SK1912004A3 - 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

Technical field

The present invention relates to the use of nicotinic acetylcholine receptor agonists for the treatment of rest / ess legs syndrome (RLS). The invention also relates to the use of nicotinic acetylcholine receptor agonists in the manufacture of a medicament for use in therapy. RLS. The invention further relates to a pharmaceutical composition for the treatment of RLS comprising a nicotinic acetylcholine receptor agonist.

BACKGROUND OF THE INVENTION

Restless Legs Syndrome is a condition of unknown origin characterized by an unpleasant but usually painful feeling in one or both legs that causes the affected individual to experience an insurmountable urge to move their legs. Occasionally this condition also occurs in the arms. Spontaneous movement through the limb in which such sensation is perceived, allegedly reduces or alleviates the intensity of the sensation. CLC occurs most frequently, even exclusively, at rest or in the evening or at night, when the individual is lying in bed. In the affected individual, movements of the toes, feet or whole limbs are typically observed when the individual sits or lies and is often misinterpreted as agitation or nervousness. RLS sufferers often have difficulty sleeping and sleeping, and it is estimated that 80% of affected individuals have periodic limb movements during the night, sometimes so often that they occur every 20 to 30 seconds and often cause partial waking that interrupts sleep. . The resulting chronic sleep deprivation and accompanying daily fatigue can often cause mood swings in the affected individual and may impair the individual's ability to work and function normally during the day.

PP 0191-2004

32269 / H

Currently, the most commonly prescribed treatment for RLS is dopaminergic (often a dopamine receptor agonist) such as Mirapex (pramipexole), Permax (pergolide) and Requip (ropinirole), or drugs that deliver a dopamine system such as Sinemet (carbidopa / levodopa). Of the dopaminergic products, Sinemet has been used the longest, but it has recently been found to induce a serious side effect, augmentation, in the vast majority of patients taking it to treat RLS. Other less commonly used treatments for RUS are sedatives, which may relieve nocturnal symptoms of RLS, analgesics (including codeine, Darvon or Darvocet (propoxyphene), Dolophin (methadone), Percocet (oxycodone), Ultram (tramadol) and Vicodin (hydrocodone) for a single person non-fading symptoms of RLS and an anticonvulsant (including Gabapentin (Neurontin)), which are effective in some, but not all, patients with severe daily symptoms, especially those with RLS associated with pain syndrome.

Nicotinic acetylcholine receptor agonists significantly increase dopamine release in the brain. Because increased dopaminergic activity results in possible mechanisms of RLS alleviation and because dopaminergic formulations are somewhat effective in the treatment of RLS, nicotinic acetylcholine specific receptor agonists provide alternative means of treating RLS by preventing some of the side effects associated with certain known dopaminergic preparations.

In particular, a large number of compounds that bind to the neuronal sites of nicotinic receptors and are useful for modulating cholinergic function are disclosed in International Patent Application Publication No. WO 97/18511. WO 01/62736, filed on Feb. 8, 2001, International Patent Application Publication No. WO 01/62736; WO 99/35131, filed Nov. 13, 1998; WO 99/55680, filed April 8, 1999; WO 98/18798, filed Oct. 15, 1997, U.S. Pat. No. 5,977,131, filed March 31, 1998, U.S. Pat. No. 6,020,335, filed Nov. 4, 1997 and European Patent

PP 0191-2004

32269 / H Application no. EP 0 955 301 A2, filed March 25, 1999. The owner and applicant of the above-mentioned publications are the same owner and applicant as the present invention, the entire texts of the above-mentioned publications serving as reference materials.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating a mammal, including a human, to Restless Legs Syndrome, which comprises administering to a mammal a nicotinic acetylcholine receptor agonist effective for treating the disorder.

The present invention further relates to a method of treating a mammal, including a human, to Restless Legs Syndrome, which comprises administering to a mammal in need of such treatment a compound of Formula I:

in which:

R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an unconjugated alkenyl group having 3 to 6 carbon atoms, a benzyl group, an XC (= O) R ¹³ group or a -CH ₂ CH ₂ -O-alkyl group in which the alkyl moiety contains 1 to 4 carbon atoms;

R ² and R ³ are independently selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, nitro, amino, halogen, cyano, -SOq -alkyl wherein the alkyl moiety contains 1 to 6 carbon atoms and q is zero, 1 or 2, an alkylamino group containing 1 to 6 carbon atoms in the alkyl moiety, an [alkyl] 2 amino group containing 1 to 6 carbon atoms in each alkyl moiety , -CO ² R ⁴ , -CONR ⁵ R ⁶ , -SO ² NR ⁷ R ⁸ , -C (= O) R ¹³ , -XC (= O) R ¹³ , an arylalkyl group containing from 0 to 3 carbon atoms in the alkyl moiety or arylalkyl-OPP 0191-2004

32269 / H group containing from 0 to 3 carbon atoms in the alkyl portion, said aryl group selected from the group consisting of phenyl and naphthyl, heteroarylalkyl containing from 0 to 3 carbon atoms, or heteroaryl-alkyl-O-group containing in the alkyl moiety of 0 to 3 carbon atoms, said heteroaryl moiety selected from the group consisting of 5- to 7-membered aromatic rings containing one to four heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, an X ² alkyl group containing from 0 to 6 alkyl carbon atoms and X ^{2 is an} alkoxyalkyl group having 1 to 6 carbon atoms in the alkoxy moiety and 0 to 6 carbon atoms in the alkyl moiety, wherein X ² is either absent or X ² is C 1-6 alkylamino or [alkyl] ₂ amino a group containing from 1 to 6 carbon atoms in each alkyl moiety and an alkyl moiety of containing from 0 to 6 carbon atoms or alkoxy-alkyl moieties containing from 1 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety of said X ² -alkyl groups containing from 0 to 6 carbon atoms or X ² alkoxy- alkyl groups having 1 to 6 carbon atoms in the alkoxy moiety and 0 to 6 carbon atoms in the alkyl moiety contain at least one carbon atom and one to three carbon atoms of said alkyl groups containing 0-6 carbon atoms or alkoxy-alkyl groups containing alkoxy parts of 1 to 6 carbon atoms and in the alkyl part of 0 to 6 carbon atoms may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two of said heteroatoms must be separated by at least two carbon atoms and any alkyl portions of said alkyl groups containing 0 up to 6 carbon atoms or alkoxyalkyl groups containing 1-6 carbon atoms; the alkoxy moieties of 1 to 6 carbon atoms and the alkyl moiety of 0 to 6 carbon atoms may be optionally substituted with two to seven fluorine atoms, and further one of the carbon atoms of each of the alkyl moieties of said aryl-alkyl group containing 0 to 3 carbon atoms in the alkyl moiety and said heteroaryl-alkyl group containing from 0 to 3 carbon atoms in the alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, and further each of the above aryl and heteroaryl groups may be optionally substituted by one or more substituents, preferably

PP 0191-2004

32269/11 embodiments with no to two substituents independently selected from the group consisting of alkyl groups of 1 to 6 carbon atoms optionally substituted with one to seven fluorine atoms, alkoxy groups of 1 to 6 carbon atoms optionally substituted with two to seven fluorine atoms, halogens (such as are, for example, chlorine, fluorine, bromine or iodine), alkenyl groups having 2 to 6 carbon atoms, alkynyl groups having 2 to 6 carbon atoms, hydroxy, nitro, cyano, amino, alkylamino groups having 1 to 6 carbon atoms in the alkyl moiety; [alkyl] ₂ amino- containing 1 to 6 carbon atoms in each alkyl moiety, -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 carbon atoms to which they are attached form a four to seven membered monocyclic, or ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three non-fused carbon atoms of said monocyclic rings, and a up to five carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula (I), may optionally be replaced independently of one another by a nitrogen, oxygen or sulfur atom, and the monocyclic or bicyclic rings may optionally be substituted by one or more substituents; preferably no to two substituents for monocyclic rings and no to three substituents for bicyclic rings independently selected from the group consisting of alkyl groups containing 0 to 6 carbon atoms or alkoxyalkyl groups having 1 to 6 carbon atoms in the alkoxy moiety and 0 to 6 carbon atoms in the alkyl moiety, wherein the total number of carbon atoms is at most six, and any one of said alkyl groups may optionally be substituted by one to seven fluorine atoms; nitro, oxo, cyano, halogens, (C 2 -C 6) alkenyl, (C 2 -C 6) alkynyl, hydroxy, amino, (C 1 -C 6) alkylamino,

PP 0191-2004

32269 / H [alkyl] ₂ amino group containing in each alkyl moiety 1 to 6 carbon atoms, -CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= O) R ¹³ , and -XC (= O) R ¹³ ;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ each independently of one another is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a pyrrolidine group, piperidine group, morpholine group, azetidine group, piperazine group, -Naalkylpiperazine group having 1 to 6 carbon atoms in the alkyl moiety or a thiomorpholine ring or thiomorpholine ring in which it is a ring sulfur atom replaced by a sulfoxide group or a sulfone group; and

X each independently represents an alkylene group having 1 to 6 carbon atoms;

with the proviso that:

(a) at least one of R ¹ , R ² , R ³ must be other than hydrogen; and (b) when R ² and R ³ are hydrogen, then R ¹ cannot be hydrogen, an alkyl group containing 1; or a non-conjugated (C 3 -C 6) alkenyl group, and pharmaceutically acceptable salts thereof.

