CN1568184A - Use of nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome - Google Patents

Abstract

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

Description

Use of nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome

Background of the invention

The present invention relates to the use of nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome (RLS). The invention also relates to the use of the nicotinic acetylcholine receptor agonist in the preparation of medicine for treating RLS. The invention further relates to a pharmaceutical composition comprising a nicotinic acetylcholine receptor agonist for use in the treatment of RLS.

Restless legs syndrome is a disorder of unknown cause characterized by a bothersome, but usually painless, sensation in one or both legs that causes the patient to experience an irresistible urge to move the leg. Occasionally the condition also occurs in the arms. Voluntary movement of the extremities while the sensation is being felt reduces or lessens the intensity of the sensation. Often RLS affects patients when the individual suffering from the condition is resting or lying down at night or during the night. Movement of the toes, feet, or legs is typically observed when the patient is sitting or lying down and is often mistaken for restlessness or nervousness. Patients with RLS often have difficulty falling asleep and staying asleep, and an estimated 80% of affected individuals have cyclical limb movements throughout the night, sometimes as frequent as every 20 to 30 seconds, often resulting in partial arousal , interrupting sleep. The resulting chronic sleep deprivation and consequent daytime fatigue can often lead to mood swings and impair a person's ability to perform tasks and basic day-to-day functions.

Currently, the most commonly prescribed treatments for RLS are dopaminergic drugs (often dopamine-receptor agonists) such as Mirapex (pramipexole), Permax (pergolide), and Requip (ropinirole), or systemic Drugs that add dopamine such as Sinnema (carbidopa/levodopa). Among the dopaminergic agents, Synemus has been used the longest, but it has recently been found to cause severe cumulative side effects in most patients taking this agent for RLS. Other less commonly used RLS medications are sedatives, which can reduce the nocturnal symptoms of RLS; pain relievers (including codeine, dextropropoxyphene, or Darvocet, Dolophine (methadone), Ultram (tramadol) and Vicodin (hydrocodone), for RLS patients with severe refractory symptoms; and anticonvulsants, including gabapentin (Neurontin), which have significant daily Effective in patients with intermediate symptoms, especially those with pain syndromes associated with their RLS.

Nicotinic acetylcholine receptor agonists can significantly increase the release of dopamine in the brain. Since enhanced dopaminergic activity has been implicated in a possible mechanism of attenuation of RLS, and dopaminergic agents have been shown to be effective in the treatment of RLS, nicotinic acetylcholine-specific receptor agonists offer an alternative for the treatment of RLS. means of avoiding some of the side effects associated with certain known dopaminergic drugs.

In particular, some compounds that bind to the nicotinic receptor site of nerve cells and can be effectively used to regulate cholinergic function can refer to the following documents: International Patent Publication WO01/62736 filed on February 8, 2001; published in 1998 International Patent Publication WO99/35131 filed on November 13, 1999; International Patent Publication WO99/55680 filed on April 8, 1999; International Patent Publication WO98/18798 filed on October 15, 1997; US Patent 5,977,131, filed on March 31; US Patent 6,020,335, filed on November 4, 1997; and European Patent Publication EP0955301A2, filed on March 25, 1999. The above application, like the present application, is owned by the applicant and is hereby incorporated by reference in its entirety.

Summary of the invention

The present invention relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment an effective amount of a nicotinic acetylcholine receptor agonist for said syndrome.

The present invention further relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment a therapeutic amount of a compound of formula I:

in

R ¹ is hydrogen, (C ₁ -C ₆ )alkyl, non-conjugated (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 independently selected from hydrogen, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, hydroxyl, nitro, amino, halogen, 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(=O)R ¹³ , -XC(=O)R ¹³ , aryl(C ₀ -C ₃ )alkyl- or aryl(C ₀ -C ₃ )alkyl-O-, wherein the aryl is selected from phenyl and naphthyl, heteroaryl-(C ₀ -C ₃ )alkyl- or heteroaryl-(C ₀ -C ₃ )alkane Group-O-, wherein the heteroaryl group is selected from 5-7 membered aromatic rings containing 1-4 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 does not exist or X ² is (C ₁ -C ₆ )alkylamino- or [(C ₁ -C ₆ ) alkyl] ₂ amino-, and wherein said X ² (C ₀ -C ₆ ) alkyl- or X ² (C ₁ -C ₆ ) alkoxy-(C ₀ -C ₆ ) alkyl- (C ₀ -C ₆ )alkyl- or (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl- moieties contain at least one carbon atom, and wherein the (C ₀ -C ₆ ) 1 to 3 carbon atoms of the alkyl- or (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl- moiety may optionally be replaced by oxygen, nitrogen or sulfur atoms, provided that any two Such heteroatoms must be separated by at least two carbon atoms, and wherein the (C ₀ -C ₆ )alkyl- or (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl- Any alkyl part of the group may be optionally substituted by 2 to 7 fluorine atoms, and wherein the aryl-(C ₀ -C ₃ )alkyl- and the heteroaryl-(C ₀ -C ₃ ) One of the carbon atoms of each alkyl portion of the alkyl group can optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the aforementioned aryl and heteroaryl groups can optionally be replaced by one or more Substituents, preferably from 0 to 2 substituents, the substituents are independently selected from: (C ₁ -C ₆ ) alkyl optionally substituted by 1 to 7 fluorine atoms, optionally substituted by 2 to 7 fluorine atoms (C ₁ -C ₆ )alkoxy, halogen (such as chlorine, fluorine, bromine or iodine), (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, hydroxyl, Nitro, cyano, 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(=O)R ¹³ and -XC(=O)R ¹³ ;

Or R ² and R ³ , together with the carbons connected to them, form a 4-7 membered monocyclic or 10-14 membered bicyclic saturated or unsaturated carbocyclic ring, which is not the benzo ring shown in formula I 1 to 3 non-fused carbon atoms of the monocyclic ring and 1 to 5 carbon atoms of the bicyclic ring of the moiety may be optionally and independently replaced by nitrogen, oxygen or sulfur, and wherein the monocyclic The ring and the bicyclic ring can be optionally substituted by one or more substituents, preferably 0 to 2 substituents for the monocyclic ring and 0 to 3 substituents for the bicyclic ring, the substituents are independently selected from: (C ₀ -C ₆ )alkyl- or (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl-, wherein the total number of carbon atoms does not exceed 6, and wherein any alkyl moiety may optionally be 1 to 7 fluorine atoms are substituted; nitro, oxo, cyano, halogen, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, hydroxyl, 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(=O)R ¹³ and -XCXC(=O)R ¹³ ;

Each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ are independently selected from hydrogen and (C ₁ -C ₆ )alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ and and The nitrogens connected to them together form pyrrolidine, piperidine, morpholine, azetidine, piperazine, -N-(C ₁ -C ₆ ) alkyl piperazine or thiomorpholine rings, or rings in which A thiomorpholine ring in which the sulfur on is replaced by a sulfoxide or sulfone; and

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 cannot be hydrogen, (C ₁ -C ₆ )alkyl or non-conjugated (C ₃ -C ₆ )alkenyl groups, and pharmaceutically acceptable salts of these compounds.

Examples of heteroaryl groups in the definition of R ^{and R} in formula I may be the following groups: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidinyl, thiazolyl, tetra Azolyl, 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 a chemical bond to the benzo ring of formula I.

