HK1079449A - Compounds for the treatment of addictive disorders - Google Patents

Description

Compounds for the treatment of addictive disorders

Technical Field

The present invention relates to the use of neuromuscular agents and their pharmacologically acceptable salts for the treatment of several nervous system disorders or for the amelioration of symptoms thereof. More particularly, the invention relates to the treatment and amelioration of symptoms associated with addictive disorders, psychiatric disorders employing psychoactive substances, nicotine addiction and tobacco addiction.

Background

Several classes of compounds have been disclosed as being effective in the treatment and management of Fibromyalgia (FMS) (or fibromyalgia syndrome) and Chronic Fatigue Immune Disorder Syndrome (CFIDS) or Chronic Fatigue Syndrome (CFS). More specifically, heterocyclic amine-type compounds, phenyl azacycloalkane-type compounds, cabergoline and cabergoline-type compounds have been disclosed to be effective in the treatment and control of these neuromuscular disorders.

Heterocyclic amine compounds and methods for their preparation are disclosed in U.S. Pat. No. 5,273,975 issued at 28.12.1993, U.S. Pat. No. 5,436,240 issued at 25.7.1995, U.S. Pat. No. 5,462,947 issued at 31.10.1995, and U.S. Pat. No. 5,594,024 issued at 14.1.1997. More specifically, compounds and methods of making compounds, formulations and methods of making medicaments are described in U.S. patent No. 5,273,975 issued 12-28, 1993; U.S. patent 5,436,240 issued on 25.7.1995 also provides a general description of compounds with therapeutic uses for FMS and CFIDS.

Phenylazacycloalkane compounds and methods for their preparation have been described in U.S. Pat. No. 5,594,024 issued 1/14 in 1997 and U.S. Pat. No. 5,462,947 issued 10/31 in 1995. These compounds are disclosed as having useful activity in the treatment of central nervous disorders associated with dopamine receptor activity.

Cabergoline and cabergoline-type compounds have been disclosed to have hypotensive and anti-prolactin activity. Commercially available from Pharmacia&UpJohn, Inc. (now Pharmacia Corporation) under the tradename DOSTINEX^TMAnd CABASER^TMIt is suitable for hyperprolactinemia and Parkinson's disease. Compounds and methods for their preparation are described in us patent 4,526,892 issued on 7/2 1985.

More recently, scientists have considered whether these compounds useful in the treatment of neuromuscular disorders can be used in the treatment of other nervous system disorders, particularly addictive disorders. In particular, the use of these compounds in neurological disorders, such as addictive disorders, psychotic disorders with the use of psychoactive substances, nicotine addiction resulting from smoking cessation or tobacco addiction has been considered.

In addition to the foregoing compounds, the potential activity of aromatic bicyclic amine compounds for the treatment of neurological disorders, such as addictive disorders, has also been investigated. Aromatic bicyclic amine compounds are reported to have activity useful for the treatment of some central nervous system disorders (e.g., schizophrenia) and cardiovascular diseases (e.g., cardiac arrhythmia and fibrillation). Bicyclic amine compounds and methods for their preparation are described in U.S. patent 5,877,317 issued 3/2 1999.

Methods of using the compounds for treating addictive neurological disorders have not been reported. Described herein are methods and dosages for treating particular addictive disorders using heterocyclic amine compounds, phenylazacycloalkane compounds, cabergoline, aromatic bicyclic amine compounds, and derivatives of these compounds.

Disclosure of Invention

The present invention provides methods for treating certain addictive disorders, such as mental disorders caused by the use of psychoactive substances, nicotine addiction, or tobacco addiction (the consequences of smoking cessation or smoking reduction). The method comprises the step of administering to a patient suffering from or susceptible to such an addiction or disorder a therapeutically effective, non-toxic amount of a heterocyclic amine, phenylazacycloalkane, cabergoline or aromatic bicyclic amine compound, or a pharmaceutically acceptable salt or derivative thereof.

Heterocyclic amines, phenylazacycloalkanes, cabergoline, aromatic bicyclic amine compounds and pharmaceutically acceptable salts or derivatives of these compounds can be used for the treatment and amelioration of neurological disorders. Such disorders may generally include, but are not limited to, addictive disorders, mental disorders resulting from the use of psychotropic substances, nicotine addiction, tobacco addiction, and other diseases or disorders involving the nervous system, particularly the central nervous system.

Several compounds that are active in the treatment of neuromuscular diseases have been recognized by the methods of the present invention. The following classes of compounds can be used to treat or inhibit conditions involving the nervous system, specifically the symptoms of addictive disorders. Examples of at least the following classes of compounds are provided for the methods of the present invention.

