Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
92/19234 2 ~ 7 PCT/US92/02808
METHOD OF TREATING/PREVENTING SUBSTANCE ABUSE USlNG l-ALKYL-5
(SUBSTITUTED OXY)-2-AMINOTETRALINS
BACKGROUNnD OF ~HEINyE~G~ON
1. Field of ~h~LventiQrJ
The present invention relat~s to am~notetralins tI) which are useful as pharmacotherapies
5 for treatment and prevention of substance abuse, both as a stand alone therapy and as an adjunct
with simultaneous psychological or alter~ative phar,macological treattnents.
2~ Des~on of the Related Art
Substance abuse, the use of chemicals for recreational mind altering purposes, represents
such a serious and well ~nown medical and social problem that it needs no documentation. This
10 is true whe~her the addiction be physical or psychological. It is also true regardless of whether the
d.-ug is ;ODâCU), a ~timuiant (cscaLne), depressant (alcohol), opiate narcodc theroin) or one of a
number of other subst~nce such as hallucinogens, synthetic opiate narcotics, anti-depressants, etc
or designer drugs thereof. Most treatment and/or prevention of substance abuse involves
~counseling~. In some cases, the treatment and/or prevention of substance abuse has been assisted
15 by chernical agents (psychopharmaceutics). For e~ample, disulfram has been used to block the
metabolism of ace~aldehyde to acetyl CoA in individuals abusing alcohol. The scientific rational
is that since the individual who is tal~ing disulfrarn will become ~siclc~ from the acetaldehyde,
he~she w01 theD quit using alcohol. Methadone has been used with opiate narcotic abusers to
"rna~ntain~ them so they w01 not need to get a ful~ and further w01 bloclc the ~high~ from the fLl~
20 if tried. The sciendfic rational here is that if the user can not get high from his/her e~pensive
(about S25) fu 2 1 times a day, the user w01 stop using the substance. With both disulfram and
me~hadone, the use is of lirLused duration to assist the individual to be ~drug free~ while they obtain
counseling and are able to live without using chemicals for recreadonal mind altering purposes.
Disulfram and methadone, while useful, have not achieved a success rate as high as desirable.
25 Further, a psychopharrnaceutic for treasrnent/prevendon is need for other substances of abuse.
Re~abOitation of drug abusers has had only minimal success. ln order to enhance the
probability for successful treatment, phannacotherapies have been introducod either as adjuncts to
psychological treatrnent programs or as sta~d-alone therapies. Such pharmacolherapies to date have
had moderate albeit not dramatic success. Por e~arnple, Nasional Insdtutes On Drug Abuse and
30 Alcoholism Research Monograph Series 50, 15 (1981) cited in Arch. Gen. Psychiatry 46, 32'
(1989) reports neuroleptic treatment blocl~s the reinforcing wphoric effects of cocaine but, because
this treatment is dysphoric. it does not reduc or even aggravales the craving for additional
cou~ne. ~owaver, ?relim~Dary stlldies reported in Arch Gen. Psychia~ry 4~, 322 (1989) with
flupenthi~ol sugges~s ~hat i~ may be possible to deveiop drugs to depress cocaine craving as well
35 as use.
International Application PCI`/US90/027~6 (International Publication W090/150.7)
,
.
'~;
WO 92/19234 ~ PCr/US92/02
discloses various arninotetralins but without a hydro~y or all~o~y group al Cs, These compounds
were disclosed as being useful for a variety of CNS disorders bu~ not the treatment or prevention
of substance abuse.
US Patent 3,751,420 discloses bicvclic aminotetralin li~;e compounds witb a double cond
S as the bond connecting the tWO rings ratn~r dnan qn .~rora~i ring ana d~es~ omr~unds na~e an
o~cygenated function at C7 not C5 as in the present invention. These compounds are useful as
analgesic muscle rela~ants and aiso as antibiotics.
J. Medicinal Chernistry 18, 362 (1975) discloses 2-amino-5-o~ygenated aminotetralins but
not baving an alkyl group at Cl. These compounds were disclcsed as bei~g dopamine receptor
10 agonist and hence possibly useful in treatment of ~ar~inson disease.
