Tropane derivatives and method for their synthesis

Details Tropane derivatives and method for their synthesis Tropane derivatives and method for their synthesis

1999-09-14

2002-02-26

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...

C546S124000, C546S127000, C546S132000

Reexamination Certificate

active

06350758

ABSTRACT:

BACKGROUND OF THE INVENTION
(R)-Cocaine or (−)-cocaine is a plant alkaloid purified from the leaves of
Erythroxylon coca
and has been a subject of scientific investigation since the late 1800s. It is one of the eight possible stereoisomeric forms of methyl 3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1]octane-2 carboxylate. Cocaine has many physiological effects. It is a local anesthetic, and this property is responsible for its early legitimate use in medicine. However, many newer compounds have been developed that are superior to cocaine for this purpose. Cocaine is also a powerful vasoconstrictant and, as such, has some current use in medicine during nasal or throat surgery where control of bleeding is desired. Cocaine also has very potent effects on the sympathetic nervous system, and it is well known to increase heart rate and blood pressure.
In both animals and humans, cocaine is one of the most reinforcing drugs known, which has given rise to a serious cocaine abuse epidemic in the United States over the last 10-15 years (see e.g., Musto,
Sci. Amer.,
256, 40 (1991)). From the point of view of drug abuse, the most relevant effects of the drug include its ability to produce euphoria and its reinforcing effect. In addition to being a powerful reinforcer, cocaine also has properties common to other drugs subject to abuse. For example, tolerance occurs to some of its effects, and its psychological withdrawal syndrome takes place over a long time period, which includes periods of craving during which relapse to drug use often occur (see, Gawin et al.,
Arch. Gen. Psychiatry,
43, 107 (1986)).
Over the past 10 years, there have been significant advances in understanding the mechanism of action of cocaine. The development of drug self-administration as a useful animal model for reinforcing properties has led to exploration of many of the physiological, neurochemical, neuroanatomical, and pharmacological correlates (Griffiths, in
Advances in Substance Abuse
, Vol., 1, N. K. Mello, ed., UAI Press Inc., Greenwich Conn. (1980) at pages 1-90)).
Several studies have shown that cocaine binds to the dopamine transporter and inhibits dopamine transport (Kubar et al.,
NIDA Research Monograph
(1988) at pages 14-22). In addition, drugs that are potent in maintaining self-administration, such as nomifensine, methylphendiate and mazindol, are also potent inhibitors of binding at the transport site for dopamine, whereas compounds that are weak in self-administration studies are correspondingly weak inhibitors of the binding site. For example, Ritz et al. (
Science,
237 1249 (1987)) showed that the relative ability of several compounds to displace [
3
H]mazindol binding to the dopamine transporter from rat striatum was correlated to drug self-administration studies in nonhuman primates. Similarly, Berman et al. (
J. Pharmacol. Exp. Ther.,
251, 150 (1989)) found a good correlation between displacement of [
3
H]-cocaine binding to the transporter and drug self-administration behavior in squirrel monkeys. The most potent compounds in binding and behavioral studies reported from both investigations were 3&bgr;-phenyltropane-2&bgr;-carboxylic acid methyl ester and 3&bgr;-(p-fluorophenyl)tropane-2&bgr;-carboxylic acid methyl ester (Clark et al.,
J. Med. Chem.,
16, 1260 (1973)).
Only a limited number of cocaine analogs have been available to study the structural requirements for binding to the dopamine transporter and for cocaine-like reinforcing properties. For example, Carroll et al. (
J. Med. Chem.,
34, 2719 (1991);
Eur. J. Pharm.,
184, 329 (1990)) synthesized and measured the binding affinity of a number of new 3&bgr;-(p-substituted phenyl)tropane-2&bgr;-carboxylic acid methyl esters and measured their ability to inhibit the binding of 0.5 nM [
3