Examples of possible heteroaryl groups which fall within the definition of R ² and R ³ of formula (I ⁾ above are: thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl , isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:

PP l l P I -2004

32269 / H

wherein one of R ⁹ and R ¹⁸ is hydrogen or C 1 -C 6 alkyl and the other is a bond to the benzene ring of a compound of formula I.

Examples of compounds of formula (I) which may be used in the method of the present invention include those wherein R ² and R ³ together with the benzene ring shown in Formula I form a bicyclic ring system selected from the following structures:

(ýxV · Ŕ ¹⁷

οχ /

Wherein R ¹⁰ and R ¹⁷ are each independently selected from hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy and C 0 -C 6 alkyl 6 carbon atoms, wherein the total number of carbon atoms is a maximum of six and wherein further any of said alkyl moieties may be optionally substituted by one to seven fluorine atoms; nitro, cyano, halogen, amino, C 1 -C 6 alkylamino, [C 1-6 amino]

PP 0191-2004

32269 / H containing in each alkyl moiety 1 to 6 carbon atoms, -CO ₂ R ⁴ , CONR ⁵ R ⁶ , -SO ₂ NR ⁷ R ⁸ , -C (= O) R ¹³ , -XC (= O) R ¹³ , a phenyl group and a monocyclic heteroaryl group, wherein said heteroaryl moiety has the same meaning as defined for R ² and R ³ in the definition of compounds of formula (I) above.

Further examples of the compounds of formula (I) used in the method of the present invention include those wherein R ² and R ³ together with the benzene ring in the compound of formula I form a bicyclic or tricyclic ring system selected from the group of the following systems :

wherein R ¹⁰ and R ¹⁷ have the same meaning as defined above, and m is zero, one or two, wherein one of the carbon atoms of ring A may optionally be replaced by oxygen or an N-alkyl group having 1 to 6 carbon atoms.

Another embodiment of the invention relates to the aforementioned compounds of formula I used in the method of the present invention wherein neither R ² nor R ³ is attached to the benzene ring of the compound of formula I via an oxygen atom.

Another aspect of the present invention relates to compounds of the above formula I and pharmaceutically acceptable salts thereof, wherein R ² and R ³ do not form a bicyclic or tricyclic ring system together with the benzene ring in the compound of formula I.

PP 0191-2004

Another aspect of the present 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. Another aspect of the present 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, or an alkyl group having 1 to 3 carbon atoms optionally substituted by one to seven fluorine atoms. Another aspect of the present invention relates to compounds of formula I wherein one of K ² or R ³ is CF ₃ , fluoro, cyano, C 2 -C 6 alkynyl, or C 2 F 5.

Examples of specific compounds of formula (I) used in the method of the present invention include the following compounds which, when there is an asymmetric center in the molecule, include racemic mixtures or a single enantiomer:

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-tricyclo [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-tricyclo [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 .0 ^4,8 ] pentadeca-2 (10), 3,6,8-tetraene;

PP 0191 - 2004

32269 / H

6-methyl-7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^4,8 .0 ²¹ °] pentadeca2 (10), 3,5,8-tetraene;

5.7.13- triazatetracyclo [9.3.1.0 ^2,10 .0 ^4,8] pentadeca-2 (10), 3,5,8-tetraene;

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

6-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^2.10 0 ^4.8 ] pentadeca-2 (10), 3,5,8-tetraene;

6.7- dimethyl-5,7,13-triazatetracyclo [9.3.1.0 ²¹⁰ .0 ^{4 '8]} pentadeca-2 (10), 3,5,8-tetraene;

7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,1 .0 ^4,8 °] pentadeca2 (10), 3,5,8-tetraene;

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

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

6-methyl-7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ² ° ¹ .0 ^4,8] pentadeca-2 (10), 3,5,8-tetraene;

7-phenyl-5,7,13-triazatetracyclo [9.3.1. The ^2,10 .0 ^4,8] pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^{4' 8]} pentadeca-2 (10), 3,5,8-tetraene;

6-methyl-7-neopentyl-5,7,13-triazatetracyclo [9.3.1.0 ^{210.0 4.8} ] -pentadeca-

2 (10), 3,5,8-tetraene;

6.7- dimethyl-5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^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), 3,5,7,9-pentaene;

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

5-oxa-7,13-diazatetracyclo [9.3.1.0 ^2,1 .0 ^4,8 °] pentadeca2 (10), 3,6,8-tetraene;

6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^2,10 .0 ^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;

PP 0191-2.4

269 / H

4-chloro-10-tricyclo [6.3.1,0 ^{2 '7]} dodeca-2 (7), 3,5-triene;

10-tricyclo [6.3.1.0 ^27] dodeca-2 (7), 3,5-trien-4-yl cyanide;

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

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

10-tricyclo [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 ^2,1 .0 ° ^48] pentadeca-2,4 (8), 6,9tetraén;

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

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

4- (1-pyrrolidinylsulfonyl) -10-tricyclo [6.3.1.0 ^{2 '7]} dodeca-2 (7), 3,5-triene;

5.13- diazatetracyclo [9.3.1.0 ^{2 '10} .0 ^48] pentadeca-2,4 (8), 9-trien-6-one;

6-oxo-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^{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 '1} ° .0 ^4,8] pentadeca-2 (10), 3,6,8-tetra ene;

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

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

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

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

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

PP 0191-2004

32269 / H

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

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

5.14- diazatetracyclo [10.3.1.0 ²¹¹ .0 ^4.9] -hexadeca-2 (11), 3,5,7,9-tetraene-6-one;

6-chloro-5,14-diazatetracyclo [10.3.1.0 ^{2 '11} .0 ^4,9] -hexadeca-2 (11), 3,5,7,9-pentaene;

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

6-chloro-10-fluoro-5,14-diazatetracyclo [10.3.1.0 ^2,11 .0 ^49] 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-tetraene-6-one;

and pharmaceutically acceptable salts and optical isomers thereof.

The present invention further relates to a method of treating a mammal, including a human, to Restless Legs Syndrome (RLS), comprising administering to the mammal a compound of Formula II:

in which:

Z is CH 2, C (= O) or CF ₂ ;

R ²¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an unconjugated alkenyl group having 3 to 6 carbon atoms, a benzyl group, an XC (= O) R ¹³ group or a -CH ₂ CH ₂ -O-alkyl group, the group contains 1 to 4 carbon atoms;

R ²² and R ²³ each independently of one another are selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, nitro, amino, halogen, cyano,

PP 019 I - 2004

32269/11 -SOq-alkyl group wherein the alkyl moiety contains 1 to 6 carbon atoms and q is zero, 1 or 2, an alkylamino group containing 1 to 6 carbon atoms in the alkyl moiety, an [alkyl] ₂ amino group containing each C 1 -C 6 alkyl, CO ₂ R ⁴ , CONR ⁵ R ⁶ , SO ² NR ⁷ R ⁸ , C (= O) R ¹³ , XC (= O) R ¹³ , an arylalkyl group containing 0 to 3 atoms in the alkyl portion or arylalkyl-O- group containing from 0 to 3 carbon atoms in the alkyl moiety, said aryl group selected from the group consisting of phenyl and naphthyl, heteroarylalkyl containing from 0 to 3 carbon atoms in the alkyl moiety or heteroaryl-alkyl-O- a group containing from 0 to 3 carbon atoms in the alkyl moiety, wherein said heteroaryl moiety is selected from the group consisting of 5- to 7-membered aromatic rings containing one to four heteroatoms selected from the group consisting of acid Shopping Cart, nitrogen and sulfur, and X ² alkoxy-alkyl of the alkoxy of 0-6 carbon atoms and the alkyl part of 0-6 carbon atoms, wherein X ² is either absent or X ² is an alkylamino group having 1 to 6 carbon atoms, or [ an alkyl] 2 amino group containing from 1 to 6 carbon atoms in each alkyl moiety, and an alkoxy alkyl group containing from 0 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety of said X ² -alkoxy alkyl group containing 0 up to 6 carbon atoms and in the alkyl moiety of 0-6 carbon atoms contain at least one carbon atom and one to three carbon atoms of said alkoxyalkyl group containing from 0-6 carbon atoms in the alkoxy moiety and optionally substituted with 0-6 carbon atoms in the alkyl moiety oxygen, nitrogen or sulfur, with the proviso that any two of said heteroatoms must be separated by at least and optionally any alkyl moieties of said alkoxyalkyl groups containing from 0 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety may optionally be substituted with two to seven fluorine atoms and one of the carbon atoms of each alkyl moiety of said moiety. the aryl-alkyl group containing from 0 to 3 carbon atoms in the alkyl moiety and said heteroaryl-alkyl group containing from 0 to 3 carbon atoms in the alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, and each of the above aryl groups

