Ibogamine congeners

Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

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C514S183000

Reexamination Certificate

active

06211360

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to ibogamine congeners and to methods for treating addictive behavior.
BACKGROUND OF THE INVENTION
Throughout this application various publications are referenced, many in parenthesis. Full citations for these publications are provided at the end of the Detailed Description. The disclosures of these publications in their entireties are hereby incorporated by reference in this application.
Ibogaine is one of several alkaloids found in the root bark of the African shrub
Tabernanthe iboga.
It has a ring skeleton common with ibogamine and has been identified as a potential interrupter of addictive behavior.
Male members of the Mitsogho people in Gabon ingest scrapings of the iboga root as part of the initiation rite into the Bwiti, a secret society of men. The rite of passage, which continues for several days, begins with a period of violent vomiting, followed by periods of drowsiness, motor incoordination, agitation, tremor, progression through a dream state, and, finally, sleep. The rite is thought to constitute an encounter with higher spiritual entities.
People who have taken purified ibogaine as an experimental drug report a similar sequence of events lasting three days, including visions, periods of high energy accompanied by flashes of light, and, eventually, sleep. Upon waking, many drug addicts reportedly lose their craving for addictive drugs over extended periods of time.
U.S. Pat. Nos. 4,499,096, 4,587,243, and 5,152,994, all to Lotsof, report that ibogaine is effective in treating opiate (heroin), stimulant (cocaine and amphetamine), nicotine, caffeine, and alcohol addictions. The treatment supposedly interrupts the physiological and psychological aspects of addiction and eliminates the desire to use drugs. In both opiate and stimulant syndromes, a single oral treatment with ibogaine or its salts, in dosages of 6 to 19 mg/kg, is said to be effective for about 6 months, and a series of four treatments is said to eliminate addictive behavior for approximately 3 years. Using an animal model of drug addiction, several studies have sought to determine whether these claims can be substantiated under controlled conditions. In one preliminary study [1], ibogaine dose-dependently decreased morphine self-administration in the hour after ibogaine treatment (acute effect) and to a lesser but significant extent, a day later (aftereffect). In some rats there was a persistent decrease in morphine intake for several days or weeks after a single injection of ibogaine, whereas other rats began to show such persistent changes after two to three weekly injections, and a few rats appeared to be entirely resistant to prolonged aftereffects. Similar effects of ibogaine on cocaine self-administration in rats were recently reported by Cappendijk and Dzoljic [2].
In humans, as in rats, ibogaine's efficacy as an anti-addictive therapy appears to vary substantially from one individual to another even the most ardent supporters of ibogaine's usefulness would probably concede that at least 30% of treated addicts do not decrease their drug intake.
Ibogaine also exhibits several side effects that limit its therapeutic utility. For example, the compound exhibits undesirable stimulant and hallucinogenic properties. In addition, ibogaine induces tremors. Very similar tremors are induced by harmaline, another natural alkaloid that is chemically related to ibogaine but derived from a different plant (
Peganum harmala
). Both ibogaine- and harmaline-induced tremors appear to be due to activation of an olivo-cerebellar pathway [3-5], and, in rats, high doses of both agents have recently been shown to damage the cerebellar vermis, presumably as a result of overstimulation of cerebellar Purkinje cells [5,6]. In addition ibogaine has an acute effect on motivated behavior during the first hour immediately following administration, as indicated by severely reduced bar pressing for water.
In view of the serious health effects and negative societal effects associated with addictive behavior, and the side effects of ibogaine treatment, the need continues for compounds which reduce addiction to addictive substances. The present invention is directed to overcoming this deficiency in the art.
SUMMARY OF THE INVENTION
The present invention relates to a compound having the formula:
wherein
n is from 0 to 8;
R
1
is CH
2
OH, CH(OH)R
5
, CH
2
OR
5
, CO
2
R
5
, C(O)NH
2
, C(O)NHR
5
, C(O)NR
5
R
6
, C(O)NHNH
2
, C(O)NHNHR
5
, C(O)NHNR
5
R
6
, C(O)NR
5
NH
2
, C(O)NR
5
NHR
6
, C(O)NR
5
NR
6
R
7
, C(O)NHNH(C(O)R
5
). C(O)NHNR
5
(C(O)R
6
), C(O)NR
5
NH(C(O)R
6
), C(O)NR
5
NR
6
(C(O)R
7
), CN, or C(O)R
5
;
R
2
is H, unsubstituted or substituted alkyl, YH, YR
8
, YC(O)R
8
, C(O)YR
8
, C(O)NH
2
, C(O)NHR
8
, C(O)NR
8
R
9
, NH
2
, NHR
8
, NR
8
R
9
, NHC(O)R
8
, or NR
8
C(O)R
9
;
R
3
and R
4
are the same or different and are selected from the group consisting of H, halogens, unsubstituted or substituted alkyl, OH, OR
10
, NH
2
, NHR
10
, NR
10
R
11
, NHC(O)R
10
, or NR
10
C(O)R
11
;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, and R
11
are the same or different and are selected from the group consisting of unsubstituted alkyl and substituted alkyl;
R
12
is selected from the group consisting of H, unsubstituted alkyl, and substituted alkyl; and
Y is O or S;
provided that when n is 0, R
2
is selected from the group consisting of H, substituted alkyl other than CH(OH)CH
3
, and unsubstituted alkyl;
further provided that when n is 2, R
2
is OH, R
12
is H, and both R
3
and R
4
are H, R
1
is not CO
2
CH
3
; and
further provided that when n is 2, R
2
is H, R
12
is H, and R
3
and R
4
are the same or different and are selected from the group consisting of H and OCH
3
, R
1
is not CO
2
CH
3
;
or pharmaceutically acceptable salts thereof.
The present invention also provides a method of treating a subject addicted to an addictive substance. The method includes administering to the addicted subject an effective amount of a compound having the above formula, a compound having the above formula where n is 0 and R
2
is CH(OH)CH
3
, a compound having the above formula where n is 2, R
2
is OH, R
12
is H, R
3
and R
4
are each H, and R
1
is CO
2
CH
3
, or a compound having the above formula where n is 2. R
2
is OH, R
12
is H, R
3
and R
4
are the same or different and are selected from the group consisting of H and OCH
3
, and R
1
is CO
2
CH
3
.
The compounds of the present invention reduce both morphine and cocaine self administration in the addicted subject but do not affect other motivated behavior, such as bar pressing to obtain water. In addition, these compounds produce very little if any tremor, and no noticeable Purkinje cell degeneration.