Examples of compounds of formula I that can be used in the methods of the invention are those wherein R ^{and R} together with the benzo ring of formula I form a bicyclic ring system selected from the group consisting of:

wherein R ¹⁰ and R ¹⁷ are independently selected from: hydrogen, (C ₁ -C ₆ )alkyl; and (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl, wherein the total number of carbon atoms No more than 6 and wherein any alkyl moiety may be optionally substituted by 1 to 7 fluorine atoms; nitro, cyano, halogen, 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(=O)R ¹³ , -XC(=O)R ¹³ , phenyl and A monocyclic heteroaryl group, wherein the definition of the heteroaryl group is the same as that of ^R2 and ^R3 in the compound of formula I above;

Another embodiment of the compound of formula I that can be used in the method of the invention is wherein R ^{and R} together with the benzo ring of formula I form a bicyclic or tricyclic ring system selected from the following:

wherein R ¹⁰ and R ¹⁷ are as defined above, and m is 0, 1 or 2, and wherein one of the carbon atoms of ring A may be optionally replaced by oxygen or N(C ₁ -C ₆ )alkyl.

Another embodiment of the compounds of formula I that are useful in the methods of this invention is wherein neither ^R2 nor ^R3 is attached to the benzo ring of formula I through an oxygen atom.

Another embodiment of the present invention relates to compounds of formula I and their pharmaceutically acceptable salts, wherein R ² and R ³ do not form a bicyclic or tricyclic ring system together with the benzo ring of formula I.

Another embodiment of this invention relates to compounds of formula I, wherein one or both of R ² and R ³ is -C(=O)R ¹³ , wherein R ¹³ is (C ₁ -C ₆ )alkyl. Additional embodiments of the present invention relate to compounds of formula I, wherein one or both of R ² and R ³ is -C(=O)R ¹³ , wherein R ¹³ is (C ₁ -C ₆ )alkyl or any A (C ₁ -C ₃ ) alkyl group substituted by 1 to 7 fluorine atoms is selected. Another embodiment of the present invention relates to compounds of formula I, wherein one of ^R2 and ^R3 is _CF3 , fluoro, cyano, _{( C2} - _C6 )alkynyl or _C2F5 .

Specific examples of compounds of formula I in the process of the invention are the following compounds, which, in the presence of one or more asymmetric centers in the molecule, may contain racemic mixtures or individual enantiomers:

10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

4-fluoro-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

4-methyl-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

4-trifluoromethyl-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

3-trifluoromethyl-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

3-Fluoro-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

4-nitro-10-azatricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

4-Amino-10-azatricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

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

6-Methyl-5-thia-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]pentadecane-2(10),3,6,8-tetraene;

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

5,7,13-Triazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,5,8-tetraene;

7-methyl-5,7,13-triazatetracyclo[ ^{9.3.1.02,10.04,8} ]-pentadecane- ² (10),3,5,8-tetraene;

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

6,7-Dimethyl-5,7,13-triazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,5,8-tetraene ;

7-Propyl-5,7,13-triazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,5,8-tetraene;

7-butyl-5,7,13-triazatetracyclo[ ^{9.3.1.02,10.04,8} ]-pentadecane-2( ¹⁰ ),3,5,8-tetraene;

7-isobutyl-5,7,13 ^- triazatetracyclo[ ^{9.3.1.02,10.04,8} ]-pentadecane-2(10),3,5,8-tetraene;

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

7-Phenyl-5,7,13-Triazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,5,8-tetraene;

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

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

6,7-Dimethyl-5,8,14-triazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]-hexadecane-2(11),3,5,7,9- pentene;

5,8,14-Triazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]-hexadecane-2(11),3,5,7,9-pentaene;

14-methyl-5,8,14-triazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]-hexadecane-2(11),3,5,7,9-pentacene;

5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetraene;

6-Methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetraene ;

2-Fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]-dodecane-2( ⁷ ),3,5-trien-5-yl)-benzo amides;

4-Chloro-10-azatricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

10-Azatricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-trien-4-yl cyanide;

3-(10-azatricyclo[6.3.1.0 ^2,7 ]dodecane-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxa Oxadiazole:

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

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

7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]pentadecane-2,4(8),6,9-tetraene;

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

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

4,5-dichloro-10-azatricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

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

4-(1-Pyrrolidinylsulfonyl)-10-azatricyclo[ ^6.3.1.02,7 ]-dodecane-2(7),3,5-triene;

5,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2,4(8),9-trien-6-one;

6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetraene ;

3-Phenyl-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

3-Hydroxy-10-aza-tricyclo[ ^6.3.1.02,7 ]dodecane-2(7),3,5-triene;

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

6-Ethyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetraene ;

6-isopropyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetracyclo alkene;

6-Benzyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 ^2,10 .0 ^4,8 ]-pentadecane-2(10),3,6,8-tetraene ;

5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

6-Methyl-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

7-Methyl-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

7-Ethyl-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

8-Methyl-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,7,9-tetraen-6-one;

6-Chloro-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

6-methoxy-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,5,7,9-pentaene;

5,8,14-Triazatetracyclo[10.3.1.0 ^2,11 .0 ^4,9 ]hexadecane-2(11),3,7,9-tetraen-6-one;

and their pharmaceutically acceptable salts and optical isomers.

The present invention further relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment a compound of formula II:

wherein Z is _CH2 , C(=O) or _CF2 ;

R ²¹ is hydrogen, (C ₁ -C ₆ )alkyl, non-conjugated (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 independently selected from the group consisting of hydrogen, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, hydroxyl, nitro, amino, halogen, 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] _2amino , CO ₂ R ⁴ , CONR ⁵ R ⁶ , SO ₂ NR ⁷ R ⁸ , C(=O)R ¹³ , XC(=O)R ¹³ , aryl-(C ₀ -C ₃ )alkyl or aryl-(C ₀ -C ₃ )alk Base-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 group is selected from 5-7 membered aromatic rings containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, and X ² (C ₀ -C ₆ )alkoxy-(C ₀ -C ₆ ) alkyl, wherein X ² does not exist or X ² is (C ₁ -C ₆ ) alkylamino or [(C ₁ -C ₆ ) alkyl] ₂ amino, and wherein said X ² (C ₀ -C ₆ The (C ₀ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl moiety of ) alkoxy-(C ₀ -C ₆ )alkyl contains at least one carbon atom, and wherein said (C ₁ - 1 to 3 carbon atoms of the C ₆ )alkoxy-(C ₀ -C ₆ )alkyl- moiety may optionally be replaced by oxygen, nitrogen or sulfur atoms, provided that any two such heteroatoms must be replaced by at least Two carbon atoms are separated, and any alkyl part of the (C ₀ -C ₆ ) alkoxy-(C ₀ -C ₆ ) alkyl group can be optionally substituted by 2 to 7 fluorine atoms, and wherein One of the carbon atoms of each alkyl moiety of the aryl-(C ₀ -C ₃ )alkyl and the heteroaryl-(C ₀ -C ₃ )alkyl may optionally be replaced by oxygen, nitrogen or Sulfur atom replacement, and wherein each of the aforementioned aryl and heteroaryl groups can optionally be substituted by one or more substituents, preferably from 0 to 2 substituents, the substituents are independently selected from: Optional C ₁ -C ₆ -alkoxy substituted by 1 to 7 fluorine atoms, C ₁ -C ₆ -alkoxy optionally substituted by 2 to 7 fluorine atoms, halogen (for example chlorine, fluorine, bromine or iodine ), hydroxyl, nitro, cyano, amino, (C ₁ -C ₆ ) alkylamino and [(C ₁ -C ₆ ) alkyl] ₂ amino;