PP 0191-2004

The 32269 / H and heteroaryl groups may be optionally substituted with one or more substituents, preferably no to two substituents, independently selected from the group consisting of C 1 -C 6 alkyl groups optionally substituted with 1 to 7 fluorine atoms, C 1 -C 6 alkoxy groups 6 carbon atoms optionally substituted by two to seven fluorine atoms, halogens (such as chlorine, fluorine, bromine or iodine), hydroxy, nitro, cyano, amino, alkylamino groups having 1 to 6 carbon atoms in the alkyl moiety, [alkyl] ₂ amino groups containing from 1 to 6 carbon atoms in each alkyl moiety;

or R ²² and R ²³ together with the carbon atoms to which they are attached form a four to seven membered monocyclic or ten to fourteen membered bicyclic, carbocyclic ring which may be saturated or unsaturated, one to three non-fused carbon atoms of said monocyclic rings and one up to five carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula II, may optionally be replaced independently of each other by nitrogen, oxygen and sulfur, and the monocyclic or bicyclic rings may optionally be substituted by one or more substituents, preferably no to two substituents for monocyclic rings and no to three substituents for bicyclic rings independently selected from the group consisting of alkoxy-alkyl groups include in the alkoxy moiety of 0 to 6 carbon atoms and in the alkyl moiety of 0 to 6 carbon atoms, wherein the total number of carbon atoms is at most six and any of said alkyl groups may be optionally substituted by one to seven fluorine atoms; nitro, oxo, cyano, halogens, hydroxy, amino, C 1 -C 6 alkylamino, C ₂ -C 6 alkyl, C ₂ -C 6 alkyl, phenyl and monocyclic heteroaryl wherein: said heteroaryl group having the same meaning as defined above for the definition of substituents R ²² and R ²³ above;

PP 01 91-2004

32269 / H

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and X have the same meaning as above;

with the proviso 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, then R ²¹ cannot be a methyl group or a hydrogen atom; and (c) none of the fluorine atoms in all of the fluorine-substituted alkyl or alkoxy portions of said substituents R ²² and R ²³ may be attached to a carbon atom which is attached to the heteroatom;

or a pharmaceutically acceptable salt thereof.

Exemplary heteroaryl groups of each of R ²² and R ²³ in the compounds of Formula II used in the method of the present invention include thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl a triazolyl group, an imidazolyl group, a tetrazolyl group, a pyrrolyl group, and the following groups:

Wherein R and R are each as defined above.

Examples of compounds of formula (II) used in the method of the present invention include those in which:

PP 0191-2004

32269 / H

R ²² and R ²³ together with the benzene ring in the compound of formula II form a bicyclic ring system selected from the following structures:

wherein R ¹⁰ and R ¹⁷ have the same meaning as previously defined.

Further aspects of the present invention pertain to compounds of formula II used in the method of the present invention wherein R ²² and R ²³ together with the benzene ring in the compound of formula II form a bicyclic or tricyclic ring system selected from the following structures:

0191-2004

32269 / H wherein m, R ¹⁰ and R ¹⁷ are as defined above, wherein the carbon atoms of ring A can optionally be replaced with oxygen or N-alkyl of 1 to 6 carbon atoms.

Other aspects of the present invention pertain to compounds of formula II used in the method of the present invention wherein none of the substituents R ²² and R ²³ is attached to the benzene ring in the compound of formula II via an oxygen atom.

Further aspects of the present invention pertain to compounds of formula II used in the method of the present invention wherein R ²¹ is not a methyl group.

In a preferred embodiment, the present invention relates to a method of treatment comprising administering a compound of Formula II, wherein the compound is selected from the group consisting of:

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 ²⁷ ] trideca-2 (7), 3,5-triene;

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

PP 0191-2004

32269 / Ή

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-n itro-11-aza-tricyclo [7.3.1.0 ^{2 7]} Classes river-2 (7), 3,5-triene;

3-nitro-11-aza-tricyclo [7.3.1 ² O ^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.O ^2,1o .O ^{4 '8]} hexadeca-2 (10), 3,8-triene;

11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo [7.3.1.0 ²⁷ trideca-2 (7), 3,5-triene;

-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;

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

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

5- (4-methoxyphenyl) -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.O ^{2 7]} trideca-2 (7), 3,5-triene;

and the pharmaceutically acceptable salts and optical isomers of these compounds.

The present invention also relates to a method of treating a mammal, including a human, to rest / ess / egs syndrome (RLS), comprising administering to the mammal a compound of formula III:

PP U191-20U4

32269 / H

(III) in which:

X ³ means:

(a) -CH ² NR ³¹ R ³² ;

(b) a group

(c) a group

In which:

he o d he

R, R and R are independently selected from the group consisting of hydrogen and alkyl groups of 1 to 6 carbon atoms,

R is selected from the group consisting of 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, or pharmaceutically acceptable salts derived therefrom.

Preferred compounds of formula III used in the method of the present invention are the following compounds:

[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;

PP 019I-2004

32269 / H

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

3- (1-Methyl-pyrrolidin-2-ylmethyl) -1-H-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) a

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

The present invention also relates to a method of treating a mammal, including a human, to rest / ess legs syndrome (RLS), comprising administering to a mammal in need of such treatment a compound of Formula IV:

(iv) in which:

R ⁴¹ , R ⁴² , R ⁴³ , R ⁴⁴ are each independently selected from the group consisting of hydrogen, -CO 2 R ⁴⁵ , aryl and heteroaryl, wherein said aryl group is selected from phenyl and naphthyl and said heteroaryl group is selected from the group consisting of pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, carbinyl, purinyl 5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinolinyl, phthalazinyl, quinoxalinyl, xantinyl, hypoxantinyl, pteridinyl, 5-azacytidinyl, 5-azauracyl, 5-azauracyl, 5-azauracyl

PP 0191 - 2004

32269 / H imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl, oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, wherein said phenyl group and said heteroaryl group may be optionally substituted with one to three substituents, preferably optionally substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl groups optionally substituted one to seven (preferably no to four) fluorine, halogen (i.e., chlorine, fluorine, bromine or iodine), phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, (C 1 -C 6) alkoxy optionally substituted with one to seven (preferably no to four) fluorine atoms, (C 1 -C 6) alkylamino and (C ₂ -C 6) alkyl amine groups an alkyl moiety of 1 to 6 carbon atoms;

R ⁴⁵ represents an alkyl group having 1 to 6 carbon atoms, an aryl group, a heteroaryl group, an alkylene-aryl group having 1 to 4 carbon atoms in the alkylene moiety and an alkylene-heteroaryl group having 1 to 4 carbon atoms in the alkylene moiety, said aryl group and the heteroaryl group is as defined above and the below alkyl group having 1 to 6 carbon atoms may be optionally substituted with one to three substituents independently selected from the group consisting of halogens, alkyl groups having 1 to 6 carbon atoms, alkoxy groups containing (C 1 -C 6), (C 1 -C 4) alkoxyalkyl, (C 1 -C 6) alkyl amine, (C 1 -C 6) alkylamino, and (C ₂ -C 6) alkyl (C ₂ -C 6 ₎ amine; and

PP 0I9I-2004

32269 / H

R ( ⁴⁶⁾ is hydrogen or (C1-C6) -alkyl;

with the proviso 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, then R ⁴¹ and R ⁴² are in the exo configuration;

(c) R ⁴¹ and R ⁴² cannot both be -CO ₂ R ⁴⁵ ;

(d) when either R ⁴³ or R ⁴⁴ is -CO ₂ R ⁴⁵ and R ⁴⁵ is alkyl or alkoxyalkyl, one of R ⁴¹ or R ⁴² must be aryl or heteroaryl; and (e) when either R ⁴¹ or R ⁴² is -CO ₂ R ⁴⁵ and R ⁴⁵ is alkyl or alkoxyalkyl, then one of R ⁴³ and R ⁴⁴ must be aryl or heteroaryl;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the present invention include those compounds of formula (IV) used in the method of the invention wherein one of R ⁴¹ or R ⁴² is optionally substituted phenyl and the other is hydrogen, and R ⁴³ and R ⁴⁴ are each hydrogen.

More preferred compounds of the present invention include those compounds of formula (IV) used in the method of the invention wherein one of R ⁴¹ or R ⁴² is phenyl substituted with fluoro or nitro, and the other substituent is hydrogen, and R ⁴³ and R ^{42 are each} . ⁴⁴ represents a hydrogen atom.