Suitable compounds may have the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R²and R³Each independently is hydrogen, C_1-6Alkyl radical, C_3-5Alkenyl radical, C_3-5Alkynyl, C_3-7Cycloalkyl radical, C_4-10Cycloalkyl-or phenyl-substituted C_1-6Alkyl, or R¹And R²Is connected to form C_3-7Cyclic amines, which may contain additional heteroatoms and/or unsaturation;

n is 0 or 1;

x is hydrogen, C_1-6Alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxy or alkoxycarbonyl;

a is CH, CH₂CH-halogen, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃、C-NHCN、SO₂Or N;

b is CH₂CH, CH-halogen, C ═ O, N, NH, N-CH₃Or O;

d is CH, CH₂CH-halogen, C ═ O, O, N, NH or N-CH₃。

Preferred compounds of the formula (I) are those in which D is N or NH, N is 0 and R¹、R²、R³X, A and B are as previously defined. Further preferred compounds of the formula (I) are those in which A is CH, CH₂、CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or C-NHCN, R¹、R²、R³N, X, B and D are as defined above.

More preferred compounds of formula (I) according to the invention are those wherein A is CH or C ═ O, R¹、R²、R³N, X, B and D are as defined above.

The compounds of formula (I) may be prepared by any suitable method. These compounds may be generally referred to as heterocyclic amine compounds. Methods for preparing compounds of formula (I) are further described in U.S. Pat. No. 5,273,975 issued 1993 at 12/28, incorporated herein by reference.

Non-limiting examples of formula (I) useful in the practice of the present invention include, but are not limited to:

(R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (unconverted CAS Name) or (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin- (2H) -one (generated by ACD/Name software);

(5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione; and

a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts include addition salts of inorganic and organic acids. Pharmaceutically acceptable salts are preferred over the corresponding free amines because they result in compounds that are more water soluble and more crystalline. Preferred pharmaceutically acceptable salts include the salts of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, methanesulfonic acid, CH₃-(CH₂)_n1-COOH (where n1 is 0 to 4), HOOC- (CH)₂)_n1-COOH (wherein n1 is as defined above) and HOOC-CH ═ CH-COOH. For other pharmaceutically acceptable salts, see int.j.pharm., 33, 201-217 (1986).

More preferably, the active agent (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione is present as the mesylate salt, which is the (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione mesylate salt. A preferred salt of (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione 2-butenedioic acid salt.

Other compounds suitable for the present invention are those having the formula:

or a pharmaceutically acceptable salt thereof, wherein:

n2 is 0 to 3;

R⁴and R⁵Independently hydrogen, -OH, CN, CH₂CN、2-CF₃、4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Vinyl, 2-propenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁷、COOR⁷、CON(R⁷)₂、SO_x1CH₃、SO_x1CF₃、O(CH₂)_x1CF₃(wherein x1 is 0-2), SO₂N(R⁷)₂、CH＝NOR⁷、COCOOR⁷、COCOON(R⁷)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁷、CH₂(R⁷)₂、NR⁷SO₂CF₃、NO₂Halogen, phenyl in position 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine; with the proviso that R⁴And R⁵Is a substituent other than hydrogen, and with the proviso that if R⁴Or R⁵is-OH, then R⁷Is not hydrogen;

R⁶is hydrogen, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁸(wherein m is 1-8), CH₂SCH₃Or C bound to said nitrogen and to adjacent carbon atoms thereof_4-8Alkyl, constituting a heterocyclic structure;

R⁷independently of each other is hydrogen, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁸(wherein m is 1 to 8))；

R⁸Is phenyl, optionally substituted by CN, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 2-thienyl, 3-thienyl, -NR⁹CONR⁹R¹⁰or-CONR⁹R¹⁰Substitution;

R⁹and R¹⁰Each independently is hydrogen, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl or C_2-8Alkynyl.

Preferred compounds are at least those of formula (II) wherein:

R⁴is CN, n2, R⁵、R⁶And R⁷Is as defined above;

R⁵is H, R⁶Is n-propyl, n2, R⁴And R⁷Is as defined above;

R⁴is-OSO₂CF₃N2 and R⁵-R⁷Is as defined above;

R⁵is H, R⁶Is C_1-8Alkyl, n2, R⁴And R⁷Is as defined above;

R⁴is 3-OH, R⁵Is H, R⁶Is n-propyl, R⁷Is C_1-8Alkyl, n2 is as previously defined;

n2 is 2, R⁴-R⁷Is as defined above; and

n2 is 0, R⁴-R⁷As previously defined.

Compounds of formula (II) are described in U.S. Pat. No. 5,594,024 issued at 14.1.1997 and U.S. Pat. No. 5,462,947 issued at 31.10.1995, each of which is incorporated herein by reference. These compounds may be generally referred to as phenylazacycloalkane compounds.

Non-limiting examples of formula (II) useful in the practice of the present invention include, but are not limited to:

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride;

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide; and

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioic acid salt.

Further compounds suitable for the present invention are the active drug cabergoline and its derivatives of the following formula:

or a pharmaceutically acceptable salt thereof, wherein:

R¹¹is hydrogen or methyl;

R¹²independently hydrogen, halogen, methyl, formyl, S-R¹⁷Or SO-R¹⁷Wherein R is¹⁷Is C_1-4Alkyl or phenyl;

R¹³is hydrogen or methoxy;

R¹⁴independently is C_1-4Alkyl radical, C_1-4Alkenyl radical, C_1-4Alkynyl, benzyl or phenyl;

R¹⁵and R¹⁶Each independently is C_1-4Alkyl, cyclohexyl, phenyl optionally substituted with halogen or methoxy, or (CH)₂)_n3N(CH₃)₂Wherein n3 is an integer.