International Publication No . WO 31/03~91 disclos~ 3-o~ygenared-2-ami;~ote~ralins userui
5-hydro~ytryptamine stimulating er^r^ect and useful in stimulating male se~ual behavior as well as
treating depression and pain.
US Patents 4.800,204 and 4.93~,429 disclose use of dopamine agonists for treatment of
15 drug abuse, particularly for cocaine and tobacco, respe~tively. Tbe compounds used in the present
invention are not dopamine agonists, they are members of a class known as preferential antagonists
of dopamine presynaptic receptors.
1. Med. Chem., 30, 602 (1987), Molecular Pharmacology 30, 2S8 (1986) and Naunyn
Schrneidenberg's Archiv. Pharmacol., 331, 234 (1986) describes the uoique pharmacology of the
20 class of compounds Icnown as DA receptor aougooists with preferential action at presynaptic
receptors. The compounds of the present invention are members of this class but have never been
disclosed as being useful in treating substance abuse.
1. Pharm. Sci., 67 880 (1978) discloses ao N-cyclopropyl aoalog of the arninotetralins (I)
of toe preseot ioventioo. The disclosed compounds were taught as being useful as local anesthe~ics.
25 However, there is no dau, or teaching, that the compounds disclosed by the reference are
preferential aotagooists of dopamine presynaptic receptors as are the aminotetralins (I) of the
present invention.
J. Med. Chem., 18, 362 (1975) teacbes that properly substituted 2-arn~notetraJins are
dopaminergic agoaists. The aminotetralins (1~ of the present invention are not substituted as taught
30 by this journal. Further, this article does not teach of preferential antagonists of doparnine
presynaptic receptors, which the arninotetralins (I) are.
The pr~sent invention is the use of ce.~qin ^~inote~r 'irs (~) tO ?r'vent md .rea~ subs~nee
abuse.
SUMMARY O~ TTO.~
Disclosed is a method of caring for humaD who is or was dependent on a substance which
comprises administering to the individual an er`fective amount oi an aminote~raliD of the formula
2 ~ 7
-`'O 92/19234 PCr/US92/02808
OR5
5~.Y-R,, n)
I
Rl R2~_~
where Rl is Cl-C3 all~yl;
R2 ~ and ~2-:2 are the saïne or different and are -~ or Cl-C5 al3cyl;
R5 is -H, Cl-C3 al~yl or -C~R5 1 where ~5-1 is C~3 al!ql or ~, and pharmaceutically
acceptable anion salts thereof.
Also disclosed is a method of reducing cocaine use in an individual using cocaine which
comprises administering to the cocaine using individual an effective amount of an arninotetralin of
formula (I) where Rl, R2 1, R2 2 and R5 are as defined above and pharmaceutically acceptable
anion salts thereof.
DFlAll ED DESCRIPllON OF THE INVENTION
Theaminotetralins(+)-cis-(lS,2R)-S-metho~y-l-methyl-2-(n-propylamino)tetralinand(+)-
cis-(lS,2R)-5-metho~ty-1 -methyl-2-(di-n-propylam~no)tetralin are lcnown, see US Patent 4,8 î6,284.
It has been found that the aminotetralins (I) are usefi~l as pharmacotherapies for treatment
and prevention of substance abuse, both as a stand alone therapv and as an adjunct with
sitnultaneous psychological or alternative phannacological treatments.
The aminotetralins (I) of the present invention are useful in a nurnber of different ways in
caring for individuals involved with substance abuse or at risl~ of becornming involved. ~Caring"
as used in this patent includes both treatment of e~isting siruations as well as preventing future
substance abuse. First, caring is treating an individual who is dependent (either physically or
psychologically) on a substance. SecoDd, cariDg is preventing an individual who is recreationally
using, but not dependent upon a substance, from becomming dependent on the same or other
substances of abuse~ Third, caring is preventing an individual who wæ previously, but not now,
30 dependent from again becornsning dependent on a substance~ Fourth, caring is preventing
individuals who have no history of substance abuse but from whos life styles and activities
clinicians believe are at risl~ of using subs~sce for recreational ?ur~oses and/or becon~ning
dependent on various substances.