Particularly preferred compounds of the present invention include the compounds of formula IV used in the method of the invention wherein:

PP 0191 - 2004

32269 / H

R ⁴³ and R ⁴⁴ are hydrogen and compounds wherein one of R ⁴¹ or R ⁴² is hydrogen and the other is: (a) 3-fluorophenyl; (b) a 4-nitrophenyl group; or a 3-fluoro-4-nitrophenyl group.

Further aspects of the present invention pertain to compounds of Formula IV and pharmaceutically acceptable salts thereof used 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-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;

β- (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;

PP 019 and -2004

32269 / 1H of 2- (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-nitrophenyl) -7-aza-bicyclo [2.2.1] heptane;

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

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

2β- (4-sulfonamidophenyl) -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-methyl-5-isoxazole) -7-aza-bicyclo [2.2.1] heptane;

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

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

2-4-methanesulfonylphenyl) -7-aza-bicyclo [2.2.1] heptane;

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

2- (4-methylsulfanylphenyl) -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-trifluoromethylphenyl) -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-nitrophenyl) -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-methanesulfinylphenyl) -7-aza-bicyclo [2.2.1] heptane;

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

PP 0191-2004

32269 / H

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

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

2- (3,4,5-trimethoxyphenyl) -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

I

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

and pharmaceutically acceptable salts and optical isomers thereof.

The present invention also relates to a method of treating a mammal, including a human, to restless legs syndrome (RMS), comprising administering to a mammal a compound of formula V:

its enantiomers, diastereomers and stereoisomers, and pharmaceutically acceptable salts and prodrugs thereof, in which:

R ⁵¹ and R ⁵² are each independently selected from the group consisting of:

(a) hydrogen, halogens, CF ₃ , hydroxy; (C 1 -C 6) alkoxy, CH ₂ OH, -C (O) R ⁵⁴ , wherein R ⁵⁴ is hydrogen, (C 1 -C 6) alkyl, (C 6 -C 10) aryl, or benzyl (including substituted alkyl, aryl or benzyl

PP0191-2004

32269 (H groups); a CsN group; C = CR ⁵⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms (including a substituted alkyl group or an aryl group); a -S (O) PR ^{55 group} in which R ⁵⁵ represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group (including a substituted alkyl or aryl group) and p is 0,1, or 2; C 1 -C 6 alkyl; (C 1 -C 6) alkenyl; H2N; a di (alkyl) amino group having 1 to 6 carbon atoms in each alkyl moiety; a monoalkylamino group having 1 to 6 carbon atoms in the alkyl moiety; an aryl-amino group containing 6 to 1 carbon atoms in the aryl moiety; a cycloalkylamino group having 3 to 8 carbon atoms in the cycloalkyl moiety; a heteroaryl-amino group; a cycloheteroarylamino group; and a CON (R ⁵⁵ ) _{2 group} wherein each of R ⁵⁵ is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, and aryl of 6 to 10 carbon atoms; and (b) a CO ₂ R ⁵⁶ group wherein R ⁵⁶ is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and benzyl; and (c) an optionally benzene-fused C 6 -C 10 aryl group, an optionally benzene-fused C 3 -C 8 cycloalkyl group, an optionally benzene-fused heteroaryl group, and an optionally benzene-fused cycloheteroalkyl group, said heteroaryl group containing five up to ten atoms comprising one to four heteroatoms, said cycloheteroalkyl group having 4 to 8 atoms comprising one or two heteroatoms selected from the group consisting of N, S and O;

wherein any of said alkyl groups, alkenyl groups, aryl groups, cycloalkyl groups, cycloheteroalkyl groups and heteroaryl groups listed above under (a), (b) and (c) is optionally substituted with one or more substituents selected from the group

PP 019 and -2004

32269 / H including halogens, (C 1 -C 6) alkyl, (C 6 -C 10) aryl, hydroxy, hydroxymethyl, CHO and CO ₂ R ⁵⁶ , wherein R ⁵⁶ is as defined above, and

R ⁵³ is selected from the group consisting of hydrogen, optionally substituted benzyl, and methyl;

with the proviso that R ⁵¹ and R ⁵² are not both hydrogen, and when R ⁵³ is hydrogen and R ⁵¹ and R ⁵² are selected from the group consisting of hydrogen, bromine and chlorine, then they are not the same.

Preferred compounds of the above general formula (V) used in the method of the present invention include those in which:

The CO substituent R is selected from the group consisting of hydrogen, benzyl or methyl and R and R are each independently selected from the group consisting of hydrogen, halogen, alkyl of 1 to 6 carbon atoms, cyano, aryl containing C 6 -C 10 heteroaryl, C 1 -C 6 heteroaryl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl-R ⁵⁵ and C (O) R ⁵⁵ in which R 6 is C ⁵⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms and a heteroaryl group having 5 to 9 carbon atoms and an amino group and a mono- and di-substituted amino group; with the proviso that, when R ⁵³ is hydrogen, R ⁵¹ and R ^{52 are} not both hydrogen, bromine and chlorine, and provided that when R ⁵³ is benzyl or methyl, R ⁵¹ and R ⁵² are not both hydrogen.

Still more preferred compounds of formula V as used herein are those wherein R ⁵¹ and R ⁵² are each independently selected from the group consisting of hydrogen, ethyl, methyl, phenyl, vinyl, fluorine, bromine, chlorine, isopropyl, tercPP 0191-2004

32269 / H butyl, trifluoromethyl, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, di [alkyl] amino containing 1 to 6 carbon atoms in each alkyl moiety, (C 1 -C 6) group, (C 6 -C 10) arylamino, (C 3 -C 8) cycloalkylamino, heteroarylamino, cycloheteroalkylamino, and CON (R ⁵⁵ ) 2, wherein each of R ⁵⁵ is selected from: a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and an aryl group having 6 to 10 carbon atoms; (C 6 -C 10) aryl and (C 5 -C 9) heteroaryl group, wherein said aryl and heteroaryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1 to 6 carbon atoms, aryl groups of 6 to 10 carbon atoms, hydroxy, hydroxymethyl, CHO and CO2R ⁵⁶ .

Still more preferred compounds of formula V as used herein are those wherein R ⁵³ is selected from optionally substituted benzyl and C 1 -C 6 alkyl, as described above. and R ⁵¹ and R ⁵² each independently of one another are selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, amino, di ( alkyl) an amino group having 1 to 6 carbon atoms in each alkyl moiety, a monoalkylamino group having 1 to 6 carbon atoms, an arylamino group having 6 to 10 carbon atoms, a cycloalkylamino group having 3 to 8 carbon atoms, a heteroarylamino group, cycloheteroa an alkylamino group and a NOC (R ⁵⁵ ) _{2 group} , wherein each R ⁵⁵ is selected from the group consisting of hydrogen, alkyl,

PP 0191 - 2004

32269 / II of 1 to 6 carbon atoms and aryl of 6 to 6 carbon atoms; a -C (O) R ^{55 group} in which R ⁵⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aryl group having 6 to 10 carbon atoms; (C hetero-Cry) aryl or (C až-C hetero) heteroaryl group, wherein said substituents are as described above.

In particular, the present invention relates to compounds of formula V as used herein, wherein R ⁵¹ and R ⁵² are each independently selected from the group consisting of hydrogen, isopropyl, tert-butyl, trifluoromethyl , acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, 2,4-difluorophenyl, 2fluorophenyl, 2-thienyl and 3-thienyl,

C 1-6 dimethylamino and R is a substituent selected from the group consisting of hydrogen, benzyl, methyl, and R ⁵¹ and R ⁵² are each independently selected from the group consisting of hydrogen, bromine, chlorine, ethyl, methyl, a fluorine atom, a vinyl group and a phenyl group.

The most preferred compounds of formula (V) used in the method of the present invention are those selected from the group consisting of:

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

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

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

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

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

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

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

PP 0191 - 2004

32269 / H

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

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

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

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

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

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

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

-phenyl-1S, 5S, 5S, 5-hexahydro-1S-methano-pyridof1-6-a] [1,5] diazocin-8-one;

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

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

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

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

9-Bromo-3-methyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocine-

8-one;

3-Benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] -diazine-

8-one; and

3-Benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido [1,2-a] [1,5] diazocine-

8-one; and pharmaceutically acceptable salts and optical isomers thereof.