Or R ²² and R ²³ , together with the carbons connected to them form a 4-7 membered monocyclic or 10-14 membered bicyclic saturated or unsaturated carbocyclic ring, which is not the benzo ring shown in formula II 1 to 3 non-fused carbon atoms of said monocyclic ring and 1 to 5 carbon atoms of said bicyclic ring of the moiety may be optionally and independently replaced by nitrogen, oxygen or sulfur, and wherein said Monocyclic and bicyclic can be optionally substituted by one or more substituents, preferably 0 to 2 substituents for monocyclic and 0 to 3 substituents for bicyclic, substituents are independently selected from: (C ₁ -C ₆ )alkoxy-(C ₀ -C ₆ )alkyl, wherein the total number of carbon atoms does not exceed 6 and wherein any alkyl moiety may be optionally substituted by 1 to 7 fluorine atoms; nitro, oxygen generation, cyano, halogen, hydroxyl, amino, (C ₁ -C ₆ ) alkylamino, [(C ₁ -C ₆ ) alkyl] ₂ amino, phenyl and monocyclic heteroaryl, wherein the heteroaryl The definition of the base is as defined above for R ²² and R ²³ ;

each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X are as defined above;

provided that: (a) at least one of R ²¹ , R ²² and R ²³ must be other than hydrogen, (b) when R ²² and R ²³ are hydrogen, R ²¹ cannot be methyl or hydrogen; and (c) R ²² and The fluorine atom in any fluorinated alkyl or alkoxy moiety of ^R23 cannot be connected to the carbon attached to the heteroatom; and the pharmaceutically acceptable salts of these compounds.

Examples of heteroaryl groups for each of R ^{and R} in the compounds of formula II in the methods of the invention are the following groups: thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, thiazole group, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:

wherein ^R9 and ^R18 are as defined above.

An example of a compound of formula II that can be used in the method of the present invention is wherein R ²² and R ²³ together with the benzo ring of formula II form a bicyclic ring system selected from the following:

wherein R ¹⁰ and R ¹⁷ are as defined above.

Another embodiment of the present invention relates to the compound of formula II in the method of the present 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:

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

Another embodiment of the present invention relates to the compound of formula II in the method of the present invention, wherein neither R ²² nor R ²³ is connected to the benzo ring of formula II through an oxygen atom.

Another embodiment of this invention relates to compounds of formula II in the methods of this invention, wherein R ²¹ is other than methyl.

A preferred embodiment of the present invention relates to a method of treatment, wherein a compound of formula II selected from the following is administered:

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

11-benzyl-6-methoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

6-methoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-6-ol;

6-Fluoro-1 1-aza-tricyclo[7.3.1.0 ^2,7 ]tridecane-2(7),3,5-triene;

11-benzyl-5-methoxy- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

11-benzyl-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-5-ol;

5-methoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-5-ol;

11-benzyl-5-difluoromethoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

5-Difluoromethoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

11-benzyl-5-ethoxy- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

5-ethoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

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

11-benzyl-4-methoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

4-methoxy-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-4-ol;

11-benzyl-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

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

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

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

11-benzyl-5-fluoro- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

5-Fluoro-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

5,7-dioxa-14-azatetracyclo[10.3.1.0 ^2,10 .0 ^4,8 ]hexadecane-2(10),3,8-triene;

11-benzyl-6-bromo-5-methoxy- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

11-benzyl-6-hydroxy-5-methoxy- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

6-Hydroxy-5-methoxy- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

11-Benzyl-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-5-yl triflate;

5-(4-trifluoromethyl-phenyl)-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

5-(4-methoxy-phenyl)-11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-triene;

Methyl 11-aza-tricyclo[7.3.1.0 ^2,7 ]tridecane-2(7),3,5-triene-5-carboxylate;

2-(11-aza-tricyclo[ ^7.3.1.02,7 ]tridecane-2(7),3,5-trien-5-yl)-propan-2-ol;

5-pyridin-3-yl- ¹¹ -aza-tricyclo[7.3.1.02,7]tridecane-2(7),3,5-triene;

and their pharmaceutically acceptable salts and optical isomers.

The present invention also relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering a therapeutic amount of a compound of formula III to a mammal in need of such treatment:

where ^X3 is:

a) -CH ₂ NR ³¹ R ³² ,

b)

or

c)

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; and

n is an integer from 0 to 2;

and their pharmaceutically acceptable salts.

Preferred compounds of formula III in the methods of the invention are:

[2-(6-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-dimethylamine;

[2-(6-Chloro-1H-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 present invention further relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment a therapeutic amount of a compound of formula IV:

wherein R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently selected from: hydrogen, -CO ₂ R ⁴⁵ , aryl and heteroaryl, wherein the aryl is selected from phenyl and naphthyl, and the heteroaryl The group is selected from pyrazinyl, benzofuryl, quinolinyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, Purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cincinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthyl Purinyl, pteridyl, 5-azacytidyl, 5-azuracilyl, triazolopyridyl, imidazopyridyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl, oxazolyl, iso Oxazolyl, thiazolyl, isothiazolyl, furyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridyl and pyrimidyl, and wherein the phenyl and the Heteroaryl can be optionally substituted by 1 to 3 substituents, preferably by one or two substituents, the substituents are independently selected from: optionally by 1 to 7 fluorine atoms (preferably 0 to 4 fluorine atoms) Substituted C ₁ -C ₆ -alkoxy, halogen (i.e. chlorine, fluorine, bromine or iodine), phenyl, benzyl, hydroxyl, acetyl, amino, cyano, nitro, optionally replaced by 1 to 7 C ₁ -C ₆ -alkoxy, (C ₁ -C ₆ )alkylamino and [(C ₁ -C ₆ )alkyl] _2amino substituted by fluorine atoms (preferably 0-4 fluorine atoms);

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, and wherein the (C ₁ -C ₆ )alkyl can be optionally substituted by 1 to 3 substituents independently selected from the following: halogen, (C ₁ - C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )alkoxy-(C ₁ -C ₄ )alkyl, amino, (C ₁ -C ₆ )alkylamino and [(C ₁ -C ₆ )alkyl] ₂ amino; and

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 neither R ⁴¹ nor R ⁴² is hydrogen, R ⁴¹ and R ⁴² in the "exo"configuration; (c) R ⁴¹ and R ⁴² cannot both be -CO ₂ R ⁴⁵ ; (d) if R ⁴³ or R ⁴⁴ is -CO ₂ R ⁴⁵ and R ⁴⁵ is alkyl or alkoxy ^{and (e) if R 41 or} R ⁴² is -CO ₂ R ⁴⁵ and R ⁴⁵ is ^alkyl or alkoxyalk group, one of R ⁴³ and R ⁴⁴ must be aryl or heteroaryl; and the pharmaceutically acceptable salts of these compounds.

Preferred compounds of the invention in the methods of the invention include compounds of formula IV, wherein one of R ⁴¹ and R ⁴² is optionally substituted phenyl and the other is hydrogen, and wherein R ⁴³ and R ⁴⁴ are hydrogen.

More preferred compounds of formula IV in the method of the invention are those wherein one of R ⁴¹ and R ⁴² is phenyl substituted by fluorine or nitro and the other is hydrogen, and wherein R ⁴³ and R ⁴⁴ are hydrogen.

