KR20050038583A - Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome - Google Patents

Abstract

This invention relates to the use of nicotinic acetylcholine receptor agonists for the treatment of restless legs syndrome (RLS). The invention further relates to the use of a nicotinic acetylcholine receptor agonist in the manufacture of a medicament for the treatment of RLS. The present invention also relates to a pharmaceutical composition for the treatment of RLS containing a nicotinic actylcholine receptor agonist.

Description

Nicotinic Acetylcholine Receptor Agonists in the Treatment of Restless Legs Syndrome

The present invention relates to nicotinic acetylcholine receptor agonists for the treatment of restless leg syndrome (RLS). The present invention also relates to the use of nicotinic acetylcholine receptor agonists in the manufacture of a medicament for the treatment of RLS. The invention further relates to pharmaceutical compositions for the treatment of RLS containing nicotinic acetylcholine receptor agonists.

Anxiety syndrome is an unknown cause of symptoms characterized by an annoying but generally painless sensation in one or both legs, which causes a diseased individual to experience irresistible irritation to move the legs. In some cases, the symptoms also occur in the arm. As the spontaneous movement of the limb feeling the sensation is transmitted, the sensory intensity is reduced or alleviated. When a sick individual rests or lies in the evening or at night, RLS most often affects these patients at worst or exclusively. Movements of toes, feet or legs are typically observed in patients with sitting or lying sickness, and are often incorrectly characterized as ecstasy or nerve hypersensitivity. RLS patients often have difficulty starting and maintaining sleep because individuals with an estimated 80% of illness often experience frequent limb movements every 20 to 30 seconds, with periodic limb movements during the night, often disturbing sleep. Can have The resulting chronic sleep disturbances and thus daytime fatigue often cause mood swings in the sick individual and may have a debilitating effect on the individual's ability to daily activities and actions.

Currently, the most prescribed treatments for RLS are dopamines (often dopamine-), such as Mirapeex (pramipexole), Permax (pergolide) and Requip (rofinirol). Dopamine is added to a system such as a receptor agonist) or cinemet (carbidopa / levodopa). Among dopamines, cinemet has been used for the longest time, but has recently been found to cause serious side effects that need to be increased in the vast majority of patients who have administered it for the treatment of RLS. Other less effective therapeutics for RLS, which are effective for patients who have some but not all significant daytime signs, especially those with pain syndrome associated with their RLS, include sedatives that can alleviate the nighttime signs of RLS; Analgesics (codeine, Darvon or Darvocet (propoxyphene), Dolophine (methadone), Percocet (oxycodone) for people with severe and persistent signs of RLS ), Including Ultram (tramadol) and Vicodin (hydrocodone); And anticonvulsants (including Gabapentin (neurontin)).

Agonists of nicotinic acetylcholine receptors significantly increase dopamine release in the brain. Since enhanced dopamine activity is associated with possible mechanisms to alleviate RLS and dopamine is rather effective in treating RLS, the agonists of nicotinic acetylcholine specific receptors treat RLS while avoiding some of the side effects associated with some known dopamine agents. Provide a separate means.

In particular, many of the compounds useful for binding to neuronal nicotinic receptor sites and modulating cholinergic function are described in International Patent Application WO 01/62736, filed Feb. 8, 2001; International Patent Application WO 99/35131, filed November 13, 1998; International Patent Application WO 99/55680, filed April 8, 1999; International Patent Application WO 98/18798, filed October 15, 1997; US Patent No. 5,977,131, filed March 31, 1998; US Patent No. 6,020,335, filed November 4, 1997; And EP 0 955 301 A2, filed March 25, 1999. The above applications are shared with the present application, the entire contents of which are hereby incorporated by reference.

Summary of the Invention

The present invention relates to a method for treating a mammal suffering from said syndrome comprising administering to a mammal, including a human, in need thereof, a nicotinic acetylcholine receptor agonist in a therapeutic amount of anxiety syndrome. .

The invention also treats a mammal suffering from the syndrome comprising administering an amount of a compound of formula I and a pharmaceutically acceptable salt thereof to a mammal, including a human, in need thereof: It is about how to.

In the above formula,

R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl, nonconjugated (C ₃ -C ₆ ) alkenyl, benzyl, XC (═O) R ¹³ or -CH ₂ CH ₂ -O- (C ₁ -C ₄ Alkyl;

R ² and R ³ are hydrogen, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, amino, halo, cyano, -SO _q (C ₁ -C ₆ ) Alkyl, where q is 0, 1 or 2, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, —CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ , -XC (= 0) R ¹³ , aryl- (C ₀ -C ₃ ) alkyl- or aryl- (C ₀ -C ₃ ) alkyl- Independently from O-, wherein the aryl is selected from phenyl and naphthyl, heteroaryl- (C ₀ -C ₃ ) alkyl- or heteroaryl- (C ₀ -C ₃ ) alkyl-O-, wherein the Heteroaryl is a 5 to 7 membered aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, X ² (C ₀ -C ₆ ) alkyl- and X ² (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- wherein X ² is absent or X ² is (C ₁ -C ₆ ) alkylamino- or [(C ₁ -C ₆ ) alkyl] ₂ amino-, Wherein said X ² (C ₀ -C ₆ ) alkyl- and Is X ² (C ₁ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl- the (C ₀ -C ₆₎ alkyl- or (C ₁ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl- The residue contains one or more carbon atoms, wherein one to three carbon atoms of the (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- residues are oxygen , Optionally substituted by nitrogen or sulfur atoms, provided that any two heteroatoms must be separated by two or more carbon atoms, wherein the (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) Any alkyl moiety of the alkoxy- (C ₀ -C ₆ ) alkyl-group may be optionally substituted with 2 to 7 fluorine atoms, wherein the aryl- (C ₀ -C ₃ ) alkyl- and the heteroaryl- One carbon atom of each alkyl moiety of (C ₀ -C ₃ ) alkyl- may be optionally substituted by oxygen, nitrogen or sulfur atoms, wherein each of said aryl and heteroaryl groups are optionally substituted with 1 to 7 fluorine atoms (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted with 2 to 7 fluorine atoms, halo (eg, chloro, fluoro, bromo or iodo), (C ₂ -C ₆ ) Alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, cyano, amino, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, -CO At least one substituent independently selected from ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ and -XC (= 0) R ¹³ , preferably 0 to 2 Optionally substituted with 4 substituents;

R ² and R ³ together with the carbon to which they are attached form a 4-7 membered monocyclic or 10-14 membered bicyclic which is a carbocyclic ring which may be saturated or unsaturated, wherein the benzo ring of formula (I) One to three unfused carbon atoms of the monocyclic ring and one to five carbon atoms of the bicyclic ring, which are not part, may be optionally and independently replaced by nitrogen, oxygen or sulfur, wherein the mono The cyclic and bicyclic rings are at least one substituent independently selected from (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl-, preferably monocyclic Optionally substituted with 0-2 substituents for the ring and 0-3 substituents for the bicyclic ring, wherein the total number of carbon atoms of the substituents does not exceed 6, wherein any alkyl moiety is Seven fluorine atoms, nitro, oxo, cyano, halo, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, hydroxy, amino, (C ₁ -C ₆₎ alkylamino -, [(C ₁ -C _{6) alkyl]} amino ^{_{-, -CO 2 R 4, -CONR}} 5 R 6, -SO 2 NR 7 R 8, -C (= O) R 13 and -XC (= O) R Optionally substituted with ¹³ ;

Each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ are attached Pyrrolidin, piperidine, morpholine, azetidine, piperazine, -N- (C ₁ -C ₆ ) alkylpiperazine or thiomorpholine ring or ring sulfur with substituted nitrogen is replaced by sulfoxide or sulfone To form a morpholine ring;

Each X is independently (C ₁ -C ₆ ) alkylene;

Provided that (a) at least one of R ¹ , R ² and R ³ must be other than hydrogen, and (b) when R ² and R ³ are hydrogen, R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl Or nonconjugated (C ₃ -C ₆ ) alkenyl.

