JPH06506951A - Substance abuse treatment/prevention methods - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Substance abuse treatment/prevention methods Background of the invention 1. Field of invention The present invention provides independent therapy as well as concurrent psychological or other pharmacological treatment. Useful as pharmacotherapy for the treatment and prevention of substance abuse, both as an adjunct measure aminotetralin (1).

2. Description of related technology Substance abuse, the use of drugs for recreational mood-altering purposes, is evidence of serious enough (known medical and social problems) that there is no need to cite supporting documents; cause. This holds true regardless of whether the drug addiction is physical or psychological. . Also, if the drug is tobacco, a stimulant (cocaine), a sedative (alcohol), or an opiate Narcotic drugs (heroin), hallucinogens, synthetic opiate drugs, antistimulants, etc., or their designers - holds regardless of whether it is one of many other substances such as drugs . Most treatment and/or prevention of substance abuse involves “counseling” . In some cases, substance abuse treatment and/or prevention may include chemical (psychotropic) drugs. I asked for help. For example, disulfuram reduces acetate in heavy alcohol drinkers. It has been used to inhibit the metabolism of aldehyde to acetyl COA. scientifically It is reasonable that individuals who take disulfram should not get "sick" from acetaldehyde. Because of this, he/she will avoid using alcohol. Mettaton is ``maintaining'' an opiate drug user, thereby allowing the person to Eliminating the need to obtain injections and, if possible, inhibiting the “high” caused by injections do. Here, scientifically speaking, it is reasonable that the abuser is using his/her expensive ( (about $25) You can't get high from injecting drugs 2-4 times a day. This means that the abuser will be able to stop using the substance. Jisle For Flam and Mettaton, the individual should receive counseling and While it is possible to live without using drugs for mood-altering purposes, if the individual The duration of its use is limited, even though it helps people with drug withdrawal. Nsulfura While useful, Mettaton and Mettaton have not been as successful as desired. Sara For treatment/prevention, psychotropic drugs require other substances of abuse.

Rehabilitation of drug abusers has had minimal success. Enhances probability of treatment success either as an adjunct to a psychological treatment program or as monotherapy to Drug therapy has been introduced. To date, such drug treatments have been used with less dramatic It has achieved moderate success. For example, arc psychiatry (Ar ch, Gen, Psychiatry) 46.322 (1989) National Institute on Drug Abuse and Alcoholism Research Monograph (National In5 posture On Drug＾buse and ^1cholis＋＊Re5earch Monograph) is a neuroleptic Although drug treatment inhibits the euphoric reinforcing effects of cocaine, this treatment causes discomfort; , does not reduce or even worsen the need for more cocaine. However, Ku Jien Psychiatry (Arch, Gen, Psychiatry) Preliminary information on flubenxol reported in 46.322 (1989) Research suggests it may be possible to develop drugs that curb cocaine craving and use It suggests.

International application PCT/US90102726 (International application W090/15047) is , various amino acids except that they have no hydroxy or alkoxy group at C6. Discloses tralin. Although these compounds are useful for a variety of CNS disorders, It is disclosed that it is not useful for treating or preventing quality abuse.

U.S. Patent No. 3,751,420 describes a bond connecting two rings that are not aromatic rings. discloses bicyclic aminotetralins such as compounds with double bonds, and these The compound has a functional group oxygenated at C5 instead of C5 as in the present invention. do. These compounds are useful not only as analgesic muscle relaxants but also as antibiotics. It is.

Journal of Medicinal Chemistry (J, Medicinal C hemistry) 18°362 (1975) is 2 which does not have an alkyl group at C4. -Amino-5-oxygenated aminotetralin is disclosed. These compounds - is a pamine receptor agonist and therefore may be useful in the treatment of Parkinson's disease. It has been disclosed that

International application WO31103491 5-Hydroxytryptamine useful for stimulatory effect 8-, which stimulates sexual activity in men and is useful in the treatment of pharyngeal disease and pain. Oxygenated-2-aminotetralin is disclosed.

U.S. Patent Nos. 4,800,204 and 4,935,429 each focus on drug abuse , discloses the use of dopamine agonists for the treatment of cocaine and tobacco. . The compounds used in this invention are not dopamine agonists; they are dopamine agonists. It is a member of a known class of selective antagonists of pre-pus receptors.

