. It has also been determined that epibatidine has a negligible affinity for opiate receptors (1/8000 times that of morphine). Based on this data, it appears that epibatidine is a very potent analgesic that acts via a non-opiate mechanism.
In 1993, it was reported that epibatidine is a nicotinic cholinergic receptor agonist. Qian, C.; Li, T.; Shen, T. Y.; Libertine, G. L.; Eckman, J.; Biftu, T.; Ip, S. Epibatidine is a nicotinic analgesic.
European J. Pharmacology,
1993, 250(3):R-13-14; Fletcher, S.; Baker, R.; Chambers, M. M.; Herbert, R. H.; Hobbs, S. C.; Thomas, S. R.; Veerler, H. M.; Watt, A. P.; Ball, R. G. Total synthesis and determination of the absolute configuration of epibatidine.
J. Org. Chem.,
1994, 59(7):1771-1778; Baldio, B.; Daly, J. W.; Epibatidine. A potent analgetic and nicotinic agonist.
FASEB Journal,
1994, 8(4-5):A875.
Mol. Pharmacol.,
1994, 45:563-569; Dukat, M.; Damaj, M. I.; Glassco, W.; Dumas, D.; May, E. I.; Martin, B. R.; Glennon, R. A. Epibatidine: A very high affinity nicotine-receptor ligand.
Medicinal Chem. Res.,
1994, 4:131-139.
Cholinergic receptors play an important role in the functioning of muscles, organs and generally in the central nervous system. There are also complex interactions between cholinergic receptors and the function of receptors of other neurotransmitters such as dopamine, serotonin and catecholamines.
Acetylcholine (ACh) serves as the neurotransmitter at all autonomic ganglia, at the postganglionic parasympathetic nerve endings, and at the postganglionic sympathetic nerve endings innervating the eccrine sweat glands. Different receptors for ACh exist on the postganglionic neurons within the autonomic ganglia and at the postjunctional autonomic effector sites. Those within the autonomic ganglia and adrenal medulla are stimulated predominantly by nicotine and are known as nicotinic receptors. Those on autonomic effector cells are stimulated primarily by the alkaloid muscarine and are known as muscarinic receptors.
The nicotinic receptors of autonomic ganglia and skeletal muscle are not homogenous because they can be blocked by different antagonists. For example, d-tubocurarine effectively blocks nicotinic responses in skeletal muscle, whereas hexamethonium and mecamylamine are more effective in blocking nicotinic responses in autonomic ganglia. The nicotinic cholinergic receptors are named the N
M
and N
N
receptors, respectively.
Muscarinic receptors are divided into at least four subtypes (M-1 through M-4). An M-5 receptor has been cloned in human cells. The M-1 receptor is localized in the central nervous system and perhaps parasympathetic ganglia. The M-2 receptor is the non-neuronal muscarinic receptor on smooth muscle, cardiac muscle and glandular epithelium. Muscarinic receptors can be blocked by administration of atropine. Bethanechol is a selective agonist for the M-2 receptor and pirenzepine is a selective antagonist of the M-1 receptor.
In light of the fact that epibatidine is a strong cholinergic receptor ligand, it would be of interest to provide new 7-azabicyclo[2.2.1]-heptane and -heptene derivatives with pharmacological activity.
Therefore, it is an object of the present invention to provide new 7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic, anti-inflammatory and other pharmaceutical activities.
It is a further object of the present invention to provide compounds which are cholinergic receptor ligands.
It is still another object of the present invention to provide compounds which are agonists and antagonists of muscarinic and nicotinic receptors.
It is still another object of the present invention to provide new methods for the treatment of pain.
It is another object of the present invention to provide compositions and methods for the treatment of cognitive, neurological, and mental disorders, as well as other disorders characterized by decreased or increased cholinergic function.
SUMMARY OF THE INVENTION
7-Azabicyclo[2.2.1]-heptane and -heptene compounds are disclosed of Formula (I):
wherein:
R
1
and R
4
are independently hydrogen, alkyl, including CH
3
; alkylhydroxy, including CH
2
OH; alkyloxyalkyl, including —CH
2
OCH
3
; alkylthioalkyl, including —CH
2
SCH
3
; alkylamino, including —CH
2
NH
2
; alkylaminoalkyl or alkylaminodialkyl, including CH
2
NH(CH
3
) and CH
2
N(CH
3
)
2
; oxyalkyl, including —OCH
3
; carboalkoxy, including carbomethoxy; allyl, aryl and thioalkyl, including —SCH
3
;
R
3
, R
5
and R
6
are independently hydrogen, alkyl, including —CH
3
; alkylhydroxy, including —CH
2
OH; alkyloxyalkyl, including —CH
2
OCH
3
; alkylthioalkyl, including —CH
2
SCH
3
; alkylamino, including —CH
2
NH
2
; alkylaminoalkyl or alkylaminodialkyl, including CH
2
NH(CH
3
) and CH
2
N(CH
3
)
2
; oxyalkyl, including —OCH
3
; thioalkyl, including —SCH
3
; halo, including Cl, F; haloalkyl, including CF
3
; NH
2
, alkylamino or dialkylamino, including —N(CH
3
)
2
and —NHCH
3
; cyclic dialkylamino, including
 amidine, cyclic amidine including
 and their N-alkyl derivatives;
 —CO
2
H; CO
2
alkyl, including —CO
2
CH
3
; —C(O)alkyl, including —C(O)CH
3
; —CN, —C(O)NH
2
, —C(O)NH(alkyl), —C(O)N(alkyl)
2
, including —C(O)N(CH
3
)
2
; allyl, —SO
2
(alkyl), —SO
2
aryl, including —SO
2
(C
6
H
5
), —S(O)alkyl, —S(O)aryl, aryl, heteroaryl;
R
5
and R
6
together can be alkylidene or haloalkylidene, including —CH
2
— and —CF
2
—; epoxide (—O—); episulfide (—S—); imino (—N(alkyl)— or —N(H)—) or a fused aryl or heteroaryl ring including a fused phenyl ring;
R
2
is independently hydrogen, alkyl, including CH
3
; alkenyl including —CH
2
—HC═CH
2
; alkylhydroxy, including —CH
2
—OH; alkyloxyalkyl including —CH
2
—O—(alkyl), alkylamine, including —CH
2
NH
2
; carboxylate, C(O)Oalkyl, including CO
2
Me; C(O)Oaryl, C(O)Oheteroaryl, COOaralkyl, —CN, —NHC(O)R
12
, —CH
2
NHC(O)R
12
, Q, C(O)Q, -alkyl(Q), -alkenyl(Q), -alkynyl(Q), —O—(Q) —S—Q, —NH—Q or —N(alkyl)—Q;
R
2
and R
3
together can be —C(O)—NR
8
—C(O) or CH(OH)—N(R
8
)—C(O)— wherein R
8
can be alkyl, aryl including phenyl, or heteroaryl;
R
7
is hydrogen, alkyl, including CH
3
, or CH
2
CH
3
; alkyl substituted with one or more halogens, including CH
2
CH
2
Cl; —CH
2
—(cycloalkyl), including —CH
2
—(cyclopropyl); —CH
2
CH═CH
2
, —CH
2
CH
2
(C
6
H
5
), alkylhydroxy, including

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