Examples of heteroaryl groups that are possible in the definitions of R ² and R ³ in Formula I include thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl , Tetrazolyl, pyrrolyl and the following formulas.

Wherein one of R ⁹ and R ¹⁸ is hydrogen or (C ₁ -C ₆ ) alkyl and the other is and a bond to the benzo ring of formula (I).

Examples of the formula of formula (I) used in the process of the invention include those in which R ² and R ³ in formula (I) together with the benzo ring of formula (I) form a bicyclic ring system selected from the following formulas.

Wherein R ¹⁰ and R ¹⁷ are hydrogen, (C ₁ -C ₆ ) alkyl; And the total number of carbon atoms does not exceed 6, and any alkyl moiety has 1 to 7 fluorine atoms, nitro, cyano, halo, amino, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, -CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ , -XC (= 0) R ¹³ , phenyl and monocy Independently from (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- which may be optionally substituted with a click heteroaryl, wherein said heteroaryl is R ^{2 as} defined in the definition of a compound of Formula I And R ³ .

Compounds of formula (I) in another embodiment in the process of the present invention form a bicyclic or tricyclic ring system wherein R ² and R ³ are taken together with the benzo ring of formula (I).

Wherein R ¹⁰ and R ¹⁷ are defined as above, m is 0, 1 or 2 and one carbon atom of ring A may be optionally substituted with oxygen or N (C ₁ -C ₆ ) alkyl .

Compounds of formula (I) in other embodiments in the process of the invention are not attached to the benzo ring of formula (I) by either of R ² and R ³ .

Another embodiment of the invention relates to compounds of formula I and pharmaceutically acceptable salts thereof, wherein neither R ² nor R ³ together with the benzo ring of formula I form a bicyclic or tricyclic ring system.

Another embodiment of the invention relates to compounds of formula I, wherein one or both of R ² and R ³ are —C (═O) R ¹³ , wherein R ¹³ is (C ₁ -C ₆ ) alkyl. A further embodiment of the invention relates to compounds of formula I, wherein one or both of R ² and R ³ are —C (═O) R ¹³ , wherein R ¹³ is optionally substituted with 1 to 7 fluorine atoms (C ₁ -C ₆ ) alkyl or (C ₁ -C ₃ ) alkyl. Another embodiment relates to compounds of Formula (I), wherein one of R ² and R ³ is CF ₃ , fluoro, cyano, (C ₂ -C ₆ ) alkynyl or C ₂ F ₅ .

Specific examples of the compounds of formula (I) in the process of the invention include the following compounds and pharmaceutically acceptable salts and optical isomers thereof, which may include racemic mixtures or single enantiomers when intramolecular asymmetric centers or centers are present There is:

10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4-fluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4-methyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4-trifluoromethyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

3-trifluoromethyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

3-fluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4-nitro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4-amino-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

N ^1- [10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl] -acetamide;

6-methyl-5-thia-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] pentadeca-2 (10), 3,6,8-tetraene;

6-methyl-7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^2.10 .0 ^4,8 ] -pentadeca-2 (10), 3,5,8-tetraene;

5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

7-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

7-butyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,10 0 ^4,8 ] -pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-7-neopentyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene;

6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene;

5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene;

14-methyl-5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene;

5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,11 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

2-Fluoro-N- (4-hydroxy-10-aza-tricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-trien-5-yl) -benzamide ;

4-chloro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl cyanide;

3- (10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl) -5-methyl-1,2,4-oxadiazole;

1- (10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone;

10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-ol;

7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.0 ^{2,10 4,0} ] pentadeca-2,4 (8), 6,9-tetraene;

4- (2-methyl-2H-pyrazol-3-yl) -10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4- (1-methyl-1H-pyrazol-3-yl) -10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4,5-dichloro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

N ⁴ , N ⁴ -dimethyl-10-azatricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-triene-4-sulfonamide;

4- (1-pyrrolidinylsulfonyl) -10-azatricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-triene;

5,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2,4 (8), 9-trien-6-one;

6-oxo-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

3-phenyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

3-hydroxy-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

4,5-difluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene;

6-ethyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

6-isopropyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

6-benzyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene;

5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

6-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

7-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

7-ethyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

8-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,7,9-tetraen-6-one;

6-chloro-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

6-methoxy-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

6-chloro-10-fluoro-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene;

5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,7,9-tetraen-6-one.

The invention also provides a method of treating a mammal suffering from said syndrome comprising administering to a mammal, including a human, in need thereof, a compound of formula II and a pharmaceutically acceptable salt thereof It is about.

In which Z is CH ₂ , C (= 0) or CF ₂ ;

R ²¹ is hydrogen, (C ₁ -C ₆ ) alkyl, nonconjugated (C ₃ -C ₆ ) alkenyl, benzyl, XC (═O) R ¹³ or -CH ₂ CH ₂ -O- (C ₁ -C ₄ Alkyl;

R ²² and R ²³ are hydrogen, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, amino, halo, cyano, -SO _q (C ₁ -C ₆ ) Alkyl, where q is 0, 1 or 2, (C ₁ -C ₆ ) alkylamino, [(C ₁ -C ₆ ) alkyl] ₂ amino, CO ₂ R ⁴ , CONR ⁵ R ⁶ , SO ₂ NR ⁷ R ⁸ , C (= 0) R ¹³ , XC (= 0) R ¹³ , aryl- (C ₀ -C ₃ ) alkyl or aryl- (C ₀ -C ₃ ) alkyl-O-, Wherein said aryl is selected from phenyl and naphthyl, heteroaryl- (C ₀ -C ₃ ) alkyl or heteroaryl- (C ₀ -C ₃ ) alkyl-O-, wherein said heteroaryl is selected from oxygen, nitrogen and sulfur 5-7 membered aromatic rings containing 1-4 heteroatoms selected and X ² (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl wherein X ² is absent or X ² is a (C ₁ -C ₆₎ alkylamino or [(C ₁ -C _{6) alkyl]} amino, wherein said X ² (C ₀ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl (C ₀ -C ₆ ) Egg The coxi- (C ₀ -C ₆ ) alkyl moiety contains one or more carbon atoms, wherein one to three carbon atoms of the (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl moiety are oxygen, Optionally substituted by a nitrogen or sulfur atom, provided that any two heteroatoms must be separated by at least two carbon atoms, wherein the (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ Any alkyl moiety of the alkyl may be optionally substituted with 2 to 7 fluorine atoms, wherein each of the alkyl moieties of the aryl- (C ₀ -C ₃ ) alkyl and the heteroaryl- (C ₀ -C ₃ ) alkyl One carbon atom may be optionally replaced by oxygen, nitrogen or sulfur atoms, wherein each of said aryl and heteroaryl groups is (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, 2 to 7 (C ₁ -C ₆ ) alkoxy, halo (eg chloro, fluoro, bromo, optionally substituted with fluorine atoms) Or iodo), hydroxy, nitro, cyano, amino, (C ₁ -C ₆ ) alkylamino and [(C ₁ -C ₆ ) alkyl] ₂ amino, independently one or more substituents, preferably 0 Optionally substituted with 2 to 2 substituents;

R ²² and R ²³ together with the carbon to which they are attached form a 4-7 membered monocyclic or 10-14 membered bicyclic which is a carbocyclic ring which may be saturated or unsaturated, wherein the benzo ring of formula (II) One to three unfused carbon atoms of the monocyclic ring and one to five carbon atoms of the bicyclic ring, which are not part, may be optionally and independently replaced by nitrogen, oxygen or sulfur, wherein the mono The cyclic and bicyclic rings are at least one substituent independently selected from (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl-, preferably 0 to 2 substituents and bicyclic for the monocyclic ring Optionally substituted with 0 to 3 substituents for the click ring, wherein the total number of carbon atoms of the substituent does not exceed 6, wherein any alkyl moiety is 1 to 7 fluorine atoms , Nitro, oxo, cyano, halo, hydroxy, amino, (C ₁ -C ₆₎ alkylamino, [(C ₁ -C _{6) alkyl]} amino, phenyl and monocyclic heteroaryl may optionally be substituted with Wherein said heteroaryl is defined as in the definitions of R ²² and R ²³ above;

Each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X is as defined above;

Provided that (a) at least one of R ²¹ , R ²² and R ²³ must be other than hydrogen, and (b) when R ²² and R ²³ are hydrogen, R ²¹ cannot be methyl or hydrogen; (c) No fluorine atom of any of the fluoro substituted alkyl or alkoxy moieties of R ²² and R ²³ can be attached to the carbon attached to the heteroatom.