Journal of Medicinal Chemistry (J, Med, Chetx ) 30.602 (1987), Molecular Pharmacology (llol ecular Pharmacology) 30.258 (1986) and NaunynSc Archive Pharmacol hmeidenberg’s Archive, Pharmacol, )3 31.234 (1986) is a DA receptor that has a selective effect on presynaptic receptors. The unique pharmacology of a class of compounds known as receptor antagonists is described. Book The compounds of the invention, which are members of this class, have been shown to be useful in the treatment of substance abuse. is not disclosed.

Journal of Pharm. Sci, ) 67880 (197g) is the aminotetralin (1) of the present invention. Discloses N-enclopropyl analogs. The disclosed compounds are topical hemp It is taught to be useful as a narcotic. However, it is not disclosed in the document. Compounds such as aminotetralin (I) of the present invention that There is no data or teaching that it is a selective antagonist of the pro-receptor.

Journal of Medicinal Chemistry (J, Med, Chet ) 18.362 (1975), in which a suitably substituted 2-amorytetralin is doped. It is taught that it is a paminergic agonist. Aminotetralin of the present invention (1 ) are not replaced as taught by this magazine. moreover , this paper shows that aminotetralin (I) is a presynaptic receptor for dopamine. It does not teach that it is a selective antagonist of the condition.

The present invention provides the use of certain aminotetralin (1) for preventing and treating substance abuse. is of use.

R5 [Wherein, R1 is C+Cs alkyl; R2-1 and R1-2 are the same or different, -H or C, -C, alkyl .

R5 is -H, C+ -C3 alkyl or -Co-R,-, where R5-1 is C, -C3 alkyl or one φ] An effective amount of aminotetralin or its pharmaceutically acceptable anion salt represented by The individual is characterized in that it is administered to a human being who is or has been dependent on a substance. Disclose a method of curing.

Detailed description of the invention Aminotetralin (+)-ns (Is, 2R)-5-methoxy-1-methane Tyl-2-(n-propylamino)tetralin and (+)-ns (IS).

2R)-5-methoxy-1-methyl-2-(di-n-propylamine) tetrali is well known. See U.S. Pat. No. 4,876,284.

The aminotetralin (1) is used in monotherapy and in simultaneous psychological or other pharmacological As a drug therapy for the treatment and prevention of substance abuse, both as an adjunct to treatment. Useful.

Aminotetralin (1) of the present invention is suitable for patients who are suffering from substance abuse or who are at risk of becoming substance abuse. It is useful in a number of different ways in the healing of sexual individuals. As used herein ``Healing involves both treatment of the existing condition as well as prevention of future substance abuse.

First, healing is the treatment of individuals who are dependent on substances (physically or psychologically). That is. Second, healing uses substances recreationally but is not dependent on them. To prevent an individual from becoming dependent on the same or other substances of abuse Ru. Third, healing involves individuals who were previously dependent on substances but are no longer dependent on them. The goal is to prevent people from becoming dependent on substances. Fourth, healing is material Although there is no history of abuse, the person's lifestyle and activities may lead the clinician to believe that recreational use at risk of using substances and/or becoming dependent on various substances It is about preventing individuals who believe they are at risk.

Treatable substances of abuse (drugs) include cocaine, opiate drugs, and barbite weights. barbituates), amphetamines, chopped tobacco, alcohol, hallucinogens, Includes marijuana. More specifically, these drugs include cocaine, heroin, Codine, morphine, meperidine, alcohol, amphetamine, MDA, L Includes SD, PCP, Marijuana, Amphetamine and Methamphetamine . The most commonly used substances of abuse for which the methods of the present invention are useful are cocaine, heroin, and alcohol, cigarettes, marijuana, PCP, amphetamines and meth Amphetamiminotetraline (I) is administered intravenously, intramuscularly, or orally.

The effective amount of aminotetralin (1) is about 200 mg/B to about 20 g/day, preferably Alternatively, from about 500 mg/day to about 5 g/day.