The present invention also relates to a method of treating a mammal, including a human, to rest / ess legs syndrome (RLS), comprising administering to the mammal a compound of formula VI:

PP 019i -2004

32269 H and pharmaceutically acceptable acid addition salts and prodrugs thereof, in which:

A is -CH (R ⁶¹ ) - and R ⁶¹ is hydrogen or optionally substituted (C 1 -C 6) alkyl, said substituents comprising one or more groups selected individually from hydroxy, (C 1 -C 6) alkoxy , oxo, C 2 -C 6 alkanoyl and NR ⁶² R ⁶³ ; and

B is a group of the formula:

NH ^Χ Λ _; w

(R ⁶⁴ / (R ⁶⁵ ) _m in which:

YW represents a group CH ₂ , NH, O, S, CH ₂ CH ₂ , CH = CH, N = CH, NHCH ₂ , OCH ₂ or SCH ₂ ;

the dotted line represents an optional bond;

Z ² is C, N, O or S;

m is 1 or 2;

r is 0, 1 or 2;

with the proviso 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;

R ⁶⁴ and R ⁶⁵ each independently of one another are selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted alkoxysupine of 1 to 6 carbon atoms, and optionally substituted alkanoyl of 2 to 6 atoms wherein the substituents on the alkyl group and the alkanoyl group are selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkyl

PP 0191-2004

32269 / H hydroxy, alkoxy of 1 to 6 carbon atoms, oxo,

C 1-6 alkanoyl having 2 to 6 carbon atoms and NR 6 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 the group consisting of N, S and O; Z ² is C wherein said substituents are selected from optionally substituted alkyl groups having 1 to 6 carbon atoms or optionally substituted alkoxy groups having 1 to 6 carbon atoms, wherein said substituents are selected from the group consisting of alkyl groups of 1 to 6 carbon atoms , optionally substituted (C 1 -C 6) alkoxy and optionally substituted (C 2 -C 6) alkanoyl, or R ⁶⁴ and one of R ⁵⁵ together form a bond, with the proviso that R ⁶⁴ cannot form a bond when Z ² represents O or S;

R ( ⁶⁰⁾ is hydrogen or halogen; and

R ⁶² and R ⁶³ each independently of one another are selected from the group consisting of hydrogen and optionally substituted alkyl of 1 to 6 carbon atoms, said substituents selected from the group of alkyl of 1 to 6 carbon atoms and halogens;

with the proviso that when -BA is attached to the 3-position of said pyridine ring and R is a hydrogen atom (a) R ⁶⁰ is 6-chloro and (i) Z ² is carbon, the dotted line is a bond, mar are both 1, R ⁶⁴ and R ⁶⁵ are both hydrogen, then WY is not CH = CH, S, CH ₂ , NH, CH = N, OCH ₂ or SCH ₂ ;

(ii) Z ² represents a nitrogen atom, the dotted line represents a bond, r

CC is 0 and m is 1, then R is not CF ₃ ;

PP 0191 -200-4

32269 / PI (iii) Z ² is carbon, the dotted line represents a bond, m and ² are both

2, and each of R ⁶⁴ and R ⁶⁵ is hydrogen, then WY is not

WITH; or (b) R ⁶⁰ is hydrogen, 6-bromo or 6-fluoro and Z ² is hydrogen, the dotted line is a bond, m and m are both 1, R ⁶⁴ and R ⁶⁵ are both hydrogen, then WY is not sulfur.

Preferred compounds of formula (VI) used in the method of the invention include those wherein Z ² is nitrogen, m is 1 or 2, WY is S or CH = CH, R ⁶⁰ is halogen or hydrogen, R ⁶⁵ is C 1 -C 6 alkyl or halogen and the dotted line represents a bond.

Other preferred compounds of formula (VI) used in the method of the present invention include those wherein Z ² is a carbon atom, R ⁶¹ is a C 1-6 alkyl group or a hydrogen atom, m is 1, WY is an atom sulfur or CH = CH, the dotted line represents a bond, R ⁶⁴ and R ⁶⁵ each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or part B corresponding to the structure:

is selected from structures

PP 0191-2004

32269 / H

Most preferred compounds of the above formula

VI used in the method of the present invention include compounds selected from the group consisting of:

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

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-ylidenamine;

3- [1- (6-Chloro-pyridin-3-yl) -ethyl] -3H- [1,3,4] thiadiazol-2-ylidenamine;

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

3-pyridin-3-ylmethyl-thiazolidin-2-ylideneamine;

5,7-Dimethyl-1-pyridin-3-ylmethyl-3H- [1,8] naphthyridin-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 pharmaceutically acceptable salts and optical isomers thereof.

The compounds of the above formulas I, II, III, IV, V and VI may have optical centers and therefore may exist in different enantiomeric configurations. The present invention includes all enantiomers, diastereomers and other stereoisomers of the compounds of formulas I, II, III, IV, V, and VI as well as racemic mixtures and other mixtures thereof.

In a preferred embodiment, a plurality of compounds of Formulas I, II, III, IV, V, and VI are administered in practicing the method of the invention to be effective in the treatment of Restless Legs Syndrome (RLS).

PP 01 y l -2004

32269 / H

Unless expressly stated otherwise, the above-mentioned halogen means fluorine, chlorine, bromine and iodine.

Unless expressly stated otherwise, the term alkyl as used herein refers to a straight-chain moiety, wherein, in cases where the number of carbon atoms is sufficient, the branched and cyclic moieties are sufficient.

The term "alkoxy", as used herein, means an "O-alkyl" or alkyl-O-group, in which the alkyl moiety has the same meaning as previously defined.

The term alkylene group, as used herein, means an alkyl radical having two accessible bonding sites (i.e. —alkyl-) wherein the alkyl moiety has the same meaning as previously described.

In the above compounds, the term "aryl" means, without limitation, optionally substituted phenyl and naphthyl, "cycloalkyl" means, without limitation, optionally substituted cyclopentyl and cyclohexyl, wherein the cycloalkyl group may also be unsaturated and the term heteroaryl "includes without limitation, thienyl, furyl, pyran, pyrrole, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl and pyridyl and the following cycloheteroalkyl includes, without limitation, pyrrolidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, and a tetrahydropyran group.

Unless expressly stated otherwise, the term "one or more substituents" as used hereinabove "means one to the maximum number of possible substituents depending on the number of binding sites.

PP 0191-2004

32269 / H

The term "nicotinic acetylcholine receptor agonist" means a term that includes both full agonists and partial nicotinic acetylcholine receptor agonists.

The term "treatment" as used herein refers to a turnaround in the development, amelioration, inhibition of the development or prevention of a disorder or condition to which the term applies, or one or more symptoms of that condition or disorder. The term treatment, as used herein, refers to a medical treatment within the meaning of the term treatment, as defined above.

The present invention also includes all radiolabeled forms of the compounds of formulas I, II, III, IV, V and VI above. Preferred radiolabeled compounds of formulas I, II, III, IV, V and VI include compounds in which the radiolabel is selected from the group consisting of ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ l, and ¹²⁵ l. . These radiolabeled compounds are suitable for research and as a diagnostic means for carrying out metabolic assays such as pharmacokinetic studies, etc., and in carrying out binding assays in both animals and humans.

The present invention also includes pharmaceutically acceptable acid addition salts derived from the compounds of Formulas I, II, III, IV, V, and VI above. Examples of pharmaceutically acceptable acid addition salts derived from the compounds of Formulas I, II, III, IV, V and VI above include salts with 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, mandelic acid, as well as salts formed with other acids , known to those skilled in the art, to obtain pharmaceutically acceptable acid addition salts from basic compounds. Other possible acid addition salts are, for example, salts

PP 0191-2004

32269 / H containing pharmaceutically acceptable anions such as hydroiodide, nitrate, sulphate or hydrogen sulphate, phosphate or hydrogen phosphate, acetate, lactate, gluconate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate and pamoate (i.e. 1,1'-methylene) (2-hydroxy-3-naphthoate)).

The present invention also includes the use of nicotinic acetylcholine receptor agonists for the preparation of a medicament for the treatment of Restless Legs Syndrome (RLS). The present invention also includes the use of nicotinic acetylcholine receptor agonists selected from the group consisting of compounds of formulas I, II, III, IV, V, and VI, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of restless legs syndrome. syndrome (RLS). The present invention also provides a pharmaceutical composition for the treatment of Restless Legs Syndrome (RLS) comprising a compound selected from the group of compounds of Formulas I, II, III, IV, V, and VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier substance.

The present invention is directed to the use of compounds that bind to the neuronal sites of nicotinic receptors and are thus suitable for modulating cholinergic function and treating restless leg syndrome. In particular, a large number of compounds suitable for the purposes of the present invention are described in International Patent Application Publication No. WO 97/32911. WO 01/62736, filed February 8, 2001 (compounds of Formula I); International Patent Application Ser. WO / 99/35131, filed Nov. 13, 1998 (compounds of Formula I); International Patent Application Ser. WO 99/55680, filed April 8, 1999 (compounds of Formula II); U.S. Pat. No. 5,977,131, filed Mar. 31, 1998 (compounds of Formula III); in European patent application no. EP 0 955 301 A2, filed March 25, 1999 (compounds of formula IV); WO 98/18798, filed October 15, 1997 (compounds of formula V);

PP 0191-2004

32269 / H and U.S. Pat. No. 6,020,335, filed Nov. 4

1997 (compounds of formula VI).

