EP0581865A1

EP0581865A1 - Method of treating/preventing substance abuse using 1-alkyl-5(substituted oxy)-2-aminotetralins

Info

Publication number: EP0581865A1
Application number: EP92911383A
Authority: EP
Inventors: Montford F. Piercey
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1991-04-26
Filing date: 1992-04-13
Publication date: 1994-02-09
Also published as: AU1915192A; CA2106197A1; WO1992019234A3; WO1992019234A2; JPH06506951A

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.Method for treating human beings who are or were addicted to drugs. It consists in administering to the individual an effective amount of an aminotetralin of formula (I). Healing is 1) treating an individual who is dependent (either physically or psychologically) on a drug; 2) prevent an individual who takes a drug for entertainment, but is not dependent on it, from becoming dependent on the same or other drugs; 3) prevent an individual who was in the past, but no longer is, dependent on a drug, from becoming again; 4) preventing drug dependence on individuals who have never used drugs but whose lifestyles and activities suggest to physicians that they are at risk of using drugs for the purpose of distraction and / or become addicted to different drugs.

Description

METHOD OF TREATING/PREVENTING SUBSTANCE ABUSE USING 1-ALKYL-5 (SUBSTITUTED OXY)-2-AMIN0TETRALINS

BACKGROUND OF THE INVENTION

1. Field of the Invention

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.

2. Description of the Related Art

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

"counseling". In some cases, the treatment and/or prevention of substance abuse has been assisted by chemical agents (psychopharmaceutics). For example, disulfram has been used to block the metabolism of acetaldehyde to acetyl CoA in individuals abusing alcohol. The scientific rational is that since the individual who is taking disulfram will become "sick" from the acetaldehyde, he/she will then quit using alcohol. Methadone has been used with opiate narcotic abusers to

" maintain" them so they will not need to get a "fix" and further will block the "high" from the fix if tried. The scientific rational here is that if the user can not get high from his/her expensive

(about $25) fix 2-4 times a day, the user will stop using the substance. With both disulfram and methadone, the use is of limited duration to assist the individual to be "drug free" while they obtain counseling and are able to live without using chemicals for recreational mind altering purposes.

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.

Rehabilitation of drug abusers has had only minimal success. In order to enhance the probability for successful treatment, pharmacotherapies have been introduced either as adjuncts to psychological treatment programs or as stand-alone therapies. Such pharmacotherapies to date have had moderate albeit not dramatic success. For example, National Institutes On Drug Abuse and Alcoholism Research Monograph Series 50, 15 (1984) cited in Arch. Gen. Psychiatry 46, 322 (1989) reports neuroleptic treatment blocks the reinforcing euphoric effects of cocaine but, because this treatment is dysphoric, it does not reduce or even aggravates the craving for additional cocaine. However, preliminary studies reported in Arch Gen. Psychiatry 46, 322 (1989) with flupenthixol suggests that it may be possible to develop drugs to depress cocaine craving as well as use.

International Application PCT/US90/02726 (International Publication WO90/15047) discloses various aminotetralins but without a hydroxy or alkoxy group at C5. These compounds were disclosed as being useful for a variety of CNS disorders but not the treatment or prevention of substance 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 C₇ not C₅ 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 C₁. These compounds were disclosed as being dopamine receptor agonist and hence possibly useful in treatment of Parkinson disease.

International Publication No. WO 81/03491 discloses 8-oxygenated-2-aminotetralins useful

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.

J. Med. Chem., 30, 602 (1987), Molecular Pharmacology 30, 258 (1986) and Naunyn

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. However, there is no data, or teaching, that the compounds disclosed by the reference are preferential antagonists of dopamine presynaptic receptors as are the aminotetralins (I) of the present invention.

J. Med. Chem., 18, 362 (1975) teaches that properly substituted 2-aminotetralins are dopaminergic agonists. The aminotetralins (I) of the present invention are not substituted as taught by this journal. Further, this article does not teach of preferential antagonists of dopamine presynaptic receptors, which the aminotetralins (I) are.

The present invention is the use of certain aminotetralins (I) to prevent and treat substance abuse.

SUMMARY OF INVENTION

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 the formula where R₁ is C₁-C₃ alkyl;

R_2-1 and R_2-2 are me same or different and are -H or C₁-C₅ alkyl;

R₅ is -H, C₁-C₃ alkyl or -CO-R_5-1 where R_5-1 is C_j1C₃ alkyl or -ɸ, 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 R₁, R_2-1, R_2-2 and R₅ are as defined above and pharmaceutically acceptable anion salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The 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.

It has been found that the 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. First, caring is treating an individual who is dependent (either physically or psychologically) on a substance. Second, 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. Third, caring is preventing an individual who was previously, but not now, dependent from again becomming 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 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.

