Epibatidine and derivatives thereof as nicotine cholinergic...

Details Epibatidine and derivatives thereof as nicotine cholinergic... Epibatidine and derivatives thereof as nicotine cholinergic...

1995-06-07

2001-01-23

MacMillan, Keith D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S304000, C514S339000, C514S413000, C514S397000, C514S253030, C514S256000

Reexamination Certificate

active

06177451

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed to methods of treatment utilizing harmaceutical compositions comprising epibatidine and/or synthetic derivatives thereof, wherein the utility of the composition is based upon the fact that the active ingredients have been found to be nicotine receptor agonists. Epibatidine has the following structure:
Epibatidine was first isolated by Daly et al. from skins of the Ecuadoran poison frog,
Epipedobates tricolor
(Daly, et al.,
J. Am. Chem. Soc.,
102: 830 (1980)). Its structure was determined by mass spectroscopy, infra red spectroscopy, and nuclear magnetic resonance as exo-2(6-chloro-3-pyridyl)-7-azabicyclo [2.2.1] heptane (1) (Spande, et al.,
J. Am. Chem. Soc.,
114: 3475 (1992)). This alkaloid has been shown to be a potent analgesic with a nonopioid mechanism of action. The analgesic effect of epibatidine was approximately 200-times higher than morphine using hot plate assay, and approximately 500-fold that of morphine in eliciting the Straub-tail response. The epibatidine-induced analgesia was not blocked by the opioid receptor antagonist naloxone. Furthermore, it has been determined that epibatidine had a negligible affinity for opioid receptor ({fraction (1/8000)} times that of morphine). See, Spande, et al.,
J. Am. Chem. Soc.,
114: 3475 (1992). The mechanism of epibatidine-induced analgesia is unknown.
The present inventors have discovered that epibatidine and synthetic analogs thereof (see, Fei and Shen,
Tet. Let.,
34: 4477 (1993); Fletcher, et al.,
J. Chem. Soc. Chem. Comm., p.
1216 (1993) and Broka,
Tet. Let.,
34
:
3251
(1993)), possess another unique and unexpected utility, one which presents the ability to treat or ameliorate disease states or conditions, not commonly associated with analgesia. Thus, the present invention is directed to methods of treatment based upon the use of epibatidine and its analogs as nicotine receptor agonists.
The present invention demonstrates that epibatidine is the third natural alkaloid nicotinic receptor agonist. The other two natural alkaloids are nicotine, first isolated from leaves of tobacco in 1828, and lobeline, first isolated from
Lobelia inflata
(India tobacco) in 1915. See, Taylor, in
Goodman and Gilman's The Pharmacological Basis of Therapeutics,
18th Ed., Gilman et al., eds., Pergamon Press, pp. 166-186 (1990).
Nicotine is a central nervous system (CNS) and ganglionic nicotinic receptor agonist and has been found to exert a potent analgesia on thermal stimuli as measured by the hot-plate or tail-flick test in both rats and mice (Tripathi, et al.,
J. Pharmacol. Exp. Therap,
221: 91 (1982); Sahley et al.,
Psychopharmacology,
65: 279 (1979); Cooley, et al.,
Pharmacol. Biochem. Behav.,
36: 413 (1990); Christensen, et al.,
J. Neural. Transm. GenSec.,
80: 189 (1990)).
SUMMARY OF THE INVENTION
One object of the present invention is to provide pharmaceutical compositions comprising as the active ingredient, epibatidine and/or derivatives thereof, useful as nicotinic agonists. Another object of the present invention is to provide pharmaceutical compositions and new methods of treatment which replace nicotine in the treatment of certain disease states or conditions, including movement disorders such as Parkinson's disease, Tourette's syndrome, and the like, Alzheimer's disease, ulcerative colitis and aphthous ulcer, and in other medical uses, e.g., smoking cessation and body weight loss.
As such, the present invention provides pharmaceutical compositions useful as a nicotine agonist, said compositions comprising an effective nicotine agonist amount of a 7-azabicyclo[2.2.1]-heptane or heptene compound having formula (2):