A more specific preferred embodiment of the invention in the process of the invention are compounds of formula IV, 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 following compounds of formula IV, and their pharmaceutically acceptable salts, in the methods of the present 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-hydroxypyridyl)-7-aza-bicyclo[2.2.1]heptane;

2β-(N-methyl-5-hydroxypyridyl)-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-pyridyl-)-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-amidophenyl)-7-aza-bicyclo[2.2.1]heptane;

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

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

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

2-(4-Methylthio-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-quinoxaline-2,3-dione;

6-(7-Aza-bicyclo[2.2.1]hept-2-yl)-quinoxaline; and

1-[4-(7-Aza-bicyclo[2.2.1]hept-2-yl)-2-fluoro-phenyl]-ethanone and their pharmaceutically acceptable salts and optical isomers.

The present invention further relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment a therapeutic amount of a compound of formula V:

Its enantiomers, diastereomers and stereoisomers, and their pharmaceutically acceptable salts and prodrugs,

Wherein R ⁵¹ and R ⁵² are each independently selected from:

^a ) H; Halogen; CF ₃ ; Hydroxy _; (C _{1 -C 6} ⁾ alkoxy; CH ₂ OH; (C ₆ -C ₁₀ )aryl or benzyl (including substituted alkyl, aryl, or benzyl); C≡N; C≡CR ⁵⁵ , where 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, (C ₆ - C ₁₀ )aryl (including substituted alkyl or aryl), and 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; and

b) CO ₂ R ⁵⁶ , wherein R ⁵⁶ is selected from H, (CC ₆ )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 said heteroaryl group contains 5 to 10 atoms containing 1 to 4 heteroatoms, said cycloheteroalkyl contains 4 to 8 atoms, and contains 1 or 2 heteroatoms selected from N, S and O; and wherein any alkyl, alkenyl, aryl, cycloalkyl, cycloheteroalkyl and The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl, hydroxyl, hydroxymethyl, CHO and CO ₂ R ⁵⁶ , wherein R ⁵⁶ is as described above; and

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

with the proviso that when ^R53 is H, ^R51 and ^R52 are not both hydrogen, and are not the same when ^R51 and ^R52 are selected from H, Br and Cl.

Preferred compounds of formula V in the method of the invention are: wherein R ⁵³ is selected from H, benzyl or methyl and R ⁵¹ and R ⁵² are each independently selected from H, halogen, (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 , where R ⁵⁵ is H, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ )aryl and (C ₅ -C ₉ )heteroaryl, and amino and mono and di - Substituted amino; with the proviso that when ^R53 is H, ^R51 and ^R52 are not both hydrogen, Br and Cl, and when ^R53 is benzyl or methyl, then ^R51 and ^R52 are not hydrogen .

More preferred compounds of formula V in the method of the present invention are compounds of formula V as follows: wherein ^R51 and ^R52 are each independently selected from the group consisting of H, ethyl, methyl, phenyl, vinyl, fluorine, bromine, chlorine, Isopropyl, tert-butyl, trifluoromethyl, acetyl, propionyl, 2,2-dimethylpropionyl, 2-methylpropionyl, butyryl, valeryl, cyano, di-[(C ₁ -C ₆ )alkyl]amino, (C ₁ -C ₆ )monoalkylamino, (C ₆ -C ₁₀ )arylamino, (C ₃ -C ₈ )cycloalkylamino, heteroarylamino, cyclo Heteroalkylamino and CON(R ⁵⁵ ) ₂ , wherein each R ⁵⁵ is selected from 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 or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, (C ₁ -C ₆ )alkyl, (C ₆ -C ₁₀ ) aryl, hydroxy, hydroxymethyl, CHO and CO ₂ R ⁵⁶ .

More preferred compounds of formula V in the methods of the invention are compounds of formula V wherein R ⁵³ is selected from optionally substituted benzyl or (CC ₆ )alkyl, wherein the substituents are as described above, and R ⁵¹ and R ⁵² are each independently selected from hydrogen, halogen, cyano, optionally substituted (C ₁ -C ₆ )alkyl, (CC ₆ )alkenyl, amino, 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 selected from 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; (C ₆ -C ₁₀ )aryl or (C ₅ -C ₉ )heteroaryl, wherein the substituents are as described above.

More particularly, the present invention relates to compounds of formula V in the methods of the present invention: wherein ^R51 and ^R52 are each independently selected from hydrogen, isopropyl, tert-butyl, trifluoromethyl, acetyl, propionyl, 2,2-Dimethylpropionyl, 2-methylpropionyl, butyryl, pentanoyl, cyano, 2,4-difluorophenyl, 2-fluorophenyl, 2- and 3-thienyl, di Methylamino, and R ⁵³ is selected from hydrogen, benzyl, methyl, and R ⁵¹ and R ⁵² are each independently selected from hydrogen, bromine, chlorine, ethyl, methyl, fluorine, vinyl and phenyl.

The most preferred compound of formula V in the method of the invention is selected from:

9-Bromo-1,2,3,4,5,6-hexahydro-1,5-methylene (methano)-pyrido[1,2-a][1,5]diazocine-8- ketone;

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

9-Chloro-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaoctane-8-one;

11-Chloro-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaoctane-8-one;

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

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

9,11-Difluoro-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine-8- ketone;

9-Ethyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaoctane-8-one;

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

9,11-diethyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine-8 -ketone;

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

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

9,11-Dimethyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine-8 -ketone;

9-Phenyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaoctane-8-one;

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

9,11-Diphenyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine-8 -ketone;

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

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

9,11-divinyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine-8 -ketone;

9-Bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazocine- 8-keto;

3-Benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazocine- 8-keto; and

3-Benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methylene-pyrido[1,2-a][1,5]diazaocine- 8-keto

And their pharmaceutically acceptable salts and optical isomers.

The present invention further relates to a method of treating restless legs syndrome in mammals, including humans, comprising administering to a mammal in need of such treatment a therapeutic amount of a compound of formula VI:

and their pharmaceutically acceptable acid addition salts and prodrugs,

wherein A is -CH(R ⁶¹ )-, and R ⁶¹ is hydrogen or optionally substituted (C ₁ -C ₆ )alkyl, wherein the substituents comprise one or more groups selected from hydroxyl, (C ₁ -C ₆ ) Alkoxy, oxo, (C ₂ -C ₆ )alkanoyl and NR ⁶² R ⁶³ groups; and

B is a group of the formula:

wherein YW is _CH2 , NH, O, S, _CH2CH2 , CH=CH, N=CH, NH- _CH2 , _OCH2 or _{SCH2 ;}

A dashed line represents an optional bond;

^Z2 is C, N, O or S;

m is 1 or 2;

r is 0, 1 or 2, provided that r is 0 when ^Z2 is O or S, R is 1 when ^Z2 is N, and r is 2 when ^Z2 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 substituents on the alkyl or alkanoyl group are selected from hydroxyl, (C ₁ -C ₆ )alkoxy, oxo, (C ₂ -C ₆ )alkanoyl and NR ⁶² R ⁶³ , or R ⁶⁴ and R ⁶⁵ together with the carbon atoms to which they are attached form an optionally substituted six-membered heteroaromatic ring containing at least one heteroatom selected from N, S and O, and Z ² is C, wherein all The substituent is selected from optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₁ -C ₆ ) alkyl or optionally substituted (C ₁ -C ₆ ) alkoxy, wherein the The substituents are selected from (C ₁ -C ₆ )alkyl, optionally substituted (C ₁ -C ₆ )alkoxy and optionally substituted (C ₂ -C ₆ )alkanoyl, or R ⁶⁴ and one R ⁶⁵ together form a chemical bond, provided that R ⁶⁴ and R ⁶⁵ cannot form a chemical bond when Z ² is O or S;

R ⁶⁰ is hydrogen or halogen; and

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 halogen;

with the proviso that when -BA is attached to the 3-position of the pyridine ring, and ^R is hydrogen, and

a) R ⁶⁰ is 6-chloro and

i) Z ² is C, the dotted line represents a chemical bond, both m and r are 1, and R ⁶⁴ and R ⁶⁵ are both hydrogen, then WY is not selected from CH=CH, S, CH ₂ , NH, CH= N, _OCH2 or _SCH2 ;

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

^{or _ _}

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

Preferred compounds of formula VI for use in the methods of the invention are compounds of formula VI wherein Z is ^N , m is 1 or 2, WY is S or CH=CH, R is ^halogen or H, R ^is ( CC ₆ ) alkyl or halogen, and the dotted line is a chemical bond.