Examples of heteroaryl groups of each R ²² and R ²³ in the compounds of formula II in the process of the present invention include thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, Triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups.

Wherein R ⁹ and R ¹⁸ are as defined above.

Examples of compounds of formula (II) in the process of the invention are those in which R ²² and R ²³ together with the benzo ring of formula (II) form a bicyclic ring system selected from the following formulas.

Wherein R ¹⁰ and R ¹⁷ are as defined above.

Another embodiment of the invention relates to compounds of formula II in the process of the invention, wherein R ²² and R ²³ together with the benzo ring of formula II form a bicyclic or tricyclic ring system selected from the following formulas: .

Wherein m, R ¹⁰ and R ¹⁷ are as defined above and one of the carbon atoms of one ring A may be optionally substituted with oxygen or N (C ₁ -C ₆ ) alkyl.

Another embodiment of the invention relates to compounds of formula II in the process of the invention, wherein neither R ²² nor R ²³ is attached to the benzo ring of formula II via an oxygen atom.

Another embodiment of the invention relates to compounds of Formula (II), wherein R ²¹ is not methyl.

Preferred embodiments of the invention provide a compound of formula II

5,6-difluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2,4,6-triene;

11-benzyl-6-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

6-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-6-ol;

6-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-ol;

5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-ol;

11-benzyl-5-difluoromethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5-difluoromethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-5-ethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5-ethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5-isopropoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-4-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

4-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-4-ol;

11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

4-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

3-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-5-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5,7-dioxa-14-azatetracyclo [10.3.1.0 ^{2,10 4,8} ] hexadeca-2 (10), 3,8-triene;

11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

Trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-yl ester;

5- (4-trifluoromethyl-phenyl) -11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

5- (4-methoxy-phenyl) -11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene;

11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene-5-carboxylic acid methyl ester;

2- (11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-yl) -propan-2-ol;

5-pyridin-3-yl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene and pharmaceutically acceptable salts and optical isomers thereof The method of treatment is selected.

The present invention also provides a method of treating a mammal suffering from said syndrome comprising administering to a mammal, including a human, in need thereof a lower amount of a compound of Formula III and a pharmaceutically acceptable salt thereof. It is about.

Wherein X ³ is

a) -CH ₂ NR ³¹ R ³² ,

b) or

c) Is

Wherein R ³⁰ , R ³¹ and R ³² are independently selected from hydrogen and C ₁ -C ₆ alkyl; R ³³ is selected from hydrogen, halogen and C ₁ -C ₆ alkyl;

v is an integer from 0 to 4;

n is an integer of 0 to 2.

Preferred compounds of formula III in the process of the invention include

[2- (6-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) ethyl] -dimethylamine;

[2- (6-chloro-lH-pyrrolo [2,3-b] pyridin-3-yl) ethyl] -methylamine;

3-pyrrolidin-2-ylmethyl-1H-pyrrolo [2,3-b] pyridine;

3- (1-methyl-pyrrolidin-2-ylmethyl) -1H-pyrrolo [2,3-b] pyridine;

Dimethyl- [2- (1H-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] -amine;

Methyl- [2- (1H-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] -amine;

2- (1H-pyrrolo [2,3-b] pyridin-3-yl-ethylamine; and

3- (2-piperidin-1-yl-ethyl-1H-pyrrolo [2,3-b] pyridine.

The invention further comprises administering to a mammal, including a human, a mammal in need thereof a pharmaceutically acceptable salt of a compound of formula IV and a pharmaceutically acceptable salt thereof. To a method of treatment.

Wherein R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently selected from hydrogen, —CO ₂ R ⁴⁵ , aryl and heteroaryl, wherein aryl is selected from phenyl and naphthyl, wherein the heteroaryl is pyra Genyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindoleyl, benzimidazolyl, purinyl, carbazolyl, 1,2,5-thia Diazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, putridinyl, 5-azacytyl, 5-azaurasilyl, Triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, tria Zolyl, thienyl, imidazolyl, pyridinyl and pyrimidinyl, wherein said phenyl and said Heteroaryl is (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 (preferably 0 to 4) fluorine atoms, halo (ie chloro, fluoro, bromo or iodo), phenyl, benzyl , Hydroxy, acetyl, amino, cyano, nitro, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino optionally substituted with 1 to 7 (preferably 0 to 4) fluorine atoms And [(C ₁ -C ₆ ) alkyl] ₂ amino optionally substituted with 1 to 3 substituents independently, optionally substituted with 1 or 2 substituents;

R ⁴⁵ is (C ₁ -C ₆ ) alkyl, aryl, heteroaryl, (C ₁ -C ₄ ) alkylene-aryl and (C ₁ -C ₄ ) alkylene-heteroaryl, wherein the aryl and heteroaryl are As defined above, wherein (C ₁ -C ₆ ) alkyl is halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxy- (C _1- Optionally substituted with 1 to 3 substituents independently selected from C ₄ ) alkyl, amino, (C ₁ -C ₆ ) alkylamino and [(C ₁ -C ₆ ) alkyl] ₂ amino;

R ⁴⁶ is hydrogen or (C ₁ -C ₆ ) alkyl;

Provided that (a) at least one of R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ must be aryl or heteroaryl; (b) when both R ⁴¹ and R ⁴² are not hydrogen, R ⁴¹ and R ⁴² are in an “exo” arrangement; (c) neither R ⁴¹ nor R ⁴² can be -CO ₂ R ⁴⁵ ; (d) when R ⁴³ or R ⁴⁴ is —CO ₂ R ⁴⁵ and R ⁴⁵ is an alkyl or alkoxyalkyl group, then one of R ⁴¹ and R ⁴² must be aryl or heteroaryl; (e) when R ⁴¹ or R ⁴² is —CO ₂ R ⁴⁵ and R ⁴⁵ is an alkyl or alkoxyalkyl group, one of R ⁴³ and R ⁴⁴ must be aryl or heteroaryl.

Preferred compounds of the invention are compounds of formula IV in the process of the invention wherein one of R ⁴¹ and R ⁴² is optionally substituted phenyl and the other is hydrogen and in the process of the invention wherein R ⁴³ and R ⁴⁴ are hydrogen It includes a compound of formula IV.

More preferred compounds of formula IV in the process of the invention are those in which one of R ⁴¹ and R ⁴² is phenyl substituted with fluoro or nitro and the other is hydrogen and R ⁴³ and R ⁴⁴ are hydrogen.

More particular embodiments of the invention include compounds of formula IV in the process of the invention wherein R ⁴³ and R ⁴⁴ are hydrogen and one of R ⁴¹ and R ⁴² is hydrogen and the other is (a) 3-fluorophenyl; (b) 4-nitrophenyl; Or 3-fluoro-4-nitrophenyl.

Another embodiment of the present invention relates to the compounds of formula IV and pharmaceutically acceptable salts and optical isomers thereof described below in the process of the invention.

