Monomeric and dimeric heterocycles, and therapeutic uses...

Details Monomeric and dimeric heterocycles, and therapeutic uses... Monomeric and dimeric heterocycles, and therapeutic uses...

1999-10-07

2002-08-27

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S326000, C514S332000, C546S186000, C546S187000, C546S189000, C546S191000, C546S209000, C546S228000, C548S131000, C549S425000, C549S426000

Reexamination Certificate

active

06440996

ABSTRACT:

BACKGROUND OF THE INVENTION
Cocaine abuse is one of the greatest concerns of the American public today, and has therefore become a focus of medical, social and political leaders. Cocaine is one of the most addictive substances known, and addicts may lose their ability to function at work or in interpersonal situations. Drug dependence and the great profits that are made throughout the distribution network of cocaine have fueled a rise in drug-associated crime in the United States and in Colombia. Although the incidence of casual cocaine use has decreased substantially in the last few years, the number of weekly users is rising. The rise has accompanied a change in the chemical form often used to free base, or “crack,” and the route of administration used from nasal to inhalation by smoking or intravenous injection.
Psychological and behavioral approaches are important in a treatment program because peer pressure and environmental cues are closely associated with a relapse to addiction. However, behavioral observations have identified a window of about ten weeks after cessation of cocaine use where the susceptibility to relapse is greatest. Clearly, there is a need to increase the success rate of outpatient detoxification programs through the development of pharmacological agents that will assist during this critical period.
Currently a number of treatment strategies are being looked at using CNS agents developed for other indications. The agents being tried include, among others, the indirect dopamine agonist, amantadine, the direct agonist bromocriptine, the partial mu opiate receptor agonist, buprenorphine, and the tricyclic antidepressant, desipramine. While these agents appear to depress either self-administration or cocaine “craving” under certain circumstances, these studies are still in their early stages and the efficacy of such treatments has not been established.
The behavioral properties of cocaine, including its abilities to act as a reinforcer, are thought to stem from its ability to inhibit the reuptake of dopamine (DA). While cocaine also has the ability to act as an inhibitor of serotonin and norepinephrine uptake as well as to bind to sigma opiate and muscarinic receptors, the potencies of cocaine and analogs in self-administration studies correlate best with their DA transporter inhibitor activities. Unfortunately, the precise mechanism by which cocaine inhibits dopamine uptake is still uncertain. Several laboratories have shown that cocaine inhibition of dopamine uptake into striatal synaptosomes is consistent with a classic, fully competitive mechanism. However these data are also consistent with more complex models, including allosteric or partially competitive, and several others involving steric hindrance, distinct but overlapping sites or multiple binding sites in which at least one is required for both cocaine and dopamine binding. In addition, a recent study using rotating disk electrode voltammetry, which is capable of monitoring uptake with a 50 msec resolution, suggests that cocaine inhibits dopamine uptake uncompetitively while competitively blocking Na
+
and Cl
−
binding to the carrier. While these data have not been validated using other experimental approaches, they further support the idea that the cocaine and dopamine binding sites are unique.
N-Ethyhmaleimide (NE) is capable of inhibiting about 95% of the specific binding of [
3
H]mazindol, and the effect of 10 mM N-ethyhmaleimide is completely prevented by 10 &mgr;M cocaine, while neither 300 &mgr;M dopamine nor d-amphetamine afforded any significant protection. Furthermore, a recent study of the structure of the dopamine transporter revealed that aspartate and serine residues lying within the first and seventh hydrophobic putative membrane spanning regions were critical for dopamine uptake, but less so for [