Another preferred compound of formula VI for use in the method of the invention is a compound of formula VI, wherein Z ² is C, R ⁶¹ is (C ₁ -C ₆ )alkyl or hydrogen, m is 1, WY is S or CH=CH, the dotted line is a chemical bond, R ⁶⁴ and R ⁶⁵ are each hydrogen or (C ₁ -C ₆ )alkyl, or correspond to part B of the following formula:

selected from:

as well as

The most preferred compound of formula VI in the method of the present invention is selected from the following group:

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]thiadiazol-2-ylideneamine;

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

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

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

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

5,7-Dimethyl-1-pyridin-3-ylmethyl-3H-[1,8]naphthyridine-2-ylidene;

6-Chloro-2-pyridin-3-ylmethyl-2H-pyridazin-3-ylideneamine; and

5-Methyl-3-pyridin-3-ylmethyl-3H-[1,3,4]thiadiazol-2-ylideneamine

and their pharmaceutically acceptable salts and optical isomers.

The compounds of formulas I, II, III, IV, V and VI may possess optical centers and thus exist in different enantiomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formulas I, II, III, IV, V, and VI, as well as their racemic and other mixtures.

Preferably, the amount of compound of formula I, II, III, IV, V and VI administered in the methods of the invention is an amount effective to treat restless legs syndrome.

Unless otherwise stated, the term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

Unless otherwise stated, the term "alkyl", as used herein, includes straight chain moieties, as well as branched and cyclic moieties in which the number of carbon atoms satisfies.

The term "alkoxy", as used herein, refers to "-O-alkyl" or "alkyl-O-", wherein "alkyl" is as defined above.

The term "alkylene", as used herein, refers to an alkyl group having two available sites of bonding (ie, -alkyl-), wherein "alkyl" is as defined above.

In the above compounds, "aryl" includes, without limitation, optionally substituted phenyl and naphthyl, "cycloalkyl" includes without limitation, optionally substituted cyclopentyl and cyclohexyl, and said cycloalkyl The group may also be unsaturated, and "heteroaryl" includes, without limitation, thienyl, furyl, pyrano, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, triazolyl, Azolyl, pyrazinyl, and pyridyl, and the term "cycloheteroalkyl" includes, without limitation, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, and tetrahydropyranyl.

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

The term "nicotinic acetylcholine receptor agonist" refers to and includes full and partial agonists of the nicotinic acetylcholine receptor.

The term "treating", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing a disease or condition, or one or more symptoms of such conditions or disorders, to which such terms apply. The term "treatment" as used herein refers to the act of treating, as defined above under "treating".

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 wherein the radioisotope is selected ^from3H , ^11C , ^14C , ^18F , ^{123I and125I} . Such radiolabeled compounds are useful as research and diagnostic tools in metabolism studies, and pharmacokinetic studies, among others, as well as in binding assays in animals and humans.

The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formulas I, II, III, IV, V and VI. Examples of pharmaceutically acceptable acid addition salts of compounds of formula I, II, III, IV, V and VI are salts formed with the following acids: hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid , salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malic acid, di-p-toluoyltartaric acid and mandelic acid, and other acids and basic compounds known to those skilled in the art. Acceptable acid addition salts. Other possible acid addition salts are, for example, salts containing pharmaceutically acceptable anions, such as hydroiodide, nitrate, sulfate or hydrogensulfate, phosphate or acid phosphate, acetate, lactic acid Salts, gluconates, sugars, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, and pamoates (i.e., 1,1′-methylenebis-( 2-hydroxy-3-naphthoic acid) salt).

The present invention further relates to the use of nicotinic acetylcholine receptor agonists in the manufacture of a medicament for the treatment of restless legs syndrome (RLS). The present invention further relates to nicotinic acetylcholine receptor agonists selected from compounds of formulas I, II, III, IV, V and VI or their pharmaceutically acceptable salts in the manufacture of a medicament for the treatment of restless legs syndrome (RLS) the use of. The present invention further relates to a pharmaceutical composition for the treatment of restless legs syndrome (RLS), comprising compounds selected from formulas I, II, III, IV, V and VI or their pharmaceutically acceptable salts and pharmaceutically acceptable Accepted carrier.

Detailed Description of the Invention

The present invention relates to the use of compounds that bind to nicotinic receptor sites of neurons and are effective for modulating cholinergic function in the treatment of restless legs syndrome. Preferably, many compounds that can be used in the present invention are found in: International Patent Publication WO01/62736, filed on February 8, 2001 (compounds of formula I); International Patent Publication WO99/35131, filed on November 13, 1998 (compound of formula I); International Patent Publication WO99/55680, filed on April 8, 1999 (compound of formula II); U.S. Patent 5,977,131, filed on March 31, 1998 (compound of formula III); European Patent Publication EP0955301A2, filed March 25, 1999 (compound of formula IV); International Patent Publication WO98/18798, filed October 15, 1997 (compound of formula V); and U.S. Patent 6,020,335, filed November 1997 Application on 4th (compound of formula VI).

Compounds of formula I, II, III, IV, V and VI and their pharmaceutically acceptable salts (hereinafter "active compounds") can be administered orally, transdermally (for example, by using a patch), intranasally, sublingually , rectal, parenteral or topical routes of administration. Transdermal and oral administration are preferred. These compounds are preferably administered in single or divided doses in a dosage range of from about 0.1 mg to up 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 depending on the The particular compound, the weight and physical condition of the patient being treated, and the particular route of administration chosen will necessarily vary. Preferably, however, dosage levels in the range of about 0.001 mg to about 10 mg per kilogram of body weight per day will be used. Variations may however occur depending on the weight and condition of the person to be treated and their individual response to the drugs, as well as the type of pharmaceutical formulation chosen and the time period and interval of administration. In some cases, doses below the lower limit of the above-mentioned range are sufficient, while in other cases even higher doses may be used without causing any harmful side effects, provided that such higher doses can be administered throughout the day at the first Divided into several smaller doses.

The active compound may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the several routes previously described. More particularly, the active compounds can be administered in a variety of different dosage forms, for example, they can be combined with various pharmaceutically acceptable inert carriers as tablets, capsules, transdermal patches, sugar lakes, troches, hard candies, powders , sprays, emulsions, ointments, suppositories, jellies, gels, ointments, lotions, salves, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents. In addition, pharmaceutical compositions for oral administration may be suitably sweetened and or flavored. Typically, the active compound is present in such dosage forms at a concentration in the range of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be mixed with various disintegrants such as starch (preferably corn, potato or tapioca starch), seaweed Acids are used with certain complexed silicates, and particulate binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers for gelatin capsules; preferred materials in this regard also include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are required for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring agents and, if desired, emulsifying and/or suspending agents, with diluents such as Water, ethanol, propylene glycol, glycerin, and combinations thereof are mixed together.