REFERENCES:
patent: 3681362 (1972-08-01), Nagata et al.
patent: 4499096 (1985-02-01), Lotsof
patent: 4587243 (1986-05-01), Lotsof
patent: 4769453 (1988-09-01), Potier et al.
patent: 5152994 (1992-10-01), Lotsof
Azoug et al, Phytochemistry, vol. 39, No. 5, pp. 1223 to 1228, Jul. 1995.*
Glick et al, Brain Research, vol. 657, pp. 14 to 22, Sep. 1994.*
Deecher et al, Brain Research, vol. 571, pp. 242 to 247, Dec. 1992.*
Singbartl et al., “Structure-Activity Relationships of Intracerebrally Injected Tremorigenic Indole Alkaloids,”Neuropharmacology, 12:239-244 (1973).
Kan et al., “Détermination de Structures par RMN du H á 400 MHz: Albifloranine, un Nouvel Alcaloïde de Tabernaemontana Albiflora,”Journal of Medicinal Plant Research, 41:72-74 (1981).
Glick et al., “Effects and Aftereffects of Ibogaine on Morphine Self-Administration in Rats,”European Journal of Pharmacology, 195:341-345 (1991).
Bornmann et al., “A Common Intermediate Providing Syntheses of &PSgr;-Tabersonine, Coronaridine, Iboxyphylline, Ibophyllidine, Vinamidin, and Vinblastine,”J. Org. Chem., 57:1752-1760 (1992).
Kuehne et al., “Formation of D-Nor Aspidosperma Alkaloids by Condensation of Nb-Benzylindoloazepine with Aldehydes,”J. Org. Chem., 58:4147-4148 (1993).
O'Hearn et al., “Ibogaine Neurotoxicity Raises New Questi

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