Cabergoline has the chemical name 1- ((6-allylergoline (ergolin) -8 β -yl) carbonyl) -1- (3- (dimethylamino) propyl) -3-ethylurea. Cabergoline is dosteine^TM(Pharmacia &UpJohn, Inc., Kalamazoo, Michigan, now Pharmacia Corporation) and CABASER^TM(Pharmacia &UpJohn, Inc.) class name of active ingredients, the former sold as a treatment for hyperprolactinemia in the united states and the latter sold as a treatment for parkinson's disease in europe. The synthesis and use of cabergoline and some of its useful derivatives is disclosed and claimed in U.S. patent 4,526,892, which is incorporated herein by reference. More specifically, the compounds disclosed generally and specifically in U.S. patent 4,526,892 claims 1-4 are incorporated herein by reference.

Another class of compounds suitable for the present invention are aromatic bicyclic amine compounds of the formula:

wherein:

n3 is 0 or 1;

n4 is 0 or 1, with the proviso that if n4 is 0, then R²⁰Is absent;

R¹⁸(1) is alpha-R^18-1:β-R^18-2Wherein R is^18-1Or R^18-2One is selected from H or C_1-6Group consisting of alkyl radicals, R^18-1Or R^18-2Is a group of the formula:

wherein R is²⁶And R²⁷Independently selected from H or C_1-6An alkyl group; r²⁸Is oxygen (O) or R²⁸Is alpha-R^28-1:β-R^28-2Wherein R is^28-1And R^28-2Independently selected from H or C_1-6An alkyl group; r²⁹Selected from the group consisting of:

wherein R is³¹And R³³Independently selected from H or C_1-6An alkyl group; r³²Is nitrogen (N-) or methine (HC-); s is 1 or 2;

and

wherein R is³⁴Selected from the group consisting of H, C_1-6Alkyl radical, C_3-7Cycloalkyl, -C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups; s2 is 0, 1 or 2;

wherein R is³⁴And s2 is as defined above;

R¹⁹is oxygen (O) or sulfur (S);

R²⁰is alpha-R^20-1:β-R^20-2Wherein R is^20-1And R^20-2One is H, C_1-6Alkyl radical, R^20-1Or R^20-2Is H, C_1-6Alkyl, phenyl, hydroxy and-O- (C)_1-3Alkyl groups);

R²¹is alpha-R^21-1:β-R^21-2Wherein R is^21-1And R^21-2One is H, C_1-6Alkyl radical, R^21-1Or R^21-2Is H, C_1-6Alkyl, phenyl, hydroxy and-O- (C)_1-3Alkyl groups);

if n4 is 1, then R^20-1Or R^20-2One of and R^21-1Or R^21-2One of which may form together with the carbon atom to which they are attached a 5-, 6-or 7-membered ringA carbocyclic ring;

R²²is H, F, Cl, Br, I, -CONR³⁵R³⁶、-SONR³⁵R³⁶、CF₃、NR³⁵R³⁶、NO₂、CN、-NR³⁵-CO-R³⁶、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁵R³⁶Group of (I) wherein R³⁵And R³⁶Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

wherein R is²²And R^21-1Or R^21-2One of which, together with the carbon atom to which they are attached, forms a 5-, 6-or 7-membered carbocyclic ring;

R²³is H, F, Cl, Br, I, -CONR³⁷R³⁸、-SONR³⁷R³⁸、CF₃、NR³⁷R³⁸、NO₂、CN、-NR³⁷-CO-R³⁸、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁷R³⁸Group of (I) wherein R³⁷And R³⁸Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-xC_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

R²⁴is H, F, Cl, Br, I, -CONR³⁹R⁴⁰、-SONR³⁹R⁴⁰、CF₃、NR³⁹R⁴⁰、NO₂、CN、-NR³⁹-CO-R⁴⁰、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁹R⁴⁰Group of (I) wherein R³⁹And R⁴⁰Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

R²⁵is H, F, Cl, Br, I, -CONR⁴¹R⁴²、-SONR⁴¹R⁴²、CF₃、NR⁴¹R⁴²、NO₂、CN、-NR⁴¹-CO-R⁴²、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR⁴¹R⁴²Group of (I) wherein R⁴¹And R⁴²Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

with the proviso that R²²、R²³、R²⁴And R²⁵No more than two of which are not H;