H]-3&bgr;-(p-fluorophenyl)tropane-2&bgr;-carboxylic acid methyl ester to the dopamine transport site of rat striata. The iodo- and chloro-substituted derivatives were found to have a potency of approximately 80 times that of (−)-cocaine in this in vitro assay. Carroll et al. (
J. Med. Chem.,
35, 969 (1992)) proposed that specific hydrogen bond donor groups are present within the cocaine recognition site which bind to the 2-carbomethoxy group.
However, despite some success, a need exists for novel analogs of cocaine. Such compounds may exhibit enhanced analgesic and/or vasoconstrictive properties, or potentially be more selective than (−)-cocaine; or such analogs may inhibit the uptake of dopamine or serotonin and, therefore, be useful for treating a disease or condition such as Parkinson's disease, depression, or obesity. Such compounds may also be useful for treating cocaine abuse. A need also exists for additional methods to synthesize cocaine analogs.
Additionally, a need exists for cocaine analogs which can be employed to further characterize the cocaine binding site(s), and to assist in the development of additional specific cocaine binding site agonists and antagonists.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula (I):
wherein
R
1
is hydrogen, aryl, aryl(C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl, OR
7
, or N(R
8
)
2
;
R
2
is aryl or aryl(C
1
-C
4
)alkyl;
R
3
is hydrogen, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl or (C
2
-C
4
)alkynyl;
R
4
and R
5
are independently hydrogen, halo, CN, OR
9
, COOR
10
, arylSO
2
—, or —CH
2
NHR
11
;
R
6
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkenyl, (C
1
-C
4
)alkynyl, aryl, or aryl(C
1
-C
4
)alkyl;
R
7
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
5
)alkanoyl, arylcarbonyl or aryl (C
1
-C
5
)alkanoyl;
each R
8
is independently hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkanoyl, aryl, aryl(C
1
-C
4
)alkyl, or arylcarbonyl;
R
9
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
5
)alkanoyl, or arylcarbonyl;
R
10
is hydrogen or (C
1
-C
4
)alkyl; and
R
11
is hydrogen or (C
1
-C
4
)alkyl;
wherein any aryl in R
1
, R
2
, and R
6
-R
9
may optionally be substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo (preferably I or Cl), CF
3
, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkenyl, (C
1
-C
4
)alkynyl, amino, nitro cyano, and aryl;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of synthesizing a compound of formula (III):
wherein
R
2
is aryl or aryl(C
1
-C
4
)alkyl;
R
4
and R
5
are independently hydrogen, halo, CN, OR
9
, COOR
10
, —CH
2
NHR
11
, or a chiral auxiliary;
R
6
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkenyl, (C
1
-C
4
)alkynyl, aryl, or aryl(C
1
-C
4
)alkyl;
R
9
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
5
)alkanoyl, or arylcarbonyl;
R
10
is hydrogen or (C
1
-C
4
)alkyl;
R
11
is hydrogen or (C
1
-C
4
)alkyl; and
R
12
and R
13
are each hydrogen; or one of R
12
and R
13
is hydrogen, and the other is a chiral auxiliary (such as for example a (+)-(R)-p-tolylsulfinyl, or a (−)-(S)-p-tolylsulfinyl substituent).
wherein any aryl in R
2
, R
6
and R
9
may optionally be substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo (preferably I or Cl), CF
3
, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl, (C
2
-C
4
)alkynyl, amino, nitro cyano, or aryl;
comprising reacting a compound of formula (IV):
with a compound of formula R
4
CH
2
═CHR
5
. Preferably, the reaction is conducted with heating in a suitable organic solvent, i.e., under reflux conditions.
The method of the invention may further comprise reacting the compound of formula (III) with R
3
—MgBr, where R
3
is (C
1
-C
4
)alkyl, (C
2
-C
4
)alkenyl or (C
2
-C
4
)alkynyl; a source of Cu(I), and a hydroxy protecting reagent such as ((C
1
-C
4
)alkyl)
3
SiCl followed by removal of the protecting group, to yield a compound of formula (V):
According to the invention, the method further comprises reducing the keto group in the compound of formula (V) to yield a compound of formula (VI):
and reacting the compound of formula (VI) with an anhydride of the formula CH
3
C(O)O—R
7
, where R
7
is (C
1
-C
5
)alkanoy

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