For parenteral administration, solutions of the active compound in sesame or peanut oil or in aqueous propylene glycol may be used. Aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and provide isotonic liquid diluents. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all such solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

The active compound may also be administered topically, through creams, patches, jellies, gels, ointments, ointments, and the like, according to standard pharmaceutical practice.

biological assay

The effect of active compounds on inhibiting the binding of nicotine to specific receptor sites is determined by the following method, which is a modification of the method of: Lippiello, PM and Fernandes, KG (see "The Binding of L-[ ^3H ]Nicotine To A Single Class of High-Affinity Sites in RatBrain Membranes", Molecular Pharm., 29:448-54 (1986)) and Anderson, DJ and Arneric, SP (see "Nicotinic Receptor Binding of ³ H-Cytisine, ³ H- Nicotine and ³ H-Methylcarmbamylcholine In Rat Brain", European J. Pharm., 253:261-67 (1994)).

method

Male Sprague-Dawley rats (200-300 g) from Charles River were raised in groups in hanging stainless steel wire cages and maintained a 12-hour light/dark cycle (7:00 am to 7:00 pm is the light period). They had free access to standard Purina rat chow and water.

Rats were killed by decapitation. Brains were removed immediately after decapitation. Membranes were prepared from brain tissue according to a modification of the method of Lippiello and Fernandez (Molecular Pharm., 29: 448-454 (1986). Whole brains were removed, rinsed with ice-cold buffer, and incubated at 0° C. at 10 Homogenize using Brinkmann Poltron ^™ (setting 6, 30 seconds) in volume buffer (w/v). Buffer consists of 50 mM Tris HCl at pH 7.5 at room temperature. By centrifugation (10 minutes; 50,000 × g; 0 to 4°C) to settle the tissue homogenate. Decant the supernatant, gently resuspend the membrane with a Poltron and centrifuge again (10 min; 50,000×g; 0 to 4°C). After the second centrifugation, the membrane Resuspend in assay buffer at a concentration of 1.0 g/100 ml. The standard assay buffer consists of 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, ₂ mM MgCl2, 2 mM CaCl2 and has a pH of _7.4 at room temperature.

Routine assays are carried out in borosilicate glass test tubes. The assay mixture typically consists of 0.9 mg of membrane protein in a final culture volume of 1.0 ml. Three sets of test tubes were prepared, each containing 50 µl of vehicle, blank or test compound solution. 200 μl of [ ³ H]-nicotine-assay buffer was added to each tube, followed by 750 μl of membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cydidine in the blank solution was 1 μM. The vehicle consisted of deionized water containing 30 μl of 1 N acetic acid per 50 ml of water. The test compound and cynicine are dissolved in the vehicle. The assay was initiated by vortexing after adding the membrane suspension to the tube. Incubate samples at 0 to 4 °C in an ice-cold shaking water bath. Incubation was terminated by rapid vacuum filtration with WhatmanGF/B ^™ glass fiber filters using a Brandel ^™ multilayer tissue harvesting device. After the initial filtration of the assay mixture, the filters were washed twice with ice-cold assay buffer (5 ml each). The filter was then placed in a counting cup and mixed vigorously with 20 ml of Ready Safe ^™ (Beckman) prior to quantification of radioactivity. Samples were counted at 40-50% efficiency in a LKB Wallach Rackbeta ^™ liquid scintillation counter. All assays were performed in triplicate.

calculate

Specific binding to the membrane (C) is the difference between the total binding (A) of the sample containing only the carrier and the membrane and the non-specific binding to cydidine (B) of the sample containing the membrane, i.e.,

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

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

% inhibition = (1 - ((E)/(C)) x 100.

The compounds of the invention tested showed _IC50 values of less than 10 [mu]M in the above assays.

Claims (15)

1. a method for the treatment of the restless legs syndrome patient comprises the nAChR agonist to this syndrome effective dose of patient's administering therapeutic of the such treatment of needs.

2. according to the process of claim 1 wherein that the nAChR agonist is the chemical compound of formula I:

Wherein

R ¹Be hydrogen, (C ₁-C ₆) alkyl, unconjugated (C ₃-C ₆) alkenyl, benzyl, XC (=O) R ¹³Or-CH ₂CH ₂-O-(C ₁-C ₄) alkyl;

R ²And R ³Be independently selected from hydrogen, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, hydroxyl, nitro, amino, halogen, cyano group ,-SO _q(C ₁-C ₆) alkyl (wherein q is 0,1 or 2), (C ₁-C ₆) alkyl amino-, [(C ₁-C ₆) alkyl] ₂Amino-,-CO ₂R ⁴,-CONR ⁵R ⁶,-SO ₂NR ⁷R ⁸,-C (=O) R ¹³,-XC (=O) 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 and contains 1～4 heteroatomic 5～7 yuan of aromatic rings that are selected from oxygen, nitrogen and sulfur; X ²(C ₀-C ₆) alkyl-and X ₂(C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl-, X wherein ²Do not exist or X ²Be (C ₁-C ₆) alkyl amino-or [(C ₁-C ₆) alkyl] ₂Amino-, and wherein said X ²(C ₀-C ₆) alkyl-or X ²(C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl-(C ₀-C ₆) alkyl-or (C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl-part contains at least one carbon atom, and wherein said (C ₀-C ₆) alkyl-or (C ₁-C ₆) alkoxyl-(C ₀-C ₆) 1～3 carbon atom of alkyl-part can be randomly substitutes by oxygen, nitrogen or sulphur atom, condition is that any two such hetero atoms must be by at least two carbon atoms separately, and wherein said (C ₀-C ₆) alkyl-or (C ₁-C ₆) alkoxyl-(C ₀-C ₆) any moieties of alkyl-group can randomly be replaced by 2～7 fluorine atoms, and wherein said aryl-(C ₀-C ₃) alkyl-and described heteroaryl-(C ₀-C ₃) alkyl-one of the carbon atom of each moieties can randomly be substituted by oxygen, nitrogen or sulphur atom, and wherein each aforesaid aryl and heteroaryl groups can be chosen wantonly by one or more substituent group, preferably 0～2 substituent group replaces, and substituent group is independently selected from: the optional (C that is replaced by 1～7 fluorine atom ₁-C ₆) alkyl, optional by the (C of 2～7 fluorine atoms replacements ₁-C ₆) alkoxyl, halogen (for example, chlorine, fluorine, bromine or iodine), (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, hydroxyl, nitro, cyano group, amino, (C ₁-C ₆) alkyl amino-, [(C ₁-C ₆) alkyl] ₂Amino-,-CO ₂R ⁴,-CONR ⁵R ⁶,-SO ₂NR ⁷R ⁸,-C (=O) R ¹³With-XC (=O) R ¹³