Treatable substaDces (drugs) of abuse include cocaine~ opia~e narcotics~ barbiruates~
35 amphetarnines, tobacco, alcohol, hallucinogens, rnarihuana. More specifically tbese agents include
cocaine, heroin, codeine~ morphine, meperidin ~ alcohol. tobacco, amphetarnine, MDA. LSD~
,
. . . .
, . . .
;
WO 92/19~3~ 9~ PCr/US92/02P'
PCP, marihuana, amphetamine and methamphesamine. The most commonJy used abused
substances for which the method of the present invention is useful are cocaine, heroin, alcohol,
cigarettes, marihuana, PCP, amphetamine and methamphetarnine.
The arninotetralins (I) are administed intravenously, intramuscularly, or orally An
effe tive amount of the aminotetralins (1) is from about 200 mg/da~ to about 20 g/day, preferrably
from about 500 mg/day to about 5 g/day.
Intramuscul~r depo~ preparations are prepared in larger quantities for long termadministration. Oral preparations in tablets, capsule, solution and suspension forrns or as powders
to be rnL~ed in food are useful with doses of about S00 mg/day to about 15 g/day total, but more
10 preferrably in the range of about 1 to about 3 g/day.
The aminote~ralins (I) are not themselves addicting (individuals do not become dependent
on them).
The aminotetralins (I) are amines, and as such fortn acid addition salts when reacted with
acids of sufficient strength. Pharmaceutically acceptable salts include salts of both inorganic and
15 organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free
arninotetralins (I) since they produce compounds which are more water soluble and rnore
crystalline. The preferred pharmaceutically acceptable salts include salts of the following acids
methanesulfonic, hydrocbloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric,
fumaric, maleic, CH3{CH2)n{~OOH where D is O thru 4, HOOC-(CH2)n~00H where n is as
20 defined a~ove.
The e~cact dosage and frequency of adm~nistration depends on the particular aminotetralin
O used, ~he particular condition being treated, the severity of the condition being treated, the age,
weight, general physical condition of the particular patient, other medication the individual may
be taking as is well lcnown to those sl~illed in the art and can be more accurately determined by
25 measuring the blood level or concentration of the arn~notetralin (1) in the patient's blood and/or the
patient's response to the particular condition being treated.
DEFINITIONS AND CONVENTIONS
The defi~itions and e~planations below are for the terms as used throughout tbis entire
document including both the specificatiion and the claims.
1. ÇQ~ ~ DEFIN~ONS OF VARIABLES
The chemical formulas representing various compounds or molecular fragmeDts in the
specification ~nd claims may contain variable substituents in additioD to e:~pressly defined struc ur31
features. r.~se ~/ariable subs;ituents are identiried by a letter or a letter followed by a numerical
subscript? for e:~arnple~ ~Zl~ or ~ where ~i~ is an integer. When chernical forrnulas are drawn
in a linear fashion~ such as those above, variable substituents contained in parentheses arc bonded
to the a~om irnmediately to the left of the Yariable substituent enclosed in parentheses. When two
vo 92/1923~ 2 1 ~ 1 9 7 PCl/US92/02808
or re consecutive variable substituents are enclosed in parentheses, each of the consecutive
variable substituents is bonded to the immediately preceding atom to the left which is not enclosed
in parentheses. Thus, in the formula above, both Ri and Rj are bonded to the preceding carbon
atom.
S For these amino~e~ralins with an established system of carbon atom numbering, the car~on
atoms are designated as Cj, where ~i" is the integer correspoDdiDg to the carbon atom number.
For example, C6 represents the 6 position or carbon atom number in the molecule as traditionally
designated by those skilled in the arn Likewise the term ~R6~ represents a variable substiment
(either monoYalent or bivalent) at the C6 position.
