WO2003037329A1 - Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome - Google Patents

Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome Download PDF

Info

Publication number
WO2003037329A1
WO2003037329A1 PCT/IB2002/004379 IB0204379W WO03037329A1 WO 2003037329 A1 WO2003037329 A1 WO 2003037329A1 IB 0204379 W IB0204379 W IB 0204379W WO 03037329 A1 WO03037329 A1 WO 03037329A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aza
triene
tricyclo
trideca
Prior art date
Application number
PCT/IB2002/004379
Other languages
French (fr)
Inventor
Mario David Saltarelli
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Priority to BR0213696-1A priority Critical patent/BR0213696A/en
Priority to EP02802239A priority patent/EP1439836A1/en
Priority to JP2003539673A priority patent/JP2005507411A/en
Priority to CA002460118A priority patent/CA2460118A1/en
Priority to SK191-2004A priority patent/SK1912004A3/en
Priority to HU0401967A priority patent/HUP0401967A2/en
Priority to IL16096702A priority patent/IL160967A0/en
Priority to MXPA04002539A priority patent/MXPA04002539A/en
Publication of WO2003037329A1 publication Critical patent/WO2003037329A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • 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 80% 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.
  • 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 (carbidopa/levodopa).
  • a dopaminergic agent forten a dopamine-receptor agonist
  • Mirapex pramipexole
  • Permax pergolide
  • Requip ropinirole
  • Sinemet a drug that adds dopamine to the system
  • Sinemet carbidopa/levodopa
  • 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.
  • RLS RLS-related 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.
  • 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
  • anti-convulsants including Gabapentin (Neurontin) which are effective for some, but not all, patients with marked
  • Agonists of nicotinic acetylcholine receptors markedly increase the release of dopamine in the brain.
  • 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.
  • 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:
  • heteroaryl groups within the definition of R 2 and R 3 in formula I are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:
  • R and R .18 is hydrogen or (C 1 -C 6 )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 R 2 and R 3 , together with the benzo ring of formula I, form a bicyclic ring system selected from the following:
  • R 10 and R 17 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 ⁇ -C 6 )alkyl.
  • 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:
  • 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
  • heteroaryl groups that each of R 22 and R 23 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:
  • R 9 and R 18 are as defined above.
  • Examples of compounds of the formula II in the methods of the invention are wherein R 22 and RR 2233 ,, t together with the benzo ring of formula II, form a bicyclic ring system selected from the following:
  • R 10 and R .1"7 are as defined above;
  • R 22 and R 23 together with the benzo ring of formula II, form a bicyclic or tricyclic ring system selected from the following: wherein m, R 10 and R 17 are as defined above and one of the carbon atoms of ring A can optionally be replaced with oxygen or -N(C 1 -C 6 )alkyl.
  • 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 III
  • X is: a) -CH 2 NR 31 R 32 , b) or c)
  • R 30 , R 31 , and R 32 are independently selected from hydrogen and C C 6 alkyl; R 33 is selected from hydrogen, halogen and C C 6 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:
  • 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:
  • R 4 ⁇ R 42 , R 43 and R 4 are selected, independently from hydrogen, -C0 2 R"°, 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, imidazo
  • R 45 is (C C 6 ) alkyl, aryl, heteroaryl, and (C ⁇ C 4 )alkyIene-heteroaryI, wherein said aryl and heteroaryl are defined as above, and wherein said (C r C 6 )alkyl may optionally be substituted with from one to three substituents independently selected from halo,
  • R 46 is hydrogen or (C C 6 )alkyl; with the proviso that: (a) at least one of R 41 , R 42 , R 43 , and R 44 must be aryl or heteroaryl;
  • R 42 can not both be -C0 2 R 45 ; (d) if either R 43 or R 44 is -C0 2 R 45 and R 45 is an alkyl or alkoxyalkyl group, then one of R 41 and R 42 must be aryl or heteroaryl; and (e) if either R 41 or R 42 is -C0 2 R 45 and R 45 is an alkyl or alkoxyalkyl group, then one of R 43 and R 44 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 R 41 and R 42 is optionally substituted phenyl and the other is hydrogen, and wherein R 43 and R 44 are hydrogen.
  • More preferred compounds of the formula IV in the methods of the invention are wherein one of R 41 and R 42 is phenyl substituted with fluoro or nitro and the other is hydrogen, and wherein R 43 and R 44 are hydrogen.
  • More specific preferred embodiments of this invention are compounds of the formula IV in the methods of the invention wherein R 43 and R 44 are hydrogen and one R 41 and R 42 is hydrogen and the other is: (a) 3-fluorophenyl; (b) 4-nitrophenyl; or 3-fluoro-4-nitrophenyI.
  • 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
  • R 5 and R 52 are each independently selected from a) H; halo; CF 3 ; hydroxy; (C r C 6 )alkoxy; CH 2 OH; -C(0)R , wherein R ,5 0 4 4 is H,
  • R is H, (C ⁇ -C 6 )alkyl, (C 6 -C 10 )aryl (including substituted alkyl or aryl); -S(0) p R , wherein R 55 is H, (C 1 -C 6 )alkyi, or (C 6 -C 10 )aryl (including substituted alkyl or aryl) and p is 0, 1 , or 2; (C ⁇ -C 6 )alkyl; (C C 6 )alkenyl; H 2 N; di-((C C 6 )alkyl)amino; mono(C C 6 )alkyl-amino; (C 6 -C 10 )aryl- amino; (C 3 -C 8 )cycloaIkyl-amino; heteroaryl-amino; cycloheteroalkyl-amino; and C0N(R 55 ) 2 wherein each R 55 is selected from hydrogen, (C C 6 )alkyI
  • R is selected from H, (C r C 6 )alkyl, phenyl and benzyl; and c) optionally benzene-fused (C 6 -C 10 )aryl, optionally benzene-fused (C 3 -C 8 )cycloalkyl, optionally benzene-fused heteroaryl and optionally benzene-fused cycloheteroalkyl, wherein said heteroaryl group contains 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,
  • R 53 is selected from H, optionally substituted benzyl and methyl; with the provisos that R 51 and R 52 are not both hydrogen and when R 53 is H, and that R 51 and R 52 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 R 53 is selected from H, benzyl or methyl and R 51 and R 52 are each independently selected from H, halo, (C ⁇ -C 6 )alkyl, cyano, (C 6 -C 10 )aryl, (C 5 -C 8 )heteroaryl, (C C 6 )alkenyl, (C 2 -C 6 )alkynyl-R 55 and -C(0)R 55 wherein R 55 is H, (C r C 6 ) alkyl, (C 6 -C 10 )aryl and (C 5 -C 9 )heteroaryl and amino and mono and di-substituted amino; with the provisos that when R 53 is H then R 51 and R 52 are not both H, Br and CI and when R 53 is benzyl or methyl then R 51 and R 52 are not hydrogen.
  • R 51 and R 52 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 1 -C 6 )alkyl]amino, (CrC 6 )monoalkylamino, (C 6 -C 10 )arylamino, (C 3 -C 8 )cycloalkyIamino, heteroarylamino, cycloheteroalkyamino and CON(R 55 ) 2 wherein each R 55 is selected from hydrogen, (C r C 6 )alkyl and (C 6 -C 10 )aryl; (C 6 -
  • R 53 is selected from optionally substituted benzyl or (C r C 6 )alkyl, wherein the substituents are described above and R 51 and R 52 are each independently selected from hydrogen, halo, cyano, optionally substituted (C C 6 )alkyl, (C 1 -C 6 )alkenyl, amino, di-[(C C 6 )alkyl]amino, (C C 6 )monoalkylamino, (C 6 -C 10 )arylamino, (C 3 -C 8 )cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R 55 ) 2 wherein each R 55 is selected from hydrogen, (C C 6 )alkyl and (C 8 -C 10 )aryl; -C(0)R 55 wherein R 55 is H, (C C 6 )alkyI, or (C 6 -C 10 )ary
  • the invention relates to compounds of the formula V in the methods of the invention wherein R 51 and R 52 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 R 53 is selected from hydrogen, benzyl, methyl and R 51 and R 52 are each independently selected from hydrogen, bromo, chloro, ethyl, methyl, fluoro, vinyl and phenyl.
  • 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:
  • A is -CH(R 61 )- and R 61 is hydrogen or optionally substituted (C r C 6 )alkyl wherein the substituents comprise one or more groups individually selected from hydroxy, (C C 6 )alkoxy, oxo, (C 2 -C 6 )alkanoyl and NR 62 R 63 ; and
  • 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; each R 64 and R 65 is independently selected from hydrogen, optionally substituted (C C 6 )alkyl, optionally substituted (CrC 6 )alkoxy and optionally substituted (C 2 -C 6 )alkanoyl, wherein the substituents on the alkyl or alkanoyl groups are selected from hydroxy, (C 1 -C 6 )alkoxy, oxo, (C 2 -C 6 )alkanoyl and NR 62 R 63 , or R 64 and R 65 together with the carbon atoms to which they are attached form an optionally substituted six membered heteroaromatic ring containing at least one heteroatom selected from N, S and O and Z 2 is C wherein said substituents are selected from optionally
  • R 60 is hydrogen or halo
  • Z is nitrogen, the dotted line represents a bond, r is 0 and m is 1 then R is not CF 3 ; or iii) Z 2 is C, the dotted line represents a bond, m and r are both 2, and each R 64 and R 65 is hydrogen, then W-Y is not S; or b) R 60 is hydrogen, 6-bromo or 6-fluoro and Z 2 is carbon, the dotted line represents a bond, m and r are both 1 , R 64 and R 65 are both hydrogen, then W-Y is not sulfur.
  • 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.
  • 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.
  • halo includes fluoro, chloro, bromo and iodo.
  • alkyl includes straight chain moieties, and where the number of carbon atoms suffices, branched and cyclic moieties.
  • alkoxy means “-O-alkyl” or “alkyl-O-”, wherein “alkyl” is defined as above.
  • alkylene as used herein, means an alkyl radical having two available bonding sites Q_e_ > -alkyl-), wherein “alkyl” is defined as above.
  • 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
  • heteroaryl includes, without limitation, thienyl, furyl, pyrano, pyrrolo, imidazolyl, oxazolyl, thiazolyl, tetrazolyl, triazolyl, pyrazinyl and pyridyl
  • said "cycloheteroalkyl” includes, without limitation, pyrrolidinyl, piperidinyl, tetrahydrofuryl and tetrahydropyrano.
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • nicotinic acetylcholine receptor agonist refers to and encompasses full agonists of and partial agonists of nicotinic acetylcholine receptors.
  • treatment 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.
  • treatment 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 3 H, 11 C, 14 C, 18 F, 123 l and 125 l.
  • 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.
  • 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).
  • 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-(
  • 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.
  • 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.
  • 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.
  • the compounds of the formulae I, II, III, IV, V and VI and their pharmaceutically acceptable salts 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.
  • 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.
  • 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.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 (w/v) 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 1.0g/100mL.
  • the composition of the standard assay buffer was 50 mM Tris HCI, 120 tnM NaCI, 5 mM KCI, 2 mM MgCI 2 , 2 mM CaCI 2 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 sets of tubes were prepared wherein the tubes in each set contained 50 ⁇ L of vehicle, blank, or test compound solution, respectively.
  • To each tube was added 200 ⁇ L of [ 3 H]-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 ⁇ L 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 BrandelTM 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 RackbetaTM liquid scintillation counter at 40-50% efficiency. All determinations were in triplicate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

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

Description

NICOTINIC ACETYLCHOLINE RECEPTOR AGONISTS IN THE TREATMENT OF RESTLESS LEGS SYNDROME
Background 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 80% 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 (carbidopa/levodopa). 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 February 8, 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:
Figure imgf000003_0001
wherein
R1 is hydrogen, (C CeJalkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or -CH2CH2-0-(C1-C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, amino, halo, cyano,
Figure imgf000003_0002
wherein q is zero, one or two, (d.CeJalkylamino-, [(C C6)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)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(C C6)alkoxy-(C0-C6)alkyl-, wherein X2 is absent or X2 is (C C6)aIkylamino- or [(CrCeJalkylfeamino-, and wherein the (C0- C6)alkyl- or (C C6)alkoxy-(Co-C6)alkyl- moieties of said X2(C0-C6)alkyl- or X2(CrC6)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-(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 (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-(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 (C 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, (C C6)alkylamino-, [(CrC6)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)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 (CrC6)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, (CrC6)alkylamino-, [(C C6)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, and -XC(=0)R13; each R4, R5, R6, R7 , R8 and R13 is selected, independently, from hydrogen and (d -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-Cβ)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 R1, R2 and R3 must be the other than hydrogen, and (b) when R2 and R3 are hydrogen, R1 cannot be hydrogen, (C C6)alkyl, or unconjugated (C3- C6)alkenyl, and pharmaceutically acceptable salts of such compounds. Examples of possible heteroaryl groups within the definition of R2 and R3 in formula I are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl, pyrrolyl and the following groups:
Figure imgf000005_0001
Figure imgf000005_0002
wherein one of R and R .18 is hydrogen or (C1-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:
Figure imgf000005_0003
Figure imgf000005_0004
wherein R10 and R 7 are selected, independently, from hydrogen, (C C6)alkyl; and (CrC6)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, (C C6)alkylamino-, [(C C6) alkyl]2amino-, -C02R4, -C0NR5R6, -S02NR7R8, - C(=0)R13, -XC(=0)R13, phenyl and monocyclic heteroaryl wherein said heteroaryl is defined as R2 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:
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004
Figure imgf000006_0005
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(Cι-C6)alkyl.
Other embodiments of the compounds of the formula I in the methods of the invention are wherein neither R2 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 R2 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 R2 and R3 are -C(=0)R13, wherein R13 is (C C6)alkyl. Further embodiments of this invention relate to compounds of the formula I wherein one or both of R2 and R3 are -C(=0)R , wherein R13 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 R is
CF3, fluoro, cyano, (C2-C6)alkynyl or C2F5. 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[6.3.1.02,7]dodeca-2(7),3,5-triene; 4-fluoro-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-tr iene;
4-methyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
3-trifluoromethyl-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene;
3-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene; 4-nitro-10-azatricyclo[6.3.1.0 ,7]dodeca-2(7),3,5-triene;
4-amino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N1-[10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl]-acetamide;
6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(10),3,6,8-tetraene;
6-methyl-7-propyl-5J,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5>8-tetraene; 5,7,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-methyl-5J,13-triazatetracyclo[9.3.1.02'10.04,B]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-5J,13-triazatetracyclo[9.3.1.02' 0.04'8]-pentadeca-2(10)l3,5,8-tetraene;
6J-dimethyl-5J,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-propyl-5J,13-triazatetracyclo[9.3.1.02'10.0 '8]-pentadeca-2(10),3,5,8-tetraene; 7-butyl-5,7,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02' 0.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-phenyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5J,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5,8-tetraene; 6-methyl-7-neopentyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
6J-dimethyl-5,8,14-triazatetracyclo[10.3.1.02'11.04'9]-hexadeca-2(11),3,5J,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02,11.0 '9]-hexadeca-2(11),3,5J,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5J,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,6,8-tetraene; 6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,6,8-tetraene;
2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]-dodeca-2(7),3,5-trien-5-yl)-benzamide;
4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl cyanide;
3-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1 ,2,4-oxadiazole; 1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;
10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-ol;
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02'10.0 ,8]pentadeca-2,4(8),6,9-tetraene; 4-(2-methyl-2H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene;
4-(1 -methyl-1 H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene;
4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N4,N4-dimethyl-10-azatricyclo[6.3.1.02'7]-dodeca-2(7),3,5-triene-4-sulfonamide; 4-(1 -pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02,7]-dodeca-2(7),3,5-triene;
5,13-diazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2,4(8),9-trien-6-one;
6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,6,8-tetraene;
3-phenyl-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene;
3-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene; 4,5-difluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
6-ethyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2(10),3,6,8-tetraene;
6-isopropyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.0 '8]-pentadeca-2(10),3,6,8-tetraene;
6-benzyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2(10),3,6,8-tetraene;
5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11),3,5,7,9-pentaene; 6-methyl-5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11),3,5J,9-pentaene;
7-methyl-5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11),3,5J,9-pentaene;
7-ethyl-5,14-diazatetracyclo[10.3.1.02, .0 '9]hexadeca-2(11),3,5J,9-pentaene;
8-methyl-5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11),3,5J,9-pentaene;
5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3J,9-tetraen-6-one; 6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5J,9-pentaene;
6-methoxy-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene;
6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02,11.0 '9]hexadeca-2(11 ),3,5J,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02'11.04'9]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
Figure imgf000008_0001
wherein Z is CH2, C(=0) or CF2; R21 is hydrogen, (C C6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or
-CHzCHz-O^d-C^alkyl; R22 and R23 are selected independently, from hydrogen, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C C6)alkyl wherein q is zero, one or two, (C1.C6)alkylamino, [(CrC6)alkyl]2amino, C02R4, CONR5R6, S02NR7R8, C(=0)R13, XC(=0)R13, aryl-(C0 -C3) alkyl or aryI-(C0-C3)aIkyl-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(Co-C6)alkoxy-(Co-C6)alkyl, wherein X2 is absent or X2 is (C C6)alkyIamino or [(C C6)alkyl]2amino, and wherein the (C0-C6)alkoxy-(C0-C6)alkyl moiety of said X2(C0-C6)alkoxy-(Co-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-(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-(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 (Ci -C6) alkyl optionally substituted with from one to seven fluorine atoms, (C^ -C_) alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), hydroxy, nitro, cyano, amino, (C^ -Cβ) alkylamino and [(C< -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 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 (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, (Cι -C6)alkylamino, [(C< -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 X is as defined above; 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.
Examples of heteroaryl groups that each of R22 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:
Figure imgf000010_0001
wherein R9 and R18 are as defined above.
Examples of compounds of the formula II in the methods of the invention are wherein R22 and RR2233,, t together with the benzo ring of formula II, form a bicyclic ring system selected from the following:
Figure imgf000010_0002
Figure imgf000010_0003
wherein R10 and R .1"7 are as defined above;
Other embodiments of this invention relate to compounds of the formula II in the methods of the invention wherein R22 and R23, together with the benzo ring of formula II, form a bicyclic or tricyclic ring system selected from the following:
Figure imgf000011_0001
wherein m, R10 and R17 are as defined above and one of the carbon atoms of ring A can optionally be replaced with oxygen or -N(C1-C6)alkyl.
Other embodiments of this invention relate to compounds of the formula II in the methods of the invention wherein neither R22 nor R23 is attached to the benzo ring of formula II via an oxygen atom.
Other embodiments of this invention relate to compounds of the formula II in the methods of the invention wherein R21 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[7.3.1.02,7]trideca-2,4,6-triene;
11-benzyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-triene;
11-benzyl-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-benzyl-11-aza-tricyclo[7.3.1.02,7_trideca-2(7),3,5-trien-5-ol;
5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-trien-5-ol; 11-benzyl-5-difluoromethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
5-difIuoromethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-benzyl-5-ethoxy-11-aza-tricycIo[7.3.1.02,7]trideca-2(7),3,5-triene;
5-ethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene; 5-isopropoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-benzyI-4-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
4-methoxy-11-aza-tricyclo[7.3.1.0 ,7_trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol;
11-benzyl-11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-triene; 4-nitro-11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
3-nitro-11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-triene;
11-benzyl-5-fluoro-11-aza-tricycIo[7.3.1.02'7]trideca-2(7),3,5-triene;
5-fluoro-11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene; 5J-dioxa-14-azatetracyclo[10.3.1.02,10.0 '8]hexadeca-2(10),3,8-triene;
11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene;
11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene; trifluoromethanesulfonic acid-11-benzyl-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien- 5-yl ester;
5-(4-trifluoromethyl-phenyl)-11 -aza-tricyclo[7.3.1.02'7_trideca-2(7),3,5-triene;
5-(4-methoxy-phenyl)-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-thcyclo[7.3.1.02,7]trideca-2(7),3,5-triene-5-carboxylic acid methyl ester;
2-(11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-yl)-propan-2-ol; 5-pyridin-3-yl-11 -aza-tricyclo[7.3.1.02,7]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 III
Figure imgf000012_0001
wherein X is: a) -CH2NR31R32, b)
Figure imgf000013_0001
or c)
Figure imgf000013_0002
wherein R30, R31, and R32 are independently selected from hydrogen and C 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-1H-pyrrolo[2,3-b]pyridine;
3-(1-methyl-pyrrolidin-2-ylmethyl)-1-H-pyrroIo[2,3-b]pyridine; dimethyl-[2-(1 H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-amine; methyl-[2-(1H-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:
Figure imgf000013_0003
-» 5 wherein R4\ R42, R43 and R4 are selected, independently from hydrogen, -C02R"°, 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 (CrCeJalkyl optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, halo Q_e_, chloro, fluoro, bromo or iodo), phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, (Cι-C6)alkoxy optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, (CrCβJalkylamino and [(C C6)alkyl]2amino;
R45 is (C C6) alkyl, aryl, heteroaryl,
Figure imgf000014_0001
and (CτC4)alkyIene-heteroaryI, wherein said aryl and heteroaryl are defined as above, and wherein said (CrC6)alkyl may optionally be substituted with from one to three substituents independently selected from halo,
(Cι-C6)alkyl, (C C6 )alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, amino, (d-CeJalkylamino, and [(Cr C6)alkyl]2amino; and
R46 is hydrogen or (C C6)alkyl; with the proviso that: (a) at least one of R41, R42, R43, and R44 must be aryl or heteroaryl;
(b) when neither R41 nor R42 is hydrogen, R41 and R42 are in the "exo" configuration; (c) R41 and
R42 can not both be -C02R45; (d) if either R43 or R44 is -C02R45 and R45 is an alkyl or alkoxyalkyl group, then one of R41 and R42 must be aryl or heteroaryl; and (e) if either R41 or R42 is -C02R45 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 R41 and R42 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 R41 and R42 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 R41 and R42 is hydrogen and the other is: (a) 3-fluorophenyl; (b) 4-nitrophenyl; or 3-fluoro-4-nitrophenyI.
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:
2β-(3,4-difluorophenyl)-7-aza-bicyclo[2.2.1]heptane; 2β-(3,5-dichIorobenzene)-7-aza-bicyclo[2.2.1]heptane;
2β-(4-nitrophenyl)-7-aza-bicyclo[2.2.1.heptane; β-(3-thiophene)-7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-4-chlorophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-flourophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-hydroxyphenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-acetophenone)-7-aza-bicyclo[2.2.1]heptane; β-(4-trifluoromethylphenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-4-methylphenyl)- 7-aza-bicyclo[2.2.1]heptane; β-(3-chlorophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(n-benzyl-5-pyridonyl)-7-aza-bicyclo[2.2.1]heptane; β-(n-methyl-5-pyridonyl)- 7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-5-nitrophenyl)-7-aza-bicyclo[2.2.1.heptane; β-(4-aminophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-4-trifluoromethyl-phenyl)-7-aza-bicyclo[2.2.1]heptane; β-(4-chlorophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3,4-methylenedioxyphenyl)-7-aza-bicyclo[2.2.1]heptane; β-(2-chloro-6-methyl-5-pyridinyl)-7-aza-bicyclo[2.2.1]heptane; β-(4-cyanophenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-4-nitro-phenyl)-7-aza-bicyclo[2.2.1]heptane; β-(4-amido-phenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-fluoro-4-amino-phenyl)-7-aza-bicyclo[2.2.1]heptane; β-(4-sulfonamido-phenyl)-7-aza-bicyclo[2.2.1]heptane; β-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1]heptane; β-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1]heptane, N-methyl; β-(3-methyl-5-isoxzazole)-7-aza-bicyclo[2.2.1]heptane, N-acetyl; b-(3,4-difluorophenyl)-7-azabicyc!o[2.2.1_heptane; -(7-aza-bicyclo[2.2.1]hept-2-yl)-benzamidine; -(4-methanesulfonyl-phenyl)-7-aza-bicyclo[2.2.1]heptane; -(7-aza-bicyclo[2.2.1_hept-2-yl)-phenol; -(4-methylsulfanyl-phenyl)-7-aza-bicyclo[2.2.1]heptane; -(7-aza-bicyclo[2.2.1]hept-2-yl)-benzoic acid methyl ester; -(7-aza-bicyclo[2.2.1]hept-2-yl)-benzoic acid; -(3-fluoro-4-tetrazol-1-yl-phenyl)-7-aza-bicyclo[2.2.1]heptane; -(4-nitro-3-trifluoromethyl-phenyl)-7-aza-bicyclo[2.2.1]heptane; -[3-fluoro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-7-aza-bicyclo[2.2.1]heptane; -(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-y!)-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
Figure imgf000016_0001
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; (CrC6)alkoxy; CH2OH; -C(0)R , wherein R ,5044 is H,
55
(C1-C6)alkyl, (C6-C10)aryl or benzyl (including substituted alkyl, aryl or benzyl); C-N; C-CR
,55 ,55 wherein R is H, (Cι-C6)alkyl, (C6-C10)aryl (including substituted alkyl or aryl); -S(0)pR , wherein R55 is H, (C1-C6)alkyi, or (C6-C10)aryl (including substituted alkyl or aryl) and p is 0, 1 , or 2; (Cι-C6)alkyl; (C C6)alkenyl; H2N; di-((C C6)alkyl)amino; mono(C C6)alkyl-amino; (C6-C10)aryl- amino; (C3-C8)cycloaIkyl-amino; heteroaryl-amino; cycloheteroalkyl-amino; and C0N(R55)2 wherein each R55 is selected from hydrogen, (C C6)alkyI and (C6-C10)aryl; and
,56 , ,56 : b) 0O2R wherein R is selected from H, (CrC6)alkyl, phenyl and benzyl; and c) optionally benzene-fused (C6-C10)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, (Cι-C6)alkyl, (C6-C10)aryl, hydroxy, hydroxymethyl, CHO and C02R56 wherein R56 is as described above; and
R53 is selected from H, optionally substituted benzyl and methyl; with the provisos that R51 and R52 are not both hydrogen and when R53 is H, and that R51 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 R51 and R52 are each independently selected from H, halo, (Cι-C6)alkyl, cyano, (C6-C10)aryl, (C5-C8)heteroaryl, (C C6)alkenyl, (C2-C6)alkynyl-R55 and -C(0)R55 wherein R55 is H, (CrC6) alkyl, (C6-C10)aryl and (C5-C9)heteroaryl and amino and mono and di-substituted amino; with the provisos that when R53 is H then R51 and R52 are not both H, Br and CI and when R53 is benzyl or methyl then R51 and R52 are not hydrogen.
More preferred compounds of formula V in the methods of the invention are those wherein R51 and R52 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-[(C1-C6)alkyl]amino, (CrC6)monoalkylamino, (C6-C10)arylamino, (C3-C8)cycloalkyIamino, heteroarylamino, cycloheteroalkyamino and CON(R55)2 wherein each R55 is selected from hydrogen, (CrC6)alkyl and (C6-C10)aryl; (C6- Cιo)aryl and (C5-C8)heteroaryl wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents selected from halogen, (CτC6)alkyl, (Cβ-C10)aryl, hydroxy, hydroxymethyl, CHO and C02R56.
More preferred compounds of formula V in the methods of the invention are those wherein R53 is selected from optionally substituted benzyl or (CrC6)alkyl, wherein the substituents are described above and R51 and R52 are each independently selected from hydrogen, halo, cyano, optionally substituted (C C6)alkyl, (C1-C6)alkenyl, amino, di-[(C C6)alkyl]amino, (C C6)monoalkylamino, (C6-C10)arylamino, (C3-C8)cycloalkylamino, heteroarylamino, cycloheteroalkyamino and CON(R55)2 wherein each R55 is selected from hydrogen, (C C6)alkyl and (C8-C10)aryl; -C(0)R55 wherein R55 is H, (C C6)alkyI, or (C6-C10)aryl; (C6-C10)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 R51 and R52 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 R51 and R52 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-l ,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-chIoro-1 ,2,3,4,5,6-hexahydro-l ,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:
Figure imgf000018_0001
and their pharmaceutically acceptable acid addition salts and prodrugs, wherein A is -CH(R61)- and R61 is hydrogen or optionally substituted (CrC6)alkyl wherein the substituents comprise one or more groups individually selected from hydroxy, (C C6)alkoxy, oxo, (C2-C6)alkanoyl and NR62R63; and
B is a group of the formula
Figure imgf000019_0001
wherein Y-W is CH2, NH, O, S, CH2CH2, CH=CH, N=CH, NH-CH2, OCH2 or SCH2; the dotted line represents an optional bond;
Z2 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 Z2 is O or S, r is 1 when Z2 is N and r is 2 when Z2 is C; each R64 and R65 is independently selected from hydrogen, optionally substituted (C C6)alkyl, optionally substituted (CrC6)alkoxy and optionally substituted (C2-C6)alkanoyl, wherein the substituents on the alkyl or alkanoyl groups are selected from hydroxy, (C1-C6)alkoxy, oxo, (C2-C6)alkanoyl and NR62R63, or R64 and R65 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 Z2 is C wherein said substituents are selected from optionally substituted (d-CeJalkyl or optionally substituted (d-Ce alkoxy wherein said substituents are selected from (CτCβ)alkyl, optionally substituted (CrC6)alkoxy and optionally substituted (C2-C6)alkanoyl or R64 and one of R65 together form a bond with the proviso that R64 and R65 cannot form a bond when Z2 is O or S;
R60 is hydrogen or halo; and
R62 and R63 are each independently selected from hydrogen and optionally substituted (C C6)alkyl wherein said substituents are selected from (C C6)alkyl and halo; with the provisos that when -B-A is attached to the 3-position of the pyridine ring and R61 is hydrogen and a) R60 is 6-chloro and i) Z2 is C, the dotted line represents a bond, m and r are both 1 , R64 and R65 are both hydrogen, then W-Y is not selected from CH=CH, S, CH2, NH, CH=N, OCH2 or SCH2;
? 65 ii) Z is nitrogen, the dotted line represents a bond, r is 0 and m is 1 then R is not CF3; or iii) Z2 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) R60 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 Z2 is N, m is 1 or 2, W-Y is S or CH=CH, R60 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 Z2 is C, R61 is (C C6)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 (C1-C6)alkyl, or the portion of B corresponding to
is selected from
Figure imgf000020_0001
and
Figure imgf000020_0002
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)-2H-pyridazin-3-ylideneamine;
3-(6-chloro-pyridin-3-ylmethyl)-3H-benzothiazol-2-ylideneamine;
3-pyridin-3-ylmethyl-3H-[1,3,4]thiadiazol-2-ylideneamine; 3-[1-(6-chloro-pyridin-3-yl)-ethyl]-3H-thiazol-2-ylideneamine;
3-[1-(6-chloro-pyridin-3-yl)-ethyl]-3H-[1,3,4]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-ylmethy!-3H-[1 ,8]naphthyridin-2-ylidene;
6-chIoro-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 Q_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, 14C, 18F, 123l and 125l. 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 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, II, 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 and/or 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
Figure imgf000024_0001
To A Single Class of High-Affinity Sites in Rat Brain Membranes", Molecular Pharm., 29: 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 light/dark 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 (w/v) using a Brinkmann Polytron™, 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 1.0g/100mL. The composition of the standard assay buffer was 50 mM Tris HCI, 120 tnM NaCI, 5 mM KCI, 2 mM MgCI2, 2 mM CaCI2 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 sets of tubes were prepared wherein the tubes in each set contained 50μL of vehicle, blank, or test compound solution, respectively. To each tube was added 200 μL of [3H]-nicotine in assay buffer followed by 750 μL 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 μM. The vehicle consisted of deionized water containing 30 μL 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/B™ glass fiber filters using a Brandel™ 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 Safe™ (Beckman) before quantification of radioactivity. Samples were counted in a LKB Wallach Rackbeta™ 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 IC50 values of less than 10 μM.

Claims

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:
Figure imgf000026_0001
wherein
R1 is hydrogen, (CrC6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or -CH2CH2-0-(C C4)alkyl;
R2 and R3 are selected, independently, from hydrogen, (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, amino, halo, cyano, -SOq(C1-C6)aIkyl wherein q is zero, one or two, (d.Q alkylamino-, [(C Ce)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)R13, aryl-(C0-C3)alkyl- or aryl-(C0-C3)alkyl-O-, wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(C0-C3)aIkyl- 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 (CrC6)alkylamino- or [(CrC6)alkyl]2amino-, and wherein the (C0- C6)alkyl- or (CrC6)alkoxy-(Co-C6)alkyl- moieties of said X2(C0-C6)alkyI- 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 (C0-C6)alkyl- or (C C6)alkoxy-(C0-C6)alkyI- 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-(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 (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 (e.g., chloro, fluoro, bromo or iodo), (C2-C6)alkenyl, (C2-C6)alkynyl, hydroxy, nitro, cyano, amino, (C C6)alkylamino-, [(C C6)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13 and -XC(=0)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,
(CrCeJalkylamino-, [(C1-C6)alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, and -XC(=0)R13; each R4, R5, R6, R7 , R8 and R13 is selected, independently, from hydrogen and (C< -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-(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-rC6)aIkylene; 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, (C 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
Figure imgf000027_0001
wherein Z is CH2, C(=0) or CF2;
R21 is hydrogen, (CrC6)alkyl, unconjugated (C3-C6)alkenyl, benzyl, XC(=0)R13 or -CH2CH2-0-(C C4)alkyI;
R22 and R23 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, (d_C6)aIkylamino, [(d-C6)alkyl]2amino, C02R4, CONR5R6, S02NR7R8, C(=0)R13, XC(=0)R13, aryl-(C0 -C3) alkyl or aryl-(C0-C3)alkyl-O- wherein said aryl is selected from phenyl and naphthyl, heteroaryl-(Co-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 X (C0-C6)alkoxy-(C0-C6)alkyl, wherein X2 is absent or X2 is (d- C6)alkylamino or [(d-C6)alkyrj2amino, and wherein the (Co-C6)alkoxy-(Co-C6)alkyl moiety of said X2(C0-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 (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 (d -Cδ) alkyl optionally substituted with from one to seven fluorine atoms, (d -C6) alkoxy optionally substituted with from two to seven fluorine atoms, halo (e.g.. chloro, fluoro, bromo or iodo), hydroxy, nitro, cyano, amino, (d -C_) alkylamino and [(d -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, (d -C6)alkylamino, [(d -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 (d -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-(d-C6)aIkylpiperazine 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 R21, R22 and R23 must be the other than
21 hydrogen, (b) when R and R are hydrogen, R 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:
Figure imgf000029_0001
Figure imgf000029_0002
wherein one of R9 and R18 is hydrogen or (d-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:
Figure imgf000029_0003
Figure imgf000029_0004
wherein R10 and R17 are selected, independently, from hydrogen, (d-C6)alkyl; and (d-C6)a!koxy- (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, (d-C6)alkylamino-, [(C C6) alkyl]2amino-, -C02R4, -CONR5R6, -S02NR7R8, -C(=0)R13, -XC(=0)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:
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000030_0005
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(d-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[6.3.1.02'7]dodeca-2(7),3,5-triene; 4-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-methyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
3-trifluoromethyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene; 3-fluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-nitro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4-amino-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N1-[10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl]-acetamide;
6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02'10.04'8]pentadeca-2(10),3,6,8-tetraene; 6-methyl-7-propyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
5,7,13-triazatetracyclo[9.3.1.02,10.04,8]-pentadeca-2(10),3,5,8-tetraene;
7-methyI-5,7,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-5J,13-triazatetracyclo[9.3.1.02,10.04,8]-pentadeca-2(10),3,5,8-tetraene;
6J-dimethyl-5J,13-triazatetracyclo[9.3.1.0 '10.04'8]-pentadeca-2(10),3,5,8-tetraene; 7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-butyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8-tetraene;
7-isobutyl-5J,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-isobutyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8- tetraene; 7-phenyl-5J,13-triazatetracyclo[9.3.1.02,10.04,8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-phenyl-5J,13-triazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,5,8-tetraene;
6-methyl-7-neopentyl-5J,13-triazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,5,8- tetraene;
6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11 ),3,5J,9-pentaene; 5,8,14-triazatetracyclo[10.3.1.02'11.04'9]-hexadeca-2(11 ),3,5J,9-pentaene;
14-methyl-5,8,14-triazatetracyclo[10.3.1.02'11.0 ,9]-hexadeca-2(11 ),3,5J,9-pentaene;
5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2(10),3,6,8-tetraene;
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2(10),3,6,8-tetraene;
2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]-dodeca-2(7),3,5-trien-5-yl)-benzamide; 4-chloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl cyanide;
3-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1 ,2,4-oxadiazoIe;
1-(10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-4-yi)-1-ethanone;
10-azatricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-4-ol; 7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02' 0.04,8]pentadeca-2,4(8),6,9-tetraene;
4-(2-methyl-2H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.0 ,7]dodeca-2(7),3,5-triene;
4-(1-methyl-1 H-pyrazol-3-yl)-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene; 4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
N4,N4-dimethyl-10-azatricyclo[6.3.1.02,7]-dodeca-2(7),3,5-triene-4-sulfonamide;
4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.02,7]-dodeca-2(7),3,5-triene;
5,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2,4(8),9-trien-6-one; 6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,6,8-tetraene;
3-phenyl-10-aza-tricyclo[6.3.1.02'7]dodeca-2(7),3,5-triene;
3-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
4,5-difluoro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene;
6-ethyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04'8]-pentadeca-2(10),3,6,8-tetraene; 6-isopropyl-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04'8]-pentadeca-2(10),3,6,8-tetraene;
6-benzyI-5-oxa-7,13-diazatetracyclo[9.3.1.02'10.04,8]-pentadeca-2(10),3,6,8-tetraene;
5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11 ),3,5J,9-pentaene;
6-methyl-5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11),3,5J,9-pentaene;
7-methyl-5,14-diazatetracyclo[10.3.1.02'11.04,9]hexadeca-2(11),3,5J,9-pentaene; 7-ethyl-5,14-diazatetracyclo[10.3.1.02'11.04,9]hexadeca-2(11 ),3,5J,9-pentaene;
8-methyl-5,14-diazatetracyclo[10.3.1.02,11.04,9jhexadeca-2(11),3,5J,9-pentaene;
5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11 ),3J,9-tetraen-6-one;
6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04'9]hexadeca-2(11 ),3,5J,9-pentaene;
6-methoxy-5,14-diazatetracycIo[10.3.1.02,11.04,9]hexadeca-2(11 ),3,5J,9-pentaene; 6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.02'11.04'9]hexadeca-2(11),3,5J,9-pentaene;
5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3J,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[7.3.1.02,7]trideca-2,4,6-triene;
11-benzyl-6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
6-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-6-ol;
6-fluoro-11-aza-tricycIo[7.3.1.02'7]trideca-2(7),3,5-triene; 11-benzyl-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11 -benzyl-11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-ol;
5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-ol;
11-benzyl-5-difIuoromethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene; 5-difluoromethoxy-11-aza-tricycIo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-benzyl-5-ethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
5-ethoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene; 5-isopropoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-benzyl-4-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
4-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-oI; 11 -benzyl-11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
4-nitro-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
5-nitro-11-aza-tricycIo[7.3.1.02,7]trideca-2(7),3,5-triene;
3-nitro-11-aza-tricyclo[7.3.1.0 ,7]trideca-2(7),3,5-triene;
11-benzyl-5-fluoro-11-aza-tricyclo[7.3.1.02'7]trideca-2(7),3,5-triene; 5-fluoro-11-aza-tricyclo[7.3.1.0 '7]trideca-2(7),3,5-triene;
5J-dioxa-14-azatetracyclo[10.3.1.02,10.04'8]hexadeca-2(10),3,8-triene;
11-benzyl-6-bromo-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene;
11-benzyl-6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene;
6-hydroxy-5-methoxy-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5 -triene; trifluoromethanesulfonic acid-11 -benzyl-11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-tπen-5- yl ester;
5-(4-trifluoromethyl-phenyl)-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
5-(4-methoxy-phenyl)-11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene;
11-aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-triene-5-carboxylic acid methyl ester; 2-(11 -aza-tricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-5-yl)-propan-2-ol;
5-pyridin-3-yl-11-aza-tricyclo[7.3.1.02,7]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
Figure imgf000033_0001
wherein X is: a) -CH2NR31R32, b)
Figure imgf000033_0002
or c)
Figure imgf000034_0001
wherein R30, R31, and R32 are independently selected from hydrogen and C C6 alkyl; R33 is selected from hydrogen, halogen and d-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).
PCT/IB2002/004379 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome WO2003037329A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR0213696-1A BR0213696A (en) 2001-10-31 2002-10-21 Nicotinic Acetylcholine Receptor Agonists In The Treatment Of Restless Leg Syndrome
EP02802239A EP1439836A1 (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
JP2003539673A JP2005507411A (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonist in the treatment of restless leg syndrome.
CA002460118A CA2460118A1 (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
SK191-2004A SK1912004A3 (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
HU0401967A HUP0401967A2 (en) 2001-10-31 2002-10-21 Use of nicotinic acetylcholine receptor agonists for preparation of pharmaceutical compositions available in the treatment of restless legs syndrome
IL16096702A IL160967A0 (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
MXPA04002539A MXPA04002539A (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US33481001P 2001-10-31 2001-10-31
US60/334,810 2001-10-31
US33585801P 2001-11-26 2001-11-26
US60/335,858 2001-11-26

Publications (1)

Publication Number Publication Date
WO2003037329A1 true WO2003037329A1 (en) 2003-05-08

Family

ID=26989404

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2002/004379 WO2003037329A1 (en) 2001-10-31 2002-10-21 Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome

Country Status (14)

Country Link
EP (1) EP1439836A1 (en)
JP (1) JP2005507411A (en)
KR (1) KR20050038583A (en)
CN (1) CN1568184A (en)
BR (1) BR0213696A (en)
CA (1) CA2460118A1 (en)
CZ (1) CZ2004524A3 (en)
HU (1) HUP0401967A2 (en)
IL (1) IL160967A0 (en)
MX (1) MXPA04002539A (en)
PL (1) PL370549A1 (en)
SK (1) SK1912004A3 (en)
TW (1) TW200300139A (en)
WO (1) WO2003037329A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103372A1 (en) * 2003-05-20 2004-12-02 Pfizer Products Inc. Pharmaceutical compositions of varenicline
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US8114909B2 (en) 2003-09-17 2012-02-14 Xenoport, Inc. Treating or preventing restless legs syndrome using prodrugs of GABA analogs
WO2016188932A2 (en) 2015-05-22 2016-12-01 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Combination compositions and their use in methods for treating obesity and obesity-related disorders
WO2018236957A1 (en) * 2017-06-20 2018-12-27 Nexien Biopharma, Inc. Method and compositions for treating restless legs syndrome
US11077119B2 (en) 2012-07-27 2021-08-03 Neurodyn Life Sciences Inc. Enhanced brain bioavailability of galantamine by selected formulations and transmucosal administration of lipophilic prodrugs
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2013294917B2 (en) * 2012-07-27 2016-12-15 Neurodyn Life Sciences Inc. Enhanced brain bioavailability of galantamine by selected formulations and transmucosal administration of lipophilic prodrugs

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5977131A (en) * 1997-04-09 1999-11-02 Pfizer Inc. Azaindole-ethylamine derivatives as nicotinic acetylcholine receptor binding agents
WO1999055680A1 (en) * 1998-04-29 1999-11-04 Pfizer Products Inc. Aryl fused azapolycyclic compounds
EP0955301A2 (en) * 1998-04-27 1999-11-10 Pfizer Products Inc. 7-aza-bicyclo[2.2.1]-heptane derivatives, their preparation and use according to their affinity for neuronal nicotinic acetylchloline receptors
US6020335A (en) * 1997-02-06 2000-02-01 Pfizer Inc (N-(pyridinylmethyl)-heterocyclic)ylideneamine compounds as nicotinic acetylcholine receptor binding agents
WO2001062736A1 (en) * 2000-02-25 2001-08-30 Pfizer Products Inc. Aryl fused azapolycyclic compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020335A (en) * 1997-02-06 2000-02-01 Pfizer Inc (N-(pyridinylmethyl)-heterocyclic)ylideneamine compounds as nicotinic acetylcholine receptor binding agents
US5977131A (en) * 1997-04-09 1999-11-02 Pfizer Inc. Azaindole-ethylamine derivatives as nicotinic acetylcholine receptor binding agents
EP0955301A2 (en) * 1998-04-27 1999-11-10 Pfizer Products Inc. 7-aza-bicyclo[2.2.1]-heptane derivatives, their preparation and use according to their affinity for neuronal nicotinic acetylchloline receptors
WO1999055680A1 (en) * 1998-04-29 1999-11-04 Pfizer Products Inc. Aryl fused azapolycyclic compounds
WO2001062736A1 (en) * 2000-02-25 2001-08-30 Pfizer Products Inc. Aryl fused azapolycyclic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STIASNY K ET AL: "RESTLESS LEGS SYNDROME AND ITS TREATMENT BY DOPAMINE AGONISTS", PARKINSONISM AND RELATED DISORDERS, ELSEVIER SCIENCE, OXFORD, GB, vol. 7, 1 November 2000 (2000-11-01), pages 21 - 25, XP000992182, ISSN: 1353-8020 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103372A1 (en) * 2003-05-20 2004-12-02 Pfizer Products Inc. Pharmaceutical compositions of varenicline
US8114909B2 (en) 2003-09-17 2012-02-14 Xenoport, Inc. Treating or preventing restless legs syndrome using prodrugs of GABA analogs
US7803839B2 (en) 2005-10-07 2010-09-28 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US7915250B2 (en) 2005-10-07 2011-03-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US8362002B2 (en) 2005-10-07 2013-01-29 Exelixis, Inc. Azetidines as MEK inhibitors for the treatment of proliferative diseases
US11597699B2 (en) 2005-10-07 2023-03-07 Exelixis, Inc. MEK inhibitors and methods of their use
US7999006B2 (en) 2006-12-14 2011-08-16 Exelixis, Inc. Methods of using MEK inhibitors
US11077119B2 (en) 2012-07-27 2021-08-03 Neurodyn Life Sciences Inc. Enhanced brain bioavailability of galantamine by selected formulations and transmucosal administration of lipophilic prodrugs
US11414396B2 (en) 2012-10-12 2022-08-16 Exelixis, Inc. Process for making compounds for use in the treatment of cancer
WO2016188932A2 (en) 2015-05-22 2016-12-01 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Combination compositions and their use in methods for treating obesity and obesity-related disorders
US10568852B2 (en) * 2015-05-22 2020-02-25 Helmholtz Zentrum Munchen - Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) Combination compositions and their use in methods for treating obesity and obesity-related disorders
US20180147163A1 (en) * 2015-05-22 2018-05-31 Helmholtz Zentrum Munchen - Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) Combination compositions and their use in methods for treating obesity and obesity-related disorders
WO2018236957A1 (en) * 2017-06-20 2018-12-27 Nexien Biopharma, Inc. Method and compositions for treating restless legs syndrome

Also Published As

Publication number Publication date
KR20050038583A (en) 2005-04-27
JP2005507411A (en) 2005-03-17
EP1439836A1 (en) 2004-07-28
CN1568184A (en) 2005-01-19
BR0213696A (en) 2004-10-26
CZ2004524A3 (en) 2004-07-14
TW200300139A (en) 2003-05-16
CA2460118A1 (en) 2003-05-08
MXPA04002539A (en) 2004-05-31
SK1912004A3 (en) 2004-09-08
PL370549A1 (en) 2005-05-30
IL160967A0 (en) 2004-08-31
HUP0401967A2 (en) 2005-01-28

Similar Documents

Publication Publication Date Title
CA2716757C (en) Kit, composition, product or medicament for treating cognitive impairment
CA2800331C (en) Antidepressant, neuroprotectant, amyloid .beta. deposition inhibitor or age retardant containing heterocyclic compound having specific structure
AU3768001A (en) A pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines
JP2004527500A (en) Nicotine receptor partial agonist, estrogen, selective estrogen modulator or combination of vitamin E and GABAA inverse agonist for the treatment of cognitive impairment
KR20030042037A (en) New treatments for restless legs syndrome
US20050250806A1 (en) Nicotinic acetylcholine receptor antagonists in the treatment of restless legs syndrome
WO2003037329A1 (en) Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
EP1145714A1 (en) Drugs
US9592239B2 (en) Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
EP1404320A2 (en) A pharmaceutical composition comprising a nicotinic receptor partial antagonist and an antiemetic agent for modulating cholinergic function
KR20040030788A (en) Derivatives of aryl(or heteroaryl) azolylcarbinols for the treatment of urinary incontinence
WO2002051440A1 (en) Combination drugs
NO315119B1 (en) Heterocycle-Condensed Morphine Derivatives, Their Use, and Pharmaceutical Mixtures Containing Them
AU2002363188A1 (en) Nicotinic acetylcholine receptor agonists in the treatment of restless legs syndrome
US20030176457A1 (en) Pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss
CA1094454A (en) Treatment for scabies
US20040167200A1 (en) Pharmaceutical composition and method of modulating cholinergic function in a mammal
US5910501A (en) Use of certain esters of hexahydro-8-hydroxy-2,6-methano-2H-quinolozin-3(4H)-one and related compounds for treating cognitive disorders
JP2002249432A (en) Combined agent
JP2000273042A (en) Medicine
AU2002258088A1 (en) A pharmaceutical composition comprising a nicotinic receptor partial antagonist and an antiemetic agent of modulating cholinergic function
AU2014200818A1 (en) Kit, composition, product or medicament for treating cognitive impairment
RU98111593A (en) PYRIDO [2,3-] PYRIMIDINE DERIVATIVES AND THEIR PHARMACEUTICAL COMPOSITIONS

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1-2004-500482

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 2004/01946

Country of ref document: ZA

Ref document number: 200401946

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 531688

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/2004/002539

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 160967

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2460118

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2002363188

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 20028200292

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2002802239

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV2004-524

Country of ref document: CZ

Ref document number: 2003539673

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1912004

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 1020047006544

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2004-524

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 2002802239

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2002802239

Country of ref document: EP