Intramuscular depot formulations are prepared in large quantities for chronic administration. tablets, capsules Oral preparations in the form of tablets, solutions and suspensions, or as powders to be mixed with food. More preferably, the agent is administered at a total dose of about 500 mg/day to about 15 g/day. Doses ranging from about 1 to about 3 g/day are useful.

Aminotetralin (I) is not addictive per se (individuals cannot become addicted to it). (not gender).

Aminotetralin (I) is an amine, and when reacted with a sufficiently strong acid, its itself forms acid addition salts. Pharmaceutically acceptable salts include salts of inorganic and organic acids. Includes both. Pharmaceutically acceptable salts are preferred over the corresponding free aminotetralin (I). Delicious. This is because they are more soluble in water and more crystalline. be. Preferred pharmaceutically acceptable salts are the following acids: methanesulfonic acid, hydrochloric acid, bromide. Hydrogen acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid, maleic acid CHs-(CH2)*-COOH, where n is 0 to 4, n is as defined above; HOOC-(CHz), including salts of COOH.

The exact dose and frequency of administration will depend on the particular aminotetralin(I) used, the the individual symptoms to be treated, the severity of the symptoms to be treated, the age and weight of the individual patient, Other dosage regimens that an individual may take, depending on the general physical condition, are well known to those skilled in the art. It also determines the blood level of aminotetralin (I) in the patient's blood or Measuring concentrations and/or patient response to the individual condition being treated more precisely determined by

Definitions and promises The following definitions and explanations appear throughout the entire document, including both the specification and claims. It is about the terminology used.

11 Promises and definitions of variables In the specification and claims, various A chemical formula that represents a compound or molecular fragment has clearly defined structural features as well as , can contain variable substituents.

These variable substituents can be a letter or a letter followed by a subscript, e.g. Identity is confirmed by "Zl" or "R5" where is an integer. chemical formula before When drawing in a line as shown, the variables placed in parentheses are It is bonded to the atom immediately to the left. Two or more consecutive variable substituents When placed in parentheses, each continuous variable substituent is replaced by the immediately preceding non-parenthesized substituent. It is bonded to the atom on the left. Thus, in the above formula, R5 and R1 are bonded to a carbon atom that

For these aminotetralins with an established system of numbering carbon atoms, Carbon atoms are designated C1, where "1" is an integer corresponding to the carbon atomic number.

For example, C6 is traditionally represented by those skilled in the art at the 6-position in the molecule or at carbon Represents the elementary atomic number. Similarly, the term "R6" refers to the variable substituent at position 06 (-valent or (bivalent).

Rigid cyclic (ring) structures for any compound herein refer to the rigid cyclic structure The configuration of the substituents attached to each carbon atom of the compound relative to the ring plane is defined. . In a standard compound with two substituents attached to a carbon atom that is part of science Therefore, the two substituents of -C(XI)(X2)- are or Ekatorial, and can vary between Akhunyar/Ekatorial. Ru.

In the chemical structure representing such a compound, a substitution below another (X2) The group (X,) is defined to be in the alpha (α) configuration, which means that it is attached to a carbon atom by a dashed, dashed or dotted line, i.e. the symbol r---J or " ..." is confirmed. With the corresponding substituent bonded “above” (X2) The other (Xl) is defined as a beta (β) configuration, and is a substance bonded to a carbon atom. Indicated by a line.

The carbon atom content of variable substituents is expressed in one of two ways. the first The method uses prefixes for all names of variables, such as rC, -C4J, and and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. example For example, "rC, -C4 alkyl" represents an alkyl of 1 to 4 carbon atoms (especially (including isomers unless otherwise specified). Whenever this single prefix is used, The prefix indicates the total carbon atom content of the variable being defined. Thus, C2-C4 alco Xycarbonyl represents the group CH3(CH2)--OCo- where n is 0.1 or 2. Describe it. According to the second method, the carbon atom content of only the defined part is rc, -C, Place the J expression in parentheses ((), just before the definition part where it should be defined (with no intervening space) (not placed). According to this arbitrary promise, (C,− C3) Alkoxycarbonyl has the same meaning as C2C4 alkoxycarbonyl do.

This is because rc+C3J refers only to the carbon atom content of the annexoxy group. Ru.