The compounds of the above formulas I, II, III, IV, V and VI and their pharmaceutically acceptable salts (referred to herein as "active compounds" or "active compounds") can be administered either by oral transdermal (such as using a patch) , intranasal, sublingual, rectal, parenteral or topical. A preferred form of administration is transdermal administration or oral administration. The compounds are most preferably administered at doses ranging from about 0.1 milligrams to about 1500 milligrams per day, preferably at doses ranging from about 0.1 to about 300 milligrams per day, according to the invention. even more preferred embodiments at doses ranging from about 0.1 to about 3 milligrams per day, being single doses or divided doses, but with variations resulting from the properties of the particular compound employed, the weight and condition of the subject being treated, and the particular mode of administration chosen. In general, however, the most preferred dosage amount will be from about 0.001 milligrams to about 10 milligrams per kilogram of body weight per day. Even in this case, however, variations may occur, depending on the body weight and condition of the person being treated and the individual responses to the drug being used, as well as the type of pharmaceutical composition or formulation selected and the time and time interval during which administration is performed. In some cases, a dosage below the lower limit of the above-mentioned range may be more than appropriate, while in other cases an amount greater than the above-mentioned upper limit of the above-mentioned range may be used without harmful side effects, provided these larger amounts are initially divided into several small doses administered during the day.

The active compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers

PP 0191-2004

32269/11 materials or solvents by any route selected from the aforementioned routes of administration. In particular, the active compounds of the present invention may be administered in a wide variety of dosage forms, for example, the active compounds may be combined with various pharmaceutically acceptable inert carrier materials in the form of tablets, capsules, transdermal patches, lozenges, dragees, hard candies. , powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, balsams, aqueous suspensions, injectable solutions, elixirs, syrups and the like. The carrier materials include strong solvents or fillers, sterile aqueous media, and various non-toxic organic solvents. In addition, oral pharmaceutical compositions may be suitably sweetened and / or flavored. In general, however, the proportion of the active compounds of the present invention in these dosage forms ranges from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, calcium phosphate and glycine may be used, while various disintegrating agents such as starch (preferably corn starch, potato starch) may be used. starch or tapioca starch), alginic acid and various complex silicates, in combination with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc may be used in the preparation of tablets. In the case of gelatin capsules, solid preparations of a similar type may be used as fillers, preferably materials such as lactose and milk sugar, as well as high molecular weight polyethylene glycols. Where 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 necessary, emulsifying and / or suspending agents in combination with solvents such as water, ethanol , propylene glycol,

PP 0191-2004

32269 / H glycerol and various combinations thereof.

For parenteral administration, a solution of the active compound in either sesame oil or peanut oil or in aqueous propylene glycol solution may be used. These aqueous solutions may be suitably buffered (preferably to a pH greater than 8) and, if desired, the liquid solvent may be first rendered isotonic. These aqueous solutions are suitable for intravenous administration by injection. The oily solutions are suitable for intraarticular, intramuscular, subcutaneous administration by injection. The preparation of all these solutions under sterile conditions can readily be accomplished using pharmaceutical methods well known to those skilled in the art.

Likewise, the active compounds of the present invention may be administered topically (topically) by means of creams, patches, jellies, gels, pastes, ointments and the like using conventional pharmaceutical practice.

Biological tests

The efficacy of the compounds of the invention in suppressing nicotine binding to specific receptor sites was determined by the following procedure, which is a modification of the procedures of 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 Arneric, SP (Nicotmic Receptor Binding of ³ HCytisine, ³ H-Nicotine and ³ H-Methylcarbamylcholine In Rat Brain, European J. Pharm., 253: 261-67, 1994).

Approach

Male River Sprague-Dawley rats (200-300 grams) from Charles River were housed in groups in suspended stainless steel wire cages, maintained in a daily rhythm with a 12 hour light / dark cycle (7 hour light period) up to 7 pm). They received standard Purina food for rats

PP 0191 - 2004

32269 / H and water ad libitum.

The rats were sacrificed by decapitation. Brains were removed immediately after decapitation. Membranes were prepared from brain tissue following the procedure of Lippiello and Fernandez (Molecular Pharm., 29: 448-454, 1986), with some modifications. Whole brains were collected, washed with ice-cold buffer and homogenized at 0 ° C in 10 volumes of buffer (w / v) using a Brinkmann Polytron ™ instrument, setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCl, pH 7.5, at room temperature. The homogenate was sedimented by centrifugation (10 minutes, 50,000 xg, 0-4 ° C). The supernatant was discarded and the membranes were gently resuspended using Polytron and re-centrifuged (10 minutes, 50,000 xg, 0-4 ° C). After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.0 g / 100 ml. The composition of the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM KCl, 2 mM MgCl ₂ , 2 mM CaCl _2, and had a pH

7.4 at room temperature.

Routine tests were performed in borosilicate glass test tubes. The test mixture typically consisted of 0.9 milligrams of membrane protein in a final incubation volume of 1.0 ml. Three sets of tubes were prepared, with tubes in each set containing 50 μΙ of vehicle, blank or test compound solution, respectively. 200 μ bolo of [ ³ H] -Nicotine in assay buffer was added to each tube, followed by 750 μΙ of the membrane suspension. The final nicotine concentration in each tube was 0.9 nM. The final concentration of cytizine in the blank was 1 μΜ. The vehicle consisted of deionized water containing 30 μΙ of 1 N acetic acid in 50 ml of water. Test compounds and cytizine were dissolved in the vehicle. Assays were initiated by vortexing after adding the membrane suspension to the tube. The samples were incubated at 0-4 ° C in an ice water bath with shaking. Incubations were terminated by rapid filtration under vacuum through Whatman GF / B ™ fiberglass filters using a Brandel ™ Multiple Tissue Sampler. After initial filtration of the test mixture, the filters were washed twice with ice cold

PP 019I-2004

32269 / H assay buffer (5 ml each). The filters were then placed in scintillation vials and mixed thoroughly with 20 milliliters of Ready Safe scintillation fluid (Beckman) prior to radioactivity counting. Samples were read on a LKB Wallach Rackbeta ™ liquid scintillation counter at 4050% efficiency. All measurements were performed in triplicate.

Evaluation.

Membrane specific binding (C) is the difference between total binding in samples containing only vehicle and membrane (A) and non-specific binding in samples containing membrane and cytizine (B), ie.

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

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

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

The compounds of the invention tested in the above assay showed IC ₅₀ values of less than 10 µΜ.

PP 0191-2004

32269 / H

Claims (15)