2β- (3,4-difluorophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3,5-dichlorobenzene) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-nitrophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-thiophene) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-4-chlorophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluorophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-hydroxyphenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-acetophenone) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-trifluoromethylphenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-4-methylphenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-chlorophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (n-benzyl-5-pyridonyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (n-methyl-5-pyridonyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-5-nitrophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-aminophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-4-trifluoromethyl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-chlorophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3,4-methylenedioxyphenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (2-chloro-6-methyl-5-pyridinyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-cyanophenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-4-nitro-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-amido-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-fluoro-4-amino-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (4-sulfonamido-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-methyl-5-isoxazole) -7-aza-bicyclo [2.2.1] heptane;

2β- (3-methyl-5-isoxazole) -7-aza-bicyclo [2.2.1] heptane, N-methyl;

2β- (3-methyl-5-isoxazole) -7-aza-bicyclo [2.2.1] heptane, N-acetyl;

2β- (3,4-difluorophenyl) -7-azabicyclo [2.2.1] heptane;

4- (7-Aza-bicyclo [2.2.1] hept-2-yl) -benzamidine;

2- (4-methanesulfonyl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

4- (7-aza-bicyclo [2.2.1] hept-2-yl) -phenol;

2- (4-methylsulfanyl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

4- (7-Aza-bicyclo [2.2.1] hept-2-yl) -benzoic acid methyl ester;

4- (7-Aza-bicyclo [2.2.1] hept-2-yl) -benzoic acid;

2- (3-fluoro-4-tetrazol-1-yl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (4-nitro-3-trifluoromethyl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- [3-fluoro-4- (5-trifluoromethyl-tetrazol-1-yl) -phenyl] -7-aza-bicyclo [2.2.1] heptane;

2- (3-chloro-4-nitro-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (4-tetrazol-1-yl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (6-methoxy-pyridin-2-yl) -7-aza-bicyclo [2.2.1] heptane;

2- (4-methanesulfinyl-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (4-bromo-3-fluoro-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (4-cyano-3-fluoro-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (3,4,5-trifluoro-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (3,4,5-trimethoxy-phenyl) -7-aza-bicyclo [2.2.1] heptane;

2- (5-nitro-furan-2-yl) -7-aza-bicyclo [2.2.1] heptane;

5- (7-aza-bicyclo [2.2.1] hept-2-yl) -3-methyl-benzo [d] isoxazole;

6- (7-aza-bicyclo [2.2.1] hept-2-yl) -3-methyl-benzo [d] isoxazole;

6- (7-aza-bicyclo [2.2.1] hept-2-yl) -1,4-dihydro-quinoxazolin-2,3-dione;

6- (7-aza-bicyclo [2.2.1] hept-2-yl) -quinoxazolin; And

1- [4- (7-Aza-bicyclo [2.2.1] hept-2-yl) -2-fluoro-phenyl] -ethanone.

The present invention further provides a predetermined amount of a compound of formula (V), its enantiomers, diastereomers and stereoisomers, and pharmaceutically acceptable salts and prodrugs to a mammal, including humans in need of treatment of restless leg syndrome It relates to a method for treating a mammal suffering from the syndrome, including.

In the above formula,

R ⁵¹ and R ⁵²

a) H, halo, CF ₃ , hydroxy, (C ₁ -C ₆ ) alkoxy, CH ₂ OH, —C (O) R ⁵⁴ , wherein R ⁵⁴ is H, (C ₁ -C ₆ ) alkyl, ( C ₆ -C ₁₀ ) aryl or benzyl (including substituted alkyl, aryl or benzyl), C≡N, C≡CR ⁵⁵ , wherein R ⁵⁵ is H, (C ₁ -C ₆ ) alkyl, ( C ₆ -C ₁₀ ) aryl (including substituted alkyl or aryl), -S (O) _p R ⁵⁵ , wherein R ⁵⁵ is H, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl (including substituted alkyl or aryl), p is 0, 1 or 2), (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkenyl, H ₂ N, di- ((C ₁ -C ₆ ) alkyl) amino, mono (C ₁ -C ₆ ) alkyl-amino, (C ₆ -C ₁₀ ) aryl-amino, (C ₃ -C ₈ ) cycloalkyl-amino, heteroaryl- Amino, cycloheteroalkyl-amino and CON (R ⁵⁵ ) ₂ , wherein each R ⁵⁵ is selected from hydrogen, (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) aryl;

b) R ⁵⁶ is _{H, (C 1 -C 6)} C0 2 R 56 selected from alkyl, phenyl and benzyl; And

c) optionally benzene-fused (C ₆ -C ₁₀ ) aryl, optionally benzene-fused (C ₃ -C ₈ ) cycloalkyl, optionally benzene-fused heteroaryl and optionally benzene-fused cycloheteroalkyl, wherein The heteroaryl group contains 5 to 10 atoms including 1 to 4 heteroatoms, and the cycloheteroalkyl contains 4 to 8 atoms including 1 or 2 heteroatoms selected from N, S and O)

Each independently selected from

Wherein any alkyl, alkenyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl groups in a), b) and c) are halogen, (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl Is optionally substituted with one or more substituents selected from hydroxy, hydroxymethyl, CHO and CO ₂ R ⁵⁶ , wherein R ⁵⁶ is as described above;

R ⁵³ is selected from H, optionally substituted benzyl and methyl;

Provided that when R ⁵³ is H, both R ⁵¹ and R ⁵² are not hydrogen and are not the same when R ⁵¹ and R ⁵² are selected from H, Br and Cl.

Preferred compounds of formula V in the process of the invention are those wherein R ⁵³ is selected from H, benzyl or methyl, and R ⁵¹ and R ⁵² are H, halo, (C ₁ -C ₆ ) alkyl, cyano, (C ₆ -C ₁₀ ) aryl, (C ₅ -C ₉ ) heteroaryl, (C ₁ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl-R ⁵⁵ and -C (O) R ⁵⁵ , wherein R ⁵⁵ is Each independently selected from H, (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₉ ) heteroaryl, and amino and one and di-substituted amino) ; However, in this case R ⁵³ is H when R ⁵¹ and R ⁵² are both not the H, Br and Cl, R ⁵³ is not a benzyl or methyl and R ⁵¹ is R ⁵² is hydrogen when.

More preferred compounds of formula V in the process of the invention are those in which R ⁵¹ and R ⁵² are H, ethyl, methyl, phenyl, vinyl, fluoro, bromo, chloro, isopropyl, tert-butyl, trifluoromethyl, acetyl, Propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, di-[(C ₁ -C ₆ ) alkyl] amino, (C ₁ -C ₆ ) Monoalkylamino, (C ₆ -C ₁₀ ) arylamino, (C ₃ -C ₈ ) cycloalkylamino, heteroarylamino, cycloheteroalkylamino and CON (R ⁵⁵ ) ₂ , wherein each R ⁵⁵ is hydrogen, ( C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) aryl; (C ₆ -C ₁₀ ) aryl and (C ₅ -C ₉ ) heteroaryl, wherein the aryl and heteroaryl groups are halogen, (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl, hydroxy, hydroxy Each independently selected from oxymethyl, CHO and CO ₂ R ⁵⁶ optionally substituted with one or more substituents.

More preferred compounds of formula V in the process of the invention are those wherein R ⁵³ is selected from optionally substituted benzyl or (C ₁ -C ₆ ) alkyl, wherein the substituents are defined above and R ⁵¹ and R ⁵² are hydrogen, halo, Cyano, optionally substituted (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkenyl, amino, di-[(C ₁ -C ₆ ) alkyl] amino, (C ₁ -C ₆ ) monoalkyl Amino, (C ₆ -C ₁₀ ) arylamino, (C ₃ -C ₈ ) cycloalkylamino, heteroarylamino, cycloheteroalkylamino and CON (R ⁵⁵ ) ₂ , wherein each R ⁵⁵ is hydrogen, (C ₁ -C ₆ ) alkyl and (C ₆ -C ₁₀ ) aryl, -C (O) R ⁵⁵ , wherein R ⁵⁵ is H, (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl Selected from), (C ₆ -C ₁₀ ) aryl or (C ₅ -C ₉ ) heteroaryl, wherein the substituents are as defined above.

More specifically, in the present invention, R ⁵¹ and R ⁵² is hydrogen, isopropyl, tert-butyl, trifluoromethyl, acetyl, propanoyl, 2, 2-dimethylpropanoyl, 2-methylpropanoyl , Butanoyl, pentanol, cyano, 2,4-difluorophenyl, 2-fluorophenyl, 2- and 3-thienyl, dimethylamino are each independently selected and R ⁵³ is hydrogen, benzyl, methyl And R ⁵¹ and R ⁵² are each independently selected from hydrogen, bromo, chloro, ethyl, methyl, fluoro, vinyl and phenyl.

