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WO1992019234A2 - Methode de traitement/prevention de l'usage de drogue - Google Patents

Methode de traitement/prevention de l'usage de drogue Download PDF

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Publication number
WO1992019234A2
WO1992019234A2 PCT/US1992/002808 US9202808W WO9219234A2 WO 1992019234 A2 WO1992019234 A2 WO 1992019234A2 US 9202808 W US9202808 W US 9202808W WO 9219234 A2 WO9219234 A2 WO 9219234A2
Authority
WO
WIPO (PCT)
Prior art keywords
caring
substance
alkyl
individual
dependent
Prior art date
Application number
PCT/US1992/002808
Other languages
English (en)
Other versions
WO1992019234A3 (fr
Inventor
Montford F. Piercey
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Priority to JP4511382A priority Critical patent/JPH06506951A/ja
Publication of WO1992019234A2 publication Critical patent/WO1992019234A2/fr
Publication of WO1992019234A3 publication Critical patent/WO1992019234A3/fr

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Classifications

    • 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

Definitions

  • the present invention relates to aminotetralins (I) which are useful as pharmacotherapies for treatment and prevention of substance abuse, both as a stand alone therapy and as an adjunct with simultaneous psychological or alternative pharmacological treatments.
  • Substance abuse the use of chemicals for recreational mind altering purposes, represents such a serious and well known medical and social problem that it needs no documentation. This is true whether the addiction be physical or psychological. It is also true regardless of whether the drug is tobacco, a stimulant (cocaine), depressant (alcohol), opiate narcotic (heroin) or one of a number of other substance such as hallucinogens, synthetic opiate narcotics, anti-depressants, etc or designer drugs thereof. Most treatment and/or prevention of substance abuse involves
  • Disulfram and methadone while useful, have not achieved a success rate as high as desirable. Further, a psychopharmaceutic for treatment/prevention is need for other substances of abuse.
  • US Patent 3,751,420 discloses bicyclic aminotetralin like compounds with a double bond as the bond connecting the two rings rather than an aromatic ring and these compounds have an oxygenated function at C 7 not C 5 as in the present invention. These compounds are useful as analgesic muscle relaxants and also as antibiotics.
  • J. Medicinal Chemistry 18, 362 (1975) discloses 2-amino-5-oxygenated aminotetralins but not having an alkyl group at C 1 . These compounds were disclosed as being dopamine receptor agonist and hence possibly useful in treatment of Parkinson disease.
  • 5-hydroxytryptamine stimulating effect and useful in stimulating male sexual behavior as well as treating depression and pain.
  • US Patents 4,800,204 and 4,935,429 disclose use of dopamine agonists for treatment of drug abuse, particularly for cocaine and tobacco, respectively.
  • the compounds used in the present invention are not dopamine agonists, they are members of a class known as preferential antagonists of dopamine presynaptic receptors.
  • Schmeidenberg's Archiv. Pharmacol., 331, 234 (1986) describes the unique pharmacology of the class of compounds known as DA receptor antagonists 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.
  • J. Pharm. Sci., 67 880 (1978) discloses an N-cyclopropyl analog of the aminotetralins (I) of the present invention.
  • the disclosed compounds were taught as being useful as local anesthetics.
  • the compounds disclosed by the reference are preferential antagonists of dopamine presynaptic receptors as are the aminotetralins (I) of the present invention.
  • the present invention is the use of certain aminotetralins (I) to prevent and treat substance abuse.
  • R 2-1 and R 2-2 are me same or different and are -H or C 1 -C 5 alkyl;
  • R 5 is -H, C 1 -C 3 alkyl or -CO-R 5-1 where R 5-1 is C j 1C 3 alkyl 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 aminotetralin of formula (I) where R 1 , R 2-1 , R 2-2 and R 5 are as defined above and pharmaceutically acceptable anion salts thereof.
  • aminotetralins (+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin and(+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin are known, see US Patent 4,876,284.
  • aminotetralins (I) are useful as pharmacotherapies for treatment and prevention of substance abuse, both as a stand alone therapy and as an adjunct with simultaneous psychological or alternative pharmacological treatments.
  • the aminotetralins (I) of the present invention are useful in a number of different ways in caring for individuals involved with substance abuse or at risk of becomming involved.
  • Caring as used in this patent includes both treatment of existing situations as well as preventing future substance abuse.
  • caring is treating an individual who is dependent (either physically or psychologically) on a substance.
  • caring 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.
  • caring is preventing an individual who was previously, but not now, dependent from again becomming dependent on a substance.
  • caring is preventing individuals who have no history of substance abuse but from whos life styles and activities clinicians believe are at risk of using substance for recreational purposes and/or becomming dependent on various substances.
  • Treatable substances (drugs) of abuse include cocaine, opiate narcotics, barbituates, amphetamines, tobacco, alcohol, hallucinogens, marihuana. More specifically these agents include cocaine, heroin, codeine, morphine, meperidine, alcohol, tobacco, amphetamine, MDA, LSD, PCP, marihuana, amphetamine and methamphetamine.
  • the most commonly used abused substances for which the method of the present invention is useful are cocaine, heroin, alcohol, cigarettes, marihuana, PCP, amphetamine and methamphetamine.
  • the aminotetralins (I) are administed intravenously, intramuscularly, or orally.
  • An effective amount of the aminotetralins (I) is from about 200 mg/day to about 20 g/day, preferrably from about 500 mg/day to about 5 g/day.