R³⁰selected from the group consisting of:

phenyl optionally substituted with one or two substituents selected from the group consisting of CF₃、COR⁴³、COOR⁴³、CN、NO₂、NR⁴⁴-CO-R⁴⁵、-S-(C_1-6Alkyl), NR)⁴⁴R⁴⁵Or from R⁴⁶A group represented by;

optionally substituted by one or two groups R⁴⁶A 2-, 3-or 4-pyridyl group substituted with the substituent represented by;

optionally substituted by one or two groups R⁴⁶A 2-, 4-or 5-pyrimidinyl group substituted with the substituent represented by (A);

wherein R is⁴³、R⁴⁴And R⁴⁵Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, -C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups; r⁴⁶Selected from F, Cl, Br, I, -CO-NR⁴⁴R⁴⁵、-SO₂NR⁴⁴R⁴⁵、OH、SH、C_1-6Alkyl radical, C_3-6Cycloalkyl, -OR⁴⁷、-CH₂-(C_3-6Cycloalkyl), -CH₂-phenyl, C_3-6Cycloalkyl, -SO₂CF₃and-CH₂CF₃Wherein R is⁴⁴And R⁴⁵Is as defined above, R⁴⁷Is C_1-6An alkyl group;

and enantiomers and diastereomers thereof, if present, and pharmaceutically acceptable salts thereof.

Compounds of formula (IV) are described in U.S. patent 5,877,317, issued 3/2 1999, which is incorporated herein by reference. Aromatic bicyclic amine compounds and methods of making and using these compounds are disclosed in U.S. patent 5,877,317. More specifically, U.S. patent 5,877,317 claims 1-18 claim aromatic bicyclic amine compounds.

Preferred compounds of the formula (IV) are those in which R is^18-1Or R^18-2One of the substituents represented is H, represented by R^18-1Or R^18-2Another substituent represented is a group of the formula:

wherein R is²⁶、R²⁷、R²⁸、R²⁹And R³⁰As previously defined.

Non-limiting examples of formula (IV) useful in the practice of the present invention include, but are not limited to, compounds selected from the group consisting of:

1- (4-fluorophenyl) -4- [2- (isochroman-1-yl) ethyl ] piperazine;

1- [2- (isochroman-1-yl) ethyl ] -4-phenylpiperazine;

1- [2- (isochroman-1-yl) ethyl ] -4- (4-methoxyphenyl) piperazine;

(-) -4- [4- [2- (isochroman-1-yl) ethyl ] piperazin-1-yl ] benzamide; and

(-) -4- [4- [2- (isochroman-1-yl) ethyl ] piperazin-1-yl ] benzenesulfonamide.

Preferred compounds are (-) -4- [4- [2- (isochroman-1-yl) ethyl ] piperazin-1-yl ] benzenesulfonamide, or (-) -4- [4- [2- (3, 4-dihydro-1H-2-benzopyran-1-yl) ethyl ] -1-piperazinyl ] benzenesulfonamide, or 4- (4- (2- [ (1S) -3, 4-dihydro-1H-isochroman-1-yl ] ethyl) -1-piperazinyl) benzenesulfonamide (generated by ACD/Name software).

The term "alkyl" as used herein denotes C_y-zNotation "C_y-z"represents a hydrocarbon chain containing from y carbon atoms to z carbon atoms. For example, the term C_1-6Alkyl represents a straight or branched chain alkyl group of about 1 to about 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl and the like.

The term "alkenyl" as used herein denotes aliphatic unsaturated hydrocarbon radicals containing at least one double bond, including branched and unbranched forms. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-methyl-1-ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, and the like.

The term "alkynyl" as used herein denotes aliphatic unsaturated hydrocarbons containing at least one triple bond, including branched and unbranched forms. Examples of alkynyl groups are 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.

The term "cycloalkyl" as used herein denotes a non-aromatic cyclic hydrocarbon group, preferably containing three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups may also have alkyl and alkoxy groups as defined above, as well as halogen substituents, such as bromo, chloro, iodo and fluoro.

The term "cycloalkyl-substituted alkyl" as used herein denotes an alkyl group as defined above wherein at least one carbon atom of the alkyl group is attached to a cycloalkyl group as defined above.

The term "phenyl-substituted alkyl" as used herein denotes an alkyl group as defined above wherein at least one carbon atom of the alkyl group is attached to a phenyl group as defined above, i.e. a substituted or unsubstituted radical derived from a benzene comprising a 6-membered aromatic ring.

The term "halogen" as used herein denotes typical halogen atoms such as bromine, chlorine, iodine and fluorine.

The term "hydroxy" denotes the group-OH.

The term "alkoxy" as used herein, means a straight or branched chain hydrocarbon group, as defined above, attached to the parent molecule through an oxygen heteroatom, typically a carbon-oxygen bond. The hydrocarbon of the alkoxy group preferably contains 1 to 6 carbon atoms. Typical alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy (1-methylpropoxy), tert-butoxy (1, 1-dimethylethoxy), n-pentoxy, tert-pentoxy (1, 1-dimethylpropoxy), and the like.

The term "aryl" as used herein denotes aromatic cyclic hydrocarbons, such as phenyl and naphthyl. Aryl, such as phenyl, may optionally be substituted with alkyl, alkoxy or halogen, such as bromo, chloro, iodo and fluoro. Examples of aryl groups include, but are not limited to, phenyl, bromophenyl, chlorophenyl, iodophenyl, fluorophenyl, bromonaphthyl, and the like.

The term "cyano" as used herein denotes the group-CN.