wherein:
R
1
and R
4
are independently selected from the group consisting of 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
NHCH
3
and —CH
2
N(CH
3
)
2
; oxyalkyl, including —OCH
3
; carboalkoxy, including carbomethoxy; allyl; aryl; heteroaryl such as pyridine or substitutes of pyridine, thioalkyl, including —SCH
3
, and Q (defined below);
each R
3
, R
5
and R
6
may be independently selected from the group consisting of 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
NHCH
3
and —CH
2
N(CH
3
)
2
; oxyalkyl, including —OCH
3
; thioalkyl, including —SCH
3
; halo, including —Cl; —CF
3
; —NH
2
; alkylamino or dialkylamino, including —N(CH
3
)
2
and —NHCH
3
—CO
2
H; —CO
2
-alkyl, including —CO
2
CH
3
; —C(O)-alkyl, including —C(O)CH
3
; —CH; —C(O)NH
2
; —C(O)NH(alkyl); —C(O)N(alkyl)
2
, including —C(O)N(CH
3
)
2
; allyl; and —SO
n
(alkyl), —SO
n
(aryl), —SO
n
(heteroaryl), wherein n=0, 1, or 2;
R
5
and R
6
together can be alkylidene or haloalkylidene, including —CH
2
— and —CF
2
—;
each R
2
may be independently selected from the group consisting of hydrogen, alkyl, including —CH
3
; —CH
2
—; HC═CH
2
; alkylhydroxy, including —CH
2
—OH; alkyloxyalkyl, including —CH
2
O—(alkyl); alkylamine, including —CH
2
NH
2
; carboxylate, —CN; —Q; —C(O)Q; and -alkyl(Q);
wherein Q is selected from the group consisting of:
and wherein the Q moiety can be optionally substituted with from 1 to 3 substituent groups W;
wherein each substituent group W is selected from the group consisting of alkyl, including —CH
3
; halo, including —Cl, —Br and —F; aryl; heteroaryl; —OH; oxyalkyl, including —OCH
3
; —SH; thioalkyl, including —SCH
3
; —SO(alkyl), including —SOCH
3
; —SO
2
alkyl, including —SO
2
CH
3
; —OCH
2
CH═CH
2
; —OCH
2
(C
6
H
5
); —CF
3
; —CN; alkylenedioxy, including methylenedioxy; —CO
2
H; —CO
2
alkyl, including —CO
2
CH
3
; —OCH
2
CH
2
OH; —NO
2
; —NH
2
; —NH(alkyl), including —NHCH
3
; —N(alkyl)
2
, including —N(CH
3
)
2
; —NCH(O)alkyl, including —NHC(O)CH
3
; —SO
2
CF
3
; and —NHCH
2
aryl, including —NHCH
2
(C
6
H
5
);
R
7
is selected from the group consisting of hydrogen; alkyl, including —CH
3
; —CH
2
-(cycloalkyl), including —CH
2
-(cyclopropyl); —CH
2
CH═CH
2
; —CH
2
CH
2
(C
6
H
5
); alkylhydroxy, including —CH
2
CH
2
OH; alkylamino(alkyl)
0-2
, including —CH
2
CH
2
N(CH
3
)
2
; alkoxyalkyl; alkylthioalkyl; and aryl;
wherein the lines—represent optional double bonds in the formula;
and a pharmaceutically acceptable carrier, excipient or diluent.
As used herein, the following definitions apply:
Alkyl means a C
1
to C
30
, preferably a C
1
to C
20
, straight or branched group. Lower alkyl means a C
1
to C
12
, preferably a C
1
to C
6
group. Typical C
1
-C
6
alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl groups.
Cycloalkyl means a C
3
to C
12
, preferably a C
3
to C
8
cyclic group. Typical C
3-8
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
Typical C
2
-C
6
carboxylic acyl groups include acetyl, propanoyl, i-propanoyl, butanoyl, s-butanoyl, pentanoyl and hexanoyl groups.
Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl and fluorene groups.
Typical aryl-substituted carboxylic acid groups include the above-mentioned carboxylic acyl groups substituted by one or more aryl groups, e.g., diphenylacetoxy and fluorenecarboxy groups.
Typical alkaryl groups include the above-listed aryl groups substituted by one or more C
1
-C
6
alkyl groups.
Typical aralkyl groups include a C
1
-C
6
alkyl group substituted by one of the above-listed aryl groups, e.g., phenethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexyl groups as well as the branched chain isomers thereof.
Typical C
1
-C
6
alkoxycarbonyl groups include carbonyl substituted by methoxy, ethoxy, propanoxy, i-propanoxy, n-butanoxy, t-butanoxy, i-butanoxy, pentanoxy, and hexanoxy groups.
Typical aralkyl groups include the above-listed C
1
-C
6
alkyl groups subst

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