  • Intramuscular depot preparations are prepared in larger quantities for long term administration.
  • Oral preparations in tablets, capsule, solution and suspension forms or as powders to be mixed in food are useful with doses of about 500 mg/day to about 15 g/day total, but more preferrably in the range of about 1 to about 3 g/day.
  • aminotetralins (I) are not themselves addicting (individuals do not become dependent on them).
  • the aminotetralins (I) are amines, and as such form acid addition salts when reacted with acids of sufficient strength.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The pharmaceutically acceptable salts are preferred over the corresponding free aminotetralins (I) since they produce compounds which are more water soluble and more crystalline.
  • the preferred pharmaceutically acceptable salts include salts of the following acids methanesulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, maleic, CH 3 -(CH 2 ) n -COOH where n is 0 thru 4, HOOC-(CH 2 )n-COOH where n is as defined above.
  • variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Z 1 " or "R i " where "i” is an integer.
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent 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.
  • both R i and R j are bonded to the preceding carbon atom.
  • C i For these aminotetralins with an established system of carbon atom numbering, the carbon atoms are designated as C i , where "i" is the integer corresponding to the carbon atom number.
  • C 6 represents the 6 position or carbon atom number in the molecule as traditionally designated by those skilled in the art.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
  • a rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound.
  • -C(X 1 )(X 2 )- me two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.
  • 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 (equatorial) rather than above or below the plane (axial), one substituent is always above the other.
  • a substituent (X 1 ) which is "below” another substituent (X 2 ) will be identified as being in the alpha (a) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol “ ⁇ " or "!.
  • the corresponding substituent attached “above” (X 2 ) the other (X 1 ) is identified as being in the beta ( ⁇ ) configuration and is indicated by an unbroken line attachment to the carbon atom.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as "C 1 -C 4 ", 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.
  • C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -O-CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is indicated separately by enclosing the "C i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • C 1 -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • Caring refers to (1) treating an individual who is presently dependent on a substance, (2) preventing an individual who is using a substance from becomming dependent on that substance,
  • Use refers to the situation where an individual uses a substance, is not dependent in any way on the substance and controls his/her own actions whether or not the use causes any physical or psychological harm or injury to the individual. Examples include an individual who socially takes a drink of wine once a month, an individual who smokes marihuana once a month or an individual who has a couple of beers. All these individuals are using 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 dependent 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. Examples include, "heroin addicts”, smokers of tobacco who "can not quit” and alcoholics. All these individuals are using a substance for recreational purposes, are dependent on that substance and can not stop its use.
  • Psychological dependence refers to the condition where the individual who has been using a substance wants and/or seeks 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 times in a given period of time and/or using 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. This may include no use at all but is not limited to that situation.
  • Alcohol refers to ethyl alcohol.
  • Tobacco refers to cigarettes, pipe tobacco, cigars, chewing tobacco.
  • LSD refers to lysergic acid diethylamide.
  • MDA refers to 3,4-methylenedioxyamphetamine.
  • PCP refers to phencyclidine
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • Marihuana refers, and included, any species and any form of Cannabis whether the vegetable material or extract thereof containing the pharmacologically active cannabinols.
  • a 60 kg, 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-(1S,2R)-5-methoxy-1-methyl-2-(n-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 next 3 to 24 months or until she was sufficiently recovered to no longer require treatment.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Addiction (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Méthode destinée à soigner l'être humain qui est ou était dépendant d'une drogue. Elle consiste à administrer à l'individu une quantité effective d'une aminotétraline de la formule (I). Soigner, c'est 1) traiter un individu qui est dépendant (soit physiquement, soit psychologiquement) d'une drogue; 2) empêcher un individu qui prend une drogue pour se distraire, mais n'en est pas dépendant, de devenir dépendant de la même drogue ou d'autres drogues; 3) empêcher un individu qui était par le passé, mais ne l'est plus, dépendant d'une drogue, de le redevenir; 4) prévenir la dépendance de la drogue d'individus qui n'ont jamais consommé de la drogue, mais dont les modes de vie et activités laissent croire aux médecins qu'ils risquent de prendre une drogue à des fins de distraction et/ou de devenir dépendants de différentes drogues.
PCT/US1992/002808 1991-04-26 1992-04-13 Methode de traitement/prevention de l'usage de drogue WO1992019234A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4511382A JPH06506951A (ja) 1991-04-26 1992-04-13 物質乱用の治療／予防方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69323891A 1991-04-26 1991-04-26
US693,238 1991-04-26