A ;igid cyclic (ring~ structure for any compounds herein defines an orientation with respect
to the plane OI the ring for substituents attached to each carbon atom of the rigid cyclic compound.
For saturated compounds which have two substituents attached to a carbon atom which is part of
a cyclic system, -C(XI)tX2)- the two substituents may be in either an axial or equatorial position
relative to the ring and may change benveen axial/equatorial. However, the position of the two
substituents relative to the ring and each other remains fixed. While either substituent at times may
lie in the plane of the ring (eguatorial) rather than above or below the plane (axial), one substituent
is always above the other. ln chemical structural formulas depicting such compounds, a substituent
(Xl) which is "below" another substituent (X2) will be identified as being in the alpha ()
configuration and is identified by a brol~en, dashed or dotted line attachment to the carbon a~om,
20 i.e., by the symbol "- - -" or ~". The corresponding substituen~ attached "above" (X~) the other
(X1) is identified as being in the beta (B) configuration and is indica~ed by an unbroken line attach-
men~ to the carbon atom.
The carbon atom con~ent of variable substituents is indicated in one of two ways. The first
method uses a prefi~ to the entire name of the variable such as ~Cl-C4~, where both ~1" and "4"
are integers representing the minimum and maximum number of carbon atoms in the variable. The
prefix is separated from the variable by a space. For example, "Cl-C4 allcyl" represents all~yl of
1 through 4 carbon atoms, (including isomeric forTns thereof unl~ss an express indication to the
contrary is given). Whenwer this single prefi~ is given, the prefix indicates the entire carbon atom
content of the variable being defined~ Thus C2-C4 alko~ycarbonyl describes a group CH3-(CH2)~,-
~CO- where n is zero, one or two. By the second method the carbon atom con~en~ of only each
portion of the definition is indicated separately by anclosing the ~Cj-Cj~ designation in parentheses
and placing it immediately tno intervening space) before ~he portion of the definition being
dafined~ By ~his optional conven~ion (Cl-C3)alkoxyc~rbonyl has the same meaning as C2~4
alkoxyc~rbonyl because the ~CI-C3~ refers only to the carbon atom content of the all~oxy group.
35 Similarly while both C2-C6 alkoxyalkyl and (C1~3)alkoxy(Cl-C3)alkyl define alkoxyallcyl groups
contai~ng from 2 to 6 carbon a~oms, the two der;ni~ions differ since the former def~nition allows
' " '' ' ' ' , " .' '
'- , - . , " ~.
WO 92/19234 ;~ 1 Pcr/us92/o28
either the allco~y or allcyl portion alone to contain 4 or 5 carbon atorns while ~he latter definition
limits either of these groups to 3 carbon atoms.
Il. DE.-I~mONS
Caring refers to (I) treating an individual who is presentlv dependent on a substance, (~)
S preventing an individual who is using a subs~ænce rrom beco~ ., de?enden~ sn ~.at subs~nce,
(3) treating an individual wbo was previosly dependeot on a substaDce from becornrning dependent
on a substance again and (4) pre~ entin~ an ir.diYidual who h~s ~eYer has been inYolYed in substance
use, but who is at ris~, from becoming dependent on a substance.
Use refers to the situation where an ir;dividual u3e3 a subst~nce, is not dependent in any
way on the substance and controls hisAler own actions whether or not ~hs use causes any physical
or psychological harm or injury to the individual. F~ampies include an indiYidual who soci~ly
takes a drinlc of wine once a month, an individual who smol~es marihuana once a month or an
individual who has a couple of beers. All ~hese individuals are usirg a substance for recreational
purposes. are not dependent on that substance and can StOp, its use, if so desired.
Abuse refers to the situation where an individual is de?endent on a substance either
physically or psychologically and and can not discontinue its use whether or not the use causes any
physical or psychological harm or injury to the individual. E~amples include, ~heroin addicts^,
smo~ers of tobacco who ~can not quit~ and alcoholics. All these individuals are using a substance
for recreational purposes, are dependeot on that substance and can not stop its use.