Most preferred compounds of formula V and their pharmaceutically acceptable salts and optical isomers in the process of the invention are selected from:

9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

11-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

11-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

11-fluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

9,11-difluoro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one ;

9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

11-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9,11-diethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

9-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

11-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9,11-dimethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

11-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9,11-diphenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

9-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

11-vinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazokin-8-one;

9,11-divinyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one;

9-bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8- On;

3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8- On; And

3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazok-8-one .

The present invention further comprises administering a compound of formula VI and a pharmaceutically acceptable salt and prodrug to a mammal, including a human, in need of treatment for anxiety syndrome. It is about.

In the above formula,

A is -CH (R ⁶¹ )-and R ⁶¹ is hydrogen or optionally substituted (C ₁ -C ₆ ) alkyl wherein the substituents are hydroxy, (C ₁ -C ₆ ) alkoxy, oxo, (C _2- C ₆ ) at least one group individually selected from alkanoyl and NR ⁶² R ⁶³ ;

B is a chemical formula It's a flag of

In the above formula,

YW is CH ₂ , NH, O, S, CH ₂ CH ₂ , CH = CH, N = CH, NH-CH ₂ , OCH ₂ or SCH ₂ ;

Dashed lines indicate selective binding;

Z ² is C, N, O or S;

m is 1 or 2;

r is 0, 1 or 2, provided that r is 0 when Z ² is O or S, r is 1 when Z ² is N, and r is 2 when Z ² is C;

Each R ⁶⁴ and R ⁶⁵ is independently selected from hydrogen, optionally substituted (C ₁ -C ₆ ) alkyl, optionally substituted (C ₁ -C ₆ ) alkoxy and optionally substituted (C ₂ -C ₆ ) alkanoyl Wherein the substituent on the alkyl or alkanoyl group is selected from hydroxy, (C ₁ -C ₆ ) alkoxy, oxo, (C ₂ -C ₆ ) alkanoyl and NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ to which they are attached Together with the carbon atom to form an optionally substituted 6-membered heteroaromatic ring containing one or more heteroatoms selected from N, S and O, Z ² is C, wherein the substituent is optionally substituted (C ₁ -C ₆ ) Alkyl or optionally substituted (C ₁ -C ₆ ) alkoxy, wherein the substituents are (C ₁ -C ₆ ) alkyl, optionally substituted (C ₁ -C ₆ ) alkoxy and optionally substituted (C _2- C ₆₎ or selected from alkanoyl, R ⁶⁴ and one R ⁶⁵ forms a bond or together, with the proviso that Z ² is 0 or S if R ⁶⁴ and R ⁶⁵ is a bond Can not generate;

R ⁶⁰ is hydrogen or halo;

R ⁶² and R ⁶³ are each independently selected from hydrogen and optionally substituted (C ₁ -C ₆ ) alkyl, wherein the substituents are selected from (C ₁ -C ₆ ) alkyl and halo;

Provided that when -BA is attached at the 3-position of the pyridine ring, R ⁶¹ is hydrogen;

a) R ⁶⁰ is 6-chloro,

i) Z ² is C, the dotted line represents a bond, m and r are both 1 and R ⁶⁴ and R ⁶⁵ are both hydrogen such that WY is CH═CH, S, CH ₂ , NH, CH═N, OCH _Not selected from ₂ or SCH ₂ ;

ii) Z ² is nitrogen, the dotted line represents a bond, r is 0 and m is 1, so that R ⁶⁵ is not CF ₃ ;

iii) Z ² is C, the dotted line represents a bond, m and r are both 2, and each R ⁶⁴ and R ⁶⁵ is hydrogen such that WY is not S;

b) R ⁶⁰ is hydrogen, 6-bromo or 6-fluoro, Z ² is carbon, the dotted line represents a bond, m and r are both 1, R ⁶⁴ and R ⁶⁵ are both hydrogen, and WY is It's not sulfur.

Preferred compounds of formula VI in the process of the present invention are those wherein Z ² is N, m is 1 or 2, WY is S or CH = CH, R ⁶⁰ is halo or H, and R ⁶⁵ is (C ₁ -C ₆ Alkyl or halo and the dotted line is a bond.

Another preferred compound of formula VI in the process of the invention is that Z ² is C, R ⁶¹ is (C ₁ -C ₆ ) alkyl or hydrogen, m is 1, WY is S or CH = CH, or a dotted line is bonded R ⁶⁴ and R ⁶⁵ are each hydrogen or (C ₁ -C ₆ ) alkyl, or

Corresponding to part B

And

Are selected from.

Most preferred compounds of formula VI in the process of the invention

3- (6-chloro-pyridin-3-ylmethyl) -3H- [1,3,4] thiadiazole-2-ylideneamine;

5-methyl-3-pyridin-3-ylmethyl-3H-thiazol-2-ylideneamine;

3- (6-chloro-pyridin-3-ylmethyl) -5-methyl-3H- [1,3,4] thiadiazole-2-ylideneamine;

6-chloro-2- (6-chloro-pyridin-3-ylmethyl) -2H-pyridazine-3-ylideneamine;

3- (6-chloro-pyridin-3-ylmethyl) -3H-benzothiazol-2-ylideneamine;

3-pyridin-3-ylmethyl-3H- [1,3,4] thiadiazole-2-ylideneamine;

3- [1- (6-Chloro-pyridin-3-yl) -ethyl] -3 H-thiazol-2-ylideneamine;

3- [1- (6-chloro-pyridin-3-yl) -ethyl] -3H- [1,3,4] thiadiazole-2-ylideneamine;

3- [1- (6-Chloro-pyridin-3-ylmethyl) -thiazolidine-2-ylideneamine;

3-pyridin-3-ylmethyl-thiazolidine-2-ylideneamine;

5,7-dimethyl-1-pyridin-3-ylmethyl-3H- [1,8] naphthyridin-2-ylidene;

6-chloro-2-pyridin-3-ylmethyl-2H-pyridazine-3-ylideneamine; And

5-methyl-3-pyridin-3-ylmethyl-3H- [1,3,4] thiadiazol-2-ylideneamine and their pharmaceutically acceptable salts and optical isomers.

Compounds of Formulas (I), (II), (III), (IV), (V) and (VI) may have optical centers and thus generate different enantiomeric configurations. The present invention includes all enantiomers, diastereomers and other stereoisomers and racemic and other mixtures thereof of the compounds of Formulas (I), (II), (III), (IV), (V) and (VI).

Preferably, the amount of the compound of formula (I), (II), (III), (IV), (V) and (VI) administered in the method of the present invention is an effective amount in the treatment of restless leg syndrome.

Unless indicated otherwise, the term "halo" as used herein includes fluoro, chloro, bromo and iodo.

Unless indicated otherwise, the term "alkyl" as used herein includes straight chain, branched and cyclic residues having sufficient carbon atoms.

The term "alkoxy" as used herein means "-O-alkyl" or "alkyl-O-", where "alkyl" is defined as above.

The term "alkylene" as used herein refers to an alkyl radical having two soluble binding sites (ie -alkyl-), where "alkyl" is defined as above.

In such compounds, "aryl" includes, without limitation, optionally substituted phenyl and naphthyl, "cycloalkyl" includes, without limitation, optionally substituted cyclopentyl and cyclohexyl, wherein the cycloalkyl group may also be unsaturated, "Heteroaryl" includes, without limitation, thienyl, furyl, pyrano, pyrrolo, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, triazolyl, pyrazinyl and pyridyl, wherein "cycloheteroalkyl" Without limitation pyrrolidinyl, piperidinyl, tetrahydrofuryl and tetrahydropyrano.

Unless indicated otherwise, the term "one or more substituents" as used herein refers to one to a maximum number of possible substituents based on the number of available binding sites.

The term "nicotinic acetylcholine receptor agonist" means and includes the whole agonist and partial agonist of nicotinic acetylcholine receptor.