Or R ²And R ³Form the saturated or undersaturated carbocyclic ring of 4～7 yuan of monocyclic or 10～14 yuan of dicyclos with the carbon that is connected with them, wherein can randomly and independently do not substituted by nitrogen, oxygen or sulfur by the carbon atom of described monocyclic 1～3 non-condensed of the part of the benzo ring shown in the formula I and 1～5 carbon atom of described dicyclo, and wherein said monocycle and dicyclo can be chosen wantonly by one or more substituent group and replace, preferably replaced by 0～2 substituent group for monocycle and replaced by 0～3 substituent group for dicyclo, substituent group is independently selected from: (C ₀-C ₆) alkyl-or (C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl-, wherein the sum of carbon atom is no more than 6, and wherein any moieties can randomly be replaced by 1～7 fluorine atom; Nitro, oxo, cyano group, halogen, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, hydroxyl, amino, (C ₁-C ₆) alkyl amino-, [(C ₁-C ₆) alkyl] ₂Amino-,-CO ₂R ⁴,-CONR ⁵R ⁶,-SO ₂NR ⁷R ⁸,-C (=O) R ¹³With-XCXC (=O) R ¹³

Each R ⁴, R ⁵, R ⁶, R ⁷, R ⁸And R ¹³Be independently selected from hydrogen and (C ₁-C ₆) alkyl, or R ⁵And R ⁶, or R ⁷And R ⁸With the nitrogen that links to each other with them form pyrrolidine, piperidines, morpholine, azetidine, piperazine ,-N-(C ₁-C ₆) alkyl piperazine or tetrahydro-1,4-thiazine ring, or the sulfur on its medium ring is by sulfoxide or the displaced tetrahydro-1,4-thiazine ring of sulfone; With

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

Condition is: (a) R ¹, R ²And R ³In at least one must not be a hydrogen, and (b) work as R ²And R ³When being hydrogen, R ¹Can not be hydrogen, (C ₁-C ₆) alkyl or unconjugated (C ₃-C ₆) alkenyl, and the acceptable salt of the pharmacy of these chemical compounds.

3. according to the process of claim 1 wherein that the nAChR agonist is the chemical compound of formula II:

Wherein Z is CH ₂, C (=O) or CF ₂

R ²¹Be hydrogen, (C ₁-C ₆) alkyl, unconjugated (C ₃-C ₆) alkenyl, benzyl, XC (=O) R ¹³Or-CH ₂CH ₂-O-(C ₁-C ₄) alkyl;

R ²²And R ²³Be independently selected from: hydrogen, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl, hydroxyl, nitro, amino, halogen, cyano group ,-SO _q(C ₁-C ₆) alkyl (wherein q is 0,1 or 2), (C ₁-C ₆) alkyl amino, [(C ₁-C ₆) alkyl] ₂Amino, CO ₂R ⁴, CONR ⁵R ⁶, SO ₂NR ⁷R ⁸, C (=O) R ¹³, XC (=O) 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 and contains 1～4 heteroatomic 5～7 yuan of aromatic rings that are selected from oxygen, nitrogen and sulfur, and X ²(C ₀-C ₆) alkoxyl-(C ₀-C ₆) alkyl, wherein X ²Do not exist or X ²Be (C ₁-C ₆) alkyl amino or [(C ₁-C ₆) alkyl] ₂Amino, and wherein said X ²(C ₀-C ₆) alkoxyl-(C ₀-C ₆) (the C of alkyl ₀-C ₆) alkoxyl-(C ₀-C ₆) moieties contains at least one carbon atom, and wherein said (C ₁-C ₆) alkoxyl-(C ₀-C ₆) 1～3 carbon atom of alkyl-part can be randomly substitutes by oxygen, nitrogen or sulphur atom, condition is that any two such hetero atoms must be by at least two carbon atoms separately, and wherein said (C ₀-C ₆) alkoxyl-(C ₀-C ₆) any moieties of alkyl can be randomly replaced by 2～7 fluorine atoms, and wherein said aryl-(C ₀-C ₃) alkyl and described heteroaryl-(C ₀-C ₃) one of the carbon atom of each moieties of alkyl can randomly substitute by oxygen, nitrogen or sulphur atom, and wherein each aforesaid aryl and heteroaryl groups can be chosen wantonly by one or more substituent group, preferably replaced by 0～2 substituent group, substituent group is independently selected from: the optional C that is replaced by 1～7 fluorine atom ₁-C ₆-alkoxyl, the optional C that is replaced by 2～7 fluorine atoms ₁-C ₆-alkoxyl, halogen (for example chlorine, fluorine, bromine or iodine), hydroxyl, nitro, cyano group, amino, (C ₁-C ₆) alkyl amino and [(C ₁-C ₆) alkyl] ₂Amino;

Or R ²²And R ²³Form the saturated or undersaturated carbocyclic ring of 4～7 yuan of monocyclic or 10～14 yuan of dicyclos with the carbon that is connected with them, wherein can randomly and independently do not substituted by nitrogen, oxygen or sulfur by the carbon atom of described monocyclic 1～3 non-condensed of the part of the benzo ring shown in the formula II and 1～5 carbon atom of described dicyclo, and wherein said monocycle and dicyclo can be chosen wantonly by one or more substituent group and replace, preferably replaced by 0～2 substituent group for monocycle and replaced by 0～3 substituent group for dicyclo, substituent group is independently selected from: (C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl, wherein the sum of carbon atom is no more than 6, and wherein any moieties can randomly be replaced by 1～7 fluorine atom; Nitro, oxo, cyano group, halogen, hydroxyl, amino, (C ₁-C ₆) alkyl amino, [(C ₁-C ₆) alkyl] ₂Amino, phenyl and bicyclic heteroaryl, the definition of wherein said heteroaryl such as above-mentioned R ²²And R ²³Definition;

Each R ⁴, R ⁵, R ⁶, R ⁷, R ⁸And R ¹³Be independently selected from hydrogen and (C ₁-C ₆) alkyl, or R ⁵And R ⁶, or R ⁷And R ⁸With the nitrogen that links to each other with them form pyrrolidine, piperidines, morpholine, azetidine, piperazine ,-N-(C ₁-C ₆) alkyl piperazine or tetrahydro-1,4-thiazine ring, or the sulfur on its medium ring is by sulfoxide or the displaced tetrahydro-1,4-thiazine ring of sulfone; And

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

Condition is: (a) R ²¹, R ²²And R ²³In at least one must not be a hydrogen, (b) work as R ²²And R ²³When being hydrogen, R ²¹Can not be methyl or hydrogen; And (c) R ²²And R ²³Any fluoric alkyl or the fluorine atom in the alkoxyl part can not be connected with the carbon that is connected with hetero atom; And the acceptable salt of the pharmacy of these chemical compounds.

4. according to the method for claim 2 or 3, the R in formula I wherein ²And R ³With the R among the formula II ²³Definition in heteroaryl be following group: thienyl, oxazolyl, isoxazolyl, pyridine radicals, pyrimidine radicals, thiazolyl, tetrazole radical, isothiazolyl, triazolyl, imidazole radicals, tetrazole radical, pyrrole radicals and following group:

R wherein ⁹And R ¹⁸One of be hydrogen or (C ₁-C ₆) alkyl, and another is the chemical bond that links to each other with the benzo ring of formula I or formula II.

5. according to the method for claim 2 or 3, the R among its Chinese style I ²And R ³, or formula II in R ²²And R ²³With the benzo ring of formula I or formula II, form and be selected from following bicyclic system:

R wherein ¹⁰And R ¹⁷Be independently selected from hydrogen, (C ₁-C ₆) alkyl; (C ₁-C ₆) alkoxyl-(C ₀-C ₆) alkyl-, wherein the sum of carbon atom be no more than 6 and wherein any moieties can choose wantonly by 1～7 fluorine atom and replace; Nitro, cyano group, halogen, amino, (C ₁-C ₆) alkyl amino-, [(C ₁-C ₆) alkyl] ₂Amino-,-CO ₂R ⁴,-CONR ⁵R ⁶,-SO ₂NR ⁷R ⁸,-C (=O) R ¹³,-XC (=O) R ¹³, phenyl and bicyclic heteroaryl.