The 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, CH₃-(CH₂)_n-COOH where n is 0 thru 4, HOOC-(CH₂)n-COOH where n is as defined above.

The exact dosage and frequency of administration depends on the particular aminotetralin

(I) used, the 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 known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the aminotetralin (I) in the patient's blood and/or the patient's response to the particular condition being treated.

DEFINITIONS AND CONVENΗONS

The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain 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, "Z₁" or "R_i" where "i" is an integer. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parentheses. When two or more 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 R_i and R_j are bonded to the preceding carbon atom.

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. For example, C₆ represents the 6 position or carbon atom number in the molecule as traditionally designated by those skilled in the art. Likewise the term "R₆" represents a variable substituent (either monovalent or bivalent) at the C₆ 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. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, -C(X₁)(X₂)- me two substituents may be in either an axial or equatorial position relative to the ring and may change between 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 (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X₁) which is "below" another substituent (X₂) 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" (X₂) the other (X₁) is identified as being in the beta (β) 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 "C₁-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, "C₁-C₄ alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C₂-C₄ alkoxycarbonyl describes a group CH₃-(CH₂)_n-O-CO- where n is zero, one or two. By the second method 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. By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaning as C₂-C₄ alkoxycarbonyl because the "C₁-C₃" refers only to the carbon atom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)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.

II. DEFINITIONS

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,

(3) treating an individual who was previosly dependent on a substance from becomming dependent on a substance again and (4) preventing an individual who has never has been involved in substance use, but who is at risk, from becoming dependent on a 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.

Physical dependence refers to the condition where the individual who has been using a substance exhibits withdrawl symptoms when they do not have the drug. The withdrawl symptoms may be different for different substances. This situation was known as "addiction".

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.

Crack is a physical form of cocaine.

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.

EXAMPLES

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. EXAMPLE 1 (+)-cis-(lS,2R)-5-Methoxy-1-methyl-2-(n-propylamino)tetralin

See US Patent 4,876,284, Example 13.

EXAMPLE 2 (+)-cis-(lS,2R)-5-Methoxy-1-methly-2-(di-n-propylamino)tetralin

See US Patent 4,876,284, Example 13.

EXAMPLE 3

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.

EXAMPLE 4

A 70 kg, 19 year old male who has been addicted to i.v. heroin, after undergoing a standard detoxification prototocol, is given an intramuscular depot injection of (+)-cis-(1S,2R)-5-methoxy-1-methly-2-(di-n-propylamino)tetralin which is supplemented by an oral daily 2 gm dose. EXAMPLE 5

A 17 year old 58 kg male who has been skipping school, has been arrested for shoplifting and who has a very poor relationship with is parents is the concen of his parents and school counselors. Others of his friends are into alcohol and marihuana.

Upon consultation of the school counselor, parents, and social worker it is decided that he has very high likelyhood of becoming involved with substance use/abuse. It is decided to put a 1 gm dose of an aminotetralin (I) in his breakfast before school and another 1 gm in a snack after school.

Claims

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

where R₁ is C₁-C₃ alkyl;

R_2-1 and R_2-2 are the same or different and are -H or C_1-C₅ alkyl;

R₅ is -H, C₁-C₃ alkyl or -CO-R_5-1 where R_5-1 is C₁-C₃ alkyl or -ɸ, 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 cocaine, opiate narcotics, barbituates, amphetamines, tobacco, alcohol, hallucinogens, marihuana.

9. A method of caring according to claim 8 where the substance is selected from the group consisting of cocaine, heroin, codeine, morphine, meperidine, alcohol, tobacco, amphetamine,

MDA, LSD, PCP, marihuana, amphetamine and methamphetamine.

10. A method of caring according to claim 9 where the substance is selected from the group consisting of cocaine, 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 R_2-1 is -H or C₂-C₄ alkyl.

16. A method of caring according to claim 15 where R_2-1 is -H or n-C₃ alkyl.

17. A method of caring according to claim 1 where R_2-2 is C₂-C₄ alkyl.

18. A method of caring according to claim 17 where R_2-2 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-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin,

(+)-cis-(1S,2R)-5-methoxy-1-methly-2-(di-n-propylamino)tetralin.

22. 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 the formula <

where R₁ is C₁-C₃ alkyl;

R_2-1 and R_2-2 are the same or different and are -H or C₁-C₅ alkyl;

23. A method of reducing cocaine 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 cocaine use according to claim 22 where the compound of formula (I) is selected from the group consisting of

(+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin,

(+ )-cis-(1S,2R)-5-methoxy-1-methly-2-(di-n-propylamino)tetralin.