As used herein, the term “treatment” refers to a disorder or condition to which the term applies, or to reverse, alleviate, inhibit, or inhibit the progression of one or more signs of the condition or disorder, or to which the term applies. Or inhibits one or more signs of the above symptoms or disorders. As used herein, the term "treating" refers to a therapeutic action, as defined "treatment" immediately above.

The invention also relates to all radiolabeled forms of the compounds of formulas (I), (II), (III), (IV), (V) and (VI). Preferred radiolabeled compounds of formulas I, II, III, IV, V and VI are those whose radiolabels are selected from ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ I and ¹²⁵ I. The radiolabelled compounds are useful as research and diagnostic tools in metabolic studies, such as pharmacokinetic studies, and the like and in binding tests in animals and humans.

The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (I), (II), (III), (IV), (V) and (VI). Examples of pharmaceutically acceptable acid addition salts of compounds of Formulas I, II, III, IV, V and VI include hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, bromic acid, phosphoric acid, methanesulfonic acid, tartaric acid , Salts of malic acid, di-p-toluoyl tartaric acid and mandelic acid, and other acids known to those skilled in the art to form pharmaceutically acceptable acid addition salts for basic compounds. Other possible acid addition salts include, for example, pharmaceutically acceptable anions such as hydroiodide, nitrates, sulfates or bisulfates, phosphates or acid phosphates, acetates, lactates, gluconates, saccharides, benzoates , Salts containing methanesulfonates, ethanesulfonates, benzenesulfonates and pamolates (ie, 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) salts).

The present invention further relates to the use of nicotinic acetylcholine receptor agonists in the manufacture of a medicament for the treatment of restless leg syndrome (RLS). The present invention further provides the use of nicotinic acetylcholine receptor agonists selected from compounds of formula (I), (II), (III), (IV), (V) and (VI) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of restless leg syndrome (RLS). It is about. The present invention further provides a pharmaceutical composition for treating Anxiety Syndrome (RLS), comprising a compound selected from compounds of Formulas (I), (II), (III), (IV), (V) and (VI), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. It is about.

The present invention describes the use of a compound that binds to a neuronicotinic receptor site and is useful for the modulation of cholinergic function for the treatment of restless leg syndrome. In particular, many of the compounds useful in the present invention are described in International Patent Application WO 01/62736 filed Feb. 8, 2001 (compound of formula I); International Patent Application WO 99/35131, filed November 13, 1998 (compound of formula I); International Patent Application WO 99/55680, filed April 8, 1999 (compound of formula II); US Patent No. 5,977,131 filed March 31, 1998 (compound of Formula III); European Patent Publication No. EP 0 955 301 A2 (compound of Formula IV), filed March 25, 1999; International Patent Application WO 98/18798 filed October 15, 1997 (compound of formula V); And US Pat. No. 6,020,335 (compound of Formula VI), filed November 4, 1997.

Compounds of Formulas (I), (II), (III), (IV), (V) and (VI) and their pharmaceutically acceptable salts (hereinafter "active compounds") may be used orally, transdermally (eg, via the use of patches), intranasal, sublingual, rectal, Administration can be by parenteral or topical routes. Transdermal and oral administration are preferred. Most preferably, these compounds are administered in single or divided doses from about 0.1 mg to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day, more preferably from about 0.1 to about 3 mg per day. Although administered in amounts, it will necessarily vary depending upon the particular compound employed, the weight and symptoms of the subject being treated, and the particular route of administration chosen. However, dosage levels of from about 0.001 mg to about 10 mg per kg of body weight per day are most preferably used. However, the weight and symptoms of the person to be treated and the individual response to the medicament may vary, as well as the type of pharmaceutical formulation selected and the time period and interval during which the administration is performed. In some instances, dosage levels below the lower limit of the range may be more appropriate, while in other cases higher dosages may be used without any detrimental side effects, provided that the higher dosage is first administered in several smaller dosages. Divided and administered throughout the day.

The active compound may be administered by any of the several routes indicated above, alone or in combination with a pharmaceutically acceptable carrier or diluent. More specifically, the active compounds can be administered in a wide variety of different dosage forms, for example they are tablets, capsules, transdermal patches, lozenges, troches, hard candy, powders, sprays, creams, plasters, suppositories, It can be combined with various pharmaceutically acceptable inert carriers in the form of jelly, gels, pastes, lotions, ointments, water suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions may be suitably flavored and / or flavored. Generally, the active compound is present in the dosage form at a concentration level of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, sodium carbonate, dicalcium phosphate and glycine, may be combined with granular binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Disintegrants, for example starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this context also include lactose or lactose, and high molecular weight polyethylene glycols. Where aqueous suspensions and / or elixirs are preferred for oral administration, the active ingredient is combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, with various sweetening or flavoring agents, colorants and, if desired, It can be combined with emulsifiers and / or suspending agents.

For parenteral administration, solutions of the active compounds in sesame oil or peanut oil or in aqueous propylene glycol can be used. If desired, the aqueous solution may suitably be buffered (preferably above pH 8) and the liquid diluent first becomes isotonic. Such aqueous solutions are suitable for intravenous purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. All such solutions are readily prepared by standard pharmaceutical techniques well known to those skilled in the art under sterile conditions.

It is also possible to administer the active compound topically, which can be carried out according to standard pharmaceutical practice in the form of creams, patches, jelly, gels, pastes, ointments and the like.

Biological test

The effects of active compounds that inhibit the binding of nicotine to specific receptor sites have been described in Lippiello, PM and Fernandes, KG ("The Binding of L- [ ³ H] Nicotine To A Single Class of High-Affinity Sites in Rat Brain Membranes ", Molecular Pharm., 29: 448-54 (1986)] and Anderson (DJ) and Aneric, SP (" Nicotinic Receptor Binding of ³ H- "). Cytisine, ³ H-Nicotine and ³ H-Methylcarmbamylcholine In Rat Brain ", European J. Pharm., 253: 261-67 (1994)]).

step

Male Sprague-Dawley rats (200-300 g) from the Charles River are housed in stainless steel wire cages in groups and 12 hour day / night circulation (7 am-7 pm weekly) ). They had free water intake with a standard Purina Rat Chow.

Killed the rat as beheading. The brain was harvested immediately after the beheading. Membranes were prepared from brain tissue according to the method of somewhat modified Rapiello and Fernandes (Molecular Pharm., 29: 448-454 (1986)). Whole brains were harvested, rinsed with ice-cold buffer, and homogenized at 0 ° in 10 volume buffer for 30 seconds using Brinkmann Poltron ™ in Set 6. The buffer consists of 50 mM Tris HCl, pH 7.5 at room temperature. Homogenates were precipitated by centrifugation (10 min; 50,000 xg; 0-4 ° C). The supernatant was decanted and the membrane was gently resuspended with poltron and centrifuged again (10 min; 50,000 xg; 0-4 ° C.). After the second centrifugation, the membrane was resuspended in test buffer at a concentration of 1.0 g / 100 mL. The composition of the standard test buffer is 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl ₂ , 2 mM CaCl ₂ , and pH 7.4 at room temperature.

The defined tests were performed in borosilicate glass test tubes. The test mixture typically consisted of 0.9 mg of membrane protein in 1.0 mL of final incubation volume. Three tube sets were prepared, where each set of tubes contained 50 μl each of the vehicle, blank or test compound solution. To each tube 200 μl of [ ³ H] -nicotine in test buffer was added followed by 750 μl of membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 μM. The vehicle consisted of deionized water containing 30 μl of 1 N acetic acid per 50 mL of water. Test compound and cyclin were dissolved in the vehicle. The test was initiated by adding a membrane suspension to the tube and then vortexing. Samples were incubated at 0-4 ° C. in shake ice baths. The incubation was terminated by rapid filtration under vacuum through Whatman GF / B ™ glass fiber filters using a Brandel ™ multi-composite tissue harvester. After initial filtration of the test mixture, the filters were washed twice with ice cold test buffer (5 ml each). The filter was then placed in a counting vial, vigorously mixed with 20 ml of Ready Safe ™ (Beckman), and then radioactivity was measured. Samples were counted on an LKB Wallach Rackbeta ™ liquid scintillation counter with a 40-50% efficiency. All measurements were taken three times.