6. according to the method for claim 2 or 3, the R among its Chinese style I ²And R ³, or formula II in R ²²And R ²³With the benzo ring of formula I or formula II, form and be selected from following dicyclo or three-ring system:

R wherein ¹⁰And R ¹⁷As defined above, m is 0,1 or 2, and the carbon atom of its medium ring A can be chosen wantonly by oxygen or N (C ₁-C ₆) alkyl replaces.

7. according to the method for claim 2 or 3, the R among its Chinese style I ²And R ³, or formula II in R ²²And R ²³The benzo ring with formula I or formula II does not form dicyclo or three-ring system.

8. according to the method for claim 2 or 3, the R among its Chinese style I ²And R ³One of or formula II in R ²²Or R ²³Be CF ₃, fluorine, cyano group, (C ₂-C ₆) alkynyl or C ₂F ₅

9. according to the method for claim 2, wherein the nAChR agonist is selected from:

10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-fluoro-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-methyl isophthalic acid 0-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-Trifluoromethyl-1 0-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

3-Trifluoromethyl-1 0-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

3-fluoro-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-nitro-10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-amino-10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

N ¹-[10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3,5-triolefin-4-yl]-acetamide;

6-methyl-5-thia-7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8] pentadecane-2 (10), 3,6, the 8-tetraene;

6-methyl-7-propyl group-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

7-methyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6-methyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6,7-dimethyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

7-propyl group-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

7-butyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

7-isobutyl group-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6-methyl-7-isobutyl group-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), (10), 3,5,8-tetraene;

7-phenyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6-methyl-7-phenyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6-methyl-7-neopentyl-5,7,13-three azepine Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,5, the 8-tetraene;

6,7-dimethyl-5,8,14-three azepine Fourth Ring [10.3.1.0 ^2,11.0 ^4,9]-hexadecane-2 (11), 3,5,7, the 9-pentaene;

5,8,14-three azepine Fourth Ring [10.3.1.0 ^2,11.0 ^4,9]-hexadecane-2 (11), 3,5,7, the 9-pentaene;

14-methyl-5,8,14-three azepine Fourth Ring [10.3.1.0 ^2,11.0 ^4,9]-hexadecane-2 (11), 3,5,7, the 9-pentaene;

5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

6-methyl-5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

2-fluoro-N-(4-hydroxyl-10-azepine-three ring [6.3.1.0 ^2,7]-dodecane-2 (7), 3,5-triolefin-5-yl)-Benzoylamide;

4-chloro-10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3,5-triolefin-4-base cyanide;

3-10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3,5-triolefin-4-yl)-the 5-methyl isophthalic acid, 2, the 4-oxadiazole;

1-(10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3,5-triolefin-4-yl)-the 1-ethyl ketone;

10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3,5-triolefin-4-alcohol;

7-methyl-5-oxa--6,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8] pentadecane-2,4 (8), 6, the 9-tetraene;

4-(2-methyl-2H-pyrazole-3-yl)-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4-(1-methyl isophthalic acid H-pyrazole-3-yl)-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4,5-two chloro-10-aza-tricycle [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

N ⁴, N ⁴-dimethyl-10-aza-tricycle [6.3.1.0 ^2,7]-dodecane-2 (7), 3,5-triolefin-4-sulfonamide;

4-(1-pyrrolidinyl sulfonyl)-10-aza-tricycle [6.3.1.0 ^2,7]-dodecane-2 (7), 3, the 5-triolefin;

5,13-diaza Fourth Ring [9.3.1,0 ^2,10.0 ^4,8]-pentadecane-2,4 (8), 9-triolefin-6-ketone;

6-oxo-5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

3-phenyl-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

3-hydroxyl-10-azepine-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

4,5-two fluoro-10-azepines-three ring [6.3.1.0 ^2,7] dodecane-2 (7), 3, the 5-triolefin;

6-ethyl-5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

6-isopropyl-5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

6-benzyl-5-oxa--7,13-diaza Fourth Ring [9.3.1.0 ^2,10.0 ^4,8]-pentadecane-2 (10), 3,6, the 8-tetraene;

5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

6-methyl-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

7-methyl-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

7-ethyl-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

8-methyl-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

5,14-diaza Fourth Ring [10 3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,7,9-tetraene-6-ketone;

6-chloro-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

6-methoxyl group-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

6-chloro-10-fluoro-5,14-diaza Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,5,7, the 9-pentaene;

5,8,14-three azepine Fourth Ring [10.3.1.0 ^2,11.0 ^4,9] hexadecane-2 (11), 3,7,9-tetraene-6-ketone;

With acceptable salt of their pharmacy and optical isomer.

10. according to the method for claim 3, wherein the nAChR agonist is selected from:

5,6-two fluoro-11-azepines-three ring [7.3.1.0 ^2,7] tridecane-2,4, the 6-triolefin;

11-benzyl-6-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

6-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-6-alcohol;

6-fluoro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-5-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-5-alcohol;

5-methoxyl group-11-azepine-three ring [7.3.1,0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-5-alcohol;

11-benzyl-5-difluoro-methoxy-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-difluoro-methoxy-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-5-ethyoxyl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-ethyoxyl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-isopropoxy-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-4-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

4-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-4-alcohol;

11-benzyl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

4-nitro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-nitro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

3-nitro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-5-fluoro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-fluoro-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5,7-two oxa-s-14-azepine Fourth Ring [10.3.1.0 ^2,10.0 ^4,8] hexadecane-2 (10), 3, the 8-triolefin;

11-benzyl-6-bromo-5-methoxyl group-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-benzyl-6-hydroxy-5-methyl Oxy-1 1-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

6-hydroxy-5-methyl Oxy-1 1-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

Trifluoromethanesulfonic acid-11-benzyl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-5-base ester;

5-(4-trifluoromethyl-phenyl)-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

5-(4-methoxyl group-phenyl)-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-5-carboxylate methyl ester;

2-(11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3,5-triolefin-5-yl)-propan-2-ol;

5-pyridin-3-yl-11-azepine-three ring [7.3.1.0 ^2,7] tridecane-2 (7), 3, the 5-triolefin;

With acceptable salt of their pharmacy and optical isomer.

11. according to the process of claim 1 wherein that the nAChR agonist is the chemical compound of formula III:

X wherein ³Be:

a)-CH ₂NR ³¹R ³²，

b)

Or

c)

R wherein ³⁰, R ³¹And R ³²Be independently selected from hydrogen and C ₁-C ₆Alkyl;

R ³³Be selected from hydrogen, halogen and C ₁-C ₆Alkyl;

V is 0 to 4 integer; With

N is 0 to 2 integer;

With the acceptable salt of their pharmacy.

12. according to the process of claim 1 wherein that the nAChR agonist is a partial agonist.

13. according to the process of claim 1 wherein that the nAChR agonist is a full agonist.

14. the purposes of nAChR agonist in the medicine of preparation treatment restless legs syndrome (RLS).

15. be selected from the purposes of nAChR agonist in the medicine of preparation treatment restless legs syndrome (RLS) of chemical compound or their the acceptable salt of pharmacy of formula I, II, III, IV, V and VI.