3
H]CFT (WIN-35428) binding. For example, replacement of the serine residues at positions 356 and 359 in the seventh hydrophobic region by alanine or glycine reduced [
3
H]DA uptake, whereas [
3
H]CFT (WIN-35428) binding was less affected. More recent experiments with DA and NE transporter chimeras show that transmembrane domains 6-8 determine cocaine binding while domains 9-12 plus the carboxy tail are responsible for DA binding affinity. Thus, these data support the hypothesis that a significant portion of the cocaine binding domain on the dopamine transporter is distinct from that of either dopamine or amphetamine. This distinction may be sufficient to allow properly designed drugs to prevent cocaine binding without inhibiting dopamine uptake.
The most promising agents for treating cocaine abuse, may be agents which possess the ability to mimic partially the effects of cocaine, thereby helping to maintain individuals in treatment programs while they slowly withdraw from cocaine. Such an agent would function like methadone, a drug widely used in the treatment of opiate abuse. A compound with methadone-type activity against cocaine abuse is likely to be a partial agonist of cocaine; namely, a substance that elicits some of the same effects in the user as cocaine itself, but without causing the same degree of euphoria. Ideally, the compound should have little or no abuse liability.
Thus there is currently a need for safe and effective therapeutic agents for treating cocaine abuse.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula (I):
X—L—X
1
  (I)
wherein X and X
1
are each independently a compound of formula II
wherein:
Y is NR
6
, —C(R
4
)(R
5
)—, or —O—;
R
1
is —C(═O)OR
a
, cyano, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, or 1,2,4-oxadiazol-5-yl optionally substituted at the 3-position by W, wherein any (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
2
-C
6
)alkenyl, or (C
2
-C
6
)alkynyl may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C
1
-C
6
)alkoxy, (C
2
-C
6
)acyloxy, trifluoromethyl, C(═O)OR
b
, C(═O)NR
c
R
d
, NR
e
R
f
, and S(═O)
n
R
g
; and R
3
is (C
6
-C
10
)aryl, 5-10 membered heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, 5-10 membered heteroaryl(C
1
-C
6
)alkyl, (C
6
-C
10
)arylcarbonyl, biphenyl, or 5-10 membered heteroarylcarbonyl, wherein any aryl, biphenyl, or heteroaryl substituent may optionally be substituted on carbon with 1, 2 or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, (C
1
-C
6
)alkoxy, (C
2
-C
6
)acyloxy, trifluoromethyl, C(═O)OR
b
, C(═O)NR
c
R
d
, NR
e
R
f
, and S(═O)
n
R
g
; or
R
1
is —CH
2
—, or —CH
2
CH
2
—, wherein R
1
is attached to a carbon at the ortho position of R
3
; and R
3
is (C
6
-C
10
)aryl, or 5-10 membered heteroaryl;
R
2
is hydrogen or (C
1
-C
6
)alkyl;
R
4
and R
5
are independently hydrogen or (C
1
-C
6
)alkyl;
R
6
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, (C
2
-C
6
)alkenyl, (C
2
-C
6
)alkynyl, trifluoromethyl, aryl, heteroaryl, aryl(C
1
-C
4
)alkyl, heteroaryl(C
1
-C
4
)alkyl, aryl(C
1
-C
4
)alkanoyl, or heteroaryl(C
1
-C
4
)alkanoyl; wherein any (C
2
-C
6
)alkyl, (C
2
-C
6
)alkanoyl, (C
2
-C
6
)alkenyl, or (C
2
-C
6
)alkynyl may optionally be substituted on a carbon other than the carbon attached to the piperidine nitrogen with 1, 2 or 3 substituents independently selected from the group consisting of nitro, cyano, hydroxy, (C
1
-C
6
)alkoxy, (C
2
-C
6
)acyloxy, trifluoromethyl, C(═O)OR
b
, C(═O)NR
c
R
d
, and S(═O)
n
R
g
;
each n is independently 0, 1 or 2;
W is (C
1
-C
6
)alkyl, or aryl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, (C
1
-C
6
)alkoxy, (C
2
-C
6
)acyloxy, trifluoromethyl, C(═O)OR
b
, C(═O)NR
c
R
d
, NR
e
R
f
, and S(═O)
n
R
g
;
R
a
is hydrogen, (C
1
-C
4
)alkyl, aryl, heteroaryl, aryl(C
1
-C
4
)alkyl, or heteroaryl(C
1
-C
4
)

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