The term "carboxamide" as used herein denotes the group-CONH₂。

The term "carboxy" as used herein denotes the group-COOH.

The term "alkoxycarbonyl" as used herein denotes the group-COOR, wherein R is lower alkyl, such as methoxycarbonyl, ethoxycarbonyl and the like.

The term "thienyl" as used herein denotes a radical derived from thiophene.

The term "furyl" as used herein denotes radicals derived from furan and derivatives thereof, including tetrahydrofuran, such as tetrahydrofuranyl.

The term "pyrrole" as used herein means all isomers of the pyrrole ring including 2H-pyrrole, 2-pyrroline and the like.

The term "cycloalkylmethyl" as used herein denotes a compound having a methylene (-CH) group₂-) cycloalkyl attached to the parent compound.

By "pharmaceutically acceptable" is meant those properties and/or substances with respect to composition, formulation, stability, patient acceptability and bioavailability which are acceptable to the patient from a pharmacological/toxicological point of view and to the chemist producing the drug from a physical/chemical point of view. More specifically, the term "pharmaceutically acceptable salts" as used herein refers to organic and inorganic acid addition salts of the parent compound.

The dosages of the above compounds to be administered can be readily determined by the skilled artisan, who has experience with prescribing biologically active drugs to modulate the central nervous system, locomotion and associated psychological and physiological disorders, preferably the disorders described herein. The active agent is generally administered once or twice daily, although the desired dose is often administered to a particular patient more or less frequently as appropriate.

Any conventional pharmaceutical formulation may be used, for example consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance; such as tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patches, and other vehicles useful for the release of the active agent, whether plain or coated. Preferably, the active agent is formulated as an oral tablet.

Preferred oral tablets comprise the active agent and a pharmaceutically acceptable carrier. Preferred pharmaceutically acceptable carriers may comprise one or more inert excipients, such as mannitol, corn starch, colloidal silicon dioxide, povidone, and magnesium stearate.

Tablets containing a heterocyclic amine compound, a phenylazacycloalkane compound and a cabergoline or cabergoline-type compound will generally contain the following mg/tablet of active drug: 0.125, 0.25, 0.5, 1.0, 1.25 and 1.5 mg. The preferred initial dose of these compounds is about 0.125 mg/day, administered to the patient three times per day (tid). The dose may be increased from the initial dose to higher doses, increasing every five to seven days up to a maximum dose of 10 mg/day. A preferred higher total daily dose is about 6 mg/day. More preferably, the higher dose is about 4.5 mg/day to about 5 mg/day.

The dosage of the aromatic bicyclic amine compound may range from about 5mg aromatic bicyclic amine active agent per day to about 120mg aromatic bicyclic amine active agent per day. Preferably, the aromatic bicyclic amine active agent is administered in an amount of from about 20 mg/day to about 100 mg/day. More preferably, the aromatic bicyclic amine active agent is administered in an amount of from about 40 mg/day to about 80 mg/day. The aromatic bicyclic amine compounds, like the other compounds suitable for the present invention, can be administered starting from an initial dosage strength and then increasing to the maximum daily dosage suitable.

For the treatment of addictive disorders described herein, the drug may also be in a chewable form, such as chewing gum. The amount of active drug included in the chewable base may be half of the recommended dosage for the tablet described above, for example starting with about 0.075mg cabergoline per chewing gum, the tid administered, and then the higher dose administered after the patient has shown drug tolerance. In addition to those mentioned for the tablets of heterocyclic amine compounds, phenylazacycloalkane compounds and cabergoline or cabergoline type compounds, chewing gum dosages encompassed within the scope of the invention include at least 0.075, 0.10, 0.125, 0.150 mg/day. Similarly, dosages for aromatic bicyclic amine compounds include from about 2.5 mg/day to about 125 mg/day. One or two pieces of chewing gum may be supplied to the patient, up to three times per day, depending on the therapeutic needs of the subject.

Transdermal administration (e.g., using a skin patch) and inhalation therapy (e.g., using an inhaler) are also envisioned, wherein the patch or inhaler will deliver the desired level of active agent to the patient. Transdermal patches containing an active agent can also eliminate patient craving for tobacco-containing products in combination with nicotine-containing patches.

Patients are usually first administered a low dose of drug to avoid nausea that may occur with a higher initial dose. The dosage is then gradually increased to higher levels until a suitable therapeutic effect is achieved.

An effective dosage of the heterocyclic amine, phenylazacycloalkane, cabergoline or cabergoline-type derivative may range from 0.01 mg/day to about 10.0 mg/day per patient. Preferred effective doses are between about 0.125 mg/day and about 6 mg/day of active drug. More preferably, the effective dose is between about 0.375 mg/day and about 5 mg/day of the active agent. Particularly preferred effective doses are between about 0.75 mg/day and about 4.5 mg/day of active agent. In addition to administration by the oral or intravenous route, the active agent may be administered transdermally or by inhalation.