Calculation

Specific binding to the membrane (C) is the difference between the total binding (A) in the sample containing the vehicle and the membrane only and the nonspecific binding (B) in the sample containing the membrane and cyticin, ie

Specific binding = (C) = (A)-(B)

to be.

The specific binding (E) in the presence of the test compound is the difference between the total binding (D) and the nonspecific binding (B) in the presence of the test compound, ie (E) = (D)-(B).

% Inhibition = (1-((E) / (C)) × 100.

Compounds of the invention tested in this test showed IC ₅₀ values of 10 μΜ.

Claims (15)

A method of treating a subject having anxiety syndrome, comprising administering a therapeutically effective amount of the nicotinic acetylcholine receptor agonist to the subject in need thereof. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a compound of formula I and a pharmaceutically acceptable salt thereof. <Formula I> In the above formula, R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl, nonconjugated (C ₃ -C ₆ ) alkenyl, benzyl, XC (═O) R ¹³ or -CH ₂ CH ₂ -O- (C ₁ -C ₄ Alkyl; R ² and R ³ are hydrogen, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, amino, halo, cyano, -SO _q (C ₁ -C ₆ ) Alkyl, where q is 0, 1 or 2, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, —CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ , -XC (= 0) R ¹³ , aryl- (C ₀ -C ₃ ) alkyl- or aryl- (C ₀ -C ₃ ) alkyl- Independently from O-, wherein the aryl is selected from phenyl and naphthyl, heteroaryl- (C ₀ -C ₃ ) alkyl- or heteroaryl- (C ₀ -C ₃ ) alkyl-O-, wherein the Heteroaryl is a 5 to 7 membered aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, X ² (C ₀ -C ₆ ) alkyl- and X ² (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- wherein X ² is absent or X ² is (C ₁ -C ₆ ) alkylamino- or [(C ₁ -C ₆ ) alkyl] ₂ amino-, Wherein said X ² (C ₀ -C ₆ ) alkyl- and Is X ² (C ₁ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl- the (C ₀ -C ₆₎ alkyl- or (C ₁ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl- The residue contains one or more carbon atoms, wherein one to three carbon atoms of the (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- residues are oxygen , Optionally substituted by nitrogen or sulfur atoms, provided that any two heteroatoms must be separated by two or more carbon atoms, wherein the (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) Any alkyl moiety of the alkoxy- (C ₀ -C ₆ ) alkyl-group may be optionally substituted with 2 to 7 fluorine atoms, wherein the aryl- (C ₀ -C ₃ ) alkyl- and the heteroaryl- One carbon atom of each alkyl moiety of (C ₀ -C ₃ ) alkyl- may be optionally substituted by oxygen, nitrogen or sulfur atoms, wherein each of said aryl and heteroaryl groups are optionally substituted with 1 to 7 fluorine atoms (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy optionally substituted with 2 to 7 fluorine atoms, halo (eg, chloro, fluoro, bromo or iodo), (C ₂ -C ₆ ) Alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, cyano, amino, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, -CO At least one substituent independently selected from ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ and -XC (= 0) R ¹³ , preferably 0 to 2 Optionally substituted with 4 substituents; R ² and R ³ together with the carbon to which they are attached form a 4-7 membered monocyclic or 10-14 membered bicyclic which is a carbocyclic ring which may be saturated or unsaturated, wherein the benzo ring of formula (I) One to three unfused carbon atoms of the monocyclic ring and one to five carbon atoms of the bicyclic ring, which are not part, may be optionally and independently replaced by nitrogen, oxygen or sulfur, wherein the mono The cyclic and bicyclic rings are at least one substituent independently selected from (C ₀ -C ₆ ) alkyl- or (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl-, preferably monocyclic Optionally substituted with 0-2 substituents for the ring and 0-3 substituents for the bicyclic ring, wherein the total number of carbon atoms of the substituents does not exceed 6, wherein any alkyl moiety is Seven fluorine atoms, nitro, oxo, cyano, halo, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ alkynyl, hydroxy, amino, (C ₁ -C ₆₎ alkylamino -, [(C ₁ -C _{6) alkyl]} amino ^{_{-, -CO 2 R 4, -CONR}} 5 R 6, -SO 2 NR 7 R 8, -C (= O) R 13 and -XC (= O) R Optionally substituted with ¹³ ; Each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ are attached Pyrrolidin, piperidine, morpholine, azetidine, piperazine, -N- (C ₁ -C ₆ ) alkylpiperazine or thiomorpholine ring or ring sulfur with substituted nitrogen is replaced by sulfoxide or sulfone To form a morpholine ring; Each X is independently (C ₁ -C ₆ ) alkylene; Provided that (a) at least one of R ¹ , R ² and R ³ must be other than hydrogen, and (b) when R ² and R ³ are hydrogen, R ¹ is hydrogen, (C ₁ -C ₆ ) alkyl Or nonconjugated (C ₃ -C ₆ ) alkenyl. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a compound of Formula II and a pharmaceutically acceptable salt thereof. <Formula II> In which Z is CH ₂ , C (= 0) or CF ₂ ; R ²¹ is hydrogen, (C ₁ -C ₆ ) alkyl, nonconjugated (C ₃ -C ₆ ) alkenyl, benzyl, XC (═O) R ¹³ or -CH ₂ CH ₂ -O- (C ₁ -C ₄ Alkyl; R ²² and R ²³ are hydrogen, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxy, nitro, amino, halo, cyano, -SO _q (C ₁ -C ₆ ) Alkyl, where q is 0, 1 or 2, (C ₁ -C ₆ ) alkylamino, [(C ₁ -C ₆ ) alkyl] ₂ amino, CO ₂ R ⁴ , CONR ⁵ R ⁶ , SO ₂ NR ⁷ R ⁸ , C (= 0) R ¹³ , XC (= 0) R ¹³ , aryl- (C ₀ -C ₃ ) alkyl or aryl- (C ₀ -C ₃ ) alkyl-O-, Wherein said aryl is selected from phenyl and naphthyl, heteroaryl- (C ₀ -C ₃ ) alkyl or heteroaryl- (C ₀ -C ₃ ) alkyl-O-, wherein said heteroaryl is selected from oxygen, nitrogen and sulfur 5-7 membered aromatic rings containing 1-4 heteroatoms selected and X ² (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl wherein X ² is absent or X ² is a (C ₁ -C ₆₎ alkylamino or [(C ₁ -C _{6) alkyl]} amino, wherein said X ² (C ₀ -C ₆₎ alkoxy - (C ₀ -C ₆₎ alkyl (C ₀ -C ₆ ) Egg The coxi- (C ₀ -C ₆ ) alkyl moiety contains one or more carbon atoms, wherein one to three carbon atoms of the (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl moiety are oxygen, Optionally substituted by a nitrogen or sulfur atom, provided that any two heteroatoms must be separated by at least two carbon atoms, wherein the (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ Any alkyl moiety of the alkyl may be optionally substituted with 2 to 7 fluorine atoms, wherein each of the alkyl moieties of the aryl- (C ₀ -C ₃ ) alkyl and the heteroaryl- (C ₀ -C ₃ ) alkyl One carbon atom may be optionally replaced by oxygen, nitrogen or sulfur atoms, wherein each of said aryl and heteroaryl groups is (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 7 fluorine atoms, 2 to 7 (C ₁ -C ₆ ) alkoxy, halo (eg chloro, fluoro, bromo, optionally substituted with fluorine atoms) Or iodo), hydroxy, nitro, cyano, amino, (C ₁ -C ₆ ) alkylamino and [(C ₁ -C ₆ ) alkyl] ₂ amino, independently one or more substituents, preferably 0 Optionally substituted with 2 to 2 substituents; R ²² and R ²³ together with the carbon to which they are attached form a 4-7 membered monocyclic or 10-14 membered bicyclic which is a carbocyclic ring which may be saturated or unsaturated, wherein the benzo ring of formula (II) One to three unfused carbon atoms of the monocyclic ring and one to five carbon atoms of the bicyclic ring, which are not part, may be optionally and independently replaced by nitrogen, oxygen or sulfur, wherein the mono The cyclic and bicyclic rings are at least one substituent independently selected from (C ₀ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl-, preferably 0 to 2 substituents and bicyclic for the monocyclic ring Optionally substituted with 0 to 3 substituents for the click ring, wherein the total number of carbon atoms of the substituent does not exceed 6, wherein any alkyl moiety is 1 to 7 fluorine atoms , Nitro, oxo, cyano, halo, hydroxy, amino, (C ₁ -C ₆₎ alkylamino, [(C ₁ -C _{6) alkyl]} amino, phenyl and monocyclic heteroaryl may optionally be substituted with Wherein said heteroaryl is defined as in the definitions of R ²² and R ²³ above; Each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ is independently selected from hydrogen and (C ₁ -C ₆ ) alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ are attached Pyrrolidin, piperidine, morpholine, azetidine, piperazine, -N- (C ₁ -C ₆ ) alkylpiperazin or thiomorpholine ring, or ring sulfur, with nitrogen being replaced by sulfoxide or