P AT Ν CLAIMS What is claimed is: 1. A method of treating a subject suffering from Restless Legs Syndrome, comprising administering to a subject in need thereof a nicotinic acetylcholine receptor agonist in an amount effective to treat the syndrome. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a compound of Formula I: in which: (D R ¹ represents a hydrogen atom, a C 1 -C 6 alkyl group, a non-conjugated C 3 -C 6 alkenyl group, a benzyl group, an XC (= O) R ¹³ group or a -CH 2 CH 2 -O-alkyl group in which the alkyl moiety contains 1 to 4 carbon atoms; R ² and R ³ are independently selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, nitro, amino, halogen, cyano, -SOq -alkyl wherein the alkyl moiety contains 1 to 6 carbon atoms and q is zero, 1 or 2, an alkylamino group containing 1 to 6 carbon atoms in the alkyl moiety, an [alkyl] 2 amino group containing 1 to 6 carbon atoms in each alkyl moiety , -CO ² R ⁴ , -CONR ⁵ R ⁶ , -SO ² NR ⁷ R ⁸ , -C (= O) R ¹³ , -XC (= O) R ¹³ , an arylalkyl group containing from 0 to 3 carbon atoms in the alkyl moiety or an arylalkyl-radical containing from 0 to 3 carbon atoms in the alkyl moiety, wherein said aryl group is selected from the group consisting of phenyl and naphthyl, a heteroarylalkyl group containing from 0 to 3 alkyl moieties PP 0191-2004 32269 / H carbon atoms or heteroaryl-alkyl-O-group containing from 0 to 3 carbon atoms in the alkyl moiety, said heteroaryl moiety selected from the group consisting of 5- to 7-membered aromatic rings containing one to four heteroatoms selected from oxygen, nitrogen and S, X ² an alkyl group having alkyl 0-6 carbon atoms and X ² -alkoxyalkyl- group having the alkoxy of 1 to 6 carbon atoms and the alkyl part of 0-6 carbon atoms, wherein X ² is either absent or X ² means a (C 1 -C 6) alkylamino group or a (alkyl) ₂ amino group having from 1 to 6 carbon atoms in each alkyl moiety, and an alkyl moiety containing from 0 to 6 carbon atoms or an alkoxy alkyl moiety having from 1 to 6 carbon atoms and in the alkyl moiety of from 0 to 6 carbon atoms of said X ² -alkyl groups containing 0-6 moieties in the alkyl moiety or X ² alkoxy-alkyl groups having 1 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety contain at least one carbon atom and one to three carbon atoms of said alkyl groups having 0 to 6 carbon atoms or alkoxy groups. alkyl groups containing from 1 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two of said heteroatoms must be separated by at least two carbon atoms and the alkyl portions of said C 1 -C 6 alkyl groups or C 1 -C 6 alkoxyalkyl and C 0 -C 6 alkyl moieties may optionally be substituted with two to seven fluorine atoms, and one of the carbon atoms of each alkyl moieties of said aryl- an alkyl group containing from 0 to 3 carbon atoms in the alkyl moiety and said heteroaryl alkyl group containing from 0 to 3 carbon atoms in the alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, and each of the above aryl and heteroaryl groups may be optionally substituted with one or more substituents, preferably no to two substituents, independently selected from the group consisting of C 1-6 alkyl groups optionally substituted with one to seven fluorine atoms, alkoxy groups PP 019 I - 2094 32269 / H having 1 to 6 carbon atoms optionally substituted by two to seven fluorine atoms, halogens (such as chlorine, fluorine, bromine or iodine), alkenyl groups having 2 to 6 carbon atoms, alkynyl groups having 2 to 6 carbon atoms, hydroxy , nitro, cyano, amino, alkylamino having 1 to 6 carbon atoms in the alkyl moiety, [alkylamino- having 1 to 6 carbon atoms in each alkyl moiety, -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 carbon atoms to which they are attached form a four to seven membered monocyclic, or ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three non-fused carbon atoms of said monocyclic rings, and a up to five carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula (I), may optionally be replaced independently of one another by a nitrogen, oxygen or sulfur atom, and the monocyclic or bicyclic rings may optionally be substituted by one or more substituents; preferably no to two substituents for monocyclic rings and no to three substituents for bicyclic rings independently selected from the group consisting of alkyl groups containing 0 to 6 carbon atoms or alkoxyalkyl groups having 1 to 6 carbon atoms in the alkoxy moiety and 0 to 6 carbon atoms in the alkyl moiety, wherein the total number of carbon atoms is at most six, and any one of said alkyl groups may optionally be substituted by one to seven fluorine atoms; nitro, oxo, cyano, halogens, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, amino, C 1 -C 6 alkylamino, [C 2 -C 6 alkyl] amino each alkyl moiety having 1 to 6 carbon atoms, -CO ² R ⁴ , -CONR ⁵ R ⁶ , -SO ² NR ⁷ R ⁸ , -C (= O) R ^13, and -XC (= O) R ¹³ ; PP 0191-2004 32269 / H R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ each independently of one another is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a pyrrolidine group, piperidine group, morpholine group, azetidine group, piperazine group, -Nalkylpiperazine group having 1 to 6 carbon atoms in the alkyl moiety or a thiomorpholine ring or thiomorpholine ring in which it is a ring sulfur atom replaced by a sulfoxide group or a sulfone group; and X each independently represents an alkylene group having 1 to 6 carbon atoms; with the proviso that: (a) at least one of R ¹ , R ² , R ³ must be other than hydrogen; and (b) when R ² and R ³ are hydrogen, then R ¹ cannot be hydrogen, an alkyl group containing 1; or a non-conjugated (C 3 -C 6) alkenyl group, and pharmaceutically acceptable salts thereof. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a compound of formula II: wherein: Z is CH 2, C (= O) or CF ₂ ; R ²¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an unconjugated alkenyl group having 3 to 6 carbon atoms, PP 0191-2004 32269 / H benzyl, XC (= O) R ^13, or -CH ₂ CH ₂ -O-alkyl, wherein the alkyl group contains 1 to 4 carbon atoms; R ²² and R ²³ each independently of one another are selected from the group consisting of hydrogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, nitro, amino, halogen, cyano, -SOq-alkyl in which the alkyl moiety contains 1 to 6 carbon atoms and q is zero, 1 or 2, an alkylamino group containing 1 to 6 carbon atoms in the alkyl moiety, an [alkyl] 2 amino group containing 1 to 6 alkyl moieties carbon atoms, CO 2 R ^4, CONR ⁵ R ^6, SO 2 NR ⁷ R ^8, C (= O) R ^13, XC <= O) R ^13, aryl- alkyl 0-3 carbon atoms or an arylalkyl-O- group, containing from 0 to 3 carbon atoms in the alkyl moiety, wherein said aryl group is selected from phenyl and naphthyl, a heteroarylalkyl group containing from 0 to 3 carbon atoms in the alkyl moiety or a heteroaryl-alkyl-O-group containing from 0 to 3 carbon atoms in the alkyl moiety, wherein said heteroaryl moiety is selected from the group consisting of five to seven membered aromatic rings containing one to four heteroatoms selected from oxygen, nitrogen and sulfur and X ² alkoxy an alkyl group containing from 0 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety, wherein X ² is either absent or X ² is an alkylamino group containing 1 to 6 carbon atoms or an [alkyl] ₂ amino group containing each alkyl of 1 to 6 carbon atoms, and further an alkoxy-alkyl moiety of the alkoxy of 0-6 carbon atoms and the alkyl part of 0-6 carbon atoms X of said ^{2-alkoxy-alkyl} group of the alkoxy of 0-6 carbon atoms and the alkyl 0 The C 1-6 carbon atoms contain at least one carbon atom and one to three carbon atoms a guided alkoxyalkyl group containing from 0 to 6 carbon atoms in the alkoxy moiety and from 0 to 6 carbon atoms in the alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two of said heteroatoms must be separated by at least two carbon atoms; and any alkyl moieties PP 0191-2004 32269 / H of said alkoxy-alkyl groups containing from 0 to 6 carbon atoms and from 0 to 6 carbon atoms may optionally be substituted by two to seven fluorine atoms and one of the carbon atoms of each of the alkyl portions of said aryl-alkyl group in the alkyl moiety of 0 to 3 carbon atoms and said heteroaryl-alkyl group containing in the alkyl moiety of 0 to 3 carbon atoms may optionally be replaced by an oxygen, nitrogen or sulfur atom, and further each of the above aryl and heteroaryl groups may be optionally substituted by one or a plurality of substituents, preferably no to two substituents, independently selected from the group consisting of C 1 -C 6 alkyl groups optionally substituted with 1 to 7 fluorine atoms, C 1 -C 6 alkoxy groups optionally substituted two to seven fluorine atoms, halogens (such as chlorine, fluorine, bromine or iodine), hydroxy, nitro, cyano, amino, alkylamino groups having 1 to 6 carbon atoms in the alkyl moiety, [alkyl] ₂ amino groups containing each of alkyl portions of 1 to 6 carbon atoms; Or R and R together with the carbon atoms to which they are attached form a four to seven membered monocyclic or ten to fourteen membered bicyclic, carbocyclic ring which may be saturated or unsaturated, wherein one to three non-fused carbon atoms of said monocyclic rings and one up to five carbon atoms of said bicyclic rings, which are not part of the benzene ring shown in formula (I), may optionally be replaced independently of each other by nitrogen, oxygen and sulfur, and the monocyclic or bicyclic rings may optionally be substituted by one or more substituents, preferably no to two substituents in the case of monocyclic rings and no to three substituents in the case of bicyclic rings independently selected from the group consisting