In the practice of the present invention, the initial dose is typically about 0.125 mg/day, administered three times per day, increasing every five to seven days until optimal therapeutic effect is achieved. The dose may be titrated to achieve maximum therapeutic effect, provided that the patient does not experience intolerable side effects. One of ordinary skill in the pharmaceutical arts, such as a physician or pharmacist, is able to determine the optimal dosage level after considering the patient's age, weight, medical history, responsiveness to drugs, and tolerance.

Addictive disorders and mental disorders caused by the use of psychoactive substances, such as toxic disorders, inhalation disorders, alcohol addiction, tobacco addiction and/or nicotine addiction, can be treated according to the invention. The treatment of tobacco and nicotine cravings is aimed at achieving smoking cessation or at least reducing the amount of tobacco and/or nicotine intake. General descriptions of addictive disorders can be found in many standard sources, including disorders involving intoxication, inhalants, and tobacco or nicotine cravings. Drug addictions and behaviors that can generally be treated with The present invention are further described, for example, in The American Psychiatric Press textbook of Psychiatric 2 nd edition, Robert E.Hales, Stuart C.Yudofsky and John A.Talbot, 1994, incorporated herein by reference, especially The pp.401 et. seq. The section on "Nicotine" is incorporated herein by reference; and manual of psychopath Therapeutics 2 nd edition, Richard I.Shader, incorporated herein by reference, especially pp.85 entitled "hypnosis" in Chapter 11.

The method is particularly useful for the treatment and alleviation of psychotic disorders caused by the use of alcohol and other psychoactive substances, such as disorders involving intoxication or inhalants, more particularly tobacco or nicotine addiction. The effect of the invention on tobacco addiction more particularly relates to the administration of active agents in a manner and form that reduces the symptoms of the disease. In particular, the tobacco and/or nicotine aspect of the invention may be used to reduce or terminate smoking or chewing of nicotine containing substances by a patient.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The person skilled in the art will quickly identify appropriate variations in the technology with respect to the reactants and the reaction conditions and techniques.

Claims (25)

1. A method of treating or inhibiting the symptoms of at least one disorder selected from the group consisting of addictive disorders, psychotropic disorders with psychotropic substances, toxic disorders, inhalation disorders, alcohol addiction, tobacco addiction and nicotine addiction, said method comprising the step of administering to a patient in need of treatment a therapeutically effective, non-toxic amount of an active agent selected from the group consisting of heterocyclic amines, phenyl azacycloalkanes, cabergoline, aromatic bicyclic amines, and pharmaceutically acceptable derivatives or salts of any of said active agents.

2. The method of claim 1, wherein the active agent is a heterocyclic amine of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R¹、R²and R³Each independently is hydrogen, C_1-6Alkyl radical, C_3-5Alkenyl radical, C_3-5Alkynyl, C_3-7Cycloalkyl radical, C_4-10Cycloalkyl-or phenyl-substituted C_1-6Alkyl, or R¹And R²Is connected to form C_3-7Cyclic amines, which may contain additional heteroatoms and/or unsaturation;

n is 0 or 1;

x is hydrogen, C_1-6Alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide, carboxy or alkoxycarbonyl;

a is CH, CH₂CH-halogen, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃、C-NHCN、SO₂Or N;

b is CH₂CH, CH-halogen, C ═ O, N, NH, N-CH₃Or O;

d is CH, CH₂CH-halogen, C ═ O, O, N, NH or N-CH₃。

3. The method of claim 2, wherein:

d is N or NH, N is O, R¹、R²、R³X, A and B are as defined in claim 2; or

A is CH, CH₂、CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or C-NHCN, R¹、R²、R³N, X, B and D are as defined in claim 2; or

A is CH or C ═ O, R¹、R²、R³N, X, B and D are as defined in claim 2.

4. The method of claim 2, wherein the active agent is selected from the group consisting of:

(5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin- (2H) -one;

(5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione;

(5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione maleate; and

(5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione 2-butenedioate.

5. The method of claim 1, wherein the active drug is a phenylazacycloalkane compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

n2 is 0 to 3;

R⁴and R⁵Independently hydrogen, -OH, CN, CH₂CN、2-CF₃、4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Vinyl, 2-propenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁷、COOR⁷、CON(R⁷)₂、SO_x1CH₃、SO_x1CF₃、O(CH₂)_x1CF₃(wherein x1 is 0-2), SO₂N(R⁷)₂、CH＝NOR⁷、COCOOR⁷、COCOON(R⁷)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁷、CH₂(R⁷)₂、NR⁷SO₂CF₃、NO₂Halogen, phenyl in position 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine; with the proviso that R⁴And R⁵Is a substituent other than hydrogen, and with the proviso that if R⁴Or R⁵is-OH, then R⁷Is not hydrogen;

R⁶is hydrogen, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁸(wherein m is 1-8), CH₂SCH₃Or C bound to said nitrogen and to adjacent carbon atoms thereof_4-8Alkyl, constituting a heterocyclic structure;

R⁷independently of each other is hydrogen, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁸(wherein m is 1 to 8);

R⁸is phenyl, optionally substituted by CN, CF₃、CH₂CF₃、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl radical, C_2-8Alkynyl, 2-thienyl, 3-thienyl, -NR⁹CONR⁹R¹⁰or-CONR⁹R¹⁰Substitution;

R⁹and R¹⁰Each independently is hydrogen, C_1-8Alkyl radical, C_3-8Cycloalkyl radical, C_4-9Cycloalkyl-methyl, C_2-8Alkenyl or C_2-8Alkynyl.