Similarly, C2-C, alkoxy/and (C, -Cs)alcokyne (C, -C3) Alkyl together defines an alkoxyalkyl group containing 2 to 6 carbon atoms However, the two definitions are different. This is because the former is alkoxy or alkyl. While allowing either moiety to be 4 or 5 carbon atoms alone, the latter because the definition limits any of these groups to up to 3 carbon atoms.

■ Definition Healing is defined as (1) treating the individual who is currently dependent on a substance; (2) stopping the substance from being used; (3) prevent individuals using the substance from becoming dependent on the substance; Treating an individual who was previously dependent on a substance because he or she becomes dependent on the substance again and (4) have never been involved in substance use but become dependent on a substance. It refers to the prevention of individuals who are at risk of becoming infected.

Use is defined as when an individual uses a substance, has no dependence on the substance, and has his/her own A situation in which the use controls behavior, and the use of which regardless of whether it causes psychological harm or not. An example of this is the social Individuals who drink alcohol, smoke marijuana a few times a month, or have a few beers. Includes individuals. All of these individuals use substances recreationally and , and you can stop using it if you wish.

Abuse is when an individual becomes physically or psychologically dependent on a substance and stops using it. a situation in which the individual cannot be physically or psychologically Regardless of whether or not it causes harm to others. An example is a ``heroin addict,'' who is unable to stop. This includes cigarette smokers and drinkers who cannot afford to smoke. All these individuals are distracted eyes A person who uses a substance for a long time, is dependent on it, and is unable to stop using it. Physical dependence is when an individual who has been using a substance shows signs of abandonment when they no longer have the drug. It refers to a situation in which the Signs of abandonment can be different for different substances. This situation is He is known as the ``rich practitioner.''

Psychological dependence is when an individual who has used a substance has a desire and/or desire for the substance. A situation in which a person has no other directly observable signs of abandonment.

Decrease, as used in this application, refers to a decrease in the number of uses over a given period of time. or less of the substance (cocaine) with each use; As a result, the amount of material used per unit time is reduced. This is completely unusable. This situation may include, but is not limited to, not using.

Alcohol refers to ethyl alcohol.

Tobacco refers to cigarettes, vibe tobacco, cigars, and chewing tobacco.

LSD refers to lysergic acid diethylamide.

MDA refers to 3,4-methylenedioxyamphetamine.

PCP refers to phencyclicine.

Crack refers to the physical form of cocaine.

Pharmaceutically acceptable means that it is acceptable to patients from a pharmacological/toxicological standpoint, and physical/chemical considerations in terms of formulation, stability, patient tolerability and bioavailability. Characteristics and/or substances that are acceptable to drug manufacturing chemists from the ground up.

Marijuana is a plant substance containing the pharmacologically active cannabinol or Refers to and includes any species and form of hemp, regardless of its extracts.

Example One skilled in the art, using the foregoing description, can fully utilize the present invention without further elaboration. I believe it can be implemented in minutes. The following detailed examples illustrate various embodiments of the invention. It describes how to make compounds and/or how to carry out various processes. , are illustrative and in no way limit the disclosure above. skilled in the art If a person will recognize it.

Example 1 (-t-)-/Su(Is, 2R)-5-methquin-1-methyl- 2-(n-propylamine)tetralin See U.S. Pat. No. 4,876,284, Example I3.

Example 2 (±)-Nosu(Is, 2R)-5-methquin-1-methyl-2-( Di-n-propylamino)tetralin U.S. Pat. No. 4,876,284, Example I3 Reference example 3 30mg to a 60kg, 32-year-old woman who had just been admitted to the hospital for long-term cocaine abuse. /h of (+)-cis-(Is,2R)-5-methquin-1-methyl-2-(n - Chronic intravenous infusion of (propylamino)tetralin, followed by daily doses for 30 days. 1 gm was injected intramuscularly 4 times per day. Then, for the next 3-24 days, or when she 3 gm orally 4 times/day until well-recovered and no longer require treatment. The patient was switched to the same drug.

Example 4 70kg who was an intravenous heroin addict after undergoing a standard detoxification protocol 119o male (+)-ns (Is, 2R)-5-methoxy-1-methyl-2 - (Di-n-propylamino)tetralin was injected intramuscularly as a depot and orally administered daily. Supplemented with a 2 gm daily dose.

