CA2106197A1 - Method of treating/preventing substance abuse - Google Patents
Method of treating/preventing substance abuseInfo
- Publication number
- CA2106197A1 CA2106197A1 CA002106197A CA2106197A CA2106197A1 CA 2106197 A1 CA2106197 A1 CA 2106197A1 CA 002106197 A CA002106197 A CA 002106197A CA 2106197 A CA2106197 A CA 2106197A CA 2106197 A1 CA2106197 A1 CA 2106197A1
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- dependent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Addiction (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Disclosed is a method of caring for human who is or was dependent on a substance which comprises administering to the individual an effective amount of an aminotetralin of formula (I) where caring is (1) treating an individual who is dependent (either physically or psychologically) on a substance, (2) preventing an individual who is recreationally using, but not dependent upon a substance, from becoming dependent on the same or other substances of abuse, (3) preventing an individual who was previously, but not now, dependent from again becoming dependent on a substance, (4) preventing individuals who have no history of substance abuse but from whose life styles and activities clinicians believe are at risk of using substance for recreational purposes and/or becoming dependent on various substances.
Description
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.
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 ***e 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 ***e 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 ***e 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 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 ***e use in an individual using ***e which comprises administering to the ***e 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 ***e~ opia~e narcotics~ barbiruates~
35 amphetarnines, tobacco, alcohol, hallucinogens, rnarihuana. More specifically tbese agents include ***e, 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 ***e, 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,
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 ***e 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 ***e 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 ***e 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 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 ***e use in an individual using ***e which comprises administering to the ***e 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 ***e~ opia~e narcotics~ barbiruates~
35 amphetarnines, tobacco, alcohol, hallucinogens, rnarihuana. More specifically tbese agents include ***e, 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 ***e, 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 (***e) 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 ***e.
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.
A 60 I~g, 32 year old female just admitted to a hospital for prolonged ***e 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.
: . . .- . .
.. , . , , ~ .
, " '
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 (***e) 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 ***e.
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.
A 60 I~g, 32 year old female just admitted to a hospital for prolonged ***e 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.
: . . .- . .
.. , . , , ~ .
, " '
Claims (24)
1. A method of caring for human who is or was dependent on a substance which comprises administering to the individual an effective amount of an aminotetralin of the formula (I) where R1 is C1-C3 alkyl;
R2-1 and R2-2 are the same or different and are -H or C1-C5 alkyl;
R5 is -H, C1-C3 alkyl or -CO-R5-1 where R5-1 is C1-C3 alkyl or -?, and pharmaceutically acceptable anion salts thereof.
R2-1 and R2-2 are the same or different and are -H or C1-C5 alkyl;
R5 is -H, C1-C3 alkyl or -CO-R5-1 where R5-1 is C1-C3 alkyl or -?, and pharmaceutically acceptable anion salts thereof.
2. A method of caring according to claim 1 where the caring is treating an individual who is presently dependent on a substance.
3. A method of caring according to claim 1 where the caring is preventing an individual who is using a substance from becoming dependent on that substance.
4. A method of caring according to claim 1 where the caring is treating an individual who was previosly dependent on a substance from becomming dependent on a substance again.
5. A method of caring according to claim 1 where the caring is preventing an individual who has never has been involved in substance use, but who is at risk, from becoming dependent on a substance.
6. A method of caring according to claim 1 where the dependence is physical dependence.
7. A method of caring according to claim 1 where the dependence is psychological.
8. A method of caring, according to claim 1 where the substance is selected from the group consisting of ***e, opiate narcotics, barbituates. amphetamines. tobacco, alcohol, hallucinogens, marihuana.
WO 92/19234 PCT/US92/028?
WO 92/19234 PCT/US92/028?
9. A method of caring according to claim 8 where the substance is selected from the group consisting of ***e, heroin, codeine, morphine, meperidine, alcohol, tobacco, amphetamine, MDA, LSD, PCP, marihuana, amphetamine and methamphetamine
10. A method of caring according m claim 9 where the substance is selected from the group consisting of ***e, heroin, alcohol, cigarettes, marihuana, PCP, amphetamine and methamphetamine.
11. A method of caring according to claim 1 where the effective amount is from about 200 mg/day to about 20 g/day.
12. A method of caring according to claim 11 where the effective amount is from about 500 mg/day to about 5 g/day.
13. A method of caring according to claim 1 where R1 is C1 or C2 alkyl.
14. A method of caring according to claim 13 where R1 is C1 alkyl.
15. A method of caring according to claim 1 where R2-1 is -H or C2-C4 alkyl.
16. A method of caring according to claim 15 where R2-1 is -H or n-C3 alkyl.
17. A method of caring according to claim 1 where R2-2 is C2-C4 alkyl.
18. A method of caring according to claim 17 where R2-2 is n-C3 alkyl.
19. A method of caring according to claim 1 where R5 is C1-C3 alkyl.
20. A method of caring according to claim 19 where R5 is C1 alkyl.
21. A method of treatment according to claim 1 where the compound of formula (I) is selected from the group consisting of (+)-cis-(lS,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin, (+)-cis-(lS,2R)-5-methoxy-1-methly-2-(di-n-propylamino)tetralin.