Publications (2)

Publication Number Publication Date
WO1992019234A2 true WO1992019234A2 (fr) 1992-11-12
WO1992019234A3 WO1992019234A3 (fr) 1993-01-07

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Application Number Title Priority Date Filing Date
PCT/US1992/002808 WO1992019234A2 (fr) 1991-04-26 1992-04-13 Methode de traitement/prevention de l'usage de drogue

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EP (1) EP0581865A1 (fr)
JP (1) JPH06506951A (fr)
AU (1) AU1915192A (fr)
CA (1) CA2106197A1 (fr)
WO (1) WO1992019234A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395558A (zh) * 2009-02-16 2012-03-28 雅培股份有限两合公司 氨基四氢萘衍生物、含有所述氨基四氢萘衍生物的药物组合物及其在治疗中的用途
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane 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
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
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine 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
US8957089B2 (en) 2008-04-01 2015-02-17 AbbVie Deutschland GmbH & Co. KG Tetrahydroisoquinolines, 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
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine 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
US9586945B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane 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

Family Cites Families (4)

* Cited by examiner, † Cited by third party
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

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8957089B2 (en) 2008-04-01 2015-02-17 AbbVie Deutschland GmbH & Co. KG Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
CN102395558A (zh) * 2009-02-16 2012-03-28 雅培股份有限两合公司 氨基四氢萘衍生物、含有所述氨基四氢萘衍生物的药物组合物及其在治疗中的用途
CN102395558B (zh) * 2009-02-16 2015-09-02 Abbvie公司 氨基四氢萘衍生物、含有所述氨基四氢萘衍生物的药物组合物及其在治疗中的用途
US9096619B2 (en) 2009-02-16 2015-08-04 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9067871B2 (en) 2009-02-16 2015-06-30 AbbVie Deutschland GmbH & Co. KG Aminotetraline 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
US9238619B2 (en) 2010-08-13 2016-01-19 AbbVie Deutschland GmbH & Co. KG Phenalkylamine 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
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9227930B2 (en) 2010-08-13 2016-01-05 Abbvie Inc. Aminoindane 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
US9586945B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy

Also Published As

Publication number Publication date
AU1915192A (en) 1992-12-21
EP0581865A1 (fr) 1994-02-09
WO1992019234A3 (fr) 1993-01-07
CA2106197A1 (fr) 1992-10-27
JPH06506951A (ja) 1994-08-04

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