of alkoxy-alkyl groups containing e in the alkoxy moiety of 0 to 6 carbon atoms and in the alkyl moiety of 0 to 6 carbon atoms, wherein the total number of carbon atoms is at most six and any of the above PP 01 9 l -2004 32269 / H alkyl groups may be optionally substituted with one to seven fluorine atoms; nitro, oxo, cyano, halogens, hydroxy, amino, C 1 -C 6 alkylamino, C ₂ -C 6 alkyl, C ₂ -C 6 alkyl, phenyl and monocyclic heteroaryl wherein: said heteroaryl group having the same meaning as defined above for the definition of substituents R ²² and R ²³ above; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ¹³ each independently of one another are selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R ⁵ and R ⁶ , or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a pyrrolidine ring, piperidine ring, morpholine ring, azetidine ring, piperazine ring, -N-alkylpiperazine ring containing from 1 to 6 carbon atoms in the alkyl moiety or a thiomorpholine ring, or a thiomorpholine ring, wherein the ring sulfur atom is replaced by a sulfoxide group or a sulfone group; and X each independently represents an alkylene group having 1 to 6 carbon atoms; with the proviso 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, then R ²¹ cannot be a methyl group or a hydrogen atom; and (c) none of the fluorine atoms in all of the fluorine-substituted alkyl or alkoxy portions of said substituents R ²² and R ²³ may be attached to a carbon atom which is attached to the heteroatom; and pharmaceutically acceptable salts thereof. PP 0191-2004 32269 / H The process according to claim 2 or 3, wherein the heteroaryl groups in the definition of the substituents R ² and R ³ in formula I or R ²² and R ²³ in formula II are thienyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, 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 of these is a bond to the benzene ring of Formula I or Formula II. A process according to claim 2 or 3, characterized in that R ² and R ³ in formula I or R ²² and R ²³ in formula II together with a benzene ring in either formula I or formula II form a bicyclic ring a system selected from the following structures: PP 0191-2004 32269 / H wherein R ¹⁰ and R ¹⁷ are each independently selected from hydrogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy and C 0 alkyl up to 6 carbon atoms, wherein the total number of carbon atoms is up to six and wherein any of the above alkyl moieties may be optionally substituted by one to seven fluorine atoms: further nitro, cyano, halogen, amino, alkylamino containing 1 to 1 alkyl 6 carbon atoms, [alkyl] 2 amino group containing from 1 to 6 carbon atoms in each alkyl moiety, -CO ² R ⁴ , CONR ⁵ R ^e , -SO ² NR ⁷ R ⁸ , -C (= O) R ¹³ , -XC (= O) R ¹³ , phenyl and monocyclic heteroaryl. A process according to claim 2 or 3, characterized in that R ² and R ³ in formula I or R and R in formula II together with the benzene ring in either formula I or formula II form a bicyclic or tricyclic ring a system selected from the following structures: PP 0191-2004 32269 / H wherein R ¹⁰ and R ¹⁷ have the same meaning as defined above, and m is zero, one or two, wherein one of the carbon atoms of ring A may optionally be replaced by oxygen or an N-alkyl group having 1 to 6 carbon atoms. A process according to claim 2 or 3, characterized in that R ² and R ³ in formula I or R ²² and R ²³ in formula II do not form together with the benzene ring in formula I or formula II bicyclic or tricyclic circular system. Process according to claim 2 or 3, characterized in that one of the substituents R ² and R ³ in formula I or R ²² or R ²³ in formula II is CF ₃ , fluoro, cyano, alkynyl containing 2 to 3 6 carbon atoms or C ₂ F ₅ . The method of claim 2, wherein the nicotinic acetylcholine receptor agonist is selected from the group consisting of: 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 ²⁷ ] 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-tricyclo [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 .0 ^4,8 ] pentadiene _and -2 (10), 3,6,8tetraene; 6-methyl-7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,1 .0 ° ^{4 '8]} pentadeca-2 (10), 3,5,8-tetraene; PP 0191-2004 32269 / H 5.7.13- triazatetracyclo [9.3.1.0 ² ' ¹ .0 ⁴ ' ⁸ ] -pentadeca-2 (10), 3,5,8-tetraene; 7-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^{4' 8]} pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,10 .0 ^4,8 ] -pentadeca-2 (10), 3,5,8-tetraene; 6.7- dimethyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,1 .0 ° ^{4 '8]} pentadeca-2 (10), 3,5,8-tetraene; 7-propyl-5,7,13-triazatetracyclo [9.3.1.0 ^2.10 0 ⁴⁸ ] pentadeca-2 (10), 3,5,8-tetraene; 7-butyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^4,8] pentadeca-2 (10), 3,5,8-tetraene; 7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^{4' 8]} pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-isobutyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^4,8] pentadeca-2 (10), 3,5,8-tetraene; 7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ² · ^{10 4} 0 ^'8] pentadeca-2 (10), 3,5,8-tetraene; 6-methyl-7-phenyl-5,7,13-triazatetracyclo [9.3.1.0 ^2,1 .0 ^4,8 °] pentadeca2 (10), 3,5,8-tetraene; 6-methyl-7-neopentyl-5,7,13-triazatetracyclo [9.3.1.0 ^{2 '10} .0 ^4,8] -pentadeka2 (10), 3,5,8-tetraene; 6.7- dimethyl-5,8,14-triazatetracyclo [10.3.1.0 ^{2 '11} .0 ^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), 3,5,7,9-pentaene; 14-methyl-5,8,14-triazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9] hexadeca-2 (11), 3,5,7,9-pentaene; 5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2 'Q1} .0 ^{4' 8]} pentadeca-2 (10), 3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^{2 '1} ° .0 ^{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-tricyclo [6.3.1.0 ^{2 '7]} dodeca-2 (7), 3,5-trien-4-yl cyanide; PP 0191-2004 32269 / H 3- (10-tricyclo [6.3.1.0 ^27] 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 '1} ° .0 ^{4' 8]} pentadeca-2,4 (8), 6,9tetraén; 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- d the Lor-10-tricyclo [6.3.1.0 ^{2 '7]} dodeca-2 (7), 3,5-triene; N ^4, N ⁴ -dimethyl-10-tricyclo [6.3.1.0 ^{2 7]} dodeca-2 (7), 3,5-triene-4-sulfonamide; 4- (1-pyrrolidinylsulfonyl) -10-tricyclo [6.3.1.0 ^{2 '7]} dodeca-2 (7), 3,5-triene; 5.13- diazatetracyclo [9.3.1.0 ^{2 'w} .0 ^{4' 8]} pentadeca-2,4 (8), 9-trien-6-one; 6-oxo-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^2,10 .0 ^4,8] pentadeca-2 (10), 3,6,8-tetraene; 3-phenyl-10-aza-tricyclo [6.3.1 ² O ^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 ^4,8 .0 ²¹ °] pentadeca2 (10), 3,6,8-tetraene; 6-isopropyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^2,1 .0 ^4,8 °] pentadeca2 (10), 3,6,8tetraén; 6-benzyl-5-oxa-7,13-diazatetracyclo [9.3.1.0 ^2,10 .O ^4,8] pentadeca-2 (10), 3,6,8-tetraene; 5.14- diazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9] hexadeca-2 (11), 3,5,7,9-pentaene; 6-methyl-5,14-diazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9] hexadeca-2 (11), 3,5,7,9-pentaene; 7-Methyl-5,14-diazatetracyclo [10.3.1.0 ²¹¹ .0 ^4.9] -hexadeca-2 (11), 3,5,7,9-pentaene; 7-ethyl-5,14-diazatetracyclo [10.3.1.0 ^2,11 .0 ^4,9] hexadeca-2 (11), 3,5,7,9-pentaene; 8-methyl-5,14-diazatetracyclo [10.3.1.0 ^2.11 .0 &apos; ⁴ ] -hexadeca-2 (11), 3,5,7,9-pentaene; PP 0191-2004 32269 / H 5.14- diazatetracyclo [10.3.1.0 ²¹¹ .0 ^4.9] -hexadeca-2 (11), 3,5,7,9-tetraene-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 .0 ^4,9] hexadeca-2 (11), 3,5,7,9-pentaene; 6-chloro-10-fluoro-5,14-diazatetracyclo [10.3.1.0 ^2,11 .0 ^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; and pharmaceutically acceptable salts and optical isomers thereof. The method of claim 3, wherein the nicotinic acetylcholine receptor agonist is selected from the group consisting of: 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 ²⁷ ] 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} ] tridexa-2 (7), 3,5-triene-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; PP 0191-2004 32269 / H 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.O ^{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 ^2,1 .0 ^4,8 ] hexadeca-2 (10), 3,8-triene; 11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo [7.3.1.O ^{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-Trifluoromethylphenyl) -11-aza-tricyclo [7.3.1.0 ²⁷ ] trideca-2 (7), 3,5-triene; 5- (4-methoxyphenyl) -11-aza-tricyclo [7.3.1.0 ^2,7 ] trideca-2 (7), 3,5-triene; methyl-11-aza-tricyclo [7.3.1,0 ^{2 7]} trideca-2 (7), 3,5-triene-5-carboxylic acid; 2- (11-aza-tricyclo [7.3.1.0 ²⁷ ] 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 the pharmaceutically acceptable salts and optical isomers of these compounds. The method of claim 1, wherein the nicotinic acetylcholine receptor agonist is a compound of formula III: PP 0191-2004 32269 / H in which: X ³ means: (a) -CH ² NR ³¹ R ³² ; (b) a group CH (CH ₂ ) _¥ (c) a group in which: R ³⁰ , R ³¹ and R ³² are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, R ³³ is selected from the group consisting of hydrogen, halogen, and alkyl groups of 1 to 6 carbon atoms, v is an integer from 0 to 4, or a pharmaceutically acceptable salt thereof. 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 full agonist. Use of a nicotinic acetylcholine receptor agonist for the preparation of a medicament for the treatment of Rest / Ess Leg Syndrome (RLS). Use of a nicotinic acetylcholine receptor agonist selected from the group consisting of compounds of Formula I, II, III, IV, V and VI or pharmaceutically acceptable salts thereof PP Ol91-2004 32269 / Ή of compounds for the preparation of a medicament for the treatment of Restless Legs Syndrome (RLS). ¾ 0191-200-4