22. A method of reducing ***e use in an individual using ***e which comprises WO 92/19234 PCT/US92/02??
administering to the ***e using individual an effective amount of an aminotetralin of the formula (I) where R1 is C1-C3 alkyl;
R2-1 and R2-2 are the same or different and are -H or C1-C5 alkyl;
R5 is -H, C1-C3 alkyl or -CO-R5-1 where R5-1 is C1-C3 alkyl or -?, and pharmaceutically acceptable anion salts thereof.
administering to the ***e using individual an effective amount of an aminotetralin of the formula (I) where R1 is C1-C3 alkyl;
R2-1 and R2-2 are the same or different and are -H or C1-C5 alkyl;
R5 is -H, C1-C3 alkyl or -CO-R5-1 where R5-1 is C1-C3 alkyl or -?, and pharmaceutically acceptable anion salts thereof.
23. A method of reducing ***e use according to claim 22 where the effective amount is from about 200 mg/day to about 20 g/day.
24. A method of reducing ***e use according to claim 22 where the compound of formula (I) is selected from the group consisting of (+)-cis-(lS,2R)-methoxy-l-methyl-2-(n-propylamino)tetralin, (+)-cis-(lS,2R)-5-methoxy-1-methly-2-(di-n-propylamino)tetralin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69323891A | 1991-04-26 | 1991-04-26 | |
| US693,238 | 1991-04-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2106197A1 true CA2106197A1 (en) | 1992-10-27 |
Family
ID=24783880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002106197A Abandoned CA2106197A1 (en) | 1991-04-26 | 1992-04-13 | Method of treating/preventing substance abuse |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0581865A1 (en) |
| JP (1) | JPH06506951A (en) |
| AU (1) | AU1915192A (en) |
| CA (1) | CA2106197A1 (en) |
| WO (1) | WO1992019234A2 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5554319B2 (en) | 2008-04-01 | 2014-07-23 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Tetrahydroisoquinolines, pharmaceutical compositions containing them and their use in therapy |
| AR075442A1 (en) * | 2009-02-16 | 2011-03-30 | Abbott Gmbh & Co Kg | AMINOTETRALINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USES IN THERAPY |
| US8846743B2 (en) | 2010-08-13 | 2014-09-30 | Abbott Laboratories | Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US8883839B2 (en) | 2010-08-13 | 2014-11-11 | Abbott Laboratories | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9045459B2 (en) | 2010-08-13 | 2015-06-02 | AbbVie Deutschland GmbH & Co. KG | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9051280B2 (en) | 2010-08-13 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US8877794B2 (en) | 2010-08-13 | 2014-11-04 | Abbott Laboratories | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9309200B2 (en) | 2011-05-12 | 2016-04-12 | AbbVie Deutschland GmbH & Co. KG | Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US8853196B2 (en) | 2011-08-05 | 2014-10-07 | AbbVie Deutschland GmbH & Co. KG | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US8846741B2 (en) | 2011-11-18 | 2014-09-30 | Abbvie Inc. | N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9365512B2 (en) | 2012-02-13 | 2016-06-14 | AbbVie Deutschland GmbH & Co. KG | Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9650334B2 (en) | 2013-03-15 | 2017-05-16 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| US9656955B2 (en) | 2013-03-15 | 2017-05-23 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
| KR20160062165A (en) | 2013-10-17 | 2016-06-01 | 아비에 도이치란트 게엠베하 운트 콤파니 카게 | Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
| WO2015055770A1 (en) | 2013-10-17 | 2015-04-23 | AbbVie Deutschland GmbH & Co. KG | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL65501A (en) * | 1981-05-08 | 1986-04-29 | Astra Laekemedel Ab | 1-alkyl-2-aminotetralin derivatives,process for their preparation and pharmaceutical compositions containing them |
| US4935429A (en) * | 1985-10-25 | 1990-06-19 | Dackis Charles A | Method of treating psychostimulant addiction |
| US4800204A (en) * | 1987-05-07 | 1989-01-24 | Mueller Peter S | Method of controlling tobacco use |
| US4994486A (en) * | 1989-05-31 | 1991-02-19 | Abbott Laboratories | Dopaminergic compounds |
-
1992
- 1992-04-13 CA CA002106197A patent/CA2106197A1/en not_active Abandoned
- 1992-04-13 JP JP4511382A patent/JPH06506951A/en active Pending
- 1992-04-13 WO PCT/US1992/002808 patent/WO1992019234A2/en not_active Application Discontinuation
- 1992-04-13 AU AU19151/92A patent/AU1915192A/en not_active Abandoned
- 1992-04-13 EP EP92911383A patent/EP0581865A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992019234A3 (en) | 1993-01-07 |
| WO1992019234A2 (en) | 1992-11-12 |
| JPH06506951A (en) | 1994-08-04 |
| AU1915192A (en) | 1992-12-21 |
| EP0581865A1 (en) | 1994-02-09 |
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