Example 5 Although she was happy to go to school, she became addicted to shoplifting and had a very poor relationship with her parents. The 57kg man, aged 7, was the subject of interest to his parents and school counselor.

His other friends are into alcohol and marijuana. school caran cellar Upon consultation with his parents, social worker, and social worker, it was determined that he It was determined that there was a strong tendency to 1gm of aminotetralin (I) for breakfast before school dose and it was decided to have another 1gm in the after school snack.

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Claims (1)

[Claims] 1. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is C1-C3 alkyl; R2-1 and R2-2 are the same or different, -H or C1-C5 alkyl ; R5 is -H, C1-C3 alkyl or -CO-R5-1, where R5-1 means C1-C3 alkyl or -φ] An effective amount of aminotetralin or its pharmaceutically acceptable anion salt represented by Treatment of a person who is or has been dependent on a substance How to heal. 2. Claim 1 wherein the cure is to treat an individual who is currently dependent on a substance. Method of curing described in section. 3. The cure does not prevent the individual using the substance from becoming dependent on the substance. A method of curing according to claim 1, wherein the method is to prevent. 4. The cure will prevent individuals who were previously dependent on substances from becoming dependent on substances again. A method of curing according to claim 1, which comprises treating. 5. The individual who has not been addicted to substance use but is at risk of becoming addicted to substances. The cure according to claim 1, which is to prevent the disease from occurring. Method. 6. The method of curing according to claim 1, wherein said dependence is physical dependence. 7. 2. The method of claim 1, wherein said addiction is psychological. 8. The substance may be cocaine, opiate drugs, barbituates, etc. ), from the group consisting of amphetamines, tobacco, alcohol, hallucinogens, and marijuana. A method of curing according to selected claim 1. 9. If the substance is cocaine, heroin, codeine, morphine, meperidine, alcohol tobacco, amphetamines, MDA, LSD, PCP, marijuana, amphetamines, Claim 8 selected from the group consisting of methamphetamine and methamphetamine. How to cure it. 10. If the substance is cocaine, heroin, alcohol, cigarettes, marijuana, P Claims selected from the group consisting of CP, alcohol and methamphetamine The method of curing according to item 8. 11. Claim 1, wherein said effective amount is about 200 mg/day to about 20 g/day. Method of curing described. 12. Claim 11, wherein said effective amount is about 500 mg/day to about 5 g/day. Method of curing described. 13. The curing agent according to claim 1, wherein R1 is C1 or C2 alkyl. Method. 14. 14. The method of claim 13, wherein R1 is C1 alkyl. 15. Claim 1, wherein R2-1 is -H or C2-C4 alkyl How to heal. 16. Claim 15, wherein R2-1 is -H or n-C3 alkyl How to heal. 17. The curing method according to claim 1, wherein R2-2 is C2-C4 alkyl. Method. 18. The curing method according to claim 17, wherein R2-2 is n-C3 alkyl. Method. 19. The method of claim 1, wherein R5 is C1-C3 alkyl. . 20. 20. The method of claim 19, wherein R5 is C1 alkyl. 21. The compound of formula (I) is (+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(n-propylene Ruamino) Tetralin, (+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(di-n-p (ropylamino)tetralin The method of claim 1, wherein the method is selected from the group consisting of: 22. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is C1-C3 alkyl: R2-1 and R2-2 are the same or different, -H or C1-C5 alkyl ;R5 is -H, -C1-C3 alkyl or R5-1 is C1-C3 alkyl or means -CO-R5-1 which is -φ] An effective amount of aminotetralin or its pharmaceutically acceptable anion salt represented by an individual who uses cocaine, characterized in that it is administered to an individual who uses cocaine; How to reduce cocaine use in. 23. Claim 22, wherein said effective amount is about 200 mg/day to about 20 g/day. Methods for reducing the use of carp as described in section. 24. The compound of formula (I) is (+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(n-propylene Ruamino) Tetralin, (+)-cis-(1S,2R)-5-methoxy-1-methyl-2-(di-n-p (ropylamino)tetralin 23. The method of treatment according to claim 22, wherein the treatment method is selected from the group consisting of: