CA2460118A1

CA2460118A1 - Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome

Info

Publication number: CA2460118A1
Application number: CA002460118A
Authority: CA
Inventors: Mario David Saltarelli
Original assignee: Individual
Current assignee: Pfizer Products Inc
Priority date: 2001-10-31
Filing date: 2002-10-21
Publication date: 2003-05-08
Also published as: TW200300139A; BR0213696A; SK1912004A3; CZ2004524A3; KR20050038583A; HUP0401967A2; CN1568184A; EP1439836A1; JP2005507411A; PL370549A1; MXPA04002539A; WO2003037329A1; IL160967A0

Abstract

This invention relates to the use of nicotinic acetylcholine receptor agonis ts 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

_1_ NICOTINIC ACETYLCHOLINE RECEPTOR AGONISTS
IN THE TREATMENT OF RESTLESS LEGS SYNDROME
Backgiround of the Invention This invention relates to the use of nicotinic acetylcholine receptor agonists for the treatment of restless legs syndrome (RLS). The invention also relates to the use of a nicotinic acetylcholine receptor agonist in the manufacture of a medicament for the treatment of RLS.
The invention further relates to a pharmaceutical composition for the treatment of RLS containing a nicotinic acetylcholine receptor agonist.
Restless legs syndrome is a condition of unknown origin characterized by a bothersome, but usually not painful, sensation in one or both legs that causes an afflicted individual to experience an irresistible urge to move the legs. Occasionally, this condition occurs in the arms as well. Voluntary movement of the limb in which such a sensation is felt reportedly.reduces or alleviates the intensity of the sensation. RLS most often affects its sufferers worst, or exclusively, when the afflicted individual is at rest or lying down in. the evening or at night.
Movement of the toes, feet or legs is typically observed in an afflicted individual when sitting or lying down, and has often been mischaracterized as fidgetiness or nervousness.
A sufferer of RLS often may have difficulty falling and staying asleep with an estimated 30%
of afflicted individuals having periodic limb movements throughout the night, sometimes as frequently as every 20 to 30 seconds, often causing partial arousal that disrupts sleep. The resulting chronic sleep deprivation and accompanying daytime fatigue often can cause mood swings in the afflicted individual and can have a debilitating effect on that individual's ability to work and function on a daily basis.
At present, the most prescribed treatment for RLS is a dopaminergic agent (often a dopamine-receptor agonist) like Mirapex (pramipexole), Permax (pergolide), and Requip (ropinirole), or a drug that adds dopamine to the system like Sinemet (carbidopahevodopa). Of the dopaminergic agents, Sinemet has been used the longest, but has recently been found to cause the serious side effect of augmentation in the vast majority of patients who take it for the treatment of RLS. Other less used treatments for RLS are sedatives, which can relieve nighttime symptoms of RLS; pain relievers (including codeine, Darvon or Darvocet (propoxyphene), Dolophine (methadone), Percocet (oxycodone), Ultram (tramadol), and Vicodin (hydrocodone) for those with severe unrelenting symptoms of RLS; and anti-convulsants (including Gabapentin (Neurontin)) which are effective for some, but not all, patients with marked daytime symptoms, particularly people who have pain syndromes associated with their RLS.
Agonists of nicotinic acetylcholine receptors markedly increase the release of dopamine in the brain. As enhanced dopaminergic activity has been implicated in possible mechanisms of alleviation of RLS and dopaminergic agents have been somewhat effective in the treatment of RLS, agonists of the nicotinic acetylcholine specific receptors provide an alternative means to treat RLS avoiding some of the side effects associated with some known dopaminergic agents.
In particular, a number of compounds which bind to neuronal nicotinic receptor sites and are useful in modulating cholinergic function are referred to in International Patent Publication No. WO 01/62736, filed February8, 2001; International Patent Publication No. WO
99/35131, filed November 13, 1998; International Patent Publication No. WO
99/55680, filed April 8, 1999; International Patent Publication No. WO 98/18798, filed October 15, 1997; U.S.
Patent No. 5,977,131, filed March 31, 1998; U.S. Patent No. 6,020,335, filed November 4, 1997; and European Patent Publication No. EP 0 955 301 A2, filed March 25, 1999. The foregoing applications are owned in common with the present application, and is incorporated herein by reference in their entirety.
Summary of the Invention The present invention relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment an amount of a nicotinic acetylcholine receptor agonist effect in treating said syndrome.
The present invention further relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment an amount of a compound of formula I:

~NR~ (I) wherein R~ is hydrogen, (C~-C6)alkyl, unconjugated (C~-C6)alkenyl, benzyl, XC(=O)R~3 or -CH~CHZ-O-(C~-C4)alkyl;
Rz and R3 are selected, independently, from hydrogen, (CZ-C6)alkenyl, (CZ-C6)alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C~-C6)alkyl wherein q is zero, one or two, (C~_C6)alkylamino-, [(C~-C6)alkyl]2amino-, -CO~R4, -CONR5R6, -SOZNR~RB, -C(=O)R'3, -XC(=O)R'3, aryl-(Co-C3)alkyl- or aryl-(Co-C3)alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(Co-C3)alkyl- or heteroaryl-(Co-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; XZ(Co-C6)alkyl- and X~(C~-C6)alkoxy-(Co-C6)alkyl-, wherein X~ is absent or X~ is (C~-C6)alkylamino- or [(C~-C6)alkyl]amino-, and wherein the (Co-Cs)alkyl- or (C~-C6)alkoxy-(Co-C6)alkyl- moieties of said X~(Co-C6)alkyl- or X2(C~-C6)alkoxy-(Co-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (Co-C6)alkyl- or (C~-Cs)alkoxy-(Co-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (Co-C6)alkyl- or (C~_C6)alkoxy-(Co-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(Co-C3)alkyl- and said heteroaryl-(Co-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C~-C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.~c ., chloro, fluoro, bromo or iodo), (C~-C6)alkenyl, (CZ-C6)alkynyl, hydroxy, nitro, cyano, amino, (C~-C6)alkylamino-, [(C~-C6)alkyl]amino-, -COZR4, -CONR5R6, -SO~NR'R8, -C(=O)R'3 and -XC(=O)R'3;
or R~ and R~, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (Co-C6)alkyl- or (C~-C6)alkoxy-(Co-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, (C~-C6)alkenyl, (C~-C6)alkynyl, hydroxy, amino, (C~-C6)alkylamino-, [(C~-C6)alkyl]2amino-, -CO~R4, -CONR5R6, -SO~NR'R8, -C(=O)R'3, and -XC(=O)R13~
each R4, R5, R6, R' , R8 and R'3 is selected, independently, from hydrogen and (C~ -C6) alkyl, or R5 and R6, or R' and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, -N-(C~-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, (C~-C6)alkylene;
with the proviso that: (a) at least one of R', R~ and R3 must be the other than hydrogen, and (b) when RZ and R3 are hydrogen, R' cannot be hydrogen, (C~-Cs)alkyl, or unconjugated (C3 C6)alkenyl, and pharmaceutically acceptable salts of such compounds.

Examples of possible heteroaryl groups within the definition of R~ and R3 in formula I are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:
R1$ j R9 R1s N 9 R1s O s ~R R
O-N
N-O N N

,'N R N~Rs R~~N
N
R1s N~ 9 N~ ~N
R R1s wherein one of R9 and R~~ is hydrogen or (Ci-C6)alkyl, and the other is a bond to the benzo ring of formula I.
Examples of compounds of the formula I used in the method of the invention are wherein R2 and R3, together with the benzo ring of formula I, form a bicyclic ring system selected from the following:
N R1o R1o ~ \~Rlo ~ R1~
O N
~N

S
O N ~ /~Rlo N

wherein R~° and R~' are selected, independently, from hydrogen, (C~-C6)alkyl; and (C~-C6)alkoxy-(C°-Cs)alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C~-C~)alkylamino-, [(C~-C6) alkyl]amino-, -C02R4, -CONR5R6, -SOZNR'R8, -C(=O)R~3, -XC(=O)R~3, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as RZ and R3 are defined in the definition of compounds of the formula I above;

Other embodiments compounds of the formula I in the method of the invention are wherein R2 and R3, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system selected from the following:

S
o N~~N o ; N O
i "~N
N 1o N
R1o R
R1o R1o R17 / N\
O ,N O ~~ \
~N~~R17 ~N

O O ~N O ~N
i R1o ~ R1o R1o \ N
O ) O N ~ ~ N A ~ ~N

wherein R'° and R" are defined as above, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(C~-C6)alkyl.
Other embodiments of the compounds of the formula I in the methods of the invention are wherein neither R~ nor R3 is attached to the benzo ring of formula I via an oxygen atom.
Other embodiments of this invention relate to compounds of the formula I, and their pharmaceutically acceptable salts, wherein RZ and R3 do not, together with the benzo ring of formula I, form a bicyclic or tricyclic ring system.
Other embodiments of this invention relate to compounds of the formula I
wherein one or both of RZ and R3 are -C(=O)R'3, wherein R'3 is (C~-C6)alkyl. Further embodiments of this invention relate to compounds of the formula I wherein one or both of RZ and R3 are -C(=O)R'~, wherein R'3 is (C~-C6)alkyl or (C~-C3)alkyl optionally substituted with from one to seven fluorine atoms. Other embodiments relate to compounds of the formula I wherein one of R~ and R3 is CF3, fluoro, cyano, (C2-C6)alkynyl or CzFS.

Examples of specific compounds of the formula I in the methods of the invention are the following compounds, which, in the instances where there is a center or centers of asymmetry in the molecule, may comprise a racemic mixture or the single enantiomer:
10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-fluoro-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
3-trifluoromethyl-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
3-fluoro-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-amino-10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
N'-[10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl]-acetamide;
6-methyl-5-this-7,13-diazatetracyclo[9.3.1.02''°.04'$]pentadeca-2(10),3,6,8-tetraene;
6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'$]-pentadeca-2(10),3,5,8-tetraene;
5,7,13-triazatetracyclo[9.3.1.02''°.04'$]-pentadeca-2(10),3,5,8-tetraene;

7-methyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-5,7,13-triazatetracyclo[9.3.1.02'' °.04'~]-pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'$]-pentadeca-2(10),3,5,8-tetraene;
7-propyl-5,7,13-triazatetracyclo[9.3.1.02'' °.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-butyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'$]-pentadeca-2(10),3,5,8-tetraene;
7-phenyl-5,7,13-triazatetracyclo[9.3.1.02'' °.04'$]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.02''°.04'$]-pentadeca-2(10),3,5,8-tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.02'" .04'9]-hexadeca-2(11 ),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02'".04'9]-hexadeca-2(11 ),3,5,7,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.02'".04'9]-hexadeca-2(11 ),3,5,7,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,6,8-tetraene;
2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02'']-dodecc-2(7),3,5-trien-5-yl)-benzamide;
4-chloro-10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl cyanide;
3-(10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;
1-(10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02''°.04'8]pentadeca-2,4(8),6,9-tetraene;

4-(2-methyl-2H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4-(1-methyl-1 H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4,5-dichloro-10-azatricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
N4,N4-dimethyl-10-azatricyclo[6.3.1.02'']-dodecc-2(7),3,5-triene-4-sulfonamide;
4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02'']-dodecc-2(7),3,5-triene;
5,13-diazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2,4(8),9-trien-6-one;
6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,6,8-tetraene;
3-phenyl-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
3-hydroxy-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.02'']dodecc-2(7),3,5-triene;
6-ethyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'' °.04'8]-pentadeca-2(10),3,6,8-tetraene;
6-isopropyl-5-oxa-7,13-diazatetracyclo[9.3.1.02''°.04'8]-pentadeca-2(10),3,6,8-tetraene;
6-benzyl-5-oxa-7,13-diazatetracyclo[9.3.1.02''°.04'~]-pentadeca-2(10),3,6,8-tetraene;
5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11 ),3,5,7,9-pentaene;
6-methyl-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11),3,5,7,9-pentaene;
7-methyl-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11 ),3,5,7,9-pentaene;
7-ethyl-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11 ),3,5,7,9-pentaene;

8-methyl-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11 ),3,5,7,9-pentaene;
5,14-diazatetracyclo[10.3.1.02'".04'9]hexadeca-2(11 ),3,7,9-tetraen-6-one;
6-chloro-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11),3,5,7,9-pentaene;
6-methoxy-5,14-diazatetracyclo[10.3.1.02'".04's]hexadeca-2(11 ),3,5,7,9-pentaene;
6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02'" .04's]hexadeca-2(11 ),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02'" .04~s]hexadeca-2(11 ),3,7,9-tetraen-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, for restless legs syndrome comprising administering to the mammal in need of such treatment an compound of formula II
NR2~

/ (II) wherein Z is CH2, C(=O) or CF2;
R2' is hydrogen, (C~-Cs)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=O)R'3 or -CH2CH2-O-(C~-C4)alkyl;

_g_ RZ~ and R~3 are selected independently, from hydrogen, (C~-C6) alkenyl, (CZ-C6) alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C~-C6)alkyl wherein q is zero, one or two, (C~_C6)alkylamino, [(C~-Cs)alkyl]zamino, COaR4, CONR5R6, SOZNR~RB, C(=O)R'3, XC(=O)R'3, aryl-(Co -C3) alkyl or aryl-(Co-C3)alkyl-O- wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(Co-C3)alkyl or heteroaryl-(Co-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and XZ(Co-C6)alkoxy-(Co-C6)alkyl, wherein X2 is absent or Xa is (C~-C6)alkylamino or [(C~-C6)alkyl]amino, and wherein the (Co-C6)alkoxy-(Co-C6)alkyl moiety of said X~(Co-C6)alkoxy-(Co-C6)alkyl contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (Co-C6)alkoxy-(Co-C6)alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (Co_C6)alkoxy-(Co-C6)alkyl may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(Co-C3)alkyl and said heteroaryl-(Co-C3)alkyl may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C~ -C6) alkyl optionally substituted with from one to seven fluorine atoms, (C~ -C6) alkoxy optionally substituted with from two to seven fluorine atoms, halo (eg, chloro, fluoro, bromo or iodo), hydroxy, nitro, cyano, amino, (C~ -C6) alkylamino and [(C~ -Cs) alkyl]~
amino;
or RZ~ and R23, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein, from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula II, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (Co-Cs) alkoxy-(Co-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, hydroxy, amino, (C1 -C6)alkylamino, [(C~ -C6) alkyl]Zamino, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as in the definition of R22 and R23 above;
each R4, R5, R6, R' , R~, and X is as defined above;
with the proviso that: (a) at least one of R~', R22 and R23 must be the other than hydrogen, (b) when R~~ and R~3 are hydrogen, R2~ cannot be methyl or hydrogen;
and (c) no _g_ fluorine atom in any of the fluoro substituted alkyl or alkoxy moieties of RaZ
and R23 can be attached to a carbon that is attached to a heteroatom;
and the pharmaceutically acceptable salts of such compounds.
Examples of heteroaryl groups that each of R~2 and R23 in the compounds of formula II
in the method of the invention are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrroyl and the following groups:
R1s N
~Rg R1s N
Rs R1 s O Rs O-N
N-O N N

R N~R9 R~~N
1s _ N , N
R ~R9 N~ N'\ 1s R
wherein R9 and R'$ are as defined above.
Examples of compounds of the formula II in the methods of the invention are wherein R~~ and R~3, together with the benzo ring of formula II, form a bicyclic ring system selected from the following:

~~R~o ~ ~ R1o ~ R17 N O ~N
R1' OvN ~ ~~R~o N

wherein R'° and R" are as defined above;
Other embodiments of this invention relate to compounds of the formula II in the methods of the invention wherein R2z and R23, together with the benzo ring of formula II, form a bicyclic or tricyclic ring system selected from the following:

N,,N o S,N
o , N
R1o R1o R R / N\
O _ N O ~~ ~ ~N O
wN R1~ N
R17 R1' R17 O ~~CN Q ~N
N N
R1o R1o R1o O R1o N N
O
N A N
R1' m 5 wherein m, R'° and R'7 are as defined above and one of the carbon atoms of ring A can optionally be replaced vdith oxygen or -N(C~-C6)alkyl.
Other embodiments of this invention relate to compounds of the formula II in the methods of the invention wherein neither R2~ nor R~3 is attached to the benzo ring of formula II
via an oxygen atom.
10 Other embodiments of this invention relate to compounds of the formula II
in the methods of the invention wherein R~~ is not methyl.
Preferred embodiments of the invention relate to methods of treatment wherein the compounds of the formula II to be administered are selected from the group consisting of 5,6-difluoro-11-aza-tricyclo[7.3.1.02'']trideca-2,4,6-triene;

11-benzyl-6-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0~'~]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.0~'~]trideca-2(7),3,5-triene;
11-benzyl-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
11-benzyl-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-trien-5-ol;
5-methoxy-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-trien-5-ol;

11-benzyl-5-difluoromethoxy-11-aza-tricyclo[7.3.1,OZ'']trideca-2(7),3,5-triene;
5-difluoromethoxy-11-aza-tricyclo[7.3.1.Ow]trideca-2(7),3,5-triene;
11-benzyl-5-ethoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5-ethoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5-isopropoxy-11~ aza-tricyclo[7.3.1.0~~']trideca-2(7),3,5-triene;
11-benzyl-4-methoxy-11-aza-tricyclo[7.3.1.Oa~']trideca-2(7),3,5-triene;
4-methoxy-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-trien-4-ol;
11-benzyl-11-aza-tricyclo[7.3.1.OZ'']trideca-2(7),3,5-triene;
4-nitro-11-aza-tricyclo[7.3.1.0z'']trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
3-nitro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
11-benzyl-5-fluoro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5,7-dioxa-14-azatetracyclo[10.3.1.02~~o.Oa.a]hexadeca-2(10),3,8-triene;
11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5 -triene;
11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5 -triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5 -triene;
trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-trien-5-yl ester;
5-(4-trifluoromethyl-phenyl)-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
5-(4-methoxy-phenyl)-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene-5-carboxylic acid methyl ester;
2-(11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-trien-5-yl)-propan-2-ol;
5-pyridin-3-yl-11-aza-tricyclo[7.3.1.02'']trideca-2(7),3,5-triene;
and pharmaceutically acceptable salts and optical isomers thereof.
The present invention also relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment an amount of a compound of formula II I
\ X3 (R33)n (III) N
wherein X3 is:
a) -CH2NR3'Rs2 b) ~---(cH~)~
or c) Rso N
(CH~)~
wherein R3°, R31, and R3~ are independently selected from hydrogen and C1-C6 alkyl;
R33 is selected from hydrogen, halogen and C~-C6 alkyl;
v is an integer from 0 to 4; and n is an integer from 0 to 2; and pharmaceutically acceptable salts thereof.
Preferred compounds of formula III in the methods of the invention are:
[2-(6-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-dimethylamine;
[2-(6-chloro-1 H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-methylamine;
3-pyrrolidin-2-ylmethyl-1 H-pyrrolo[2,3-b]pyridine;
3-(1-methyl-pyrrolidin-2-ylmethyl)-1-H-pyrrolo[2,3-b]pyrid,ine;
dimethyl-[2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-amine;
methyl-[2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-amine;
2-(1 H-pyrrolo[2,3-b]pyridin-3-yl-ethylamine; and 3-(2-piperidin-1-yl-ethyl-1 H-pyrrolo[2,3-b]pyridine.
The present invention further relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment an amount of a compound of formula IV:

I

R4~
(IV) R43 ~ R42 H
wherein R4~, R42, R4s and R44 are selected, independently from hydrogen, -CO2R45, aryl and heteroaryl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl, and wherein said phenyl and said heteroaryl may optionally be substituted with from one to three substituents, and are preferably substituted with one or two substituents, independently selected form (C~-C6)alkyl optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, halo (i.e., chloro, fluoro, bromo or iodo), phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, (C~-C6)alkoxy optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, (C~-C6)alkylamino and [(C~
C6)alkyl]Zamino;
R45 is (C~-C6) alkyl, aryl, heteroaryl, (C~-C4)alkylene-aryl and (C~-C4)alkylene-heteroaryl, wherein said aryl and heteroaryl are defined as above, and wherein said (C~-C6)alkyl may optionally be substituted with from one to three substituents independently selected from halo, (C~-C6)alkyl, (C~-Cs )alkoxy, (C~-C4)alkoxy-(C~-C4)alkyl, amino, (C~-C6)alkylamino, and [(C1 C6)alkyl]zamino; and R46 is hydrogen or (C~-C6)alkyl;
with the proviso that: (a) at least one of R''~, R4~, R43, and R44 must be aryl or heteroaryl;
(b) when neither R4~ nor R42 is hydrogen, R4' and R4~ are in the "exo"
configuration; (c) R4' and R4a can not both be -CO2R45; (d) if either R43 or R44 is -CO~R45 and R45 is an alkyl or alkoxyalkyl group, then one of R4~ and R4~ must be aryl or heteroaryl; and (e) if either R4~ or R42 is -COZR4s and R45 is an alkyl or alkoxyalkyl group, then one of R43 and R44 must be aryl or heteroaryl;
and the pharmaceutically acceptable salts of such compounds.
Preferred compounds of this invention include compounds of the formula IV in the methods of the invention wherein one of R4' and R4~ is optionally substituted phenyl and the other is hydrogen, and wherein R43 and R44 are hydrogen.
More preferred compounds of the formula IV in the methods of the invention are wherein one of R4~ and R4~ is phenyl substituted with fluoro or nitro and the other is hydrogen, and wherein R43 and R44 are hydrogen.
More specific preferred embodiments of this invention are compounds of the formula IV
in the methods of the invention wherein R43 and R44 are hydrogen and one R'"
and R4~ is hydrogen and the other is: (a) 3-fluorophenyl; (b) 4-nitrophenyl; or 3-fluoro-4-nitrophenyl.
Other embodiments of this invention relate to the following compounds of the formula IV
and their pharmaceutically acceptable salts in the methods of the invention:
2[i-(3,4-difluorophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2(3-(3,5-dichlorobenzene)-7-aza-bicyclo[2.2.1]heptane;
2a-(4-nitrophenyl)-7-aza-bicyclo[2.2.1 ]heptane;

2[3-(3-thiophene)-7-aza-bicyclo[2.2.1]heptane;
2[i-(3-fluoro-4-chlorophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(3-flourophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2(3-(3-hydroxyphenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[3-(3-acetophenone)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(4-trifluoromethylphenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2(3-(3-fluoro-4-methylphenyl)- 7-aza-bicyclo[2.2.1]heptane;
2a-(3-chlorophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(n-benzyl-5-pyridonyl)-7-aza-bicyclo[2.2.1 ]heptane;
2a-(n-methyl-5-pyridonyl)- 7-aza-bicyclo[2.2.1]heptane;
2[i-(3-fluoro-5-n itrophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(4-aminophenyl)-7-aza-bicyclo[2.2.1]heptane;
2~-(3-fluoro-4-trifluoromethyl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2~3-(4-chlorophenyl)-7-aza-bicyclo[2.2.1]heptane;
2[i-(3,4-methylenedioxyphenyl)-7-aza-bicyclo[2.2.1]heptane;
2a-(2-chloro-6-methyl-5-pyridinyl)-7-aza-bicyclo[2.2.1]heptane;
2[i-(4-cyanophenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(3-fluoro-4-nitro-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2~3-(4-amido-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(3-fluoro-4-amino-phenyl)-7-aza-bicyclo[2.2.1]heptane;
2(3-(4-sulfonamido-phenyl)-7-aza-bicyclo[2.2.1]heptane;
2[i-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1 ]heptane;
2[i-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1]heptane, N-methyl;
2[3-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1]heptane, N-acetyl;
2b-(3,4-difluorophenyl)-7-azabicyclo[2.2.1]heptane;
4-(7-aza-bicyclo[2.2.1 ]hept-2-yl)-benzamidine;
2-(4-methanesulfonyl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
4-(7-aza-bicyclo[2.2.1 ]hept-2-yl)-phenol;
2-(4-methylsulfanyl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
4-(7-aza-bicyclo[2.2.1]hept-2-yl)-benzoic acid methyl ester;
4-(7-aza-bicyclo[2.2.1]hept-2-yl)-benzoic acid;
2-(3-fluoro-4-tetrazol-1-yl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(4-nitro-3-trifluoromethyl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-[3-fluoro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-7-aza-bicyclo[2.2.1 ]heptane;
2-(3-chloro-4-nitro-phenyl)-7-aza-bicyclo[2.2.1]heptane;

2-(4-tetrazol-1-yl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(6-methoxy-pyridin-2-yl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(4-methanesulfinyl-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(4-bromo-3-fluoro-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(4-cyano-3-fluoro-phenyl)-7-aza-bicyclo[2.2.1]heptane;
2-(3,4,5-trifluoro-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(3,4,5-trimethoxy-phenyl)-7-aza-bicyclo[2.2.1 ]heptane;
2-(5-nitro-furan-2-yl)-7-aza-bicyclo[2.2.1 ]heptane;
5-(7-aza-bicyclo[2.2.1 ]hept-2-yl)-3-methyl-benzo[d]isoxazole;
6-(7-aza-bicyclo[2.2.1]hept-2-yl)-3-methyl-benzo[d]isoxazole;
6-(7-aza-bicyclo[2.2.1 ]hept-2-yl)-1,4-dihydro-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 pharmaceutically acceptable salts and optical isomers thereof.
The present invention further relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment an amount of a compound of formula V

I
N
Rsa ~V ) N
O
Rs~
its enantiomers, diastereomers and stereoisomers, and their pharmaceutically acceptable salts and prodrugs, wherein R5' and R52 are each independently selected from a) H; halo; CF3; hydroxy; (C~-C5)alkoxy; CH~OH; -C(O)R54, wherein R54 is H, (C~-Cs)alkyl, (C5-C~o)aryl or benzyl (including substituted alkyl, aryl or benzyl); C=N; C-CR55, wherein Rs5 is H, (C~-C5)alkyl, (C5-C~o)aryl (including substituted alkyl or aryl); -S(O)PRSS, wherein R55 is H, (C~-C5)alkyi, or (C6-C~o)aryl (including substituted alkyl or aryl) and p is 0, 1, or 2;
(C~-C5)alkyl; (C~-C6)alkenyl; HEN; di-((C~-C5)alkyl)amino; mono(C~-C6)alkyl-amino; (C6-C~o)aryl-amino; (C3-C8)cycloalkyl-amino; heteroaryl-amino; cycloheteroalkyl-amino; and CON(R55)2 wherein each R55 is selected from hydrogen, (C1-C5)alkyl and (C5-C~o)aryl; and b) C02R56 wherein Rss is selected from H, (C~-C5)alkyl, phenyl and benzyl; and c) optionally benzene-fused (C5-C~o)aryl, optionally benzene-fused (C3-C8)cycloalkyl, optionally benzene-fused heteroaryl and optionally benzene-fused cycloheteroalkyl, wherein said heteroaryl group contains five to ten atoms comprising one to four heteroatoms, said cycloheteroalkyl contains 4 to 8 atoms comprising one or two heteroatoms selected from N, S
and O;
and wherein any of the alkyl, alkenyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl groups in a), b) and c) are optionally substituted with one or more substituents selected from halogen, (C~-Cs)alkyl, (Cs-C~o)aryl, hydroxy, hydroxymethyl, CHO and CO~RSS
wherein Rss is as described above; and R53 is selected from H, optionally substituted benzyl and methyl;
with the provisos that Rs' and R52 are not both hydrogen and when R53 is H, and that R5' and R52 when selected from H, Br and CI are not be the same.
Preferred compounds of formula V in the methods of the invention are those wherein R53 is selected from H, benzyl or methyl and RS' and R5~ are each independently selected from H, halo, (Ci-Cs)alkyl, cyano, (Cs-C~o)aryl, (C5-C9)heteroaryl, (C~-Cs)alkenyl, (C2-Cs)alkynyl-Rss and -C(O)R55 wherein R55 is H, (C~-Cs) alkyl, (Cs-C~o)aryl and (C5-C9)heteroaryl and amino and mono and di-substituted amino; with the provisos that when R53 is H then Rs' and R52 are not both H, Br and CI and when R53 is benzyl or methyl then R5' and R5~ are not hydrogen.
More preferred compounds of formula V in the methods of the invention are those wherein R5' and R5~ are each independently selected from H, ethyl, methyl, phenyl, vinyl, fluoro, bromo, chloro, isopropyl, tert-butyl, trifluoromethyl, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, di-[(C~-Cs)alkyl]amino, (C~-Cs)monoalkylamino, (Cs-C~o)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R55)~ wherein each R55 is selected from hydrogen, (C~-Cs)alkyl and (C6-C~o)aryl; (Cs C~o)aryi and (C5-C9)heteroaryl wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halogen, (C~-Cs)alkyl, (Cs-C~o)aryl, hydroxy, hydroxymethyl, CHO and C02R56.
More preferred compounds of formula V in the methods of the invention are those wherein R5~ is selected from optionally substituted benzyl or (C~-Cs)alkyl, wherein the substituents are described above and Rs' and R5~ are each independently selected from hydrogen, halo, cyano, optionally substituted (Ci-Cs)alkyl, (C~-Cs)alkenyl, amino, di-[(C~-Cs)alkyl]amino, (C~-Cs)monoalkylamino, (Cs-C~o)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R55)2 wherein each R55 is selected from hydrogen, (C~-Cs)alkyl and (Cs-C~o)aryl; -C(O)Rs5 wherein R55 is H, (C~-Cs)alkyl, or (Cs-C~o)aryl;
(C6-C~o)aryl or (C5-C9)heteroaryl wherein the substituents are described above.
More particularly, the invention relates to compounds of the formula V in the methods of the invention wherein R5' and Rsa are each independently selected from hydrogen isopropyl, tert butyl, trifluoromethyl, acetyl, propanoyl, 2,2-dimethylpropanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, cyano, 2,4-difluorophenyl, 2-fluorophenyl, 2- and 3-thienyl, dimethylamino and R53 is selected from hydrogen, benzyl, methyl and R5' and R5~ are each independently selected from hydrogen, bromo, chloro, ethyl, methyl, fluoro, vinyl and phenyl.
Most preferred compounds of the formula V in the methods of the invention are selected from:
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;
11-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-flouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9,11-diflouro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
9-ethyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
11-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;
11-phenyl-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-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;
11-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]diazocin-8-one;
3-benzyl-9-bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one;
and 3-benzyl-9-chloro-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one and pharmaceutically acceptable salts and optical isomers thereof.
The present invention further relates to a method of treating a mammal, including a human, for restless legs syndrome comprising administering to the mammal in need of such treatment a compound of formula VI:
Rso A_B ~VI) N
and their pharmaceutically acceptable acid addition salts and prodrugs, wherein A is -CH(Rsi)- and Rs~ is hydrogen or optionally substituted (C~-Cs)alkyl wherein the substituents comprise one or more groups individually selected from hydroxy, (C~-C6)alkoxy, oxo, (C~-Cs)alkanoyl and NRs~Rs3; and B is a group of the formula NH
~N~Y
Zz W
_I
~Rsa)O ~(Rss) m wherein Y-W is CHa, NH, O, S, CH2CH~, CH=CH, N=CH, NH-CH2, OCH2 or SCH~;
the dotted line represents an optional bond;
Z~ 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 Zz is O or S, r is 1 when Z~
is N and r is 2 when ZZ is C;
each Rs4 and Rs5 is independently selected from hydrogen, optionally substituted (C~-Cs)alkyl, optionally substituted (Ci-Cs)alkoxy and optionally substituted (CZ-Cs)alkanoyl, wherein the substituents on the alkyl or alkanoyl groups are selected from hydroxy, (C~-Cs)alkoxy, oxo, (CZ-Cs)alkanoyl and NRs~Rs3, or Rs4 and Rs5 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~ is C wherein said substituents are selected from optionally substituted (C~-Cs)alkyl or optionally substituted (C1-Cs)alkoxy wherein said substituents are selected from (C~-Cs)alkyl, optionally substituted (Ci-Cs)alkoxy and optionally substituted (C2-Cs)alkanoyl or Rs4 and one of Rs5 together form a bond with the proviso that Rsa and Rs5 cannot form a bond when Z~ is O or S;
Rs° is hydrogen or halo; and Rs2 and Rs3 are each independently selected from hydrogen and optionally substituted (C~-Cs)alkyl wherein said substituents are selected from (C~-Cs)alkyl and halo;
with the provisos that when -B-A is attached to the 3-position of the pyridine ring and R6' is hydrogen and a) Rs°is 6-chloro and i) Z~ is C, the dotted line represents a bond, m and r are both 1, R64 and Rs5 are both hydrogen, then W-Y is not selected from CH=CH, S, CHz, NH, CH=N, OCH2 or SCH2;
ii) Zz is nitrogen, the dotted line represents a bond, r is 0 and m is 1 then Rss is not CF3;
or iii) ZZ is C, the dotted line represents a bond, m and r are both 2, and each R64 and R65 is hydrogen, then W-Y is not S; or b) R6° is hydrogen, 6-bromo or 6-fluoro and Z2 is carbon, the dotted line represents a bond, m and r are both 1, R64 and R65 are both hydrogen, then W-Y is not sulfur.
Preferred compounds of the formula VI in the methods of the invention are those wherein ZZ is N, m is 1 or 2, W-Y is S or CH=CH, R6° is halo or H, R65 is (C~-C6)alkyl or halo, and the dotted line is a bond.
Other preferred compounds of the formula VI in the methods of the invention are those wherein ZZ is C, R6' is (C~-Cs)alkyl or hydrogen, m is 1, W-Y is S or CH=CH, the dotted line is a bond, R64 and R65 are each hydrogen or (C~-C6)alkyl, or the portion of B
corresponding to W
___ Y
Z
~R~)/ yRz) m is selected from Y
N W
and Y
N W
HsC
Most preferred compounds of the formula VI in the methods of the invention are selected from the group comprising 3-(6-chloro-pyridin-3-ylmethyl)-3H-[1,3,4]thiadiazol-2-ylideneamine;
5-methyl-3-pyridin-3-ylmethyl-3H-thiazol-2-ylideneamine;
3-(6-chloro-pyridin-3-ylmethyl)-5-methyl-3H-[1,3,4]thiadiozol-2-ylideneamine;
6-chloro-2-(6-chloro-pyridin-3-ylmethyl)-ZH-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]thiadiazol-2-ylideneamine;
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 formulae I, II, III, IV, V and VI may have optical centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the formulae I, II, III, IV, V and VI as well as racemic and other mixtures thereof.
Preferably, the amount of the compounds of the formulae I, II, III, IV, V and VI
administered in the methods of the invention are that which is effective in treating restless legs syndrome.
Unless otherwise indicated, the term "halo", as used herein, includes fluoro, chloro, bromo and iodo.
Unless otherwise indicated, the term "alkyl", as used herein, includes straight chain moieties, and where the number of carbon atoms suffices, branched and cyclic moieties.
The term "alkoxy", as used herein, means "-O-alkyl" or "alkyl-O-", wherein "alkyl" is defined as above.
The term "alkylene, as used herein, means an alkyl radical having two available bonding sites i.e., -alkyl-), wherein "alkyl" is defined as 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 group may also be unsaturated, and "heteroaryl" includes, without limitation, thienyl, furyl, pyrano, pyrrolo, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, triazolyl, pyrazinyl and pyridyl, and said "cycloheteroalkyl" includes, without limitation, pyrrolidinyl, piperidinyl, tetrahydrofuryl and tetrahydropyrano.
Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
The term "nicotinic acetylcholine receptor agonist" refers to and encompasses full agonists of and partial agonists of nicotinic acetylcholine receptors.
The term "treatment", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.
The present invention also relates to all radiolabeled forms of the compounds of the formulae I, II, III, IV, V and VI. Preferred radiolabeled compounds of the formulae I, II, III, IV, V
and VI are those wherein the radiolabels are selected from as 3H, 11C, ~4C, ~BF, X231 and ~~51.
Such radiolabeled compounds are useful as research and diagnostic 'tools in metabolism studies, such as pharmacokinetics studies, etc., and in binding assays in both animals and man.
This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of the formulae I, II, III, IV, V and VI. Examples of pharmaceutically acceptable acid addition salts of the compounds of the formulae I, II, III, IV, V and VI are the salts of 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-toluoyl tartaric acid, and mandelic acid, as well salts formed from other acids known to those of skill in the art to form pharmaceutically acceptable acid addition salts to basic compounds. Other x possible acid addition salts are, e.g., salts containing pharmaceutically acceptable anions, such as the hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and pamoate (i.e., 1.1'-methylene-bis-(2-hydroxy-3-naphthoate) salts).
This 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).
This invention further relates to the use of nicotinic acetylcholine receptor agonists selected from compounds of formulae I, II, III, IV, V and VI or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of restless legs syndrome (RLS). The present invention further relates to a pharmaceutical composition for the treatment of restless legs syndrome (RLS) comprising a compound selected from compounds of formulae I, II, III, IV, V
and VI or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Detailed Description of the Invention The present invention is drawn to the use of compounds which bind to neuronal nicotinic receptor sites and are useful in modulating cholinergic function for the treatment of restless legs syndrome. In particular, a number of compounds useful in the present invention are referred to in International Patent Publication No. WO 01/62736, filed February 8, 2001 (compounds of formula I); International Patent Publication No. WO 99/35131, filed November 13, 1998 (compounds of formula I); International Patent Publication No. WO
99/55680, filed April 8, 1999 (compounds of formula II); U.S. Patent No. 5,977,131, filed March 31, 1998 (compounds of formula III); European Patent Publication No. EP 0 955 301 A2, filed March 25, 1999 (compounds of formula IV); International Patent Publication No. WO
98/18798, filed October 15, 1997 (compounds of formula V); and U.S. Patent No. 6,020,335, filed November 4, 1997 (compounds of formula VI).
The compounds of the formulae I, 11, III, IV, V and VI and their pharmaceutically acceptable salts (hereafter "the active compounds") can be administered via either the oral, transdermal (e;g_, through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. These compounds are, most desirably, administered in dosages ranging from about 0.1 mg 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 in single or divided doses, although variations will necessarily occur depending upon the particular compound used, the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated.
More particularly, the active compounds can be administered in a wide variety of different dosage forms, e.g_, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from 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 may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions andlor elixirs are desired for oral administration the active ingredient may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, a solution of an active compound in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is also possible to administer the active compounds topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
Biological Assay The effectiveness of the active compounds in suppressing nicotine binding to specific receptor sites is determined by the following procedure which is a modification of the methods of Lippiello, P. M. and Fernandes, K. G. (in "The Binding of L-[~H]Nicotine To A
Single Class of High-Affinity Sites in Rat Brain Membranes", Molecular Pharm., 2J: 448-54 (1986)) and Anderson, D. J. and Arneric, S. P. (in "Nicotinic Receptor Binding of 3H-Cytisine, 3H-Nicotine and 3H-Methylcarmbamylcholine In Rat Brain", European J. Pharm., 253: 261-67 (1994)).
Procedure Male Sprague-Dawley rats (200-300 g) from Charles River were housed in groups in hanging stainless steel wire cages and were maintained on a 12 hour lightidark cycle (7 a.m.-7 p.m. light period). They received standard Purina Rat Chow and water ad libitum.
The rats were killed by decapitation. Brains were removed immediately following decapitation. Membranes were prepared from brain tissue according to the methods of Lippiello and Fernandez (Molecular Pharm., 29: 448-454 (1986) with some modifications.
Whole brains were removed, rinsed with ice-cold buffer, and homogenized at 0° in 10 volumes of buffer (wiv) using a Brinkmann PolytronTM, setting 6, for 30 seconds. The buffer consisted of 50 mM Tris HCI at a pH of 7.5 at room temperature. The homogenate was sedimented by centrifugation (10 minutes; 50,000 x g; 0 to 4°C. The supernatant was poured off and the membranes were gently resuspended with the Polytron and centrifuged again (10 minutes; 50,000 x g; 0 to 4°C. After the second centrifugation, the membranes were resuspended in assay buffer at a concentration of 1.Og/100mL. The composition of the standard assay buffer was 50 mM Tris HCI, 120 mM NaCI, mM KCI, 2 mM MgCh, 2 mM CaCh and has a pH of 7.4 at room temperature.
Routine assays were performed in borosilicate glass test tubes. The assay mixture typically consisted of 0.9 mg of membrane protein in a final incubation volume of 1.0 mL. Three 5 sets of tubes were prepared wherein the tubes in each set contained 50pL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 ~L of [3H]-nicotine in assay buffer followed by 750 ~L of the membrane suspension. The final concentration of nicotine in each tube was 0.9 nM. The final concentration of cytisine in the blank was 1 ~M. The vehicle consisted of deionized water containing 30 pL of 1 N acetic acid per 50 mL of water. The test compounds and cytisine were dissolved in vehicle. Assays were initiated by vortexing after addition of the membrane suspension to the tube. The samples were incubated at 0 to 4° C in an iced shaking water bath. Incubations were terminated by rapid filtration under vacuum through Whatman GF/BTM glass fiber filters using a BrandelT"" multi-manifold tissue harvester. Following the initial filtration of the assay mixture, filters were washed two times with ice-cold assay buffer (5 m each). The filters were then placed in counting vials and mixed vigorously with 20 ml of Ready SafeTM (Beckman) before quantification of radioactivity. Samples were counted in a LKB
Wallach RackbetaT"" liquid scintillation counter at 40-50% efficiency. All determinations were in triplicate.
Calculations Specific binding (C) to the membrane is the difference between total binding in the samples containing vehicle only and membrane (A) and non-specific binding in the samples containing the membrane and cytisine (B), i.e., Specific binding = (C) _ (A) - (B).
Specific binding in the presence of the test compound (E) is the difference between the total binding in the presence of the test compound (D) and non-specific binding (B), i.e., (E) __ (D) _ (B).
Inhibition = (1-((E)/(C)) times 100.
The compounds of the invention that were tested in the above assay exhibited ICSo values of less than 10 p,M.

Claims

1. A method of treating a subject suffering from restless legs syndrome comprising administering a nicotinic acetylcholine receptor agonist to the subject in need thereof in an amount effective to treat the syndrome.

2. The method according to claim 1 wherein the nicotinic acetylcholine receptor agonist is a compound of formula I:

wherein R1 is hydrogen, (C1-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=O)R13 or -CH2CH2-O-(C1-C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C1-C6)alkyl wherein q is zero, one or two, (C1-C6)alkylamino-, [(C1-C6)alkyl]amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C(=O)R13, -XC(=O)R13, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl- or heteroaryl-(C0-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur; X2(C0-C6)alkyl- and X2(C1-C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C1-C6)alkylamino- or [(C1-C6)alkyl]2amino-, and wherein the (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(C1-C6)alkoxy-(C0-C6)alkyl- contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- moieties may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl- groups may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(Co-C3)alkyl- and said heteroaryl-(Co-C3)alkyl- may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, amino, (C1-C6)alkylamino-, [(C1-C6)alkyl]2amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C(=O)R13 and -XC(=O)R13;
or R2 and R3, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the non-fused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6)alkyl- or (C1-C6)alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, amino, (C1-C6)alkylamino-, [(C1-C6)alkyl]amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C(=O)R13, and -XC(=O)R13;
each R4, R5, R6, R7, R8 and R13 is selected, independently, from hydrogen and (C1-C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, -N-(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, (C1-C6)alkylene;
with the proviso that: (a) at least one of R1, R2 and R3 must be the other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 cannot be hydrogen, (C1-C6)alkyl, or unconjugated (C3-C6)alkenyl, and pharmaceutically acceptable salts of such compounds.

3. The method according to claim 1 wherein the nicotinic acetylcholine receptor agonist is a compound of formula II

wherein Z is CH2, C(=O) or CF2;
R21 is hydrogen, (C1-C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=O)R13 or -CH2CH2-O-(C1-C4)alkyl;
R22 and R23 are selected independently, from hydrogen, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy, nitro, amino, halo, cyano, -SO q(C1-C6)alkyl wherein q is zero, one or two, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, CO2R4, CONR5R6, SO2NR7R8, C(=O)R13, XC(=O)R13, aryl-(C0-C3) alkyl or aryl-(C0-C3)alkyl-O- wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)alkyl or heteroaryl-(C0-C3)alkyl-O-, wherein said heteroaryl is selected from five to seven membered aromatic rings containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, and X2(C0-C6)alkoxy-(C0-C6)alkyl, wherein X2 is absent or X2 is (C1-C6)alkylamino or [(C1-C6)alkyl]2amino, and wherein the (C0-C6)alkoxy-(C0-C6)alkyl moiety of said X2(C0-C6)alkoxy-(C0-C6)alkyl contains at least one carbon atom, and wherein from one to three of the carbon atoms of said (C0-C6)alkoxy-(C0-C6)alkyl moiety may optionally be replaced by an oxygen, nitrogen or sulfur atom, with the proviso that any two such heteroatoms must be separated by at least two carbon atoms, and wherein any of the alkyl moieties of said (C0-C6)alkoxy-(C0-C6)alkyl may be optionally substituted with from two to seven fluorine atoms, and wherein one of the carbon atoms of each of the alkyl moieties of said aryl-(C0-C3)alkyl and said heteroaryl-(C0-C3)alkyl may optionally be replaced by an oxygen, nitrogen or sulfur atom, and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to two substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6) alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), hydroxy, nitro, cyano, amino, (C1-C6) alkylamino and [(C1-C6) alkyl]2 amino;
or R22 and R23, together with the carbons to which they are attached, form a four to seven membered monocyclic, or a ten to fourteen membered bicyclic, carbocyclic ring that can be saturated or unsaturated, wherein from one to three of the nonfused carbon atoms of said monocyclic rings, and from one to five of the carbon atoms of said bicyclic rings that are not part of the benzo ring shown in formula I, may optionally and independently be replaced by a nitrogen, oxygen or sulfur, and wherein said monocyclic and bicyclic rings may optionally be substituted with one or more substituents, preferably from zero to two substituents for the monocyclic rings and from zero to three substituents for the bicyclic rings, that are selected, independently, from (C0-C6) alkoxy-(C0-C6)alkyl-, wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, oxo, cyano, halo, hydroxy, amino, (C1-C6)alkylamino, [(C1-C6) alkyl]2amino, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as in the definition of R22 and R23 above;
each R4, R5, R6, R7, R8 and R13 is selected, independently, from hydrogen and (C1-C6) alkyl, or R5 and R6, or R7 and R8 together with the nitrogen to which they are attached, form a pyrrolidine, piperidine, morpholine, azetidine, piperazine, -N-(C1-C6)alkylpiperazine or thiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur is replaced with a sulfoxide or sulfone; and each X is, independently, (C1-C6)alkylene;

with the proviso that: (a) at least one of R21, R22 and R23 must be the other than hydrogen, (b) when R22 and R23 are hydrogen, R21 cannot be methyl or hydrogen;
and (c) no fluorine atom in any of the fluoro substituted alkyl or alkoxy moieties of R22 and R23 can be attached to a carbon that is attached to a heteroatom;
and the pharmaceutically acceptable salts of such compounds.

4. The method according to claim 2 or 3 wherein the heteroaryl groups within the definition of R2 and R3 in formula I or R22 and R23 in formula II are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:

wherein one of R9 and R18 is hydrogen or (C1-C6)alkyl, and the other is a bond to the benzo ring of formula I of formula II.

5. The method according to claim 2 or 3 wherein R2 and R3 in formula I or R22 and R23 in formula II, together with the benzo ring of either of formula I or formula II, form a bicyclic ring system selected from the following:

wherein R10 and R17 are selected, independently, from hydrogen, (C1-C6)alkyl;
and (C1-C6)alkoxy-(C0-C6)alkyl- wherein the total number of carbon atoms does not exceed six and wherein any of the alkyl moieties may optionally be substituted with from one to seven fluorine atoms; nitro, cyano, halo, amino, (C1-C6)alkylamino-, [(C1-C6) alkyl]amino-, -CO2R4, -CONR5R6, -SO2NR7R8, -C(=O)R13, -XC(=O)R13, phenyl and monocyclic heteroaryl.

6. The method according to claim 2 or 3 wherein R2 and R3 in formula I or R22 and R23 in formula II, together with the benzo ring of formula I or formula II, form a bicyclic or tricyclic ring system selected from the following:

wherein R10 and R17 are defined as above, and m is zero, one or two, and wherein one of the carbon atoms of ring A can optionally be replaced with oxygen or N(C1-C6)alkyl.

7. The method according to claim 2 or 3 wherein R2 and R3 in formula I or R22 or R23 in formula II do not, together with the benzo ring of formula I or formula II, form a bicyclic or tricyclic ring system.

8. The method according to claim 2 or 3 wherein one of R2 and R3 in formula I
or R22 or R23 in formula II is CF3, fluoro, cyano, (C2-C6)alkynyl or C2F5.

9. The method according to claim 2 wherein the nicotinic acetylcholine receptor agonist is selected from:
10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;

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

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

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

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

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

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

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

N1-[10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-trien-4-yl]-acetamide;

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

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

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

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

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

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

6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0 2,10 .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 2,10 .0 4,8]-pentadeca-2(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;

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

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

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

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

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

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

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

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

4,5-dichloro-10-azatricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
N4,N4-dimethyl-10-azatricyclo[6.3.1.0 2,7]-dodeca-2(7),3,5-triene-4-sulfonamide;
4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0 2,7]-dodeca-2(7),3,5-triene;
5,13-diazatetracyclo[9.3.1.0 2,10 .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[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
3-hydroxy-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.0 2,7]dodeca-2(7),3,5-triene;
6-ethyl-5-oxa-7,13-diazatetracyclo[9.3.1.0 2,10 .0 4,8]-pentadeca-2(10),3,6,8-tetraene;
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;
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 2,11 .0 4,9]hexadeca-2(11),3,7,9-tetraen-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 4,9]hexadeca-2(11),3,5,7,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.0 2,11 .0 4,9]hexadeca-2(11),3,7,9-tetraen-6-one;
and pharmaceutically acceptable salts and optical isomers thereof.

10. The method according to claim 3 wherein the nicotinic acetylcholine receptor agonist is selected from:
5,6-difluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2,4,6-triene;
11-benzyl-6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
6-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-benzyl-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-benzyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-ol;
5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-ol;
11-benzyl-5-difluoromethoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-difluoromethoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-benzyl-5-ethoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-ethoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;

5-isopropoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-benzyl-4-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-4-ol;
11-benzyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
4-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
3-nitro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-benzyl-5-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-fluoro-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5,7-dioxa-14-azatetracyclo[10.3.1.0 2,10 .0 4,8]hexadeca-2(10),3,8-triene;
11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5 -triene;
11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5 -triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5 -triene;
trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl ester;
5-(4-trifluoromethyl-phenyl)-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
5-(4-methoxy-phenyl)-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene-5-carboxylic acid methyl ester;
2-(11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-trien-5-yl)-propan-2-ol;
5-pyridin-3-yl-11-aza-tricyclo[7.3.1.0 2,7]trideca-2(7),3,5-triene;
and pharmaceutically acceptable salts and optical isomers thereof.

11. The method according to claim 1 wherein the nicotinic acetylcholine receptor agonist is a compound of formula III
wherein X3 is:
a) -CH2NR31R32, c) wherein R30, R31, and R32 are independently selected from hydrogen and C1-C6 alkyl;
R33 is selected from hydrogen, halogen and C1-C6 alkyl;
v is an integer from 0 to 4; and n is an integer from 0 to 2; and pharmaceutically acceptable salts thereof.

12. The method according to claim 1 wherein the nicotinic acetylcholine receptor agonist is a partial agonist.

13. The method according to claim 1 wherein the nicotinic acetylcholine receptor agonist is a full agonist.

14. The use of a nicotinic acetylcholine receptor agonist in the manufacture of a medicament for the treatment of restless legs syndrome (RLS).

15. The use of a nicotinic acetylcholine receptor agonist selected from the group consisting of compounds of formulae I, II, III, IV, V and VI or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of restless legs syndrome (RLS).