Physical dependence refers to the condition where the individual who has been using a
substance e~hibits withdrawl symptoms wheD they do not have the drug. The withdrawl symptoms
may be different for different substances. Tnis situation was !cnown as "addic~ion^.
Psychological dependence refers to the condition where the individual who has been UsiDg
a substance wants and/or seelts the substance but does not have any other directly observable
withdrawl symptoms.
Reducing as used in this patent means either or both of using fewer tirnes jD a given period
of time and/or UsiDg less of an amount of a substance (cocaine) at each use with the over all result
of a decrease in the amount of substance used per unit time. Ibis may include DO use at all but
is not limited to that situation.
Alcohol refers to ethyl alcohol.
Tobacco refers to cig~rettes, pipe tobacco~ cigars, chewing tobacco.
LSD refers to Iysergic acid die~llylamid~
MDA refers to 3,1 methyienedio~yampn~am~ne.
PCP refers to phencyclidine.
Cracl~ is a pbysical form of cocaine.
Pharmaceutically acceptable refers to tnose proper~ies ~nd/or substances which are
2~r!6 L.'~7
~"0 92/19234 PCr/US92/0280#
acceptàble to the patient from a pharmacological/toxicological point of view and to the
manu&cturing pharmaceutical chemist from a physicaJ/chemical point of view regarding
composition. formulation, stability, patient acceptance and bioavailability
Marihuana refers. and included. any sDecies and any form of Cannabts whether the vegetable materia~ or extract ~ereor con~ainir., ~e pnarTnacoio ,iu~h, active cannabinols.
EXA ~fPL~
Without further elabora~ion, it is belie~-ed ~hat one skilled in the art can, using the
preceding description, practice the present invention to its fullest e~tent. The following detailed
e~tamples describe how to prepare the various cor.~.nounds andlor perfor;u the various proc~sses of
10 the inveDtion and are to be construed as merely illustrative. and not limitations of the preceding
disclosure in any way whatsoeYer. rnose s~ille~ in ~he art will promptly re ognlze appropriate
variations from the procedures both as to reactants and as to reaction conditions and techniques.
EXAMPLE 1 (+)-cis-(lS,2~)-5-~Iethoxy-l-methyl-'-~n-propylam~no)terralin
See US Patent 4,876,2~4, E~ample I3.
15 EXAMPLE 2 (+)-cis-(lS,2R)-5-Metho~y-l-methly-''-(di-n-propylam~no)tetralin
See US Patent 4,876,284, E~a nple I3.
EXAMPLE 3
A 60 I~g, 32 year old female just admitted to a hospital for prolonged cocaine abuse is put
on a chronic intravenous infusion of 30 mg/hr of (+~cis-(lS,2R)-5-metho~y-1-me~yl-2-(n-
20 propylamino)tetralin 24 - 48 hours after which she is given 1 gm intramuscular injections 4 times
a day for 30 days~ She is then switched to 3 gm oral of the same item, 4 times/day for the ne~t
3 to 24 months or uDtil she was sufficiently recovered to no longer require treatmeDt.
EXA~LE 4
A 70 Icg, 19 year old male who has been addicted to i.v. heroin, after uDdergoiDg a
25 standard deto~ification prototocol, is given an intramuscular depo~ injection of (+)-cis-(lS,2R)-5-
metho~y-l-methly-2-(di-n-propylarnino)tetralin which is supplemented by an oral daily 2 gm dose.
EXAMPLE S
A 17 year old 58 I~g male who has been s~ipping school, has been arres~ed for shoplifting
and who has a very poor relationship with is parents is the concen of his parents and school
30 counselors. Others of his friends are into alcohol and marihuana.
Upon consultation of the school courselor, paren~s~ and social wor~er it is decided that he has very
high lil~elyhood of becomlng involYed with sub~;ar.ci u se!3buse. It is d~^ided to put a I gm dose
of an amiDotetralin (I) iD his brealcfast before s.,nool and anolher 1 gm in a snac~ arter school.
: . . .- . .
.. , . , , ~ .
, " '