6. The method of claim 5, wherein:

R⁴is CN, n2, R⁵、R⁶And R⁷Is as defined in claim 5; or

R⁵Is H, R⁶Is n-propyl, n2, R⁴And R⁷Is as defined in claim 5; or

R⁴is-OSO₂CF₃N2 and R⁵-R⁷Is as defined in claim 5; or

R⁵Is H, R⁶Is C_1-8Alkyl, n2, R⁴And R⁷Is as defined in claim 5; or

R⁴Is 3-OH, R⁵Is H, R⁶Is n-propyl, R⁷Is C_1-8Alkyl, n2 is as defined in claim 5; or

n2 is 2, R⁴-R⁷Is as defined in claim 5; or

n2 is 0, R⁴-R⁷As defined in claim 5.

7. The method of claim 5, wherein the phenylazacycloalkane compound is selected from the group consisting of:

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride;

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide; and

(3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioic acid salt.

8. The method of claim 1, wherein the active agent is cabergoline of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R¹¹is hydrogen or methyl;

R¹²independently hydrogen, halogen, methyl, formyl, S-R¹⁷Or SO-R¹⁷Wherein R is¹⁷Is C_1-4Alkyl or phenyl;

R¹³is hydrogen or methoxy;

R¹⁴independently is C_1-4Alkyl radical, C_1-4Alkenyl radical, C_1-4Alkynyl, benzyl or phenyl;

R¹⁵and R¹⁶Each independently is C_1-4Alkyl, cyclohexyl, phenyl optionally substituted with halogen or methoxy, or (CH)₂)_n3N(CH₃)₂Wherein n3 is an integer.

9. The method of claim 8, wherein the active agent is 1- ((6-allylergoline-8 β -yl) carbonyl) -1- (3- (dimethylamino) propyl) -3-ethylurea.

10. The method of claim 1, wherein the active drug is an aromatic bicyclic amine compound of the formula:

wherein:

n3 is 0 or 1;

n4 is 0 or 1, with the proviso that if n4 is 0, then R²⁰Is absent;

R¹⁸(1) is alpha-R^18-1:β-R^18-2Wherein R is^18-1Or R^18-2One is selected from H or C_1-6Group consisting of alkyl radicals, R^18-1Or R^18-2Is a group of the formula:

wherein R is²⁶And R²⁷Independently selected from H or C_1-6An alkyl group; r²⁸Is oxygen (O) or R²⁸Is alpha-R^28-1:β-R^28-2Wherein R is^28-1And R^28-2Independently selected from H or C_1-6An alkyl group; r²⁹Selected from the group consisting of:

wherein R is³¹And R³³Independently selected from H or C_1-6An alkyl group; r³²Is nitrogen (N-) or methine (HC-);

s is 1 or 2;

and

wherein R is³⁴Selected from the group consisting of H, C_1-6Alkyl radical, C_3-7Cycloalkyl, -C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups; s2 is 0, 1 or 2;

wherein R is³⁴And s2 is as defined above;

R¹⁹is oxygen (O) or sulfur (S);

R²⁰is alpha-R^20-1:β-R^20-2Wherein R is^20-1And R^20-2One is H, C_1-6Alkyl radical, R^20-1Or R^20-2Is H, C_1-6Alkyl, phenyl, hydroxy and-O- (C)_1-3Alkyl groups);

R²¹is alpha-R^21-1:β-R^21-2Wherein R is^21-1And R^21-2One is H, C_1-6Alkyl radical, R^21-1Or R^21-2Is H, C_1-6Alkyl, phenyl, hydroxy and-O- (C)_1-3Alkyl groups);

if n4 is 1, then R^20-1Or R^20-2One of and R^21-1Or R^21-2One may form a 5-, 6-or 7-membered carbocyclic ring together with the carbon atom to which they are attached;

R²²is H, F, Cl, Br, I, -CONR³⁵R³⁶、-SONR³⁵R³⁶、CF₃、NR³⁵R³⁶、NO₂、CN、-NR³⁵-CO-R³⁶、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And optionallyPhenyl substituted by one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁵R³⁶Group of (I) wherein R³⁵And R³⁶Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

wherein R is²²And R^21-1Or R^21-2One of which, together with the carbon atom to which they are attached, forms a 5-, 6-or 7-membered carbocyclic ring;

R²³is H, F, Cl, Br, I, -CONR³⁷R³⁸、-SONR³⁷R³⁸、CF₃、NR³⁷R³⁸、NO₂、CN、-NR³⁷-CO-R³⁸、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁷R³⁸Group of (I) wherein R³⁷And R³⁸Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

R²⁴is H, F, Cl, Br, I, -CONR³⁹R⁴⁰、-SONR³⁹R⁴⁰、CF₃、NR³⁹R⁴⁰、NO₂、CN、-NR³⁹-CO-R⁴⁰、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR³⁹R⁴⁰Group of (I) wherein R³⁹And R⁴⁰Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

R²⁵is H, F, Cl, Br, I, -CONR⁴¹R⁴²、-SONR⁴¹R⁴²、CF₃、NR⁴¹R⁴²、NO₂、CN、-NR⁴¹-CO-R⁴²、-SO₂CF₃、C_1-4Alkyl, Si (CH)₃)₃And phenyl optionally substituted with one or two substituents selected from the group consisting of F, Cl, Br, I and-CO-NR⁴¹R⁴²Group of (I) wherein R⁴¹And R⁴²Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl and-C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups;

with the proviso that R²²、R²³、R²⁴And R²⁵No more than two of which are not H;

R³⁰selected from the group consisting of:

phenyl optionally substituted with one or two substituents selected from the group consisting of CF₃、COR⁴³、COOR⁴³、CN、NO₂、NR⁴⁴-CO-R⁴⁵、-S-(C_1-6Alkyl), NR)⁴⁴R⁴⁵Or from R⁴⁶A group represented by;

optionally substituted by one or two groups R⁴⁶A 2-, 3-or 4-pyridyl group substituted with the substituent represented by;

optionally substituted by one or two groups R⁴⁶A 2-, 4-or 5-pyrimidinyl group substituted with the substituent represented by (A);

wherein R is⁴³、R⁴⁴And R⁴⁵Independently selected from H, C_1-6Alkyl radical, C_3-7Cycloalkyl, -C_1-3Alkyl radical- (C)_3-7Cycloalkyl) groups; r⁴⁶Selected from the group consisting of F, Cl, Br, I, -CO-NR⁴⁴R⁴⁵、-SO₂NR⁴⁴R⁴⁵、OH、SH、C_1-6Alkyl radical, C_3-6Cycloalkyl, -OR⁴⁷、-CH₂-(C_3-6Cycloalkyl), -CH₂-phenyl, C_3-6Cycloalkyl, -SO₂CF₃and-CH₂CF₃Wherein R is⁴⁴And R⁴⁵Is as defined above, R⁴⁷Is C_1-6An alkyl group;

and enantiomers and diastereomers thereof, if present, and pharmaceutically acceptable salts thereof.

11、The method of claim 10 wherein R is substituted with^18-1Or R^18-2One of the substituents represented is H, represented by R^18-1Or R^18-2Another substituent represented is a group of the formula:

wherein R is²⁶、R²⁷、R²⁸、R²⁹And R³⁰As defined in claim 10.

12. The method of claim 10, wherein the active agent is selected from the group consisting of:

1- (4-fluorophenyl) -4- [2- (isochroman-1-yl) ethyl ] piperazine;

1- [2- (isochroman-1-yl) ethyl ] -4-phenylpiperazine;

1- [2- (isochroman-1-yl) ethyl ] -4- (4-methoxyphenyl) piperazine;

(-) -4- [4- [2- (isochroman-1-yl) ethyl ] piperazin-1-yl ] benzamide; and

(-) -4- [4- [2- (isochroman-1-yl) ethyl ] piperazin-1-yl ] benzenesulfonamide.

13. The method of claim 1, wherein the active agent is used to treat or enhance the treatment of tobacco and/or nicotine cravings.

14. The method of claim 1, wherein the active agent is used to reduce craving for tobacco and/or nicotine containing products.

15. The method of claim 1, wherein the active agent is used to reduce smoking and/or chewing of a tobacco or nicotine containing product.

16. The method of claim 1, wherein the active agent is administered to the patient three times per day.

17. The method of claim 1, wherein the active agent is selected from the group consisting of heterocyclic amines, phenylazacycloalkanes, and cabergoline and is administered in a dose of about 0.01 mg/day to about 10.0 mg/day.

18. The method of claim 17, wherein the active agent is selected from the group consisting of heterocyclic amines, phenylazacycloalkanes, cabergoline and cabergoline-type derivatives, administered at a dose of about 0.125 mg/day to about 6 mg/day.

19. The method of claim 18, wherein the active agent is administered in an amount of from about 0.375 mg/day to about 5 mg/day.

20. The method of claim 19, wherein the active agent is administered in an amount of from about 0.75 mg/day to about 4.5 mg/day.

21. The method of claim 17, wherein the patient is administered an initial dose of the active agent three times daily of about 0.125 mg/day titrated to higher levels every five to seven days until a therapeutic effect is achieved.

22. The method of claim 1, wherein the active agent is an aromatic bicyclic amine administered in an amount of from about 5 mg/day to about 120 mg/day.

23. The method of claim 22, wherein the aromatic bicyclic amine is administered in an amount of about 20 mg/day to about 100 mg/day.

24. The method of claim 23 wherein the aromatic bicyclic amine is administered in an amount of about 40 mg/day to about 80 mg/day.

25. The method of claim 22, wherein the patient is administered an initial dose of the active agent three times daily at about 5 mg/day titrated to higher levels every five to seven days until a therapeutic effect is achieved.