sulfone To form a thiomorpholine ring; Each X is independently (C ₁ -C ₆ ) alkylene; Provided that (a) at least one of R ²¹ , R ²² and R ²³ must be other than hydrogen, and (b) when R ²² and R ²³ are hydrogen, R ²¹ cannot be methyl or hydrogen; (c) No fluorine atom of any of the fluoro substituted alkyl or alkoxy moieties of R ²² and R ²³ can be attached to the carbon attached to the heteroatom. A heteroaryl group according to claim ² or ^{3 in} the definition of R ² and R ^{3 in} formula (I) or R ²² and R ²³ in formula (II) is thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thia Zolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups. Wherein one of R ⁹ and R ¹⁸ is hydrogen or (C ₁ -C ₆ ) alkyl and the other is and a bond to the benzo ring of formula I or formula II. 4. A compound according to claim 2 or 3, wherein R ² and R ^{3 in} formula (I) or R ²² and R ²³ in formula (II) together with the benzo ring of formula (I) or formula (II) form a bicyclic ring system selected from the following formulas How to do. Wherein R ¹⁰ and R ¹⁷ are hydrogen, (C ₁ -C ₆ ) alkyl; And the total number of carbon atoms does not exceed 6, and any alkyl moiety has 1 to 7 fluorine atoms, nitro, cyano, halo, amino, (C ₁ -C ₆ ) alkylamino-, [(C ₁ -C ₆ ) alkyl] ₂ amino-, -CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= 0) R ¹³ , -XC (= 0) R ¹³ , phenyl and monocy Independently from (C ₁ -C ₆ ) alkoxy- (C ₀ -C ₆ ) alkyl- which may be optionally substituted with a click heteroaryl. 4. The bicyclic or tricyclic ring according to claim 2, wherein R ² and R ³ in Formula I or R ²² and R ²³ in Formula II are selected from the following formula together with the benzo ring of Formula I or Formula II. To form a system. Wherein R ¹⁰ and R ¹⁷ are defined as above, m is 0, 1 or 2 and one carbon atom of ring A may be optionally substituted with oxygen or N (C ₁ -C ₆ ) alkyl . 4. A compound according to claim 2 or 3, wherein R ² and R ³ in Formula I or R ²² and R ²³ in Formula II do not form a bicyclic or tricyclic ring system with the benzo ring of Formula I or Formula II. How to be. 4. A compound according to claim 2 or 3 wherein R ² and R ^{3 in} formula (I) or R ²² and R ^{23 in} formula (II) are CF ₃ , fluoro, cyano, (C ₂ -C ₆ ) alkynyl or C ₂ F ₅ person way. The method of claim 2, wherein the nicotinic acetylcholine receptor agonist 10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4-fluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4-methyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4-trifluoromethyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 3-trifluoromethyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 3-fluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4-nitro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4-amino-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; N ^1- [10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl] -acetamide; 6-methyl-5-thia-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^2.10 .0 ^4,8 ] -pentadeca-2 (10), 3,5,8-tetraene; 5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 7-butyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,10 0 ^4,8 ] -pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-neopentyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,5,8-tetraene; 6,7-dimethyl-5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene; 5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene; 14-methyl-5,8,14-triazatetracyclo [10.3.1.0 ^{2,11 4,9} ] -hexadeca-2 (11), 3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,11 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 2-Fluoro-N- (4-hydroxy-10-aza-tricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-trien-5-yl) -benzamide ; 4-chloro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl cyanide; 3- (10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl) -5-methyl-1,2,4-oxadiazole; 1- (10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-yl) -1-ethanone; 10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo [9.3.1.0 ^{2,10 4,0} ] pentadeca-2,4 (8), 6,9-tetraene; 4- (2-methyl-2H-pyrazol-3-yl) -10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4- (1-methyl-1H-pyrazol-3-yl) -10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4,5-dichloro-10-azatricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; N ⁴ , N ⁴ -dimethyl-10-azatricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-triene-4-sulfonamide; 4- (1-pyrrolidinylsulfonyl) -10-azatricyclo [6.3.1.0 ^2,7 ] -dodeca-2 (7), 3,5-triene; 5,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2,4 (8), 9-trien-6-one; 6-oxo-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 3-phenyl-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 3-hydroxy-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 4,5-difluoro-10-aza-tricyclo [6.3.1.0 ^2,7 ] dodeca-2 (7), 3,5-triene; 6-ethyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 6-isopropyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 6-benzyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2,10 4,8} ] -pentadeca-2 (10), 3,6,8-tetraene; 5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 6-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 7-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 7-ethyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 8-methyl-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,7,9-tetraen-6-one; 6-chloro-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 6-methoxy-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 6-chloro-10-fluoro-5,14-diazatetracyclo [10.3.1.0 ^{2,11 4,9} ] hexadeca-2 (11), 3,5,7,9-pentaene; 5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9 ] hexadeca-2 (11), 3,7,9-tetraen-6-one; And pharmaceutically acceptable salts and optical isomers thereof. The method of claim 3, wherein the nicotinic acetylcholine receptor agonist 5,6-difluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2,4,6-triene; 11-benzyl-6-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 6-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-6-ol; 6-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-ol; 5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-ol; 11-benzyl-5-difluoromethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5-difluoromethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-5-ethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5-ethoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5-isopropoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-4-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 4-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-4-ol; 11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 4-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 3-nitro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-5-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5-fluoro-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5,7-dioxa-14-azatetracyclo [10.3.1.0 ^{2,10 4,8} ] hexadeca-2 (10), 3,8-triene; 11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 6-hydroxy-5-methoxy-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; Trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-yl ester; 5- (4-trifluoromethyl-phenyl) -11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 5- (4-methoxy-phenyl) -11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; 11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene-5-carboxylic acid methyl ester; 2- (11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-trien-5-yl) -propan-2-ol; 5-pyridin-3-yl-11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; And pharmaceutically acceptable salts and optical isomers thereof. The method of claim 1 wherein the nicotinic acetylcholine receptor agonist is a compound of Formula III and a pharmaceutically acceptable salt thereof. <Formula III> Wherein X ³ is a) -CH ₂ NR ³¹ R ³² , b) or c) Is Wherein R ³⁰ , R ³¹ and R ³² are independently selected from hydrogen and C ₁ -C ₆ alkyl; R ³³ is selected from hydrogen, halogen and C ₁ -C ₆ alkyl; v is an integer from 0 to 4; n is an integer of 0 to 2. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a partial agonist. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a total agonist. Use of nicotinic acetylcholine receptor agonists in the manufacture of a medicament for the treatment of lower extremity anxiety syndrome (RLS). Use of a nicotinic acetylcholine receptor agonist selected from the group consisting of a compound of formula (I), (II), (III), (IV), (V) and (VI) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of lower extremity anxiety syndrome (RLS).